Tag Archives: germline editing

Toronto’s ArtSci Salon and The Mutant Project March 15, 2021

The Mutant Project is both a book (The Mutant Project: Inside the Global Race to Genetically Modify Humans) and an event about gene editing with special reference to the CRISPR (clustered regularly interspaced short palindromic repeats) twins, Lulu and Nana. The event is being held by Toronto’s ArtSci Salon. Here’s more from their March 3, 2021 announcement (received via email),

The Mutant Project

A talk and discussion with Eben Kirksey

Discussants:

Dr. Elizabeth Koester, Postdoctoral fellow, Department of History, UofT [University of Toronto]

Vincent Auffrey, PhD student, IHPST [Institute for the History and Philosophy of Science and Technology], UofT

Fan Zhang, PhD student, IHPST, UofT

This event will be streamed on Zoom and on Youtube

Here is the link to register to Zoom on the 15th:

https://utoronto.zoom.us/meeting/registe/tZErcemoqzwrG9foNF5Ud86uJXdNeIzQSfDw

Event on FB: https://www.facebook.com/events/4033393163381012/

YouTube: https://www.youtube.com/watch?v=pEFfj3Ovsfk&feature=youtu.be

At a conference in Hong Kong in November 2018, Dr. He Jiankui announced that he had created the first genetically modified babies—twin girls named Lulu and Nana—sending shockwaves around the world. A year later, a Chinese court sentenced Dr. He to three years in prison for “illegal medical practice.”

As scientists elsewhere start to catch up with China’s vast genetic research program, gene editing is fueling an innovation economy that threatens to widen racial and economic inequality. Fundamental questions about science, health, and social justice are at stake: Who gets access to gene editing technologies? As countries loosen regulations around the globe, from the U.S. to Indonesia, can we shape research agendas to promote an ethical and fair society?

Join us to welcome Dr. Kirksey, who will discuss key topics from his book “The Mutant Project”.

The talk will be followed by a Q&A

EBEN KIRKSEY is an American anthropologist who finished his latest book as a Member of the Institute for Advanced Study in Princeton, New Jersey. He has been published in Wired, The Atlantic, The Guardian and The Sunday Times. He is sought out as an expert on science in society by the Associated Press, The Wall Street Journal, The New York Times, Democracy Now, Time and the BBC, among other media outlets. He speaks widely at the world’s leading academic institutions including Oxford, Yale, Columbia, UCLA, and the International Summit of Human Genome Editing, plus music festivals, art exhibits, and community events. Professor Kirksey holds a long-term position at Deakin University in Melbourne, Australia. For more information, please visit https://eben-kirksey.space/.

Elizabeth Koester currently holds a SSHRC [Social Science and Humanities Research Council of Canada] Postdoctoral Fellowship in the Department of History at the University of Toronto. After practising law for many years, she undertook graduate studies in the history of medicine at the Institute for the History and Philosophy of
Science and Technology at the University of Toronto and was awarded a PhD in 2018. A book based on her dissertation, In the Public Good: Eugenics and Law in Ontario, will be published by McGill-Queen’s University Press and is anticipated for Fall 2021.

Vincent Auffrey is pursuing his PhD at the Institute for the History of Philosophy of Science and Technology (IHPST) at the University of Toronto. His focus is set primarily on the social history of medicine and the history of eugenics in Canada. Secondary interests include the histories of scientific racism and of anatomy, and the interplay between knowledge and power.

Fan Zhang is a PhD student at the History of Philosophy of Science and Technology (IHPST) at the University of Toronto

Kirksey’s eponymous website,

Gene therapy in Canada; a November 2020 report and two events in December 2020

There’s a lot of action, albeit quiet and understated, in the Canadian gene therapy ‘discussion’. One major boost to the discussion was the Nov. 3, 2020 release of a report by the Canadian Council of Academies (CCA), “From Research to Reality; The Expert Panel on the Approval and Use of Somatic Gene Therapies in Canada.”

Dec. 2 – 3, 2020 Breaking Through

Another boost is the the free and virtual, upcoming 2020 Gairdner Ontario International Symposium “Breaking Through: Delivering on the Promise of Gene Therapy“; an international symposium on gene therapy research and practice, which will feature a presentation on the CCA’s report,

Breaking Through brings together Canadian and international leaders to explore the past, present, and future of somatic gene therapy research and practice. This two-day virtual event will examine the successes, challenges and opportunities from the bench to the bedside. It will also feature:

  • Speaker sessions from Canadian and international researchers at the forefront of gene therapy research.
  • A panel discussion exploring the opportunities and challenges facing Canadian scientists, regulators, clinicians, decision-makers, and patients (Presented by NRC).
  • A presentation and Expert Panel discussion on the Council of Canadian Academies’ latest report, From Research to Reality, and a closing panel discussion about the future of gene therapies and gene editing (Presented by Genome Canada).

The title for the CCA report bears an uncanny resemblance to the name for a Canadian initiative highlighting science research, Research2Reality (R2R). (If you’re curious, you can check out my past postings on R2R by using ‘Research2Reality’ as the term for the blog’s search engine.

Glybera

This name stood out: Michael Hayden (scroll down to his name and click), one of the featured speakers for this Dec. 2 – 3, 2020 event, reminded me of the disturbing Glybera story,

Dr. Hayden identified the first mutations underlying lipoprotein lipase (LPL) deficiency and developed gene therapy approaches to treat this condition, the first approved gene therapy (Glybera) in the western world.

Kelly Crowe’s Nov. 17, 2018 story for the Canadian Broadcasting Corporation (CBC) lays it out,

It is one of this country’s great scientific achievements.

The first drug ever approved that can fix a faulty gene.

It’s called Glybera, and it can treat a painful and potentially deadly genetic disorder with a single dose — a genuine made-in-Canada medical breakthrough.

But most Canadians have never heard of it.

A team of researchers at the University of British Columbia spent decades developing the treatment for people born with a genetic mutation that causes lipoprotein lipase defficiency (LPLD).

If you have the time, do read Crowe’s Nov. 17, 2018 story but as I warned in another post, it’s heartbreaking.

Fora brief summary, the company which eventually emerged with the licensing rights to Glybera, charged $1m per dose and a single dose is good for 10 years. It seems governments are reluctant to approve the cost and for many individuals, it’s an impossible price to meet, every 10 years. So, the drug is dead. Or perhaps not? Take a look at the symposium’s agenda (scroll down) for description,

GLYBERA REINVENTED: A WINDING STORY OF COMMITMENT, CREATIVITY, AND INNOVATION

Michael Hayden, MB, ChB, PhD, FRCP(C), FRSC, C.M., O.B.C University Killam Professor, Senior Scientist, Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics,

University of British Columbia (Vancouver, BC)

Money issues

One theme from the agenda jumped out at me: money. The focus seems to be largely on accessibility and costs. The Nov. 3, 2020 CCA news release (also on EurekAlert) about the report also prominently featured costs,

Gene therapies are being approved for use in Canada, but could strain healthcare budgets and exacerbate existing treatment inequities [emphasis mine] across the country. However, there are opportunities to control spending, streamline approvals and support fair access through innovation, coordination and collaboration, according to a new expert panel report from the Council of Canadian Academies (CCA).

“Rapid scientific advances mean potentially life-changing treatments are approaching the clinic at an accelerated pace,” said Janet Rossant, PhD, C.C., FRSC, and Chair of the Expert Panel. “These new therapies, however, pose a number of challenges in terms of their introduction into the Canadian healthcare system and ensuring access to those who would most benefit.”

Gene therapies and gene editing

Before moving on, you might find it useful to know (if you don’t already) that gene therapy can be roughly divided into somatic cell gene therapy and germline gene therapy as per the Gene Therapy entry in Wikipedia.

Two other items on the symposium’s agenda (scroll down) drew my attention,

Genome editing and the promise for future therapies

Ronald Cohn, MD, FACMG, FCAHS President and CEO,
The Hospital for Sick Children (SickKids) (Toronto, ON)

COMING SOON: THE FUTURE OF GENE EDITING AND GENE THERAPIES

Presented by: Genome Canada

Rob Annan, PhD President and CEO,
Genome Canada (Ottawa, ON)

R. Alta Charo, J.D. Warren P. Knowles Professor of Law & Bioethics,
University of Wisconsin Law School (Madison, USA)

Jay Ingram, C.M. Science broadcaster and writer, Former Co-Host, Discovery Channel’s “Daily Planet” (Calgary, AB)

Vardit Ravitsky, PhD, FCAHS Full Professor, Bioethics Program, Department of Social and Preventative Medicine, School of Public Health, Université de Montréal; President, International Association of Bioethics (Montréal, QC)

Janet Rossant, PhD, C.C., FRSC President,
Gairdner Foundation (Toronto, ON) [also a member of the CCA expert panel for report on somatic cell therapies ‘From research to reality …’)

Genome editing, by the way and if you don’t know, is also known as gene editing. The presence of the word ‘future’ in both the presentations has my antennae quivering. Could they be hinting at germline editing possibilities? At this time, the research is illegal in Canada.

If you don’t happen to know, somatic gene editing, covered in the CCA report, does not affect future generations as opposed to germline gene editing, which does. Should you be curious about the germline gene editing discussion in Canada, I covered as much information as I could uncover in an April 26, 2019 posting on topic.

Jay Ingram’s presence on the panel sponsored by Genome Canada is a bit of a surprise.

I saw him years ago as the moderator for a panel presentation sponsored by Genome British Columbia. The discussion was about genetics and ethics, which was illustrated by clips from the television programme, ReGenesis (from its IMDB entry),

[Fictional] Geneticist David Sandstrom is the chief scientist at the prestigious virology/micro-biology NORBAC laboratory, a joint enterprise between the USA, Canada and Mexico for countering bio-terrorism.

Ingram (BA in microbiology and an MA that’s not identified in his Wikipedia entry) was a television science presenter for a number of years and has continued to work in the field of science communication. He didn’t seem all that knowledgeable about genetics when he moderated the ReGenesis panel but perhaps his focus will be about the communication element?

For anyone interested in attending the free and virtual “Breaking Through” event, you can register here.

CAR-T cell therapies (a type of somatic cell therapy)

One final note, the first week of December seems to be gene therapy week in Canada. There is another free and virtual event, the second session of the Summit for Cancer Immunotherapy: 2020 Speaker Series (Hosted by BioCanRx, Canada’s Immunotherapy Network), Note: I made a few changes to make this excerpt a bit easier to read,

Session Two: Developing better CAR T-Cell Therapies by engaging patients, performing systematic reviews and assessing real-world and economic evidence
Wednesday, December 9, 1:30 pm – 3:15pm EST [emphasis mine]

Chimeric Antigen Receptor T-cell (CAR-T) therapy is a personalized immunotherapy, currently being assessed in a Canadian Phase I/II clinical trial to test safety and feasibility for relapsed/refractory blood cancer (CD19+ Acute Lymphoblastic Leukemia and non-Hodgkin’s Lymphoma).

This virtual seminar will provide an overview of a multidisciplinary team’s collaborative efforts to synthesize evidence for the development of this clinical trial protocol, using a novel approach (the ‘Excelerator’ model). This approach involved the completion of a systematic review (objective review of existing trial data), engagement of patients and clinicians, and drawing from real world and economic evidence.

Dr. Fergusson will provide a brief introduction. Dr. Kednapa Thavorn will discuss the team’s use of economic modelling to select trial factors to maximize economic feasibility of the therapy, and Mackenzie Wilson (HQP) will discuss the current efforts and future directions to engage diverse stakeholders to inform this work. Gisell Castillo (HQP) will speak about the interviews that were conducted with patients and hematologists to identify potential barriers and enablers to participation and recruitment to the trial.

The team will also discuss two ongoing projects which build on this work. Dr. Lalu will provide an overview on the team’s patient engagement program throughout development of the trial protocol and plans to expand this program to other immunotherapy trials. Joshua Montroy (HQP) will also discuss ongoing work building on the initial systematic review, to use individual participant data meta-analysis to identify factors that may impact the efficacy of CAR-T cell therapy.

Dr. Justin Presseau will moderate the question and answer period.

And there’s this,

Who should attend?

Scientific and health care community including researchers, clinicians and HQP along with patients and caregivers. Note: There will be a plain language overview before the session begins and an opportunity to ask questions after the discussion.

If you want to know more about CAR T-cell therapy, sometimes called gene or cell therapy or immune effect cell therapy, prior to the Dec., 9, 2020 event, this page on the cancer.org website should prove helpful.

July 2020 update on Dr. He Jiankui (the CRISPR twins) situation

This was going to be written for January 2020 but sometimes things happen (e.g., a two-part overview of science culture in Canada from 2010-19 morphed into five parts with an addendum and, then, a pandemic). By now (July 28, 2020), Dr. He’s sentencing to three years in jail announced by the Chinese government in January 2020 is old news.

Regardless, it seems a neat and tidy ending to an international scientific scandal concerned with germline-editing which resulted in at least one set of twins, Lulu and Nana. He claimed to have introduced a variant (“Delta 32” variation) of their CCR5 gene. This does occur naturally and scientists have noted that people with this mutation seem to be resistant to HIV and smallpox.

For those not familiar with the events surrounding the announcement, here’s a brief recap. News of the world’s first gene-edited twins’ birth was announced in November 2018 just days before an international meeting group of experts who had agreed on a moratorium in 2015 on exactly that kind of work. The scientist making the announcement about the twins was scheduled for at least one presentation at the meeting, which was to be held in Hong Kong. He did give his presentation but left the meeting shortly afterwards as shock was beginning to abate and fierce criticism was rising. My November 28, 2018 posting (First CRISPR gene-edited babies? Ethics and the science story) offers a timeline of sorts and my initial response.

I subsequently followed up with two mores posts as the story continued to develop. My May 17, 2019 posting (Genes, intelligence, Chinese CRISPR (clustered regularly interspaced short palindromic repeats) babies, and other children) featured news that Dr. He’s gene-editing may have resulted in the twins having improved cognitive skills. Then, more news broke. The title for my June 20, 2019 posting (Greater mortality for the CRISPR twins Lulu and Nana?) is self-explanatory.

I have roughly organized my sources for this posting into two narratives, which I’m contrasting with each other. First, there is one found in the mainstream media (English language), ‘The Popular Narrative’. Second, there is story where Dr. He is viewed more sympathetically and as part of a larger community where there isn’t nearly as much consensus over what should or shouldn’t be done as ‘the popular narrative’ insists.

The popular narrative: Dr. He was a rogue scientist

A December 30, 2019 article for Fast Company by Kristin Toussaint lays out the latest facts (Note: A link has been removed),

… Now, a court in China has sentenced He to three years in prison, according to Xinhua, China’s state-run press agency, for “illegal medical practices.”

The court in China’s southern city of Shenzhen says that He’s team, which included colleagues Zhang Renli and Qin Jinzhou from two medical institutes in Guangdong Province, falsified ethical approval documents and violated China’s “regulations and ethical principles” with their gene-editing work. Zhang was sentenced to two years in jail, and Qin to 18 months with a two-year reprieve, according to Xinhau.

Ian Sample’s December 31, 2020 article for the Guardian offers more detail (Note: Links have been removed),

The court in Shenzhen found He guilty of “illegal medical practices” and in addition to the prison sentence fined him 3m yuan (£327,360), according to the state news agency, Xinhua. Two others on He’s research team received lesser fines and sentences.

“The three accused did not have the proper certification to practise medicine, and in seeking fame and wealth, deliberately violated national regulations in scientific research and medical treatment,” the court said, according to Xinhua. “They’ve crossed the bottom line of ethics in scientific research and medical ethics.”

[…] the court found He had forged documents from an ethics review panel that were used to recruit couples for the research. The couples that enrolled had a man with HIV and a woman without and were offered IVF in return for taking part.

Zhang Renli, who worked with He, was sentenced to two years in prison and fined 1m yuan. Colleague Qin Jinzhou received an 18-month sentence, but with a two-year reprieve, and a 500,000 yuan fine.

He’s experiments, which were carried out on seven embryos in late 2018, sent shockwaves through the medical and scientific world. The work was swiftly condemned for deceiving vulnerable patients and using a risky, untested procedure with no medical justification. Earlier this month, MIT Technology Review released excerpts from an early manuscript of He’s work. It casts serious doubts on his claims to have made the children immune to HIV.

Even as the scientific community turned against He, the scientist defended his work and said he was proud of having created Lulu and Nana. A third child has since been born as a result of the experiments.

Robin Lovell-Badge at the Francis Crick Institute in London said it was “far too premature” for anyone to pursue genome editing on embryos that are intended to lead to pregnancies. “At this stage we do not know if the methods will ever be sufficiently safe and efficient, although the relevant science is progressing rapidly, and new methods can look promising. It is also important to have standards established, including detailed regulatory pathways, and appropriate means of governance.”

A December 30, 2019 article, by Carolyn Y. Johnson for the Washington Post, covers much the same ground although it does go on to suggest that there might be some blame to spread around (Note: Links have been removed),

The Chinese researcher who stunned and alarmed the international scientific community with the announcement that he had created the world’s first gene-edited babies has been sentenced to three years in prison by a court in China.

He Jiankui sparked a bioethical crisis last year when he claimed to have edited the DNA of human embryos, resulting in the birth of twins called Lulu and Nana as well as a possible third pregnancy. The gene editing, which was aimed at making the children immune to HIV, was excoriated by many scientists as a reckless experiment on human subjects that violated basic ethical principles.

The judicial proceedings were not public, and outside experts said it is hard to know what to make of the punishment without the release of the full investigative report or extensive knowledge of Chinese law and the conditions under which He will be incarcerated.

Jennifer Doudna, a biochemist at the University of California at Berkeley who co-invented CRISPR, the gene editing technology that He utilized, has been outspoken in condemning the experiments and has repeatedly said CRISPR is not ready to be used for reproductive purposes.

R. Alta Charo, a fellow at Stanford’s Center for Advanced Study in the Behavioral Sciences, was among a small group of experts who had dinner with He the night before he unveiled his controversial research in Hong Kong in November 2018.

“He Jiankui is an example of somebody who fundamentally didn’t understand, or didn’t want to recognize, what have become international norms around responsible research,” Charo said. “My impression is he allowed his personal ambition to completely cloud rational thinking and judgment.”

Scientists have been testing an array of powerful biotechnology tools to fix genetic diseases in adults. There is tremendous excitement about the possibility of fixing genes that cause serious disease, and the first U.S. patients were treated with CRISPR this year.

But scientists have long drawn a clear moral line between curing genetic diseases in adults and editing and implanting human embryos, which raises the specter of “designer babies.” Those changes and any unanticipated ones could be inherited by future generations — in essence altering the human species.

“The fact that the individual at the center of the story has been punished for his role in it should not distract us from examining what supporting roles were played by others, particularly in the international scientific community and also the environment that shaped and encouraged him to push the limits,” said Benjamin Hurlbut [emphasis mine], associate professor in the School of Life Sciences at Arizona State University.

Stanford University cleared its scientists, including He’s former postdoctoral adviser, Stephen Quake, finding that Quake and others did not participate in the research and had expressed “serious concerns to Dr. He about his work.” A Rice University spokesman said an investigation continues into bioengineering professor Michael Deem, He’s former academic adviser. Deem was listed as a co-author on a paper called “Birth of Twins After Genome Editing for HIV Resistance,” submitted to scientific journals, according to MIT Technology Review.

It’s interesting that it’s only the Chinese scientists who are seen to be punished, symbolically at least. Meanwhile, Stanford clears its scientists of any wrongdoing and Rice University continues to investigate.

Watch for the Hurlbut name (son, Benjamin and father, William) to come up again in the ‘complex narrative’ section.

Criticism of the ‘twins’ CRISPR editing’ research

Antonio Regalado’s December 3, 2020 article for the MIT (Massachusetts Institute of Technology) Technology Review features comments from various experts on an unpublished draft of Dr. He Jiankui’s research

Earlier this year a source sent us a copy of an unpublished manuscript describing the creation of the first gene-edited babies, born last year in China. Today, we are making excerpts of that manuscript public for the first time.

Titled “Birth of Twins After Genome Editing for HIV Resistance,” and 4,699 words long, the still unpublished paper was authored by He Jiankui, the Chinese biophysicist who created the edited twin girls. A second manuscript we also received discusses laboratory research on human and animal embryos.

The metadata in the files we were sent indicate that the two draft papers were edited by He in late November 2018 and appear to be what he initially submitted for publication. Other versions, including a combined manuscript, may also exist. After consideration by at least two prestigious journals, Nature and JAMA, his research remains unpublished.

The text of the twins paper is replete with expansive claims of a medical breakthrough that can “control the HIV epidemic.” It claims “success”—a word used more than once—in using a “novel therapy” to render the girls resistant to HIV. Yet surprisingly, it makes little attempt to prove that the twins really are resistant to the virus. And the text largely ignores data elsewhere in the paper suggesting that the editing went wrong.

We shared the unpublished manuscripts with four experts—a legal scholar, an IVF doctor, an embryologist, and a gene-editing specialist—and asked them for their reactions. Their views were damning. Among them: key claims that He and his team made are not supported by the data; the babies’ parents may have been under pressure to agree to join the experiment; the supposed medical benefits are dubious at best; and the researchers moved forward with creating living human beings before they fully understood the effects of the edits they had made.

1. Why aren’t the doctors among the paper’s authors?

The manuscript begins with a list of the authors—10 of them, mostly from He Jiankui’s lab at the Southern University of Science and Technology, but also including Hua Bai, director of an AIDS support network, who helped recruit couples, and Michael Deem, an American biophysicist whose role is under review by Rice University. (His attorney previously said Deem never agreed to submit the manuscript and sought to remove his name from it.)

It’s a small number of people for such a significant project, and one reason is that some names are missing—notably, the fertility doctors who treated the patients and the obstetrician who delivered the babies. Concealing them may be an attempt to obscure the identities of the patients. However, it also leaves unclear whether or not these doctors understood they were helping to create the first gene-edited babies.

To some, the question of whether the manuscript is trustworthy arises immediately.

Hank Greely, professor of law, Stanford University: We have no, or almost no, independent evidence for anything reported in this paper. Although I believe that the babies probably were DNA-edited and were born, there’s very little evidence for that. Given the circumstances of this case, I am not willing to grant He Jiankui the usual presumption of honesty. 

That last article by Regalado is the purest example I have of how fierce the criticism is and how almost all of it is focused on Dr. He and his Chinese colleagues.

A complex, measured narrative: multiple players in the game

The most sympathetic and, in many ways, the most comprehensive article is an August 1, 2019 piece by Jon Cohen for Science magazine (Note: Links have been removed),

On 10 June 2017, a sunny and hot Saturday in Shenzhen, China, two couples came to the Southern University of Science and Technology (SUSTech) to discuss whether they would participate in a medical experiment that no researcher had ever dared to conduct. The Chinese couples, who were having fertility problems, gathered around a conference table to meet with He Jiankui, a SUSTech biophysicist. Then 33, He (pronounced “HEH”) had a growing reputation in China as a scientist-entrepreneur but was little known outside the country. “We want to tell you some serious things that might be scary,” said He, who was trim from years of playing soccer and wore a gray collared shirt, his cuffs casually unbuttoned.

He simply meant the standard in vitro fertilization (IVF) procedures. But as the discussion progressed, He and his postdoc walked the couples through informed consent forms [emphasis mine] that described what many ethicists and scientists view as a far more frightening proposition. Seventeen months later, the experiment triggered an international controversy, and the worldwide scientific community rejected him. The scandal cost him his university position and the leadership of a biotech company he founded. Commentaries labeled He, who also goes by the nickname JK, a “rogue,” “China’s Frankenstein,” and “stupendously immoral.” [emphases mine]

But that day in the conference room, He’s reputation remained untarnished. As the couples listened and flipped through the forms, occasionally asking questions, two witnesses—one American, the other Chinese—observed [emphasis mine]. Another lab member shot video, which Science has seen [emphasis mine], of part of the 50-minute meeting. He had recruited those couples because the husbands were living with HIV infections kept under control by antiviral drugs. The IVF procedure would use a reliable process called sperm washing to remove the virus before insemination, so father-to-child transmission was not a concern. Rather, He sought couples who had endured HIV-related stigma and discrimination and wanted to spare their children that fate by dramatically reducing their risk of ever becoming infected. [emphasis mine]

He, who for much of his brief career had specialized in sequencing DNA, offered a potential solution: CRISPR, the genome-editing tool that was revolutionizing biology, could alter a gene in IVF embryos to cripple production of an immune cell surface protein, CCR5, that HIV uses to establish an infection. “This technique may be able to produce an IVF baby naturally immunized against AIDS,” one consent form read.[emphasis mine]

The couples’ children could also pass the protective mutation to future generations. The prospect of this irrevocable genetic change is why, since the advent of CRISPR as a genome editor 5 years earlier, the editing of human embryos, eggs, or sperm has been hotly debated. The core issue is whether such germline editing would cross an ethical red line because it could ultimately alter our species. Regulations, some with squishy language, arguably prohibited it in many countries, China included.

Yet opposition was not unanimous. A few months before He met the couples, a committee convened by the U.S. National Academies of Sciences, Engineering, and Medicine (NASEM) concluded in a well-publicized report that human trials of germline editing “might be permitted” if strict criteria were met. The group of scientists, lawyers, bioethicists, and patient advocates spelled out a regulatory framework but cautioned that “these criteria are necessarily vague” because various societies, caregivers, and patients would view them differently. The committee notably did not call for an international ban, arguing instead for governmental regulation as each country deemed appropriate and “voluntary self-regulation pursuant to professional guidelines.”

[…] He hid his plans and deceived his colleagues and superiors, as many people have asserted? A preliminary investigation in China stated that He had forged documents, “dodged supervision,” and misrepresented blood tests—even though no proof of those charges was released [emphasis mine], no outsiders were part of the inquiry, and He has not publicly admitted to any wrongdoing. (CRISPR scientists in China say the He fallout has affected their research.) Many scientists outside China also portrayed He as a rogue actor. “I think there has been a failure of self-regulation by the scientific community because of a lack of transparency,” virologist David Baltimore, a Nobel Prize–winning researcher at the California Institute of Technology (Caltech) in Pasadena and co-chair of the Hong Kong summit, thundered at He after the biophysicist’s only public talk on the experiment.

Because the Chinese government has revealed little and He is not talking, key questions about his actions are hard to answer. Many of his colleagues and confidants also ignored Science‘s requests for interviews. But Ryan Ferrell, a public relations specialist He hired, has cataloged five dozen people who were not part of the study but knew or suspected what He was doing before it became public. Ferrell calls it He’s circle of trust. [emphasis mine]

That circle included leading scientists—among them a Nobel laureate—in China and the United States, business executives, an entrepreneur connected to venture capitalists, authors of the NASEM report, a controversial U.S. IVF specialist [John Zhang] who discussed opening a gene-editing clinic with He [emphasis mine], and at least one Chinese politician. “He had an awful lot of company to be called a ‘rogue,’” says geneticist George Church [emphases mine], a CRISPR pioneer at Harvard University who was not in the circle of trust and is one of the few scientists to defend at least some aspects of He’s experiment.

Some people sharply criticized He when he brought them into the circle; others appear to have welcomed his plans or did nothing. Several went out of their way to distance themselves from He after the furor erupted. For example, the two onlookers in that informed consent meeting were Michael Deem, He’s Ph.D. adviser at Rice University in Houston, Texas, and Yu Jun, a member of the Chinese Academy of Sciences (CAS) and co-founder of the Beijing Genomics Institute, the famed DNA sequencing company in Shenzhen. Deem remains under investigation by Rice for his role in the experiment and would not speak with Science. In a carefully worded statement, Deem’s lawyers later said he “did not meet the parents of the reported CCR5-edited children, or anyone else whose embryos were edited.” But earlier, Deem cooperated with the Associated Press (AP) for its exclusive story revealing the birth of the babies, which reported that Deem was “present in China when potential participants gave their consent and that he ‘absolutely’ thinks they were able to understand the risks. [emphasis mine]”

Yu, who works at CAS’s Beijing Institute of Genomics, acknowledges attending the informed consent meeting with Deem, but he told Science he did not know that He planned to implant gene-edited embryos. “Deem and I were chatting about something else,” says Yu, who has sequenced the genomes of humans, rice, silkworms, and date palms. “What was happening in the room was not my business, and that’s my personality: If it’s not my business, I pay very little attention.”

Some people who know He and have spoken to Science contend it is time for a more open discussion of how the biophysicist formed his circle of confidants and how the larger circle of trust—the one between the scientific community and the public—broke down. Bioethicist William Hurlbut at Stanford University [emphasis mine] in Palo Alto, California, who knew He wanted to conduct the embryo-editing experiment and tried to dissuade him, says that He was “thrown under the bus” by many people who once supported him. “Everyone ran for the exits, in both the U.S. and China. I think everybody would do better if they would just openly admit what they knew and what they did, and then collectively say, ‘Well, people weren’t clear what to do. We should all admit this is an unfamiliar terrain.’”

Steve Lombardi, a former CEO of Helicos, reacted far more charitably. Lombardi, who runs a consulting business in Bridgewater, Connecticut, says Quake introduced him to He to help find investors for Direct Genomics. “He’s your classic, incredibly bright, naïve entrepreneur—I run into them all the time,” Lombardi says. “He had the right instincts for what to do in China and just didn’t know how to do it. So I put him in front of as many people as I could.” Lombardi says He told him about his embryo-editing ambitions in August 2017, asking whether Lombardi could find investors for a new company that focused on “genetic medical tourism” and was based in China or, because of a potentially friendlier regulatory climate, Thailand. “I kept saying to him, ‘You know, you’ve got to deal with the ethics of this and be really sure that you know what you’re doing.’”

In April 2018, He asked Ferrell to handle his media full time. Ferrell was a good fit—he had an undergraduate degree in neuroscience, had spent a year in Beijing studying Chinese, and had helped another company using a pre-CRISPR genome editor. Now that a woman in the trial was pregnant, Ferrell says, He’s “understanding of the gravity of what he had done increased.” Ferrell had misgivings about the experiment, but he quit HDMZ and that August moved to Shenzhen. With the pregnancy already underway, Ferrell reasoned, “It was going to be the biggest science story of that week or longer, no matter what I did.”

MIT Technology Review had broken a story early that morning China time, saying human embryos were being edited and implanted, after reporter Antonio Regalado discovered descriptions of the project that He had posted online, without Ferrell’s knowledge, in an official Chinese clinical trial registry. Now, He gave AP the green light to post a detailed account, which revealed that twin girls—whom He, to protect their identifies, named Lulu and Nana—had been born. Ferrell and He also posted five unfinished YouTube videos explaining and justifying the unprecedented experiment.

“He was fearful that he’d be unable to communicate to the press and the onslaught in a way that would be in any way manageable for him,” Ferrell says. One video tried to forestall eugenics accusations, with He rejecting goals such as enhancing intelligence, changing skin color, and increasing sports performance as “not love.” Still, the group knew it had lost control of the news. [emphasis mine]

… On 7 March 2017, 5 weeks after the California gathering, He submitted a medical ethics approval application to the Shenzhen HarMoniCare Women and Children’s Hospital that outlined the planned CCR5 edit of human embryos. The babies, it claimed, would be resistant to HIV as well as to smallpox and cholera. (The natural CCR5 mutation may have been selected for because it helps carriers survive smallpox and plague, some studies suggest—but they don’t mention cholera.) “This is going to be a great science and medicine achievement ever since the IVF technology which was awarded the Nobel Prize in 2010, and will also bring hope to numerous genetic disease patients,” the application says. Seven people on the ethics committee, chaired by Lin Zhitong—a one-time Direct Genomics director and a HarMoniCare administrator—signed the application, indicating they approved it.

[…] John Zhang, […] [emphasis mine] earned his medical degree in China and a Ph.D. in reproductive biology at the University of Cambridge in the United Kingdom. Zhang had made international headlines himself in September 2016, when New Scientist revealed that he had created the world’s first “three-parent baby” by using mitochondrial DNA from a donor egg to revitalize the egg of a woman with infertility and then inseminating the resulting egg. “This technology holds great hope for ladies with advanced maternal age to have their own children with their own eggs,” Zhang explains in the center’s promotional video, which alternates between Chinese and English. It does not mention that Zhang did the IVF experiment in Mexico because it is not now allowed in the United States. [emphasis mine]

When Science contacted Zhang, the physician initially said he barely knew He: [emphases mine] “I know him just like many people know him, in an academic meeting.”

After his talk [November 2018 at Hong Kong meeting], He immediately drove back to Shenzhen, and his circle of trust began to disintegrate. He has not spoken publicly since. “I don’t think he can recover himself through PR,” says Ferrell, who no longer works for He but recently started to do part-time work for He’s wife. “He has to do other service to the world.”

Calls for a moratorium on human germline editing have increased, although at the end of the Hong Kong summit, the organizing committee declined in its consensus to call for a ban. China has stiffened its regulations on work with human embryos, and Chinese bioethicists in a Nature editorial about the incident urged the country to confront “the eugenic thinking that has persisted among a small proportion of Chinese scholars.”

Church, who has many CRISPR collaborations in China, finds it inconceivable that He’s work surprised the Chinese government. China has “the best surveillance system in the world,” he says. “I conclude that they were totally aware of what he was doing at every step of the way, especially because he wasn’t particularly secretive about it.”

Benjamin Hurlbut, William’s son and a historian of biomedicine at Arizona State University in Tempe, says leaders in the scientific community should take a hard look at their actions, too. [emphases mine] He thinks the 2017 NASEM report helped give rise to He by following a well-established approach to guiding science: appointing an elite group to decide how scientists should be regulated. Benjamin Hurlbut, whose book Experiments in Democracy explores the governance of embryo research and bioethics, questions why small, scientist-led groups—à la the totemic Asilomar conference held in 1975 to discuss the future of recombinant DNA research—are seen as the best way to shape thinking about new technologies. Hurlbut has called for a “global observatory for gene editing” to convene meetings with diverse perspectives.

The prevailing notion that the scientific community simply “failed to see the rogue among the responsible,” Hurlbut says, is a convenient narrative for those scientific leaders and inhibits their ability to learn from such failures. [emphases mine] “It puts them on the right side of history,” he says. They failed to paint a bright enough red line, Hurlbut contends. “They are not on the right side of history because they contributed to this.”

If you have the time, I strongly recommend reading Cohen’s piece in its entirety. You’ll find links to the reports and more articles with in-depth reporting on this topic.

A little kindness and no regrets

William Hurlbut was interviewed in an As it happens (Canadian Broadcasting Corporation’ CBC) radio programme segment on December 30, 2020. This is an excerpt from the story transcript written by Sheena Goodyear (Note: A link has been removed),

Dr. William Hurlbut, a physician and professor of neural-biology at Stanford University, says he tried to warn He to slow down before it was too late. Here is part of his conversation with As It Happens guest host Helen Mann.

What was your reaction to the news that Dr. He had been sentenced to three years in prison?

My first reaction was one of sadness because I know Dr. He — who we call J.K., that’s his nickname.

I spent quite a few hours talking with him, and I’m just sad that this worked out this way. It didn’t work out well for him or for his country or for the world, in some sense.

Except the one good thing is it’s alerted us, it’s awakened the world, to the seriousness of the issues that are coming down toward us with biotechnology, especially in genetics.

How does he feel about [how] not just the Chinese government, but the world generally, responded to his experiment?

He was surprised, personally. But I had actually warned him that he was proceeding too fast, and I didn’t know he had implanted embryos.

We had several conversations before this was disclosed, and I warned him to go more slowly and to keep in conversation with the rest of the international scientific community, and more broadly the international perspectives on social and ethical matters.

He was doing that to some extent, but not deeply enough and not transparently enough.

It sounds like you were very thoughtful in the conversations you had with him and the advice you gave him. And I guess you operated with what you had. But do you have any regrets yourself?

I don’t have any regrets about the way I conducted myself. I regret that this happened this way for J.K., who is a very bright person, and a very nice person, a humble person.

He grew up in a poor urban farming village. He told me that at one point he wanted to ask out a certain girl that he thought was really pretty … but he was embarrassed to do so because her family owned the restaurant. And so you see how humble his origins were.

By the way, he did end up asking her out and he ended up marrying her, which is a happy story, except now they’re separated for years of crucial time, and they have little children. 

I know this is a bigger story than just J.K. and his family. But there’s a personal story to it too.

What happens He Jiankui? … Is his research career over?

It’s hard to imagine that a nation like China would not give him some some useful role in their society. A very intelligent and very well-educated young man. 

But on the other hand, he will be forever a sign of a very crucial and difficult moment for the human species. He’s not going outlive that.

It’s going to be interesting. I hope I get a chance to have good conversations with him again and hear his internal ruminations and perspectives on it all.

This (“I don’t have any regrets about the way I conducted myself”) is where Hurlbut lost me. I think he could have suggested that he’d reviewed and rethought everything and feels that he and others could have done better and maybe they need to rethink how scientists are trained and how we talk about science, genetics, and emerging technology. Interestingly, it’s his son who comes up with something closer to what I’m suggesting (this excerpt was quoted earlier in this posting from a December 30, 2019 article, by Carolyn Y. Johnson for the Washington Post),

“The fact that the individual at the center of the story has been punished for his role in it should not distract us from examining what supporting roles were played by others, particularly in the international scientific community and also the environment that shaped and encouraged him to push the limits,” said Benjamin Hurlbut [emphasis mine], associate professor in the School of Life Sciences at Arizona State University.

The man who CRISPRs himself approves

Josiah Zayner publicly injected himself with CRISPR in a demonstration (see my January 25, 2018 posting for details about Zayner, his demonstration, and his plans). As you might expect, his take on the He affair is quite individual. From a January 2, 2020 article for STAT, Zayner presents the case for Dr. He’s work (Note: Links have been removed),

When I saw the news that He Jiankui and colleagues had been sentenced to three years in prison for the first human embryo gene editing and implantation experiments, all I could think was, “How will we look back at what they had done in 100 years?”

When the scientist described his research and revealed the births of gene edited twin girls at the [Second] International Summit on Human Genome Editing in Hong Kong in late November 2018, I stayed up into the early hours of the morning in Oakland, Calif., watching it. Afterward, I couldn’t sleep for a few days and couldn’t stop thinking about his achievement.

This was the first time a viable human embryo was edited and allowed to live past 14 days, much less the first time such an embryo was implanted and the baby brought to term.

The majority of scientists were outraged at the ethics of what had taken place, despite having very little information on what had actually occurred.

To me, no matter how abhorrent one views [sic] the research, it represents a substantial step forward in human embryo editing. Now there is a clear path forward that anyone can follow when before it had been only a dream.

As long as the children He Jiankui engineered haven’t been harmed by the experiment, he is just a scientist who forged some documents to convince medical doctors to implant gene-edited embryos. The 4-minute mile of human genetic engineering has been broken. It will happen again.

The academic establishment and federal funding regulations have made it easy to control the number of heretical scientists. We rarely if ever hear of individuals pushing the ethical and legal boundaries of science.

The rise of the biohacker is changing that.

A biohacker is a scientist who exists outside academia or an institution. By this definition, He Jiankui is a biohacker. I’m also part of this community, and helped build an organization to support it.

Such individuals have much more freedom than “traditional” scientists because scientific regulation in the U.S. is very much institutionally enforced by the universities, research organizations, or grant-giving agencies. But if you are your own institution and don’t require federal grants, who can police you? If you don’t tell anyone what you are doing, there is no way to stop you — especially since there is no government agency actively trying to stop people from editing embryos.

… When a human embryo being edited and implanted is no longer interesting enough for a news story, will we still view He Jiankui as a villain?

I don’t think we will. But even if we do, He Jiankui will be remembered and talked about more than any scientist of our day. Although that may seriously aggravate many scientists and bioethicists, I think he deserves that honor.

Josiah Zayner is CEO of The ODIN, a company that teaches people how to do genetic engineering in their homes.

You can find The ODIN here.

Final comments

There can’t be any question that this was inevitable. One needs only to take a brief stroll through the history of science to know that scientists are going to push boundaries or, as in this case, press past an ill-defined grey zone.

The only scientists who are being publicly punished for hubris are Dr. He Jiankui and his two colleagues in China. Dr. Michael Deem is still working for Rice University as far as I can determine. Here’s how the Wikipedia entry for the He Jiankui Affair describes the investigation (Note: Links have been removed),

Michael W. Deem, an American bioengineering professor at Rice University and He’s doctoral advisor, was involved in the research, and was present when people involved in He’s study gave consent.[24] He was the only non-Chinese out of 10 authors listed in the manuscript submitted to Nature.[30] Deem came under investigation by Rice University after news of the work was made public.[58] As of 31 December 2019, the university had not released a decision.[59] [emphasis mine]

Meanwhile the scientists at Stanford are cleared. While there are comments about the Chinese government not being transparent, it seems to me that US universities are just as opaque.

What seems missing from all this discussion and opprobrium is that the CRISPR technology itself is problematic. My September 20, 2019 post features research into off-target results from CRISPR gene-editing and, prior, there was this July 17, 2018 posting (The CRISPR [clustered regularly interspaced short palindromic repeats]-CAS9 gene-editing technique may cause new genetic damage kerfuffle).

I’d like to see more discussion and, in line with Benjamin Hurlbut’s thinking, I’d like to see more than a small group of experts talking to each other as part of the process especially here in Canada and in light of efforts to remove our ban on germline-editing (see my April 26, 2019 posting for more about those efforts).

The decade that was (2010-19) and the decade to come (2020-29): Science culture in Canada (5 of 5)

At long last, the end is in sight! This last part is mostly a collection of items that don’t fit elsewhere or could have fit elsewhere but that particular part was already overstuffed.

Podcasting science for the people

March 2009 was the birth date for a podcast, then called Skeptically Speaking and now known as Science for the People (Wikipedia entry). Here’s more from the Science for the People About webpage,

Science for the People is a long-format interview podcast that explores the connections between science, popular culture, history, and public policy, to help listeners understand the evidence and arguments behind what’s in the news and on the shelves.

Every week, our hosts sit down with science researchers, writers, authors, journalists, and experts to discuss science from the past, the science that affects our lives today, and how science might change our future.

THE TEAM

Rachelle Saunders: Producer & Host

I love to learn new things, and say the word “fascinating” way too much. I like to talk about intersections and how science and critical thinking intersect with everyday life, politics, history, and culture. By day I’m a web developer, and I definitely listen to way too many podcasts.

….

H/t to GeekWrapped’s 20 Best Science Podcasts.

Science: human contexts and cosmopolitanism

situating science: Science in Human Contexts was a seven-year project ending in 2014 and funded by the Social Sciences and Humanities Research Council of Canada (SSHRC). Here’s more from their Project Summary webpage,

Created in 2007 with the generous funding of the Social Sciences and Humanities Research Council of Canada Strategic Knowledge Cluster grant, Situating Science is a seven-year project promoting communication and collaboration among humanists and social scientists that are engaged in the study of science and technology.

You can find out more about Situating Science’s final days in my August 16, 2013 posting where I included a lot of information about one of their last events titled, “Science and Society 2013 Symposium; Emerging Agendas for Citizens and the Sciences.”

The “think-tank” will dovetail nicely with a special symposium in Ottawa on Science and Society Oct. 21-23. For this symposium, the Cluster is partnering with the Institute for Science, Society and Policy to bring together scholars from various disciplines, public servants and policy workers to discuss key issues at the intersection of science and society. [emphasis mine]  The discussions will be compiled in a document to be shared with stakeholders and the wider public.

The team will continue to seek support and partnerships for projects within the scope of its objectives. Among our top priorities are a partnership to explore sciences, technologies and their publics as well as new partnerships to build upon exchanges between scholars and institutions in India, Singapore and Canada.

The Situating Science folks did attempt to carry on the organization’s work by rebranding the organization to call it the Canadian Consortium for Situating Science and Technology (CCSST). It seems to have been a short-lived volunteer effort.

Meanwhile, the special symposium held in October 2013 appears to have been the springboard for another SSHRC funded multi-year initiative, this time focused on science collaborations between Canada, India, and Singapore, Cosmopolitanism and the Local in Science and Nature from 2014 – 2017. Despite their sunset year having been in 2017, their homepage boasts news about a 2020 Congress and their Twitter feed is still active. Harking back, here’s what the project was designed to do, from the About Us page,

Welcome to our three year project that will establish a research network on “Cosmopolitanism” in science. It closely examines the actual types of negotiations that go into the making of science and its culture within an increasingly globalized landscape. This partnership is both about “cosmopolitanism and the local” and is, at the same time, cosmopolitan and local.

Anyone who reads this blog with any frequency will know that I often comment on the fact that when organizations such as the Council of Canadian Academies bring in experts from other parts of the world, they are almost always from the US or Europe. So, I was delighted to discover the Cosmopolitanism project and featured it in a February 19, 2015 posting.

Here’s more from Cosmopolitanism’s About Us page

Specifically, the project will:

  1. Expose a hitherto largely Eurocentric scholarly community in Canada to widening international perspectives and methods,
  2. Build on past successes at border-crossings and exchanges between the participants,
  3. Facilitate a much needed nation-wide organization and exchange amongst Indian and South East Asian scholars, in concert with their Canadian counterparts, by integrating into an international network,
  4. Open up new perspectives on the genesis and place of globalized science, and thereby
  5. Offer alternative ways to conceptualize and engage globalization itself, and especially the globalization of knowledge and science.
  6. Bring the managerial team together for joint discussion, research exchange, leveraging and planning – all in the aid of laying the grounds of a sustainable partnership

Eco Art (also known as ecological art or environmental art)

I’m of two minds as to whether I should have tried to stuff this into the art/sci subsection in part 2. On balance, I decided that this merited its own section and that part 2 was already overstuffed.

Let’s start in Newfoundland and Labrador with Marlene Creates (pronounced Kreets), here’s more about her from her website’s bio webpage,

Marlene Creates (pronounced “Kreets”) is an environmental artist and poet who works with photography, video, scientific and vernacular knowledge, walking and collaborative site-specific performance in the six-acre patch of boreal forest in Portugal Cove, Newfoundland and Labrador, Canada, where she lives.

For almost 40 years her work has been an exploration of the relationship between human experience, memory, language and the land, and the impact they have on each other. …

Currently her work is focused on the six acres of boreal forest where she lives in a ‘relational aesthetic’ to the land. This oeuvre includes Water Flowing to the Sea Captured at the Speed of Light, Blast Hole Pond River, Newfoundland 2002–2003, and several ongoing projects:

Marlene Creates received a Governor General’s Award in Visual and Media Arts for “Lifetime Artistic Achievement” in 2019. …

As mentioned in her bio, Creates has a ‘forest’ project. The Boreal Poetry Garden,
Portugal Cove, Newfoundland 2005– (ongoing)
. If you are interested in exploring it, she has created a virtual walk here. Just click on one of the index items on the right side of the screen to activate a video.

An October 1, 2018 article by Yasmin Nurming-Por for Canadian Art magazine features 10 artists who focus on environmental and/or land art themes,

As part of her 2016 master’s thesis exhibition, Fredericton [New Brunswick] artist Gillian Dykeman presented the video Dispatches from the Feminist Utopian Future within a larger installation that imagined various canonical earthworks from the perspective of the future. It’s a project that addresses the inherent sense of timelessness in these massive interventions on the natural landscape from the perspective of contemporary land politics. … she proposes a kind of interaction with the invasive and often colonial gestures of modernist Land art, one that imagines a different future for these earthworks, where they are treated as alien in a landscape and as beacons from a feminist future.

A video trailer featuring “DISPATCHES FROM THE FEMINIST UTOPIAN FUTURE” (from Dykeman’s website archive page featuring the show,

If you have the time, I recommend reading the article in its entirety.

Oddly, I did not expect Vancouver to have such an active eco arts focus. The City of Vancouver Parks Board maintains an Environmental Art webpage on its site listing a number of current and past projects.

I cannot find the date for when this Parks Board initiative started but I did find a document produced prior to a Spring 2006 Arts & Ecology think tank held in Vancouver under the auspices of the Canada Council for the Arts, the Canadian Commission for UNESCO, the Vancouver Foundation, and the Royal Society for the Encouragement of the Arts, Manufactures and Commerce (London UK).

In all likelihood, Vancouver Park Board’s Environmental Art webpage was produced after 2006.

I imagine the document and the think tank session helped to anchor any then current eco art projects and encouraged more projects.

The document (MAPPING THE TERRAIN OF CONTEMPORARY ECOART PRACTICE AND COLLABORATION) while almost 14 years old offers a fascinating overview of what was happening internationally and in Canada.

While its early days were in 2008, EartHand Gleaners (Vancouver-based) wasn’t formally founded as an arts non-for-profit organization until 2013. You can find out more about them and their projects here.

Eco Art has been around for decades according to the eco art think tank document but it does seemed to have gained momentum here in Canada over the last decade.

Photography and the Natural Sciences and Engineering Research Council of Canada (NSERC)

Exploring the jack pine tight knit family tree. Credit: Dana Harris Brock University (2018)

Pictured are developing phloem, cambial, and xylem cells (blue), and mature xylem cells (red), in the outermost portion of a jack pine tree. This research aims to identify the influences of climate on the cellular development of the species at its northern limit in Yellowknife, NT. The differences in these cell formations is what creates the annual tree ring boundary.

Science Exposed is a photography contest for scientists which has been run since 2016 (assuming the Past Winners archive is a good indicator for the programme’s starting year).

The 2020 competition recently closed but public voting should start soon. It’s nice to see that NSERC is now making efforts to engage members of the general public rather than focusing its efforts solely on children. The UK’s ASPIRES project seems to support the idea that adults need to be more fully engaged with STEM (science, technology, engineering, and mathematics) efforts as it found that children’s attitudes toward science are strongly influenced by their parents’ and relatives’ attitudes.(See my January 31, 2012 posting.)

Ingenious, the book and Ingenium, the science museums

To celebrate Canada’s 150th anniversary in 2017, then Governor General David Johnston and Tom Jenkins (Chair of the board for Open Text and former Chair of the federal committee overseeing the ‘Review of Federal Support to R&’D [see my October 21, 2011 posting about the resulting report]) wrote a boo about Canada’s inventors and inventions.

Johnston and Jenkins jaunted around the country launching their book (I have more about their June 1, 2017 Vancouver visit in a May 30, 2017 posting; scroll down about 60% of the way]).

The book’s full title, “Ingenious: How Canadian Innovators Made the World Smarter, Smaller, Kinder, Safer, Healthier, Wealthier and Happier ” outlines their thesis neatly.

Not all that long after the book was launched, there was a name change (thankfully) for the Canada Science and Technology Museums Corporation (CSTMC). It is now known as Ingenium (covered in my August 10, 2017 posting).

The reason that name change was such a relief (for those who don’t know) is that the corporation included three national science museums: Canada Aviation and Space Museum, Canada Agriculture and Food Museum, and (wait for it) Canada Science and Technology Museum. On the list of confusing names, this ranks very high for me. Again, I give thanks for the change from CSTMC to Ingenium, leaving the name for the museum alone.

2017 was also the year that the newly refurbished Canada Science and Technology Museum was reopened after more than three years (see my June 23, 2017 posting about the November 2017 reopening and my June 12, 2015 posting for more information about the situation that led to the closure).

A Saskatchewan lab, Convergence, Order of Canada, Year of Science, Animated Mathematics, a graphic novel, and new media

Since this section is jampacked, I’m using subheads.

Saskatchewan

Dr. Brian Eames hosts an artist-in-residence, Jean-Sebastien (JS) Gauthier at the University of Saskatchewan’s College of Medicine Eames Lab. A February 16, 2018 posting here featured their first collaboration together. It covered evolutionary biology, the synchrotron (Canadian Light Source [CLS]) in Saskatoon, and the ‘ins and outs’ of a collaboration between a scientist an artist. Presumably the art-in-residence position indicates that first collaboration went very well.

In January 2020, Brian kindly gave me an update on their current projects. Jean-Sebastin successfully coded an interactive piece for an exhibit at the 2019 Nuit Blanche Saskatoon event using Connect (Xbox). More recently, he got a VR [virtual reality] helmet for an upcoming project or two.

After much clicking on the Nuit Blanche Saskatoon 2019 interactive map, I found this,

Our Glass is a work of interactive SciArt co-created by artist JS Gauthier and biologist Dr Brian F. Eames. It uses cutting-edge 3D microscopic images produced for artistic purposes at the Canadian Light Source, Canada’s only synchrotron facility. Our Glass engages viewers of all ages to peer within an hourglass showing how embryonic development compares among animals with whom we share a close genetic heritage.

Eames also mentioned they were hoping to hold an international SciArt Symposium at the University of Saskatchewan in 2021.

Convergence

Dr. Cristian Zaelzer-Perez, an instructor at Concordia University (Montreal; read this November 20, 2019 Concordia news release by Kelsey Rolfe for more about his work and awards), in 2016 founded the Convergence Initiative, a not-for-profit organization that encourages interdisciplinary neuroscience and art collaborations.

Cat Lau’s December 23, 2019 posting for the Science Borealis blog provides insight into Zaelzer-Perez’s relationship to science and art,

Cristian: I have had a relationship with art and science ever since I have had memory. As a child, I loved to do classifications, from grouping different flowers to collecting leaves by their shapes. At the same time, I really loved to draw them and for me, both things never looked different; they (art and science) have always worked together.

I started as a graphic designer, but the pursuit to learn about nature was never dead. At some point, I knew I wanted to go back to school to do research, to explore and learn new things. I started studying medical technologies, then molecular biology and then jumped into a PhD. At that point, my life as a graphic designer slipped down, because of the focus you have to give to the discipline. It seemed like every time I tried to dedicate myself to one thing, I would find myself doing the other thing a couple years later.

I came to Montreal to do my post-doc, but I had trouble publishing, which became problematic in getting a career. I was still loving what I was doing, but not seeing a future in that. Once again, art came back into my life and at the same time I saw that science was becoming really hard to understand and scientists were not doing much to bridge the gap.

The Convergence Initiative has an impressive array of programmes. Do check it out.

Order of Canada and ‘The Science Lady’

For a writer of children’s science books, an appointment to the Order of Canada is a singular honour. I cannot recall a children’s science book writer previous to Shar Levine being appointed as a Member of the Order of Canada. Known as ‘The Science Lady‘, Levine was appointed in 2016. Here’s more from her Wikipedia entry, Note: Links have been removed,

Shar Levine (born 1953) is an award-winning, best selling Canadian children’s author, and designer.

Shar has written over 70 books and book/kits, primarily on hands-on science for children. For her work in Science literacy and Science promotion, Shar has been appointed to the 2016 Order of Canada. In 2015, she was recognized by the University of Alberta and received their Alumni Honour Award. Levine, and her co-author, Leslie Johnstone, were co-recipients of the Eve Savory Award for Science Communication from the BC Innovation Council (2006) and their book, Backyard Science, was a finalist for the Subaru Award, (hands on activity) from the American Association for the Advancement of Science, Science Books and Films (2005). The Ultimate Guide to Your Microscope was a finalist-2008 American Association for the Advancement of Science/Subaru Science Books and Films Prize Hands -On Science/Activity Books.

To get a sense of what an appointment to the Order of Canada means, here’s a description from the government of Canada website,

The Order of Canada is how our country honours people who make extraordinary contributions to the nation.

Since its creation in 1967—Canada’s centennial year—more than 7 000 people from all sectors of society have been invested into the Order. The contributions of these trailblazers are varied, yet they have all enriched the lives of others and made a difference to this country. Their grit and passion inspire us, teach us and show us the way forward. They exemplify the Order’s motto: DESIDERANTES MELIOREM PATRIAM (“They desire a better country”).

Year of Science in British Columbia

In the Fall of 2010, the British Columbia provincial government announced a Year of Science (coinciding with the school year) . Originally, it was supposed to be a provincial government-wide initiative but the idea percolated through any number of processes and emerged as a year dedicated to science education for youth (according to the idea’s originator, Moira Stilwell who was then a Member of the Legislative Assembly [MLA]’ I spoke with her sometime in 2010 or 2011).

As the ‘year’ drew to a close, there was a finale ($1.1M in funding), which was featured here in a July 6, 2011 posting.

The larger portion of the money ($1M) was awarded to Science World while $100,000 ($0.1 M) was given to the Pacific Institute of Mathematical Sciences To my knowledge there have been no followup announcements about how the money was used.

Animation and mathematics

In Toronto, mathematician Dr. Karan Singh enjoyed a flurry of interest due to his association with animator Chris Landreth and their Academy Award (Oscar) Winning 2004 animated film, Ryan. They have continued to work together as members of the Dynamic Graphics Project (DGP) Lab at the University of Toronto. Theirs is not the only Oscar winning work to emerge from one or more of the members of the lab. Jos Stam, DGP graduate and adjunct professor won his third in 2019.

A graphic novel and medical promise

An academic at Simon Fraser University since 2015, Coleman Nye worked with three other women to produce a graphic novel about medical dilemmas in a genre described as’ ethno-fiction’.

Lissa: A Story about Medical Promise, Friendship, and Revolution (2017) by Sherine Hamdy and Coleman Nye, two anthropologists and Art by Sarula Bao and Caroline Brewer, two artists.

Here’s a description of the book from the University of Toronto Press website,

As young girls in Cairo, Anna and Layla strike up an unlikely friendship that crosses class, cultural, and religious divides. Years later, Anna learns that she may carry the hereditary cancer gene responsible for her mother’s death. Meanwhile, Layla’s family is faced with a difficult decision about kidney transplantation. Their friendship is put to the test when these medical crises reveal stark differences in their perspectives…until revolutionary unrest in Egypt changes their lives forever.

The first book in a new series [ethnoGRAPIC; a series of graphic novels from the University of Toronto Press], Lissa brings anthropological research to life in comic form, combining scholarly insights and accessible, visually-rich storytelling to foster greater understanding of global politics, inequalities, and solidarity.

I hope to write more about this graphic novel in a future posting.

New Media

I don’t know if this could be described as a movement yet but it’s certainly an interesting minor development. Two new media centres have hosted, in the last four years, art/sci projects and/or workshops. It’s unexpected given this definition from the Wikipedia entry for New Media (Note: Links have been removed),

New media are forms of media that are computational and rely on computers for redistribution. Some examples of new media are computer animations, computer games, human-computer interfaces, interactive computer installations, websites, and virtual worlds.[1][2]

In Manitoba, the Video Pool Media Arts Centre hosted a February 2016 workshop Biology as a New Art Medium: Workshop with Marta De Menezes. De Menezes, an artist from Portugal, gave workshops and talks in both Winnipeg (Manitoba) and Toronto (Ontario). Here’s a description for the one in Winnipeg,

This workshop aims to explore the multiple possibilities of artistic approaches that can be developed in relation to Art and Microbiology in a DIY situation. A special emphasis will be placed on the development of collaborative art and microbiology projects where the artist has to learn some biological research skills in order to create the artwork. The course will consist of a series of intense experimental sessions that will give raise to discussions on the artistic, aesthetic and ethical issues raised by the art and the science involved. Handling these materials and organisms will provoke a reflection on the theoretical issues involved and the course will provide background information on the current diversity of artistic discourses centred on biological sciences, as well a forum for debate.

VIVO Media Arts Centre in Vancouver hosted the Invasive Systems in 2019. From the exhibition page,

Picture this – a world where AI invades human creativity, bacteria invade our brains, and invisible technological signals penetrate all natural environments. Where invasive species from plants to humans transform spaces where they don’t belong, technology infiltrates every aspect of our daily lives, and the waste of human inventions ravages our natural environments.

This weekend festival includes an art-science exhibition [emphasis mine], a hands-on workshop (Sat, separate registration required), and guided discussions and tours by the curator (Sat/Sun). It will showcase collaborative works by three artist/scientist pairs, and independent works by six artists. Opening reception will be on Friday, November 8 starting at 7pm; curator’s remarks and performance by Edzi’u at 7:30pm and 9pm. 

New Westminster’s (British Columbia) New Media Gallery recently hosted an exhibition, ‘winds‘ from June 20 – September 29, 2019 that could be described as an art/sci exhibition,

Landscape and weather have long shared an intimate connection with the arts.  Each of the works here is a landscape: captured, interpreted and presented through a range of technologies. The four artists in this exhibition have taken, as their material process, the movement of wind through physical space & time. They explore how our perception and understanding of landscape can be interpreted through technology. 

These works have been created by what might be understood as a sort of scientific method or process that involves collecting data, acute observation, controlled experiments and the incorporation of measurements and technologies that control or collect motion, pressure, sound, pattern and the like. …

Council of Canadian Academies, Publishing, and Open Access

Established in 2005, the Council of Canadian Academies (CCA) (Wikipedia entry) is tasked by various departments and agencies to answer their queries about science issues that could affect the populace and/or the government. In 2014, the CCA published a report titled, Science Culture: Where Canada Stands. It was in response to the Canada Science and Technology Museums Corporation (now called Ingenium), Industry Canada, and Natural Resources Canada and their joint request that the CCA conduct an in-depth, independent assessment to investigate the state of Canada’s science culture.

I gave a pretty extensive analysis of the report, which I delivered in four parts: Part 1, Part 2 (a), Part 2 (b), and Part 3. In brief, the term ‘science culture’ seems to be specifically, i.e., it’s not used elsewhere in the world (that we know of), Canadian. We have lots to be proud of. I was a little disappointed by the lack of culture (arts) producers on the expert panel and, as usual, I bemoaned the fact that the international community included as reviewers, members of the panel, and as points for comparison were drawn from the usual suspects (US, UK, or somewhere in northern Europe).

Science publishing in Canada took a bit of a turn in 2010, when the country’s largest science publisher, NRC (National Research Council) Research Publisher was cut loose from the government and spun out into the private, *not-for-profit publisher*, Canadian Science Publishing (CSP). From the CSP Wikipedia entry,

Since 2010, Canadian Science Publishing has acquired five new journals:

Since 2010, Canadian Science Publishing has also launched four new journals

Canadian Science Publishing offers researchers options to make their published papers freely available (open access) in their standard journals and in their open access journal, (from the CSP Wikipedia entry)

Arctic Science aims to provide a collaborative approach to Arctic research for a diverse group of users including government, policy makers, the general public, and researchers across all scientific fields

FACETS is Canada’s first open access multidisciplinary science journal, aiming to advance science by publishing research that the multi-faceted global community of research. FACETS is the official journal of the Royal Society of Canada’s Academy of Science.

Anthropocene Coasts aims to understand and predict the effects of human activity, including climate change, on coastal regions.

In addition, Canadian Science Publishing strives to make their content accessible through the CSP blog that includes plain language summaries of featured research. The open-access journal FACETS similarly publishes plain language summaries.

*comment removed*

CSP announced (on Twitter) a new annual contest in 2016,

Canadian Science Publishing@cdnsciencepub

New CONTEST! Announcing Visualizing Science! Share your science images & win great prizes! Full details on the blog http://cdnsciencepub.com/blog/2016-csp-image-contest-visualizing-science.aspx1:45 PM · Sep 19, 2016·TweetDeck

The 2016 blog posting is no longer accessible. Oddly for a contest of this type, I can’t find an image archive for previous contests. Regardless, a 2020 competition has been announced for Summer 2020. There are some details on the VISUALIZING SCIENCE 2020 webpage but some are missing, e.g., no opening date, no deadline. They are encouraging you to sign up for notices.

Back to open access, in a January 22, 2016 posting I featured news about Montreal Neuro (Montreal Neurological Institute [MNI] in Québec, Canada) and its then new policy giving researchers world wide access to its research and made a pledge that it would not seek patents for its work.

Fish, Newfoundland & Labrador, and Prince Edward Island

AquAdvantage’s genetically modified salmon was approved for consumption in Canada according to my May 20, 2016 posting. The salmon are produced/farmed by a US company (AquaBounty) but the the work of genetically modifying Atlantic salmon with genetic material from the Chinook (a Pacific ocean salmon) was mostly undertaken at Memorial University in Newfoundland & Labrador.

The process by which work done in Newfoundland & Labrador becomes the property of a US company is one that’s well known here in Canada. The preliminary work and technology is developed here and then purchased by a US company, which files patents, markets, and profits from it. Interestingly, the fish farms for the AquAdvantage salmon are mostly (two out of three) located on Prince Edward Island.

Intriguingly, 4.5 tonnes of the modified fish were sold for consumption in Canada without consumers being informed (see my Sept. 13, 2017 posting, scroll down about 45% of the way).

It’s not all sunshine and roses where science culture in Canada is concerned. Incidents where Canadians are not informed let alone consulted about major changes in the food supply and other areas are not unusual. Too many times, scientists, politicians, and government policy experts want to spread news about science without any response from the recipients who are in effect viewed as a ‘tabula rasa’ or a blank page.

Tying it all up

This series has been my best attempt to document in some fashion or another the extraordinary range of science culture in Canada from roughly 2010-19. Thank you! This series represents a huge amount of work and effort to develop science culture in Canada and I am deeply thankful that people give so much to this effort.

I have inevitably missed people and organizations and events. For that I am very sorry. (There is an addendum to the series as it’s been hard to stop but I don’t expect to add anything or anyone more.)

I want to mention but can’t expand upon,the Pan-Canadian Artificial Intelligence Strategy, which was established in the 2017 federal budget (see a March 31, 2017 posting about the Vector Institute and Canada’s artificial intelligence sector).

Science Borealis, the Canadian science blog aggregator, owes its existence to Canadian Science Publishing for the support (programming and financial) needed to establish itself and, I believe, that support is still ongoing. I think thanks are also due to Jenny Ryan who was working for CSP and championed the initiative. Jenny now works for Canadian Blood Services. Interestingly, that agency added a new programme, a ‘Lay Science Writing Competition’ in 2018. It’s offered n partnership with two other groups, the Centre for Blood Research at the University of British Columbia and Science Borealis

While the Royal Astronomical Society of Canada does not fit into my time frame as it lists as its founding date December 1, 1868 (18 months after confederation), the organization did celebrate its 150th anniversary in 2018.

Vancouver’s Electric Company often produces theatrical experiences that cover science topics such as the one featured in my June 7, 2013 posting, You are very star—an immersive transmedia experience.

Let’s Talk Science (Wikipedia entry) has been heavily involved with offering STEM (science, technology, engineering, and mathematics) programming both as part of curricular and extra-curricular across Canada since 1993.

This organization predates confederation having been founded in 1849 by Sir Sandford Fleming and Kivas Tully in Toronto. for surveyors, civil engineers, and architects. It is the Royal Canadian Institute of Science (Wikipedia entry)_. With almost no interruption, they have been delivering a regular series of lectures on the University of Toronto campus since 1913.

The Perimeter Institute for Theoretical Physics is a more recent beast. In 1999 Mike Lazirides, founder of Research In Motion (now known as Blackberry Limited), acted as both founder and major benefactor for this institute in Waterloo, Ontario. They offer a substantive and imaginative outreach programmes such as Arts and Culture: “Event Horizons is a series of unique and extraordinary events that aim to stimulate and enthral. It is a showcase of innovative work of the highest international standard, an emotional, intellectual, and creative experience. And perhaps most importantly, it is a social space, where ideas collide and curious minds meet.”

While gene-editing hasn’t seemed to be top-of-mind for anyone other than those in the art/sci community that may change. My April 26, 2019 posting focused on what appears to be a campaign to reverse Canada’s criminal ban on human gene-editing of inheritable cells (germline). With less potential for controversy, there is a discussion about somatic gene therapies and engineered cell therapies. A report from the Council of Canadian is due in the Fall of 2020. (The therapies being discussed do not involve germline editing.)

French language science media and podcasting

Agence Science-Presse is unique as it is the only press agency in Canada devoted to science news. Founded in 1978, it has been active in print, radio, television, online blogs, and podcasts (Baladodiffusion). You can find their Twitter feed here.

I recently stumbled across ‘un balados’ (podcast), titled, 20%. Started in January 2019 by the magazine, Québec Science, the podcast is devoted to women in science and technology. 20%, the podcast’s name, is the statistic representing the number of women in those fields. “Dans les domaines de la science et de la technologie, les femmes ne forment que 20% de la main-d’oeuvre.” (from the podcast webpage) The podcast is a co-production between “Québec Science [founded in 1962] et l’Acfas [formerly, l’Association Canadienne-Française pour l’Avancement des Sciences, now, Association francophone pour le savoir], en collaboration avec la Commission canadienne pour l’UNESCO, L’Oréal Canada et la radio Choq.ca.” (also from the podcast webpage)

Does it mean anything?

There have been many developments since I started writing this series in late December 2019. In January 2020, Iran shot down one of its own planes. That error killed some 176 people , many of them (136 Canadians and students) bound for Canada. The number of people who were involved in the sciences, technology, and medicine was striking.

It was a shocking loss and will reverberate for quite some time. There is a memorial posting here (January 13, 2020), which includes links to another memorial posting and an essay.

As I write this we are dealing with a pandemic, COVID-19, which has us all practicing physical and social distancing. Congregations of large numbers are expressly forbidden. All of this is being done in a bid to lessen the passage of the virus, SARS-CoV-2 which causes COVID-19.

In the short term at least, it seems that much of what I’ve described in these five parts (and the addendum) will undergo significant changes or simply fade away.

As for the long term, with this last 10 years having hosted the most lively science culture scene I can ever recall, I’m hopeful that science culture in Canada will do more than survive but thrive.

For anyone who missed them:

Part 1 covers science communication, science media (mainstream and others such as blogging) and arts as exemplified by music and dance: The decade that was (2010-19) and the decade to come (2020-29): Science culture in Canada (1 of 5).

Part 2 covers art/science (or art/sci or sciart) efforts, science festivals both national and local, international art and technology conferences held in Canada, and various bar/pub/café events: The decade that was (2010-19) and the decade to come (2020-29): Science culture in Canada (2 of 5).

Part 3 covers comedy, do-it-yourself (DIY) biology, chief science advisor, science policy, mathematicians, and more: The decade that was (2010-19) and the decade to come (2020-29): Science culture in Canada (3 of 5)

Part 4 covers citizen science, birds, climate change, indigenous knowledge (science), and the IISD Experimental Lakes Area: The decade that was (2010-19) and the decade to come (2020-29): Science culture in Canada (4 of 5)

*”for-profit publisher, Canadian Science Publishing (CSP)” corrected to “not-for-profit publisher, Canadian Science Publishing (CSP)” and this comment “Not bad for a for-profit business, eh?” removed on April 29, 2020 as per Twitter comments,

Canadian Science Publishing @cdnsciencepub

Hi Maryse, thank you for alerting us to your blog. To clarify, Canadian Science Publishing is a not-for-profit publisher. Thank you as well for sharing our image contest. We’ve updated the contest page to indicate that the contest opens July 2020!

10:01am · 29 Apr 2020 · Twitter Web App

Detecting off-target effects of CRISPR gene-editing

In amidst all the hyperbole about CRISPR (clustered regularly interspaced short palindromic repeats), the gene editing technology, you will sometimes find a mild cautionary note. It seems that CRISPR is not as precise as you might think.

Some months ago there was a story about research into detecting possible unanticipated (off target) effects from using CRISPR, from an April 19, 2019 news item on ScienceDaily,

Since the CRISPR genome editing technology was invented in 2012, it has shown great promise to treat a number of intractable diseases. However, scientists have struggled to identify potential off-target effects in therapeutically relevant cell types, which remains the main barrier to moving therapies to the clinic. Now, a group of scientists at the Gladstone Institutes and the Innovative Genomics Institute (IGI), with collaborators at AstraZeneca, have developed a reliable method to do just that.

An April 19, 2019 Gladstone Institutes press release by Julie Langelier, which originated the press release, provides details,

CRISPR edits a person’s genome by cutting the DNA at a specific location. The challenge is to ensure the tool doesn’t also make cuts elsewhere along the DNA—damage referred to as “off-target effects,” which could have unforeseen consequences.

In a study published in the journal Science, the two first authors, Beeke Wienert and Stacia Wyman, found a new way to approach the problem.

“When CRISPR makes a cut, the DNA is broken,” says Wienert, PhD, who began the work in Jacob E. Corn’s IGI laboratory and who is now a postdoctoral scholar in Bruce R. Conklin’s laboratory at Gladstone. “So, in order to survive, the cell recruits many different DNA repair factors to that particular site in the genome to fix the break and join the cut ends back together. We thought that if we could find the locations of these DNA repair factors, we could identify the sites that have been cut by CRISPR.”

To test their idea, the researchers studied a panel of different DNA repair factors. They found that one of them, called MRE11, is one of the first responders to the site of the cut. Using MRE11, the scientists developed a new technique, named DISCOVER-Seq, that can identify the exact sites in the genome where a cut has been made by CRISPR.

“The human genome is extremely large—if you printed the entire DNA sequence, you would end up with a novel as tall as a 16-story building,” explains Conklin, MD, senior investigator at Gladstone and deputy director at IGI. “When we want to cut DNA with CRISPR, it’s like we’re trying to remove one specific word on a particular page in that novel.”

“You can think of the DNA repair factors as different types of bookmarks added to the book,” Conklin adds. “While some may bookmark an entire chapter, MRE11 is a bookmark that drills down to the exact letter than has been changed.”

Different methods currently exist to detect CRISPR off-target effects. However, they come with limitations that range from producing false-positive results to killing the cells they’re examining. In addition, the most common method used to date is currently limited to cultured cells in the laboratory, excluding its use in patient-derived stem cells or animal tissue.

“Because our method relies on the cell’s natural repair process to identify cuts, it has proven to be much less invasive and much more reliable,” says Corn, PhD, who now runs a laboratory at ETH Zurich. “We were able to test our new DISCOVER-Seq method in induced pluripotent stem cells, patient cells, and mice, and our findings indicate that this method could potentially be used in any system, rather than just in the lab.”

The DISCOVER-Seq method, by being applied to new cell types and systems, has also revealed new insights into the mechanisms used by CRISPR to edit the genome, which will lead to a better understanding of the biology of how this tool works.

“The new method greatly simplifies the process of identifying off-target effects while also increasing the accuracy of the results,” says Conklin, who is also a professor of medical genetics and molecular pharmacology at UC San Francisco (UCSF). “This could allow us to better predict how genome editing would work in a clinical setting. As a result, it represents an essential step in improving pre-clinical studies and bringing CRISPR-based therapies closer to the patients in need.”

###

About the Study

The paper “Unbiased detection of CRISPR off-targets in vivo 1 using DISCOVER-Seq” was published by the journal Science on April 19, 2019. Gladstone’s Hannah L. Watry and Luke M. Judge (who is also at UCSF) contributed to this study. Other authors also include Christopher D. Richardson, Jonathan T. Vu, and Katelynn R. Kazane from IGI, Charles D. Yeh from ETH Zurich, as well as Pinar Akcakaya, Michelle J. Porritt, and Michaela Morlock from AstraZeneca.

The work was supported by Gladstone, the National Institutes of Health (grants EY028249 and HL13535801), the Li Ka Shing Foundation, the Heritage Medical Research Institute, the Fanconi Anemia Research Foundation, a Sir Keith Murdoch Fellowship from the American Australian Association, and an Early Career Fellowship from the National Health and Medical Research Council.

About the Gladstone Institute

To ensure our work does the greatest good, the Gladstone Institutes focuses on conditions with profound medical, economic, and social impact—unsolved diseases. Gladstone is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease. It has an academic affiliation with the University of California, San Francisco.

Before getting to the link and citation that I usually offer you might find this July 17, 2018 posting, The CRISPR ((clustered regularly interspaced short palindromic repeats)-CAS9 gene-editing technique may cause new genetic damage kerfuffle of interest. I wonder if this latest news affected the CRISPR market as the did the news in 2018.

In addition to the link in the press release, I am including a link and a citation for the study,

Unbiased detection of CRISPR off-targets in vivo using DISCOVER-Seq by Beeke Wienert, Stacia K. Wyman, Christopher D. Richardson, Charles D. Yeh, Pinar Akcakaya, Michelle J. Porritt, Michaela Morlock, Jonathan T. Vu, Katelynn R. Kazane, Hannah L. Watry, Luke M. Judge, Bruce R. Conklin, Marcello Maresca, Jacob E. Corn. Science 19 Apr 2019: Vol. 364, Issue 6437, pp. 286-289 DOI: 10.1126/science.aav9023

This paper is behind a paywall.

Money

Over the last 10 or more years, I have, on occasion made a point, of finding out about the funding for various non-profit agencies and projects. I find that sort of thing interesting and have hoped that my readers might feel the same way.

It seems that my readers and I might not be the only ones to care about the source of funding. Joi Ito who held appointments with Harvard University and the Massachusetts Institute of Technology (MIT) resigned from his various appointments on Sept. 7, 2019 after news of major donations from Jeffrey Epstein (a disgraced financier and sex offender) to MIT were revealed. From the Joi Ito’s entry on Wikipedia (Note: Links have been removed),

Joichi “Joi” Ito (伊藤 穰一 Itō Jōichi, born June 19, 1966) is a Japanese activist, entrepreneur and venture capitalist. He is the former director of the MIT Media Lab, and a former professor of the practice of media arts and sciences at MIT. He is a former visiting professor of practice at the Harvard Law School.[1][2]

Ito has received recognition for his role as an entrepreneur focused on Internet and technology companies and has founded, among other companies, PSINet Japan, Digital Garage and Infoseek Japan. Ito is a strategic advisor to Sony Corporation[3] and general partner of Neoteny Labs.[4] Ito writes a monthly column in the Ideas section of Wired.[5]

Ito resigned from his roles at MIT, Harvard, the John D. and Catherine T. MacArthur Foundation, the Knight Foundation, PureTech Health and The New York Times Company on September 7, 2019, following allegations of financial ties to sex offender and financier Jeffrey Epstein.[2][6][7]

Many, many institutions have accepted funds from sketchy characters and orgnaizations. It’s not new to academia, the sciences, or the arts. For a contemporary view of how some of this works, take a look at Anand Giridharadas’s 2018 book, Winners Take All. From the webepage for the book,

WINNERS TAKE ALL
The Elite Charade of Changing the World
 
An insider’s groundbreaking investigation of how the global elite’s efforts to “change the world” preserve the status quo and obscure their role in causing the problems they later seek to solve.

Former New York Times columnist Anand Giridharadas takes us into the inner sanctums of a new gilded age, where the rich and powerful fight for equality and justice any way they can–except ways that threaten the social order and their position atop it. We see how they rebrand themselves as saviors of the poor; how they lavishly reward “thought leaders” who redefine “change” in winner-friendly ways; and how they constantly seek to do more good, but never less harm. We hear the limousine confessions of a celebrated foundation boss; witness an American president hem and haw about his plutocratic benefactors; and attend a cruise-ship conference where entrepreneurs celebrate their own self-interested magnanimity.

I don’t recall any mention of Epstein in Giridharadas’s book but he did have this to say on Twitter about Epstein,

Anand Giridharadas‏Verified account @AnandWrites



Everything that made Epstein’s life possible remains in place after his arrest: the Caribbean tax havens, the hidden real-estate deals, the buying of politicians, the nonprofits that sell reputational glow, the editors who cover for people of their class.

7:34 PM – 8 Jul 2019

it can’t be easy to withstand the temptation to take the money and hope that the misdoings have been exaggerated or that they have stopped. I imagine Ito and others are under constant pressure to get funds.

AstraZeneca

One of the partners in this research about CRISPR, AstraZeneca, is a pharmaceutical company. In fact, it’s one of the largest in the world (from the AstraZeneca Wikipedia entry; Note: Links have been removed),

AstraZeneca plc[4] is a British-Swedish multinational pharmaceutical and biopharmaceutical company. In 2013, it moved its headquarters to Cambridge, UK, and concentrated its R&D in three sites: Cambridge; Gaithersburg, Maryland, USA (location of MedImmune) for work on biopharmaceuticals; and Mölndal (near Gothenburg) in Sweden, for research on traditional chemical drugs.[5] AstraZeneca has a portfolio of products for major disease areas including cancer, cardiovascular, gastrointestinal, infection, neuroscience, respiratory and inflammation.[6]

The company was founded in 1999 through the merger of the Swedish Astra AB and the British Zeneca Group[7][8] (itself formed by the demerger of the pharmaceutical operations of Imperial Chemical Industries in 1993). Since the merger it has been among the world’s largest pharmaceutical companies and has made numerous corporate acquisitions, including Cambridge Antibody Technology (in 2006), MedImmune (in 2007), Spirogen (in 2013) and Definiens (by MedImmune in 2014).

Controversies

Seroquel
In April 2010 AstraZeneca settled a qui tam lawsuit brought by Stefan P. Kruszewski for $520 million to settle allegations that the company defrauded Medicare, Medicaid, and other government-funded health care programs in connection with its marketing and promotional practices for the blockbuster atypical antipsychotic, Seroquel.[76]
In March 2011, AstraZeneca settled a lawsuit in the United States totalling $68.5 million to be divided up to 38 states.[77]
Nexium
The company’s most commercially successful medication is esomeprazole (Nexium). The primary uses are treatment of gastroesophageal reflux disease, treatment and maintenance of erosive esophagitis, treatment of duodenal ulcers caused by Helicobacter pylori, prevention of gastric ulcers in those on chronic NSAID therapy, and treatment of gastrointestinal ulcers associated with Crohn’s disease. When it is manufactured the result is a mixture of two mirror-imaged molecules, R and S. Two years before the omeprazole patent expired, AstraZeneca patented S-omeprazole in pure form, pointing out that since some people metabolise R-omeprazole slowly, pure S-omeprazole treatment would give higher dose efficiency and less variation between individuals.[78] In March 2001, the company began to market Nexium, as it would a brand new drug.[79]

In 2007, Marcia Angell, former editor-in-chief of the New England Journal of Medicine and a lecturer in social medicine at the Harvard Medical School, said in Stern, a German-language weekly newsmagazine, that AstraZeneca’s scientists had misrepresented their research on the drug’s efficiency, saying “Instead of using presumably comparable doses [of each drug], the company’s scientists used Nexium in higher dosages. They compared 20 and 40 mg Nexium with 20 mg Prilosec. With the cards having been marked in that way, Nexium looked like an improvement – which however was only small and shown in only two of the three studies.”[83]
Bildman fraud, and faithless servant clawback

Study
In 2004, University of Minnesota research participant Dan Markingson committed suicide while enrolled in an industry-sponsored pharmaceutical trial comparing three FDA-approved atypical antipsychotics: Seroquel (quetiapine), Zyprexa (olanzapine), and Risperdal (risperidone). University of Minnesota Professor of Bioethics Carl Elliott noted that Markingson was enrolled in the study against the wishes of his mother, Mary Weiss, and that he was forced to choose between enrolling in the study or being involuntarily committed to a state mental institution.[89] Further investigation revealed financial ties to AstraZeneca by Markingson’s psychiatrist, Stephen C. Olson, oversights and biases in AstraZeneca’s trial design, and the inadequacy of university Institutional Review Board (IRB) protections for research subjects.[90][unreliable source?] A 2005 FDA investigation cleared the university. Nonetheless, controversy around the case has continued. A Mother Jones article[89] resulted in a group of university faculty members sending a public letter to the university Board of Regents urging an external investigation into Markingson’s death.[91]

Is it ok to take money and/or other goods and services from them?

Innovative Genomics Institute (IGI)

Also mentioned as a partner in the research, is the Innovative Genomics Institute (IGI). Here’s more from the company’s Overview webpage (Note: Links have been removed),,

The IGI began in 2014 through the Li Ka Shing Center for Genetic Engineering, which was created thanks to a generous donation from the Li Ka Shing Foundation. [emphasis mine] The Innovative Genomics Initiative formed as a partnership between the University of California, Berkeley and the University of California, San Francisco. Combining the fundamental research expertise and the biomedical talent at UCB and UCSF, the Innovative Genomics Initiative focused on unraveling the mechanisms underlying CRISPR-based genome editing and applying this technology to improve human health. Early achievements include improving the efficiency of gene replacement and foundational work toward a treatment for sickle cell disease.

In late 2015, generous philanthropic donations enabled a bolder vision and broader mission for the IGI. With this expansion came a significant enhancement of the organization, and in January 2017, the IGI officially re-launched as the Innovative Genomics Institute.

As it turns out, there is a Li Ka-shing and he has a bit of a history with Vancouver (Canada). First, here’s more about him from the Li Ka-shing Wikipedia entry,(Note: Links have been removed),

Sir Li Ka-shing GBM KBE JP[4] (born 13 June 1928)[5][6] is a Hong Kong business magnate, investor, and philanthropist. As of June 2019, Li is the 30th richest person in the world, with an estimated net wealth of US$29.4 billion.[3] He is the senior advisor for CK Hutchison Holdings,[7] after he retired from the Chairman of the Board in May 2018;[8] through it, he is the world’s leading port investor, developer, and operator of the largest health and beauty retailer in Asia and Europe.[9]

Besides business through his flagship companies Cheung Kong Property Holdings and CK Hutchison Holdings Limited, Li Ka-shing has also personally invested extensively in real estate in Singapore and Canada. He was the single largest shareholder of Canadian Imperial Bank of Commerce (CIBC), the fifth largest bank in Canada, until the sale of his share in 2005 (with all proceedings donated, see below). He is also the majority shareholder of a major energy company, Husky Energy, based in Alberta, Canada.[48]

In January 2005, Li announced plans to sell his $1.2 billion CAD stake in the Canadian Imperial Bank of Commerce, with all proceeds going to private charitable foundations established by Li, including the Li Ka Shing Foundation in Hong Kong and the Li Ka Shing (Canada) Foundation based in Toronto, Ontario.[49]

His son Victor Li was kidnapped in 1996 on his way home after work by gangster “Big Spender” Cheung Tze-keung. Li Ka-shing paid a ransom of HK$1 billion, directly to Cheung who had come to his house.[53] A report was never filed with Hong Kong police. Instead the case was pursued by Mainland authorities, leading to Cheung’s execution in 1998, an outcome not possible under Hong Kong law. Rumours circulated of a deal between Li and the Mainland.[53] In interviews, when this rumor was brought up, Li brushed it off and dismissed it completely.

Li Ka-shing was well known here in Vancouver due to his purchase of a significant chunk of land in the city. This January 9, 2015 article by Glen Korstrum for Business in Vancouver notes some rather interesting news and contextualizes with Li’s Vancouver history,

Hong Kong billionaire Li Ka-shing is restructuring his empire and shifting his base to the Cayman Islands and away from the Chinese special administrative region.

His January 9 [2015] announcement came the same day that Forbes ranked him as Hong Kong’s richest man for the 17th consecutive year, with a total wealth of US$33.5 billion.

Li is best known in Vancouver for buying an 82.5-hectare parcel of land around False Creek for $328 million in 1988 along with partners, who included fellow Hong Kong tycoons, Lee Shau Kee and Cheng Yu Tung.

The group formed Concord Pacific, which redeveloped the site that had been home to Vancouver’s 1986 world’s fair, Expo ’86.

Li cashed out of Concord Pacific in the late 1990s and, in 2007, invested in Deltaport through his Hutchison Port Holdings.

Li’s biggest Canadian holding is his controlling stake in Husky Energy. …

Intriguing, yes? It also makes the prospect of deciding whose money you’re going to accept a bit more complicated than it might seem.

Gladstone Institutes

In what seems to be a decided contrast to the previous two partners, here’s more from the Gladstone Institutes, About Us, History webpage,

Born in London in 1910, J. David Gladstone was orphaned as a boy and came to North America at age 10. He began a career in real estate in Southern California at age 28, eventually making his fortune as the first developer to create the region’s enclosed shopping malls (such as the Northridge Fashion Center mall). His accidental death in 1971 left an estate valued at about $8 million to support medical students interested in research.

It soon became clear to the three trustees administering Mr. Gladstone’s trust that his legacy could support a far more substantial philanthropic enterprise. In 1979, they launched The J. David Gladstone Institutes under the leadership of Robert W. Mahley, MD, PhD, a leading cardiovascular scientist who at the time was working at the National Institutes of Health.

In 2010, after three decades of leading Gladstone, Dr. Mahley stepped down in order to return to more active research. That same year, R. Sanders “Sandy” Williams, MD, left Duke University, where he had been Dean of the School of Medicine—as well as Senior Vice Chancellor and Senior Advisor for International Strategy—to become Gladstone’s new president. The following year, the S.D. Bechtel, Jr. Foundation [emphasis mine] helped launch the Center for Comprehensive Alzheimer’s Disease Research with a generous $6M lead gift, while the Roddenberry Foundation [emphasis mine] gave $5 million to launch the Roddenberry Center for Stem Cell Biology and Medicine. Also in 2011, the independent and philanthropic Gladstone Foundation formed with the mission of expanding the financial resources available to drive’s Gladstone’s mission.

The S. D. Bechtel jr. mentioned is associated with Bechtel, an international engineering firm. I did not find any scandals or controversies in the Bechtel Wikipedia entry. That seemed improbable so I did a little digging and found a January 30, 2015 (?) article by Matthew Brunwasser for foreignpolicy.com (Note: A link has been removed),

Steamrolled; A special investigation into the diplomacy of doing business abroad.

One of Europe’s poorest countries wanted a road, so U.S. mega-contractor Bechtel sold it a $1.3 billion highway, with the backing of a powerful American ambassador. Funny thing is, the highway is barely being used—and the ambassador is now working for Bechtel.

Bechtel, the largest contractor by revenue in the United States and the third-largest internationally, according to an annual list compiled by the Engineering News-Record, has in recent years constructed expensive highways in Kosovo, Croatia, Romania, and Albania. A six-month investigation by the Investigative Reporting Program at the University of California at Berkeley Graduate School of Journalism has found that these highways were boondoggles for the countries in which they were constructed, and that members of governments and international institutions often saw problems coming before Bechtel (along with its Turkish joint venture partner, Enka) even began work on the roads.

My other source is a May 8, 1988 article by Walter Russell Mead for the Los Angeles Time,s

From San Francisco to Saudi Arabia, the Bechtel Group Inc. has left its mark around the world. Yet the privately owned Bechtel Group is one of the country’s most mysterious operations–or was, until the publication of Laton McCartney’s critical and controversial “Friends in High Places.”

Those who believe that “Dynasty” and “Falcon Crest” describe life at the top of America’s corporate pyramids will find a picture here that makes the most far-fetched TV plots look dull. One Bechtel executive was torn to pieces by an angry mob; another, kidnaped, survived two days in the trunk of a Mercedes that had been driven over the edge of a cliff but caught on an obstacle half way down. Wheeling and dealing from Beirut to the Bohemian Grove, Bechtel executives fought off Arab and Jewish nationalists, angry senators, bitter business rivals, and furious consumer groups to build the world’s largest construction and engineering firm.

Poor Bechtel sometimes seems damned if it does and damned if it doesn’t. No major corporation could undertake foreign operations on Bechtel’s scale without some cooperation from the U.S. government–and few companies could refuse a government request that, in return, they provide cover for intelligence agents. Given the enormous scope of Bechtel’s operations in global trouble spots–a $20-billion industrial development in Saudi Arabia, for example–it could only proceed with assurances that its relations with both Saudi and American governments were good. Where, exactly, is the line between right and wrong? [emphasis mine]

… The white elephants Bechtel scattered across the American landscape–particularly the nuclear power plants that threaten to bankrupt some of the country’s largest utility systems–are monuments to wasted talent and misdirected resources.

Finally, I get to the Roddenberry Foundation, which was founded by Gene Roddenberry’s (Star Trek) son. Here’s more from the About Us, Origin webpage,

Gene Roddenberry, creator of the Star Trek series, brought to his audiences meaningful and thought-provoking science fiction to “think, question, and challenge the status quo” with the intention of creating “a brighter future”. His work has touched countless lives and continues to entertain and inspire audiences worldwide. In 2010, Gene’s son Rod established the Roddenberry Foundation to build on his father’s legacy and philosophy of inclusion, diversity, and respect for life to drive social change and meaningfully improve the lives of people around the world.

While there are many criticisms of Mr. Roddenberry, there doesn’t seem to be anything that would be considered a serious scandal on the order of a Jeffrey Epstein or the whisper of scandal on the order of Sir Li Ka-shing or Bechtel.

Final comments

It’s a good thing when research is funded and being able to detect off-target effects from CRISPR is very good, assuming the research holds up to closer scrutiny.

As for vetting your donors, that’s tricky. Of course, Epstein was already a convicted sex offender when Ito accepted his funding for MIT but I cannot emphasize enough the amount of pressure these folks are under. Academia is always hungry for money. Hopefully this incident will introduce checks and balances in the donor process.

Greater mortality for the CRISPR twins Lulu and Nana?

Every time I think this CRISPR (clustered regularly interspaced short palindromic repeats) story is winding down, something new happens. The latest (I think) is in a June 3, 2019 news item on ScienceDaily,

A genetic mutation that a Chinese scientist attempted to create in twin babies born last year, ostensibly to help them fend off HIV infection, is also associated with a 21% increase in mortality in later life, according to an analysis by University of California, Berkeley, scientists.

The researchers scanned more than 400,000 genomes and associated health records contained in a British database, UK Biobank, and found that people who had two mutated copies of the gene had a significantly higher death rate between ages 41 and 78 than those with one or no copies.

Sarah Zhang’s June 3, 2019 article for The Atlantic provides an overview of the situation before exploring the current controversy,

In the 1990s, virologists in New York learned of a genetic mutation that would become one of the most famous ever discovered. They found it in a man who could not be infected with HIV. He turned out to be missing just 32 letters in a gene called CCR5, and remarkably, it was enough to make him resistant to the virus killing so many others. About 1 percent of people of European descent carry two copies of this mutation, now known as CCR5-Δ32.

In 2018, a Chinese scientist named He Jiankui made the mutation infamous when he attempted to use CRISPR to edit CCR5-Δ32 (pronounced “CCR5-delta-32”) into human embryos. He chose this mutation, he said, because the babies’ father was HIV-positive, and he wanted to make the resulting twin girls resistant to the virus. CCR5-Δ32 is also, after all, one of the most studied mutations.

He’s work immediately provoked outrage among scientists, who knew enough to know how much they did not know about the risks of altering CCR5. And now a new study suggests that CCR5-Δ32 is indeed harmful overall.

The girls’ CCR5 genes were altered, according to data He presented, but they do not exactly match the 32-letter deletion; it’s unclear whether either of them is actually resistant to HIV. Even if they were unable to get HIV, a body of research already suggested that CCR5-Δ32 made people more vulnerable to the flu and West Nile virus. A “good” mutation in the context of HIV can be “bad” in another context. No one knew, exactly, the net effect of a CCR5-Δ32 mutation.

For some reason, Zhang makes no mention of the possibly enhanced cognitive abilities that the twins may have as a consequence of the gene editing assuming that He Jiankui successfully edited the genes. (To my knowledge, the results and data have not been released for review by colleagues.)

Regardless, Zhang’s article provides a handy overview and update.

For anyone who’s interested in more detail about this latest research into mortality and CCR5, there’s a June 3, 2019 University of California at Berkeley news release (also on EurekAlert) by Robert Sanders, which also originated the ScienceDaily news item, details the latest research,

Previous studies have associated two mutated copies of the gene, CCR5, with a fourfold increase in the death rate after influenza infection, and the higher overall mortality rate may reflect this greater susceptibility to death from the flu. But the researchers say there could be any number of explanations, since the protein that CCR5 codes for, and which no longer works in those having the mutation in both copies of the gene, is involved in many body functions.

“Beyond the many ethical issues involved with the CRISPR babies, the fact is that, right now, with current knowledge, it is still very dangerous to try to introduce mutations without knowing the full effect of what those mutations do,” said Rasmus Nielsen, a UC Berkeley professor of integrative biology. “In this case, it is probably not a mutation that most people would want to have. You are actually, on average, worse off having it.”

“Because one gene could affect multiple traits, and because, depending on the environment, the effects of a mutation could be quite different, I think there can be many uncertainties and unknown effects in any germline editing,” said postdoctoral fellow Xinzhu “April” Wei.
Wei is first author and Nielsen is senior author of a paper describing the research that will appear online on Monday, June 3, in the journal Nature Medicine.

Mutation prevents HIV infection

The gene CCR5 codes for a protein that, among other things, sits on the surface of immune cells and helps some strains of HIV, including the most common ones, to enter and infect them. Jiankui He, the Chinese scientist who last November shocked the world by announcing he had experimented with CCR5 on at least two babies, said he wanted to introduce a mutation in the gene that would prevent this. Naturally-occurring mutations that disable the protein are rare in Asians, but a mutation found in about 11% of Northern Europeans protects them against HIV infection.

The genetic mutation, ∆32 (Delta 32), refers to a missing 32-base-pair segment in the CCR5 gene. This mutation interferes with the localization on the cell surface of the protein for which CCR5 codes, thwarting HIV binding and infection. He was unable to duplicate the natural mutation, but appears to have generated a similar deletion that would also inactivate the protein. One of the twin babies reportedly had one copy of CCR5 modified by CRISPR-Cas9 gene editing, while the other baby had both copies edited.

But inactivating a protein found in all humans and most animals is likely to have negative effects, Nielsen said, especially when done to both copies of the gene — a so-called homozygous mutation

“Here is a functional protein that we know has an effect in the organism, and it is well-conserved among many different species, so it is likely that a mutation that destroys the protein is, on average, not good for you,” he said. “Otherwise, evolutionary mechanisms would have destroyed that protein a long time ago.”

After He’s experiment became public, Nielsen and Wei, who study current genetic variation to understand the origin of human, animal and plant traits, decided to investigate the effect of the CCR5-∆32 mutation using data from UK Biobank. The database houses genomic information on a half million U.K. citizens that is linked to their medical records. The genomic information is much like that acquired by Ancestry.com and 23andMe: details on nearly a million individual variations in the genetic sequence, so-called single nucleotide polymorphisms (SNPs).

Two independent measures indicated a higher mortality rate for those with two mutated genes. Fewer people than expected with two mutations enrolled in the database, indicating that they had died at a higher rate than the general population. And fewer than expected survived from ages 40 to 78.

“Both the proportions before enrollment and the survivorship after enrollment tell the same story, which is that you have lower survivability or higher mortality if you have two copies of the mutation,” Nielsen said. “There is simply a deficiency of individuals with two copies.”

Because the ∆32 mutation is relatively common in Northern Europeans, it must have been favored by natural selection at some point, Nielsen said, though probably not to protect against HIV, since the virus has circulated among humans only since the 1980s.

Wei said that some evidence links the mutation to increased survival after stroke and protection against smallpox and flaviviruses, a group that includes the dengue, Zika and West Nile viruses.

Despite these possible benefits, the potential unintended effects of creating genetic mutations, in both adult somatic cells and in embryonic, germline cells, argue for caution, the researchers said.

“I think there are a lot of things that are unknown at the current stage about genes’ functions,” Wei said. “The CRISPR technology is far too dangerous to use right now for germline editing.”

Here’s a link to and a citation for the latest paper,

CCR5-∆32 is deleterious in the homozygous state in humans by Xinzhu Wei & Rasmus Nielsen. Nature Medicine (2019) DOI: https://doi.org/10.1038/s41591-019-0459-6 Published 03 June 2019

This paper is behind a paywall.

For those who have an insatiable appetite for detail, there’s my November 28, 2018 posting which covers what happened when the CRISPR twins, Lulu and Nana, was first announced, along with a few updates to January 23, 2019. The May 17, 2019 posting covers the news of possible cognitive advantages for the CCR5-Δ32 gene-edited twins and explores some of the social implications.

Genes, intelligence, Chinese CRISPR (clustered regularly interspaced short palindromic repeats) babies, and other children

This started out as an update and now it’s something else. What follows is a brief introduction to the Chinese CRISPR twins; a brief examination of parents, children, and competitiveness; and, finally, a suggestion that genes may not be what we thought. I also include a discussion about how some think scientists should respond when they know beforehand that one of their kin is crossing an ethical line. Basically, this is a complex topic and I am attempting to interweave a number of competing lines of query into one narrative about human nature and the latest genetics obsession.

Introduction to the Chinese CRISPR twins

Back in November 2018 I covered the story about the Chinese scientist, He Jiankui , who had used CRISPR technology to edit genes in embryos that were subsequently implanted in a waiting mother (apparently there could be as many as eight mothers) with the babies being brought to term despite an international agreement (of sorts) not to do that kind of work. At this time, we know of the twins, Lulu and Nana but, by now, there may be more babies. (I have much more detail about the initial controversies in my November 28, 2018 posting.)

It seems the drama has yet to finish unfolding. There may be another consequence of He’s genetic tinkering.

Could the CRISPR babies, Lulu and Nana, have enhanced cognitive abilities?

Yes, according to Antonio Regalado’s February 21, 2019 article (behind a paywall) for MIT’s (Massachusetts Institute of Technology) Technology Review, those engineered babies may have enhanced abilities for learning and remembering.

For those of us who can’t get beyond the paywall, others have been successful. Josh Gabbatiss in his February 22, 2019 article for independent.co.uk provides some detail,

The world’s first gene edited babies may have had their brains unintentionally altered – and perhaps cognitively enhanced – as a result of the controversial treatment undertaken by a team of Chinese scientists.

Dr He Jiankui and his team allegedly deleted a gene from a number of human embryos before implanting them in their mothers, a move greeted with horror by the global scientific community. The only known successful birth so far is the case of twin girls Nana and Lulu.

The now disgraced scientist claimed that he removed a gene called CCR5 [emphasis mine] from their embroyos in an effort to make the twins resistant to infection by HIV.

But another twist in the saga has now emerged after a new paper provided more evidence that the impact of CCR5 deletion reaches far beyond protection against dangerous viruses – people who naturally lack this gene appear to recover more quickly from strokes, and even go further in school. [emphasis mine]

Dr Alcino Silva, a neurobiologist at the University of California, Los Angeles, who helped identify this role for CCR5 said the work undertaken by Dr Jiankui likely did change the girls’ brains.

“The simplest interpretation is that those mutations will probably have an impact on cognitive function in the twins,” he told the MIT Technology Review.

The connection immediately raised concerns that the gene was targeted due to its known links with intelligence, which Dr Silva said was his immediate response when he heard the news.

… there is no evidence that this was Dr Jiankui’s goal and at a press conference organised after the initial news broke, he said he was aware of the work but was “against using genome editing for enhancement”.

..

Claire Maldarelli’s February 22, 2019 article for Popular Science provides more information about the CCR5 gene/protein (Note: Links have been removed),

CCR5 is a protein that sits on the surface of white blood cells, a major component of the human immune system. There, it allows HIV to enter and infect a cell. A chunk of the human population naturally carries a mutation that makes CCR5 nonfunctional (one study found that 10 percent of Europeans have this mutation), which often results in a smaller protein size and one that isn’t located on the outside of the cell, preventing HIV from ever entering and infecting the human immune system.

The goal of the Chinese researchers’ work, led by He Jiankui of the Southern University of Science and Technology located in Shenzhen, was to tweak the embryos’ genome to lack CCR5, ensuring the babies would be immune to HIV.

But genetics is rarely that simple.

In recent years, the CCR5 gene has been a target of ongoing research, and not just for its relationship to HIV. In an attempt to understand what influences memory formation and learning in the brain, a group of researchers at UCLA found that lowering the levels of CCR5 production enhanced both learning and memory formation. This connection led those researchers to think that CCR5 could be a good drug target for helping stroke victims recover: Relearning how to move, walk, and talk is a key component to stroke rehabilitation.

… promising research, but it begs the question: What does that mean for the babies who had their CCR5 genes edited via CRISPR prior to their birth? Researchers speculate that the alternation will have effects on the children’s cognitive functioning. …

John Loeffler’s February 22, 2019 article for interestingengineering.com notes that there are still many questions about He’s (scientist’s name) research including, did he (pronoun) do what he claimed? (Note: Links have been removed),

Considering that no one knows for sure whether He has actually done as he and his team claim, the swiftness of the condemnation of his work—unproven as it is—shows the sensitivity around this issue.

Whether He did in fact edit Lulu and Nana’s genes, it appears he didn’t intend to impact their cognitive capacities. According to MIT Technology Review, not a single researcher studying CCR5’s role in intelligence was contacted by He, even as other doctors and scientists were sought out for advice about his project.

This further adds to the alarm as there is every expectation that He should have known about the connection between CCR5 and cognition.

At a gathering of gene-editing researchers in Hong Kong two days after the birth of the potentially genetically-altered twins was announced, He was asked about the potential impact of erasing CCR5 from the twins DNA on their mental capacity.

He responded that he knew about the potential cognitive link shown in Silva’s 2016 research. “I saw that paper, it needs more independent verification,” He said, before adding that “I am against using genome editing for enhancement.”

The problem, as Silva sees it, is that He may be blazing the trail for exactly that outcome, whether He intends to or not. Silva says that after his 2016 research was published, he received an uncomfortable amount of attention from some unnamed, elite Silicon Valley leaders who seem to be expressing serious interest in using CRISPR to give their children’s brains a boost through gene editing. [emphasis mine]

As such, Silva can be forgiven for not quite believing He’s claims that he wasn’t intending to alter the human genome for enhancement. …

The idea of designer babies isn’t new. As far back as Plato, the thought of using science to “engineer” a better human has been tossed about, but other than selective breeding, there really hasn’t been a path forward.

In the late 1800s, early 1900s, Eugenics made a real push to accomplish something along these lines, and the results were horrifying, even before Nazism. After eugenics mid-wifed the Holocaust in World War II, the concept of designer children has largely been left as fodder for science fiction since few reputable scientists would openly declare their intention to dabble in something once championed and pioneered by the greatest monsters of the 20th century.

Memories have faded though, and CRISPR significantly changes this decades-old calculus. CRISPR makes it easier than ever to target specific traits in order to add or subtract them from an embryos genetic code. Embryonic research is also a diverse enough field that some scientist could see pioneering designer babies as a way to establish their star power in academia while getting their names in the history books, [emphasis mine] all while working in relative isolation. They only need to reveal their results after the fact and there is little the scientific community can do to stop them, unfortunately.

When He revealed his research and data two days after announcing the births of Lulu and Nana, the gene-scientists at the Hong Kong conference were not all that impressed with the quality of He’s work. He has not provided access for fellow researchers to either his data on Lulu, Nana, and their family’s genetic data so that others can verify that Lulu and Nana’s CCR5 genes were in fact eliminated.

This almost rudimentary verification and validation would normally accompany a major announcement such as this. Neither has He’s work undergone a peer-review process and it hasn’t been formally published in any scientific journal—possibly for good reason.

Researchers such as Eric Topol, a geneticist at the Scripps Research Institute, have been finding several troubling signs in what little data He has released. Topol says that the editing itself was not precise and show “all kinds of glitches.”

Gaetan Burgio, a geneticist at the Australian National University, is likewise unimpressed with the quality of He’s work. Speaking of the slides He showed at the conference to support his claim, Burgio calls it amateurish, “I can believe that he did it because it’s so bad.”

Worse of all, its entirely possible that He actually succeeded in editing Lulu and Nana’s genetic code in an ad hoc, unethical, and medically substandard way. Sadly, there is no shortage of families with means who would be willing to spend a lot of money to design their idea of a perfect child, so there is certainly demand for such a “service.”

It’s nice to know (sarcasm icon) that the ‘Silicon Valley elite’ are willing to volunteer their babies for scientific experimentation in a bid to enhance intelligence.

The ethics of not saying anything

Natalie Kofler, a molecular biologist, wrote a February 26, 2019 Nature opinion piece and call to action on the subject of why scientists who were ‘in the know’ remained silent about He’s work prior to his announcements,

Millions [?] were shocked to learn of the birth of gene-edited babies last year, but apparently several scientists were already in the know. Chinese researcher He Jiankui had spoken with them about his plans to genetically modify human embryos intended for pregnancy. His work was done before adequate animal studies and in direct violation of the international scientific consensus that CRISPR–Cas9 gene-editing technology is not ready or appropriate for making changes to humans that could be passed on through generations.

Scholars who have spoken publicly about their discussions with He described feeling unease. They have defended their silence by pointing to uncertainty over He’s intentions (or reassurance that he had been dissuaded), a sense of obligation to preserve confidentiality and, perhaps most consistently, the absence of a global oversight body. Others who have not come forward probably had similar rationales. But He’s experiments put human health at risk; anyone with enough knowledge and concern could have posted to blogs or reached out to their deans, the US National Institutes of Health or relevant scientific societies, such as the Association for Responsible Research and Innovation in Genome Editing (see page 440). Unfortunately, I think that few highly established scientists would have recognized an obligation to speak up.

I am convinced that this silence is a symptom of a broader scientific cultural crisis: a growing divide between the values upheld by the scientific community and the mission of science itself.

A fundamental goal of the scientific endeavour is to advance society through knowledge and innovation. As scientists, we strive to cure disease, improve environmental health and understand our place in the Universe. And yet the dominant values ingrained in scientists centre on the virtues of independence, ambition and objectivity. That is a grossly inadequate set of skills with which to support a mission of advancing society.

Editing the genes of embryos could change our species’ evolutionary trajectory. Perhaps one day, the technology will eliminate heritable diseases such as sickle-cell anaemia and cystic fibrosis. But it might also eliminate deafness or even brown eyes. In this quest to improve the human race, the strengths of our diversity could be lost, and the rights of already vulnerable populations could be jeopardized.

Decisions about how and whether this technology should be used will require an expanded set of scientific virtues: compassion to ensure its applications are designed to be just, humility to ensure its risks are heeded and altruism to ensure its benefits are equitably distributed.

Calls for improved global oversight and robust ethical frameworks are being heeded. Some researchers who apparently knew of He’s experiments are under review by their universities. Chinese investigators have said He skirted regulations and will be punished. But punishment is an imperfect motivator. We must foster researchers’ sense of societal values.

Fortunately, initiatives popping up throughout the scientific community are cultivating a scientific culture informed by a broader set of values and considerations. The Scientific Citizenship Initiative at Harvard University in Cambridge, Massachusetts, trains scientists to align their research with societal needs. The Summer Internship for Indigenous Peoples in Genomics offers genomics training that also focuses on integrating indigenous cultural perspectives into gene studies. The AI Now Institute at New York University has initiated a holistic approach to artificial-intelligence research that incorporates inclusion, bias and justice. And Editing Nature, a programme that I founded, provides platforms that integrate scientific knowledge with diverse cultural world views to foster the responsible development of environmental genetic technologies.

Initiatives such as these are proof [emphasis mine] that science is becoming more socially aware, equitable and just. …

I’m glad to see there’s work being done on introducing a broader set of values into the scientific endeavour. That said, these programmes seem to be voluntary, i.e., people self-select, and those most likely to participate in these programmes are the ones who might be inclined to integrate social values into their work in the first place.

This doesn’t address the issue of how to deal with unscrupulous governments pressuring scientists to create designer babies along with hypercompetitive and possibly unscrupulous individuals such as the members of the ‘Silicon Valley insiders mentioned in Loeffler’s article, teaming up with scientists who will stop at nothing to get their place in the history books.

Like Kofler, I’m encouraged to see these programmes but I’m a little less convinced that they will be enough. What form it might take I don’t know but I think something a little more punitive is also called for.

CCR5 and freedom from HIV

I’ve added this piece about the Berlin and London patients because, back in November 2018, I failed to realize how compelling the idea of eradicating susceptibility to AIDS/HIV might be. Reading about some real life remissions helped me to understand some of He’s stated motivations a bit better. Unfortunately, there’s a major drawback described here in a March 5, 2019 news item on CBC (Canadian Broadcasting Corporation) online news attributed to Reuters,

An HIV-positive man in Britain has become the second known adult worldwide to be cleared of the virus that causes AIDS after he received a bone marrow transplant from an HIV-resistant donor, his doctors said.

The therapy had an early success with a man known as “the Berlin patient,” Timothy Ray Brown, a U.S. man treated in Germany who is 12 years post-transplant and still free of HIV. Until now, Brown was the only person thought to have been cured of infection with HIV, the virus that causes AIDS.

Such transplants are dangerous and have failed in other patients. They’re also impractical to try to cure the millions already infected.

In the latest case, the man known as “the London patient” has no trace of HIV infection, almost three years after he received bone marrow stem cells from a donor with a rare genetic mutation that resists HIV infection — and more than 18 months after he came off antiretroviral drugs.

“There is no virus there that we can measure. We can’t detect anything,” said Ravindra Gupta, a professor and HIV biologist who co-led a team of doctors treating the man.

Gupta described his patient as “functionally cured” and “in remission,” but cautioned: “It’s too early to say he’s cured.”

Gupta, now at Cambridge University, treated the London patient when he was working at University College London. The man, who has asked to remain anonymous, had contracted HIV in 2003, Gupta said, and in 2012 was also diagnosed with a type of blood cancer called Hodgkin’s lymphoma.

In 2016, when he was very sick with cancer, doctors decided to seek a transplant match for him.

“This was really his last chance of survival,” Gupta told Reuters.

Doctors found a donor with a gene mutation known as CCR5 delta 32, which confers resistance to HIV. About one per cent of people descended from northern Europeans have inherited the mutation from both parents and are immune to most HIV. The donor had this double copy of the mutation.

That was “an improbable event,” Gupta said. “That’s why this has not been observed more frequently.”

Most experts say it is inconceivable such treatments could be a way of curing all patients. The procedure is expensive, complex and risky. To do this in others, exact match donors would have to be found in the tiny proportion of people who have the CCR5 mutation.

Specialists said it is also not yet clear whether the CCR5 resistance is the only key [emphasis mine] — or whether the graft-versus-host disease may have been just as important. Both the Berlin and London patients had this complication, which may have played a role in the loss of HIV-infected cells, Gupta said.

Not only is there some question as to what role the CCR5 gene plays, there’s also a question as to whether or not we know what role genes play.

A big question: are genes what we thought?

Ken Richardson’s January 3, 2019 article for Nautilus (I stumbled across it on May 14, 2019 so I’m late to the party) makes and supports a startling statement, It’s the End of the Gene As We Know It We are not nearly as determined by our genes as once thought (Note: A link has been removed),

We’ve all seen the stark headlines: “Being Rich and Successful Is in Your DNA” (Guardian, July 12); “A New Genetic Test Could Help Determine Children’s Success” (Newsweek, July 10); “Our Fortunetelling Genes” make us (Wall Street Journal, Nov. 16); and so on.

The problem is, many of these headlines are not discussing real genes at all, but a crude statistical model of them, involving dozens of unlikely assumptions. Now, slowly but surely, that whole conceptual model of the gene is being challenged.

We have reached peak gene, and passed it.

The preferred dogma started to appear in different versions in the 1920s. It was aptly summarized by renowned physicist Erwin Schrödinger in a famous lecture in Dublin in 1943. He told his audience that chromosomes “contain, in some kind of code-script, the entire pattern of the individual’s future development and of its functioning in the mature state.”

Around that image of the code a whole world order of rank and privilege soon became reinforced. These genes, we were told, come in different “strengths,” different permutations forming ranks that determine the worth of different “races” and of different classes in a class-structured society. A whole intelligence testing movement was built around that preconception, with the tests constructed accordingly.

The image fostered the eugenics and Nazi movements of the 1930s, with tragic consequences. Governments followed a famous 1938 United Kingdom education commission in decreeing that, “The facts of genetic inequality are something that we cannot escape,” and that, “different children … require types of education varying in certain important respects.”

Today, 1930s-style policy implications are being drawn once again. Proposals include gene-testing at birth for educational intervention, embryo selection for desired traits, identifying which classes or “races” are fitter than others, and so on. And clever marketizing now sees millions of people scampering to learn their genetic horoscopes in DNA self-testing kits.[emphasis mine]

So the hype now pouring out of the mass media is popularizing what has been lurking in the science all along: a gene-god as an entity with almost supernatural powers. Today it’s the gene that, in the words of the Anglican hymn, “makes us high and lowly and orders our estate.”

… at the same time, a counter-narrative is building, not from the media but from inside science itself.

So it has been dawning on us is that there is no prior plan or blueprint for development: Instructions are created on the hoof, far more intelligently than is possible from dumb DNA. That is why today’s molecular biologists are reporting “cognitive resources” in cells; “bio-information intelligence”; “cell intelligence”; “metabolic memory”; and “cell knowledge”—all terms appearing in recent literature.1,2 “Do cells think?” is the title of a 2007 paper in the journal Cellular and Molecular Life Sciences.3 On the other hand the assumed developmental “program” coded in a genotype has never been described.


It is such discoveries that are turning our ideas of genetic causation inside out. We have traditionally thought of cell contents as servants to the DNA instructions. But, as the British biologist Denis Noble insists in an interview with the writer Suzan Mazur,1 “The modern synthesis has got causality in biology wrong … DNA on its own does absolutely nothing [ emphasis mine] until activated by the rest of the system … DNA is not a cause in an active sense. I think it is better described as a passive data base which is used by the organism to enable it to make the proteins that it requires.”

I highly recommend reading Richardson’s article in its entirety. As well, you may want to read his book, ” Genes, Brains and Human Potential: The Science and Ideology of Intelligence .”

As for “DNA on its own doing absolutely nothing,” that might be a bit of a eye-opener for the Silicon Valley elite types investigating cognitive advantages attributed to the lack of a CCR5 gene. Meanwhile, there are scientists inserting a human gene associated with brain development into monkeys,

Transgenic monkeys and human intelligence

An April 2, 2019 news item on chinadaily.com describes research into transgenic monkeys,

Researchers from China and the United States have created transgenic monkeys carrying a human gene that is important for brain development, and the monkeys showed human-like brain development.

Scientists have identified several genes that are linked to primate brain size. MCPH1 is a gene that is expressed during fetal brain development. Mutations in MCPH1 can lead to microcephaly, a developmental disorder characterized by a small brain.

In the study published in the Beijing-based National Science Review, researchers from the Kunming Institute of Zoology, Chinese Academy of Sciences, the University of North Carolina in the United States and other research institutions reported that they successfully created 11 transgenic rhesus monkeys (eight first-generation and three second-generation) carrying human copies of MCPH1.

According to the research article, brain imaging and tissue section analysis showed an altered pattern of neuron differentiation and a delayed maturation of the neural system, which is similar to the developmental delay (neoteny) in humans.

Neoteny in humans is the retention of juvenile features into adulthood. One key difference between humans and nonhuman primates is that humans require a much longer time to shape their neuro-networks during development, greatly elongating childhood, which is the so-called “neoteny.”

Here’s a link to and a citation for the paper,

Transgenic rhesus monkeys carrying the human MCPH1 gene copies show human-like neoteny of brain development by Lei Shi, Xin Luo, Jin Jiang, Yongchang Chen, Cirong Liu, Ting Hu, Min Li, Qiang Lin, Yanjiao Li, Jun Huang Hong Wang, Yuyu Niu, Yundi Shi, Martin Styner, Jianhong Wang, Yi Lu, Xuejin Sun, Hualin Yu, Weizhi Ji, Bing Su. National Science Review, nwz043, https://doi.org/10.1093/nsr/nwz043 Published: 27 March 2019

This appears to be an open access paper,

Transgenic monkeys and an ethical uproar

Predictably, this research set off alarms as Sharon Kirkey’s April 12, 2019 article for the National Post describes in detail (Note: A link has been removed)l,

Their brains may not be bigger than normal, but monkeys created with human brain genes are exhibiting cognitive changes that suggest they might be smarter — and the experiments have ethicists shuddering.

In the wake of the genetically modified human babies scandal, Chinese scientists [as a scientist from the US] are drawing fresh condemnation from philosophers and ethicists, this time over the announcement they’ve created transgenic monkeys with elements of a human brain.

Six of the monkeys died, however the five survivors “exhibited better short-term memory and shorter reaction time” compared to their wild-type controls, the researchers report in the journa.

According to the researchers, the experiments represent the first attempt to study the genetic basis of human brain origin using transgenic monkeys. The findings, they insist, “have the potential to provide important — and potentially unique — insights into basic questions of what actually makes humans unique.”

For others, the work provokes a profoundly moral and visceral uneasiness. Even one of the collaborators — University of North Carolina computer scientist Martin Styner — told MIT Technology Review he considered removing his name from the paper, which he said was unable to find a publisher in the West.

“Now we have created this animal which is different than it is supposed to be,” Styner said. “When we do experiments, we have to have a good understanding of what we are trying to learn, to help society, and that is not the case here.” l

In an email to the National Post, Styner said he has an expertise in medical image analysis and was approached by the researchers back in 2011. He said he had no input on the science in the project, beyond how to best do the analysis of their MRI data. “At the time, I did not think deeply enough about the ethical consideration.”

….

When it comes to the scientific use of nonhuman primates, ethicists say the moral compass is skewed in cases like this.

Given the kind of beings monkeys are, “I certainly would have thought you would have had to have a reasonable expectation of high benefit to human beings to justify the harms that you are going to have for intensely social, cognitively complex, emotional animals like monkeys,” said Letitia Meynell, an associate professor in the department of philosophy at Dalhousie University in Halifax.

“It’s not clear that this kind of research has any reasonable expectation of having any useful application for human beings,” she said.

The science itself is also highly dubious and fundamentally flawed in its logic, she said.
“If you took Einstein as a baby and you raised him in the lab he wouldn’t turn out to be Einstein,” Meynell said. “If you’re actually interested in studying the cognitive complexity of these animals, you’re not going to get a good representation of that by raising them in labs, because they can’t develop the kind of cognitive and social skills they would in their normal environment.”

The Chinese said the MCPH1 gene is one of the strongest candidates for human brain evolution. But looking at a single gene is just bad genetics, Meynell said. Multiple genes and their interactions affect the vast majority of traits.

My point is that there’s a lot of research focused on intelligence and genes when we don’t really know what role genes actually play and when there doesn’t seem to be any serious oversight.

Global plea for moratorium on heritable genome editing

A March 13, 2019 University of Otago (New Zealand) press release (also on EurekAlert) describes a global plea for a moratorium,

A University of Otago bioethicist has added his voice to a global plea for a moratorium on heritable genome editing from a group of international scientists and ethicists in the wake of the recent Chinese experiment aiming to produce HIV immune children.

In an article in the latest issue of international scientific journal Nature, Professor Jing-Bao Nie together with another 16 [17] academics from seven countries, call for a global moratorium on all clinical uses of human germline editing to make genetically modified children.

They would like an international governance framework – in which nations voluntarily commit to not approve any use of clinical germline editing unless certain conditions are met – to be created potentially for a five-year period.

Professor Nie says the scientific scandal of the experiment that led to the world’s first genetically modified babies raises many intriguing ethical, social and transcultural/transglobal issues. His main personal concerns include what he describes as the “inadequacy” of the Chinese and international responses to the experiment.

“The Chinese authorities have conducted a preliminary investigation into the scientist’s genetic misadventure and issued a draft new regulation on the related biotechnologies. These are welcome moves. Yet, by putting blame completely on the rogue scientist individually, the institutional failings are overlooked,” Professor Nie explains.

“In the international discourse, partly due to the mentality of dichotomising China and the West, a tendency exists to characterise the scandal as just a Chinese problem. As a result, the global context of the experiment and Chinese science schemes have been far from sufficiently examined.”

The group of 17 [18] scientists and bioethicists say it is imperative that extensive public discussions about the technical, scientific, medical, societal, ethical and moral issues must be considered before germline editing is permitted. A moratorium would provide time to establish broad societal consensus and an international framework.

“For germline editing to even be considered for a clinical application, its safety and efficacy must be sufficient – taking into account the unmet medical need, the risks and potential benefits and the existence of alternative approaches,” the opinion article states.

Although techniques have improved in recent years, germline editing is not yet safe or effective enough to justify any use in the clinic with the risk of failing to make the desired change or of introducing unintended mutations still unacceptably high, the scientists and ethicists say.

“No clinical application of germline editing should be considered unless its long-term biological consequences are sufficiently understood – both for individuals and for the human species.”

The proposed moratorium does not however, apply to germline editing for research uses or in human somatic (non-reproductive) cells to treat diseases.

Professor Nie considers it significant that current presidents of the UK Royal Society, the US National Academy of Medicine and the Director and Associate Director of the US National Institute of Health have expressed their strong support for such a proposed global moratorium in two correspondences published in the same issue of Nature. The editorial in the issue also argues that the right decision can be reached “only through engaging more communities in the debate”.

“The most challenging questions are whether international organisations and different countries will adopt a moratorium and if yes, whether it will be effective at all,” Professor Nie says.

A March 14, 2019 news item on phys.org provides a précis of the Comment in Nature. Or, you ,can access the Comment with this link

Adopt a moratorium on heritable genome editing; Eric Lander, Françoise Baylis, Feng Zhang, Emmanuelle Charpentier, Paul Berg and specialists from seven countries call for an international governance framework.signed by: Eric S. Lander, Françoise Baylis, Feng Zhang, Emmanuelle Charpentier, Paul Berg, Catherine Bourgain, Bärbel Friedrich, J. Keith Joung, Jinsong Li, David Liu, Luigi Naldini, Jing-Bao Nie, Renzong Qiu, Bettina Schoene-Seifert, Feng Shao, Sharon Terry, Wensheng Wei, & Ernst-Ludwig Winnacker. Nature 567, 165-168 (2019) doi: 10.1038/d41586-019-00726-5

This Comment in Nature is open access.

World Health Organization (WHO) chimes in

Better late than never, eh? The World Health Organization has called heritable gene editing of humans ‘irresponsible’ and made recommendations. From a March 19, 2019 news item on the Canadian Broadcasting Corporation’s Online news webpage,

A panel convened by the World Health Organization said it would be “irresponsible” for scientists to use gene editing for reproductive purposes, but stopped short of calling for a ban.

The experts also called for the U.N. health agency to create a database of scientists working on gene editing. The recommendation was announced Tuesday after a two-day meeting in Geneva to examine the scientific, ethical, social and legal challenges of such research.

“At this time, it is irresponsible for anyone to proceed” with making gene-edited babies since DNA changes could be passed down to future generations, the experts said in a statement.

Germline editing has been on my radar since 2015 (see my May 14, 2015 posting) and the probability that someone would experiment with viable embryos and bring them to term shouldn’t be that much of a surprise.

Slow science from Canada

Canada has banned germline editing but there is pressure to lift that ban. (I touched on the specifics of the campaign in an April 26, 2019 posting.) This March 17, 2019 essay on The Conversation by Landon J Getz and Graham Dellaire, both of Dalhousie University (Nova Scotia, Canada) elucidates some of the discussion about whether research into germline editing should be slowed down.

Naughty (or Haughty, if you prefer) scientists

There was scoffing from some, if not all, members of the scientific community about the potential for ‘designer babies’ that can be seen in an excerpt from an article by Ed Yong for The Atlantic (originally published in my ,August 15, 2017 posting titled: CRISPR and editing the germline in the US (part 2 of 3): ‘designer babies’?),

Ed Yong in an Aug. 2, 2017 article for The Atlantic offered a comprehensive overview of the research and its implications (unusually for Yong, there seems to be mildly condescending note but it’s worth ignoring for the wealth of information in the article; Note: Links have been removed),

” … the full details of the experiment, which are released today, show that the study is scientifically important but much less of a social inflection point than has been suggested. “This has been widely reported as the dawn of the era of the designer baby, making it probably the fifth or sixth time people have reported that dawn,” says Alta Charo, an expert on law and bioethics at the University of Wisconsin-Madison. “And it’s not.”

Then about 15 months later, the possibility seemed to be realized.

Interesting that scientists scoffed at the public’s concerns (you can find similar arguments about robots and artificial intelligence not being a potentially catastrophic problem), yes? Often, nonscientists’ concerns are dismissed as being founded in science fiction.

To be fair, there are times when concerns are overblown, the difficulty is that it seems the scientific community’s default position is to uniformly dismiss concerns rather than approaching them in a nuanced fashion. If the scoffers had taken the time to think about it, germline editing on viable embryos seems like an obvious and inevitable next step (as I’ve noted previously).

At this point, no one seems to know if He actually succeeded at removing CCR5 from Lulu’s and Nana’s genomes. In November 2018, scientists were guessing that at least one of the twins was a ‘mosaic’. In other words, some of her cells did not include CCR5 while others did.

Parents, children, competition

A recent college admissions scandal in the US has highlighted the intense competition to get into high profile educational institutions. (This scandal brought to mind the Silicon Valey elite who wanted to know more about gene editing that might result in improved cognitive skills.)

Since it can be easy to point the finger at people in other countries, I’d like to note that there was a Canadian parent among these wealthy US parents attempting to give their children advantages by any means, legal or not. (Note: These are alleged illegalities.) From a March 12, 2019 news article by Scott Brown, Kevin Griffin, and Keith Fraser for the Vancouver Sun,

Vancouver businessman and former CFL [Canadian Football League] player David Sidoo has been charged with conspiracy to commit mail and wire fraud in connection with a far-reaching FBI investigation into a criminal conspiracy that sought to help privileged kids with middling grades gain admission to elite U.S. universities.

In a 12-page indictment filed March 5 [2019] in the U.S. District Court of Massachusetts, Sidoo is accused of making two separate US$100,000 payments to have others take college entrance exams in place of his two sons.

Sidoo is also accused of providing documents for the purpose of creating falsified identification cards for the people taking the tests.

In what is being called the biggest college-admissions scam ever prosecuted by the U.S. Justice Department, Sidoo has been charged with nearly 50 other people. Nine athletic coaches and 33 parents including Hollywood actresses Felicity Huffman and Lori Loughlin. are among those charged in the investigation, dubbed Operation Varsity Blues.

According to the indictment, an unidentified person flew from Tampa, Fla., to Vancouver in 2011 to take the Scholastic Aptitude Test (SAT) in place of Sidoo’s older son and was directed not to obtain too high a score since the older son had previously taken the exam, obtaining a score of 1460 out of a possible 2400.

A copy of the resulting SAT score — 1670 out of 2400 — was mailed to Chapman University, a private university in Orange, Calif., on behalf of the older son, who was admitted to and ultimately enrolled in the university in January 2012, according to the indictment.

It’s also alleged that Sidoo arranged to have someone secretly take the older boy’s Canadian high school graduation exam, with the person posing as the boy taking the exam in June 2012.

The Vancouver businessman is also alleged to have paid another $100,000 to have someone take the SAT in place of his younger son.

Sidoo, an investment banker currently serving as CEO of Advantage Lithium, was awarded the Order of B.C. in 2016 for his philanthropic efforts.

He is a former star with the UBC [University of British Columbia] Thunderbirds football team and helped the school win its first Vanier Cup in 1982. He went on to play five seasons in the CFL with the Saskatchewan Roughriders and B.C. Lions.

Sidoo is a prominent donor to UBC and is credited with spearheading an alumni fundraising campaign, 13th Man Foundation, that resuscitated the school’s once struggling football team. He reportedly donated $2 million of his own money to support the program.

Sidoo Field at UBC’s Thunderbird Stadium is named in his honour.

In 2016, he received the B.C. [British Columbia] Sports Hall of Fame’s W.A.C. Bennett Award for his contributions to the sporting life of the province.

The question of whether or not these people like the ‘Silicon Valley elite’ (mentioned in John Loeffler’s February 22, 2019 article) would choose to tinker with their children’s genome if it gave them an advantage, is still hypothetical but it’s easy to believe that at least some might seriously consider the possibility especially if the researcher or doctor didn’t fully explain just how little is known about the impact of tinkering with the genome. For example, there’s a big question about whether those parents in China fully understood what they signed up for.

By the way, cheating scandals aren’t new (see Vanity Fair’s Schools For Scandal; The Inside Dramas at 16 of America’s Most Elite Campuses—Plus Oxford! Edited by Graydon Carter, published in August 2018 and covering 25 years of the magazine’s reporting). On a similar line, there’s this March13, 2019 essay which picks apart some of the hierarchical and power issues at play in the US higher educational system which led to this latest (but likely not last) scandal.

Scientists under pressure

While Kofler’s February 26, 2019 Nature opinion piece and call to action seems to address the concerns regarding germline editing by advocating that scientists become more conscious of how their choices impact society, as I noted earlier, the ideas expressed seem a little ungrounded in harsh realities. Perhaps it’s time to give some recognition to the various pressures put on scientists from their own governments and from an academic environment that fosters ‘success’ at any cost to peer pressure, etc. (For more about the costs of a science culture focused on success, read this March 2, 2019 blog posting by Jon Tennant on digital-science.com for a breakdown.)

One other thing I should mention, for some scientists getting into the history books, winning Nobel prizes, etc. is a very important goal. Scientists are people too.

Some thoughts

There seems to be a great disjunction between what Richardson presents as an alternative narrative to the ‘gene-god’ and how genetic research is being performed and reported on. What is clear to me is that no one really understands genetics and this business of inserting and deleting genes is essentially research designed to satisfy curiosity and/or allay fears about being left behind in a great scientific race to a an unknown destination.

I’d like to see some better reporting and a more agile response by the scientific community, the various governments, and international agencies. What shape or form a more agile response might take, I don’t know but I’d like to see some efforts.

Back to the regular programme

There’s a lot about CRISPR here on this blog. A simple search of ‘CRISPR ‘in the blog’s search engine should get you more than enough information about the technology and the various issues ranging from intellectual property to risks and more.

The three part series (CRISPR and editing the germline in the US …), mentioned previously, was occasioned by the publication of a study on germline editing research with nonviable embryos in the US. The 2017 research was done at the Oregon Health and Science University by Shoukhrat Mitalipov following similar research published by Chinese scientists in 2015. The series gives relatively complete coverage of the issues along with an introduction to CRISPR and embedded video describing the technique. Here’s part 1 to get you started..

First CRISPR gene-edited babies? Ethics and the science story

Scientists, He Jiankui and Michael Deem, may have created the first human babies born after being subjected to CRISPR (clustered regularly interspaced short palindromic repeats) gene editing.  At this point, no one is entirely certain that these babies  as described actually exist since the information was made public in a rather unusual (for scientists) fashion.

The news broke on Sunday, November 25, 2018 through a number of media outlets none of which included journals associated with gene editing or high impact journals such as Cell, Nature, or Science.The news broke in MIT Technology Review and in Associated Press. Plus, this all happened just before the Second International Summit on Human Genome Editing (Nov. 27 – 29, 2018) in Hong Kong. He Jiankui was scheduled to speak today, Nov. 27, 2018.

Predictably, this news has caused quite a tizzy.

Breaking news

Antonio Regalado broke the news in a November 25, 2018  article for MIT [Massachusetts Institute of Technology] Technology Review (Note: Links have been removed),

According to Chinese medical documents posted online this month (here and here), a team at the Southern University of Science and Technology, in Shenzhen, has been recruiting couples in an effort to create the first gene-edited babies. They planned to eliminate a gene called CCR5 in hopes of rendering the offspring resistant to HIV, smallpox, and cholera.

The clinical trial documents describe a study in which CRISPR is employed to modify human embryos before they are transferred into women’s uteruses.

The scientist behind the effort, He Jiankui, did not reply to a list of questions about whether the undertaking had produced a live birth. Reached by telephone, he declined to comment.

However, data submitted as part of the trial listing shows that genetic tests have been carried out on fetuses as late as 24 weeks, or six months. It’s not known if those pregnancies were terminated, carried to term, or are ongoing.

Apparently He changed his mind because Marilynn Marchione in a November 26, 2018 article for the Associated Press confirms the news,

A Chinese researcher claims that he helped make the world’s first genetically edited babies — twin girls born this month whose DNA he said he altered with a powerful new tool capable of rewriting the very blueprint of life.

If true, it would be a profound leap of science and ethics.

A U.S. scientist [Dr. Michael Deem] said he took part in the work in China, but this kind of gene editing is banned in the United States because the DNA changes can pass to future generations and it risks harming other genes.

Many mainstream scientists think it’s too unsafe to try, and some denounced the Chinese report as human experimentation.

There is no independent confirmation of He’s claim, and it has not been published in a journal, where it would be vetted by other experts. He revealed it Monday [November 26, 2018] in Hong Kong to one of the organizers of an international conference on gene editing that is set to begin Tuesday [November 27, 2018], and earlier in exclusive interviews with The Associated Press.

“I feel a strong responsibility that it’s not just to make a first, but also make it an example,” He told the AP. “Society will decide what to do next” in terms of allowing or forbidding such science.

Some scientists were astounded to hear of the claim and strongly condemned it.

It’s “unconscionable … an experiment on human beings that is not morally or ethically defensible,” said Dr. Kiran Musunuru, a University of Pennsylvania gene editing expert and editor of a genetics journal.

“This is far too premature,” said Dr. Eric Topol, who heads the Scripps Research Translational Institute in California. “We’re dealing with the operating instructions of a human being. It’s a big deal.”

However, one famed geneticist, Harvard University’s George Church, defended attempting gene editing for HIV, which he called “a major and growing public health threat.”

“I think this is justifiable,” Church said of that goal.

h/t Cale Guthrie Weissman’s Nov. 26, 2018 article for Fast Company.

Diving into more detail

Ed Yong in a November 26, 2018 article for The Atlantic provides more details about the claims (Note: Links have been removed),

… “Two beautiful little Chinese girls, Lulu and Nana, came crying into the world as healthy as any other babies a few weeks ago,” He said in the first of five videos, posted yesterday {Nov. 25, 2018] to YouTube [link provided at the end of this section of the post]. “The girls are home now with their mom, Grace, and dad, Mark.” The claim has yet to be formally verified, but if true, it represents a landmark in the continuing ethical and scientific debate around gene editing.

Late last year, He reportedly enrolled seven couples in a clinical trial, and used their eggs and sperm to create embryos through in vitro fertilization. His team then used CRISPR to deactivate a single gene called CCR5 in the embryos, six of which they then implanted into mothers. CCR5 is a protein that the HIV virus uses to gain entry into human cells; by deactivating it, the team could theoretically reduce the risk of infection. Indeed, the fathers in all eight couples were HIV-positive.

Whether the experiment was successful or not, it’s intensely controversial. Scientists have already begun using CRISPR and other gene-editing technologies to alter human cells, in attempts to treat cancers, genetic disorders, and more. But in these cases, the affected cells stay within a person’s body. Editing an embryo [it’s often called, germline editing] is very different: It changes every cell in the body of the resulting person, including the sperm or eggs that would pass those changes to future generations. Such work is banned in many European countries, and prohibited in the United States. “I understand my work will be controversial, but I believe families need this technology and I’m willing to take the criticism for them,” He said.

“Was this a reasonable thing to do? I would say emphatically no,” says Paula Cannon of the University of Southern California. She and others have worked on gene editing, and particularly on trials that knock out CCR5 as a way to treat HIV. But those were attempts to treat people who were definitively sick and had run out of other options. That wasn’t the case with Nana and Lulu.

“The idea that being born HIV-susceptible, which is what the vast majority of humans are, is somehow a disease state that requires the extraordinary intervention of gene editing blows my mind,” says Cannon. “I feel like he’s appropriating this potentially valuable therapy as a shortcut to doing something in the sphere of gene editing. He’s either very naive or very cynical.”

“I want someone to make sure that it has happened,” says Hank Greely, an ethicist at Stanford University. If it hasn’t, that “would be a pretty bald-faced fraud,” but such deceptions have happened in the past. “If it is true, I’m disappointed. It’s reckless on safety grounds, and imprudent and stupid on social grounds.” He notes that a landmark summit in 2015 (which included Chinese researchers) and a subsequent major report from the National Academies of Science, Engineering, and Medicine both argued that “public participation should precede any heritable germ-line editing.” That is: Society needs to work out how it feels about making gene-edited babies before any babies are edited. Absent that consensus, He’s work is “waving a red flag in front of a bull,” says Greely. “It provokes not just the regular bio-Luddites, but also reasonable people who just wanted to talk it out.”

Societally, the creation of CRISPR-edited babies is a binary moment—a Rubicon that has been crossed. But scientifically, the devil is in the details, and most of those are still unknown.

CRISPR is still inefficient. [emphasis mine] The Chinese teams who first used it to edit human embryos only did so successfully in a small proportion of cases, and even then, they found worrying levels of “off-target mutations,” where they had erroneously cut parts of the genome outside their targeted gene. He, in his video, claimed that his team had thoroughly sequenced Nana and Lulu’s genomes and found no changes in genes other than CCR5.

That claim is impossible to verify in the absence of a peer-reviewed paper, or even published data of any kind. “The paper is where we see whether the CCR5 gene was properly edited, what effect it had at the cellular level, and whether [there were] any off-target effects,” said Eric Topol of the Scripps Research Institute. “It’s not just ‘it worked’ as a binary declaration.”

In the video, He said that using CRISPR for human enhancement, such as enhancing IQ or selecting eye color, “should be banned.” Speaking about Nana and Lulu’s parents, he said that they “don’t want a designer baby, just a child who won’t suffer from a disease that medicine can now prevent.”

But his rationale is questionable. Huang [Junjiu Huang of Sun Yat-sen University ], the first Chinese researcher to use CRISPR on human embryos, targeted the faulty gene behind an inherited disease called beta thalassemia. Mitalipov, likewise, tried to edit a gene called MYBPC3, whose faulty versions cause another inherited disease called hypertrophic cardiomyopathy (HCM). Such uses are still controversial, but they rank among the more acceptable applications for embryonic gene editing as ways of treating inherited disorders for which treatments are either difficult or nonexistent.

In contrast, He’s team disableda normal gene in an attempt to reduce the risk of a disease that neither child had—and one that can be controlled. There are already ways of preventing fathers from passing HIV to their children. There are antiviral drugs that prevent infections. There’s safe-sex education. “This is not a plague for which we have no tools,” says Cannon.

As Marilynn Marchione of the AP reports, early tests suggest that He’s editing was incomplete [emphasis mine], and at least one of the twins is a mosaic, where some cells have silenced copies of CCR5 and others do not. If that’s true, it’s unlikely that they would be significantly protected from HIV. And in any case, deactivating CCR5 doesn’t confer complete immunity, because some HIV strains can still enter cells via a different protein called CXCR4.

Nana and Lulu might have other vulnerabilities. …

It is also unclear if the participants in He’s trial were fully aware of what they were signing up for. [emphasis mine] The team’s informed-consent document describes their work as an “AIDS vaccine development project,” and while it describes CRISPR gene editing, it does so in heavily technical language. It doesn’t mention any of the risks of disabling CCR5, and while it does note the possibility of off-target effects, it also says that the “project team is not responsible for the risk.”

He owns two genetics companies, and his collaborator, Michael Deem of Rice University,  [emphasis mine] holds a small stake in, and sits on the advisory board of, both of them. The AP’s Marchione reports, “Both men are physics experts with no experience running human clinical trials.” [emphasis mine]

Yong’s article is well worth reading in its entirety. As for YouTube, here’s The He Lab’s webpage with relevant videos.

Reactions

Gina Kolata, Sui-Lee Wee, and Pam Belluck writing in a Nov. 26, 2018 article for the New York Times chronicle some of the response to He’s announcement,

It is highly unusual for a scientist to announce a groundbreaking development without at least providing data that academic peers can review. Dr. He said he had gotten permission to do the work from the ethics board of the hospital Shenzhen Harmonicare, but the hospital, in interviews with Chinese media, denied being involved. Cheng Zhen, the general manager of Shenzhen Harmonicare, has asked the police to investigate what they suspect are “fraudulent ethical review materials,” according to the Beijing News.

The university that Dr. He is attached to, the Southern University of Science and Technology, said Dr. He has been on no-pay leave since February and that the school of biology believed that his project “is a serious violation of academic ethics and academic norms,” according to the state-run Beijing News.

In a statement late on Monday, China’s national health commission said it has asked the health commission in southern Guangdong province to investigate Mr. He’s claims.

“I think that’s completely insane,” said Shoukhrat Mitalipov, director of the Center for Embryonic Cell and Gene Therapy at Oregon Health and Science University. Dr. Mitalipov broke new ground last year by using gene editing to successfully remove a dangerous mutation from human embryos in a laboratory dish. [I wrote a three-part series about CRISPR, which included what was then the latest US news, Mitalipov’s announcement, along with a roundup of previous work in China. Links are at the end of this section.’

Dr. Mitalipov said that unlike his own work, which focuses on editing out mutations that cause serious diseases that cannot be prevented any other way, Dr. He did not do anything medically necessary. There are other ways to prevent H.I.V. infection in newborns.

Just three months ago, at a conference in late August on genome engineering at Cold Spring Harbor Laboratory in New York, Dr. He presented work on editing the CCR₅ gene in the embryos of nine couples.

At the conference, whose organizers included Jennifer Doudna, one of the inventors of Crispr technology, Dr. He gave a careful talk about something that fellow attendees considered squarely within the realm of ethically approved research. But he did not mention that some of those embryos had been implanted in a woman and could result in genetically engineered babies.

“What we now know is that as he was talking, there was a woman in China carrying twins,” said Fyodor Urnov, deputy director of the Altius Institute for Biomedical Sciences and a visiting researcher at the Innovative Genomics Institute at the University of California. “He had the opportunity to say ‘Oh and by the way, I’m just going to come out and say it, people, there’s a woman carrying twins.’”

“I would never play poker against Dr. He,” Dr. Urnov quipped.

Richard Hynes, a cancer researcher at the Massachusetts Institute of Technology, who co-led an advisory group on human gene editing for the National Academy of Sciences and the National Academy of Medicine, said that group and a similar organization in Britain had determined that if human genes were to be edited, the procedure should only be done to address “serious unmet needs in medical treatment, it had to be well monitored, it had to be well followed up, full consent has to be in place.”

It is not clear why altering genes to make people resistant to H.I.V. is “a serious unmet need.” Men with H.I.V. do not infect embryos. …

Dr. He got his Ph.D., from Rice University, in physics and his postdoctoral training, at Stanford, was with Stephen Quake, a professor of bioengineering and applied physics who works on sequencing DNA, not editing it.

Experts said that using Crispr would actually be quite easy for someone like Dr. He.

After coming to Shenzhen in 2012, Dr. He, at age 28, established a DNA sequencing company, Direct Genomics, and listed Dr. Quake on its advisory board. But, in a telephone interview on Monday, Dr. Quake said he was never associated with the company.

Deem, the US scientist who worked in China with He is currently being investigated (from a Nov. 26, 2018 article by Andrew Joseph in STAT),

Rice University said Monday that it had opened a “full investigation” into the involvement of one of its faculty members in a study that purportedly resulted in the creation of the world’s first babies born with edited DNA.

Michael Deem, a bioengineering professor at Rice, told the Associated Press in a story published Sunday that he helped work on the research in China.

Deem told the AP that he was in China when participants in the study consented to join the research. Deem also said that he had “a small stake” in and is on the scientific advisory boards of He’s two companies.

Megan Molteni in a Nov. 27, 2018 article for Wired admits she and her colleagues at the magazine may have dismissed CRISPR concerns about designer babies prematurely while shedding more light on this  latest development (Note: Links have been removed),

We said “don’t freak out,” when scientists first used Crispr to edit DNA in non-viable human embryos. When they tried it in embryos that could theoretically produce babies, we said “don’t panic.” Many years and years of boring bench science remain before anyone could even think about putting it near a woman’s uterus. Well, we might have been wrong. Permission to push the panic button granted.

Late Sunday night, a Chinese researcher stunned the world by claiming to have created the first human babies, a set of twins, with Crispr-edited DNA….

What’s perhaps most strange is not that He ignored global recommendations on conducting responsible Crispr research in humans. He also ignored his own advice to the world—guidelines that were published within hours of his transgression becoming public.

On Monday, He and his colleagues at Southern University of Science and Technology, in Shenzhen, published a set of draft ethical principles “to frame, guide, and restrict clinical applications that communities around the world can share and localize based on religious beliefs, culture, and public-health challenges.” Those principles included transparency and only performing the procedure when the risks are outweighed by serious medical need.

The piece appeared in the The Crispr Journal, a young publication dedicated to Crispr research, commentary, and debate. Rodolphe Barrangou, the journal’s editor in chief, where the peer-reviewed perspective appeared, says that the article was one of two that it had published recently addressing the ethical concerns of human germline editing, the other by a bioethicist at the University of North Carolina. Both papers’ authors had requested that their writing come out ahead of a major gene editing summit taking place this week in Hong Kong. When half-rumors of He’s covert work reached Barrangou over the weekend, his team discussed pulling the paper, but ultimately decided that there was nothing too solid to discredit it, based on the information available at the time.

Now Barrangou and his team are rethinking that decision. For one thing, He did not disclose any conflicts of interest, which is standard practice among respectable journals. It’s since become clear that not only is He at the helm of several genetics companies in China, He was actively pursuing controversial human research long before writing up a scientific and moral code to guide it.“We’re currently assessing whether the omission was a matter of ill-management or ill-intent,” says Barrangou, who added that the journal is now conducting an audit to see if a retraction might be warranted. …

“There are all sorts of questions these issues raise, but the most fundamental is the risk-benefit ratio for the babies who are going to be born,” says Hank Greely, an ethicist at Stanford University. “And the risk-benefit ratio on this stinks. Any institutional review board that approved it should be disbanded if not jailed.”

Reporting by Stat indicates that He may have just gotten in over his head and tried to cram a self-guided ethics education into a few short months. The young scientist—records indicate He is just 34—has a background in biophysics, with stints studying in the US at Rice University and in bioengineer Stephen Quake’s lab at Stanford. His resume doesn’t read like someone steeped deeply in the nuances and ethics of human research. Barrangou says that came across in the many rounds of edits He’s framework went through.

… China’s central government in Beijing has yet to come down one way or another. Condemnation would make He a rogue and a scientific outcast. Anything else opens the door for a Crispr IVF cottage industry to emerge in China and potentially elsewhere. “It’s hard to imagine this was the only group in the world doing this,” says Paul Knoepfler, a stem cell researcher at UC Davis who wrote a book on the future of designer babies called GMO Sapiens. “Some might say this broke the ice. Will others forge ahead and go public with their results or stop what they’re doing and see how this plays out?”

Here’s some of the very latest information with the researcher attempting to explain himself.

What does He have to say?

After He’s appearance at the Second International Summit on Human Genome Editing today, Nov. 27, 2018, David Cyranoski produced this article for Nature,

He Jiankui, the Chinese scientist who claims to have helped produce the first people born with edited genomes — twin girls — appeared today at a gene-editing summit in Hong Kong to explain his experiment. He gave his talk amid threats of legal action and mounting questions, from the scientific community and beyond, about the ethics of his work and the way in which he released the results.

He had never before presented his work publicly outside of a handful of videos he posted on YouTube. Scientists welcomed the fact that he appeared at all — but his talk left many hungry for more answers, and still not completely certain that He has achieved what he claims.

“There’s no reason not to believe him,” says Robin Lovell-Badge, a developmental biologist at the Francis Crick Institute in London. “I’m just not completely convinced.”

Lovell-Badge, like others at the conference, says that an independent body should confirm the test results by performing an in-depth comparison of the parents’ and childrens’ genes.

Many scientists faulted He for a lack of transparency and the seemingly cavalier nature in which he embarked on such a landmark, and potentially risky, project.

“I’m happy he came but I was really horrified and stunned when he described the process he used,” says Jennifer Doudna, a biochemist at the University of California, Berkeley and a pioneer of the CRISPR/Cas-9 gene-editing technique that He used. “It was so inappropriate on so many levels.”

He seemed shaky approaching the stage and nervous during the talk. “I think he was scared,” says Matthew Porteus, who researches genome-editing at Stanford University in California and co-hosted a question-and-answer session with He after his presentation. Porteus attributes this either to the legal pressures that He faces or the mounting criticism from the scientists and media he was about to address.

He’s talk leaves a host of other questions unanswered, including whether the prospective parents were properly informed of the risks; why He selected CCR5 when there are other, proven ways to prevent HIV; why he chose to do the experiment with couples in which the fathers have HIV, rather than mothers who have a higher chance of passing the virus on to their children; and whether the risks of knocking out CCR5 — a gene normally present in people, which could have necessary but still unknown functions — outweighed the benefits in this case.

In the discussion following He’s talk, one scientist asked why He proceeded with the experiments despite the clear consensus among scientists worldwide that such research shouldn’t be done. He didn’t answer the question.

He’s attempts to justify his actions mainly fell flat. In response to questions about why the science community had not been informed of the experiments before the first women were impregnated, he cited presentations that he gave last year at meetings at the University of California, Berkeley, and at the Cold Spring Harbor Laboratory in New York. But Doudna, who organized the Berkeley meeting, says He did not present anything that showed he was ready to experiment in people. She called his defence “disingenuous at best”.

He also said he discussed the human experiment with unnamed scientists in the United States. But Porteus says that’s not enough for such an extraordinary experiment: “You need feedback not from your two closest friends but from the whole community.” …

Pressure was mounting on He ahead of the presentation. On 27 November, the Chinese national health commission ordered the Guangdong health commission, in the province where He’s university is located, to investigate.

On the same day, the Chinese Academy of Sciences issued a statement condemning his work, and the Genetics Society of China and the Chinese Society for Stem Cell Research jointly issued a statement saying the experiment “violates internationally accepted ethical principles regulating human experimentation and human rights law”.

The hospital cited in China’s clinical-trial registry as the that gave ethical approval for He’s work posted a press release on 27 November saying it did not give any approval. It questioned the signatures on the approval form and said that the hospital’s medical-ethics committee never held a meeting related to He’s research. The hospital, which itself is under investigation by the Shenzhen health authorities following He’s revelations, wrote: “The Company does not condone the means of the Claimed Project, and has reservations as to the accuracy, reliability and truthfulness of its contents and results.”

He has not yet responded to requests for comment on these statements and investigations, nor on why the hospital was listed in the registry and the claim of apparent forged signatures.

Alice Park’s Nov. 26, 2018 article for Time magazine includes an embedded video of He’s Nov. 27, 2018 presentation at the summit meeting.

What about the politics?

Mara Hvistendahl’s Nov. 27, 2018 article about this research for Slate.com poses some geopolitical questions (Note: Links have been removed),

The informed consent agreement for He Jiankui’s experiment describes it as an “AIDS vaccine development project” and used highly technical language to describe the procedure that patients would undergo. If the reality for some Chinese patients is that such agreements are glossed over, densely written, or never read, the reality for some researchers working in the country is that the appeal of cutting-edge trials is too great to resist. It is not just Chinese scientists who can be blinded by the lure of quick breakthroughs. Several of the most notable breaches of informed consent on the mainland have involved Western researchers or co-authors. … When people say that the usual rules don’t apply in China, they are really referring to authoritarian science, not some alternative communitarian ethics.

For the many scientists in China who adhere to recognized international standards, the incident comes as a disgrace. He Jiankui now faces an ethics investigation from provincial health authorities, and his institution, Southern University of Science and Technology, was quick to issue a statement noting that He was on unpaid leave. …

It would seem that US [and from elsewhere]* scientists wanting to avoid pesky ethics requirements in the US have found that going to China could be the answer to their problems. I gather it’s not just big business that prefers deregulated environments.

Guillaume Levrier’s  (he’ studying for a PhD at the Universté Sorbonne Paris Cité) November 16, 2018 essay for The Conversation sheds some light on political will and its impact on science (Note: Links have been removed),

… China has entered a “genome editing” race among great scientific nations and its progress didn’t come out of nowhere. China has invested heavily in the natural-sciences sector over the past 20 years. The Ninth Five-Year Plan (1996-2001) mentioned the crucial importance of biotechnologies. The current Thirteenth Five-Year Plan is even more explicit. It contains a section dedicated to “developing efficient and advanced biotechnologies” and lists key sectors such as “genome-editing technologies” intended to “put China at the bleeding edge of biotechnology innovation and become the leader in the international competition in this sector”.

Chinese embryo research is regulated by a legal framework, the “technical norms on human-assisted reproductive technologies”, published by the Science and Health Ministries. The guidelines theoretically forbid using sperm or eggs whose genome have been manipulated for procreative purposes. However, it’s hard to know how much value is actually placed on this rule in practice, especially in China’s intricate institutional and political context.

In theory, three major actors have authority on biomedical research in China: the Science and Technology Ministry, the Health Ministry, and the Chinese Food and Drug Administration. In reality, other agents also play a significant role. Local governments interpret and enforce the ministries’ “recommendations”, and their own interpretations can lead to significant variations in what researchers can and cannot do on the ground. The Chinese National Academy of Medicine is also a powerful institution that has its own network of hospitals, universities and laboratories.

Another prime actor is involved: the health section of the People’s Liberation Army (PLA), which has its own biomedical faculties, hospitals and research labs. The PLA makes its own interpretations of the recommendations and has proven its ability to work with the private sector on gene editing projects. …

One other thing from Levrier’s essay,

… And the media timing is just a bit too perfect, …

Do read the essay; there’s a twist at the end.

Final thoughts and some links

If I read this material rightly, there are suspicions there may be more of this work being done in China and elsewhere. In short, we likely don’t have the whole story.

As for the ethical issues, this is a discussion among experts only, so far. The great unwashed (thee and me) are being left at the wayside. Sure, we’ll be invited to public consultations, one day,  after the big decisions have been made.

Anyone who’s read up on the history of science will tell you this kind of breach is very common at the beginning. Richard Holmes’  2008 book, ‘The Age of Wonder: How the Romantic Generation Discovered the Beauty and Terror of Science’ recounts stories of early scientists (European science) who did crazy things. Some died, some shortened their life spans; and, some irreversibly damaged their health.  They also experimented on other people. Informed consent had not yet been dreamed up.

In fact, I remember reading somewhere that the largest human clinical trial in history was held in Canada. The small pox vaccine was highly contested in the US but the Canadian government thought it was a good idea so they offered US scientists the option of coming here to vaccinate Canadian babies. This was in the 1950s and the vaccine seems to have been administered almost universally. That was a lot of Canadian babies. Thankfully, it seems to have worked out but it does seem mind-boggling today.

For all the indignation and shock we’re seeing, this is not the first time nor will it be the last time someone steps over a line in order to conduct scientific research. And, that is the eternal problem.

Meanwhile I think some of the real action regarding CRISPR and germline editing is taking place in the field (pun!) of agriculture:

My Nov. 27, 2018 posting titled: ‘Designer groundcherries by CRISPR (clustered regularly interspaced short palindromic repeats)‘ and a more disturbing Nov. 27, 2018 post titled: ‘Agriculture and gene editing … shades of the AquAdvantage salmon‘. That second posting features a company which is trying to sell its gene-editing services to farmers who would like cows that  never grow horns and pigs that never reach puberty.

Then there’s this ,

The Genetic Revolution‘, a documentary that offers relatively up-to-date information about gene editing, which was broadcast on Nov. 11, 2018 as part of The Nature of Things series on CBC (Canadian Broadcasting Corporation).

My July 17, 2018 posting about research suggesting that scientists hadn’t done enough research on possible effects of CRISPR editing titled: ‘The CRISPR ((clustered regularly interspaced short palindromic repeats)-CAS9 gene-editing technique may cause new genetic damage kerfuffle’.

My 2017 three-part series on CRISPR and germline editing:

CRISPR and editing the germline in the US (part 1 of 3): In the beginning

CRISPR and editing the germline in the US (part 2 of 3): ‘designer babies’?

CRISPR and editing the germline in the US (part 3 of 3): public discussions and pop culture

There you have it.

Added on November 30, 2018: David Cyanowski has written one final article (Nov. 30, 2018 for Nature) about He and the Second International Summit on Human Genome Editing. He did not make his second scheduled appearance at the summit, returning to China before the summit concluded. He was rebuked in a statement produced by the Summit’s organizing committee at the end of the three-day meeting. The situation with regard to his professional status in China is ambiguous. Cyanowski ends his piece with the information that the third summit will take place in London (likely in the UK) in 2021. I encourage you to read Cyanowski’s Nov. 30, 2018 article in its entirety; it’s not long.

Added on Dec. 3, 2018: The story continues. Ed Yong has written a summary of the issues to date in a Dec. 3, 2018 article for The Atlantic (even if you know the story ift’s eyeopening to see all the parts put together.

J. Benjamin Hurlbut, Associate Professor of Life Sciences at Arizona State University (ASU) and Jason Scott Robert, Director of the Lincoln Center for Applied Ethics at Arizona State University have written a provocative (and true) Dec. 3, 2018 essay titled, CRISPR babies raise an uncomfortable reality – abiding by scientific standards doesn’t guarantee ethical research, for The Conversation. h/t phys.org

*[and from elsewhere] added January 17, 2019.

Added on January 23, 2019: He has been fired by his university (Southern University of Science and Technology in Shenzhen) as announced on January 21, 2019.  David Cyranoski provides a details accounting in his January 22, 2019 article for Nature.

Why don’t you CRISPR yourself?

It must have been quite the conference. Josiah Zayner plunged a needle into himself and claimed to have changed his DNA (deoxyribonucleic acid) while giving his talk. (*Segue: There is some Canadian content if you keep reading.*) From an Oct. 10, 2017 article by Adele Peters for Fast Company (Note: A link has been removed),

“What we’ve got here is some DNA, and this is a syringe,” Josiah Zayner tells a room full of synthetic biologists and other researchers. He fills the needle and plunges it into his skin. “This will modify my muscle genes and give me bigger muscles.”

Zayner, a biohacker–basically meaning he experiments with biology in a DIY lab rather than a traditional one–was giving a talk called “A Step-by-Step Guide to Genetically Modifying Yourself With CRISPR” at the SynBioBeta conference in San Francisco, where other presentations featured academics in suits and the young CEOs of typical biotech startups. Unlike the others, he started his workshop by handing out shots of scotch and a booklet explaining the basics of DIY [do-it-yourwelf] genome engineering.

If you want to genetically modify yourself, it turns out, it’s not necessarily complicated. As he offered samples in small baggies to the crowd, Zayner explained that it took him about five minutes to make the DNA that he brought to the presentation. The vial held Cas9, an enzyme that snips DNA at a particular location targeted by guide RNA, in the gene-editing system known as CRISPR. In this case, it was designed to knock out the myostatin gene, which produces a hormone that limits muscle growth and lets muscles atrophy. In a study in China, dogs with the edited gene had double the muscle mass of normal dogs. If anyone in the audience wanted to try it, they could take a vial home and inject it later. Even rubbing it on skin, Zayner said, would have some effect on cells, albeit limited.

Peters goes on to note that Zayner has a PhD in molecular biology and biophysics and worked for NASA (US National Aeronautics and Space Administration). Zayner’s Wikipedia entry fills in a few more details (Note: Links have been removed),

Zayner graduated from the University of Chicago with a Ph.D. in biophysics in 2013. He then spent two years as a researcher at NASA’s Ames Research Center,[2] where he worked on Martian colony habitat design. While at the agency, Zayner also analyzed speech patterns in online chat, Twitter, and books, and found that language on Twitter and online chat is closer to how people talk than to how they write.[3] Zayner found NASA’s scientific work less innovative than he expected, and upon leaving in January 2016, he launched a crowdfunding campaign to provide CRISPR kits to let the general public experiment with editing bacterial DNA. He also continued his grad school business, The ODIN, which sells kits to let the general public experiment at home. As of May 2016, The ODIN had four employees and operates out of Zayner’s garage.[2]

He refers to himself as a biohacker and believes in the importance in letting the general public participate in scientific experimentation, rather than leaving it segregated to labs.[2][4][1] Zayner found the biohacking community exclusive and hierarchical, particularly in the types of people who decide what is “safe”. He hopes that his projects can let even more people experiment in their homes. Other scientists responded that biohacking is inherently privileged, as it requires leisure time and money, and that deviance from the safety rules of concern would lead to even harsher regulations for all.[5] Zayner’s public CRISPR kit campaign coincided with wider scrutiny over genetic modification. Zayner maintained that these fears were based on misunderstandings of the product, as genetic experiments on yeast and bacteria cannot produce a viral epidemic.[6][7] In April 2015, Zayner ran a hoax on Craigslist to raise awareness about the future potential of forgery in forensics genetics testing.[8]

In February 2016, Zayner performed a full body microbiome transplant on himself, including a fecal transplant, to experiment with microbiome engineering and see if he could cure himself from gastrointestinal and other health issues. The microbiome from the donors feces successfully transplanted in Zayner’s gut according to DNA sequencing done on samples.[2] This experiment was documented by filmmakers Kate McLean and Mario Furloni and turned into the short documentary film Gut Hack.[9]

In December 2016, Zayner created a fluorescent beer by engineering yeast to contain the green fluorescent protein from jellyfish. Zayner’s company, The ODIN, released kits to allow people to create their own engineered fluorescent yeast and this was met with some controversy as the FDA declared the green fluorescent protein can be seen as a color additive.[10] Zayner, views the kit as a way that individual can use genetic engineering to create things in their everyday life.[11]

I found the video for Zayner’s now completed crowdfunding campaign,

I also found The ODIN website (mentioned in the Wikipedia essay) where they claim to be selling various gene editing and gene engineering kits including the CRISPR editing kits mentioned in Peters’ article,

In 2016, he [Zayner] sold $200,000 worth of products, including a kit for yeast that can be used to brew glowing bioluminescent beer, a kit to discover antibiotics at home, and a full home lab that’s roughly the cost of a MacBook Pro. In 2017, he expects to double sales. Many kits are simple, and most buyers probably aren’t using the supplies to attempt to engineer themselves (many kits go to classrooms). But Zayner also hopes that as people using the kits gain genetic literacy, they experiment in wilder ways.

Zayner sells a full home biohacking lab that’s roughly the cost of a MacBook Pro. [Photo: The ODIN]

He questions whether traditional research methods, like randomized controlled trials, are the only way to make discoveries, pointing out that in newer personalized medicine (such as immunotherapy for cancer, which is personalized for each patient), a sample size of one person makes sense. At his workshop, he argued that people should have the choice to self-experiment if they want to; we also change our DNA when we drink alcohol or smoke cigarettes or breathe in dirty city air. Other society-sanctioned activities are more dangerous. “We sacrifice maybe a million people a year to the car gods,” he said. “If you ask someone, ‘Would you get rid of cars?’–no.” …

US researchers both conventional and DIY types such as Zayner are not the only ones who are editing genes. The Chinese study mentioned in Peters’ article was written up in an Oct. 19, 2015 article by Antonio Regalado for the MIT [Massachusetts Institute of Technology] Technology Review (Note: Links have been removed),

Scientists in China say they are the first to use gene editing to produce customized dogs. They created a beagle with double the amount of muscle mass by deleting a gene called myostatin.

The dogs have “more muscles and are expected to have stronger running ability, which is good for hunting, police (military) applications,” Liangxue Lai, a researcher with the Key Laboratory of Regenerative Biology at the Guangzhou Institutes of Biomedicine and Health, said in an e-mail.

Lai and 28 colleagues reported their results last week in the Journal of Molecular Cell Biology, saying they intend to create dogs with other DNA mutations, including ones that mimic human diseases such as Parkinson’s and muscular dystrophy. “The goal of the research is to explore an approach to the generation of new disease dog models for biomedical research,” says Lai. “Dogs are very close to humans in terms of metabolic, physiological, and anatomical characteristics.”

Lai said his group had no plans breed to breed the extra-muscular beagles as pets. Other teams, however, could move quickly to commercialize gene-altered dogs, potentially editing their DNA to change their size, enhance their intelligence, or correct genetic illnesses. A different Chinese Institute, BGI, said in September it had begun selling miniature pigs, created via gene editing, for $1,600 each as novelty pets.

People have been influencing the genetics of dogs for millennia. By at least 36,000 years ago, early humans had already started to tame wolves and shape the companions we have today. Charles Darwin frequently cited dog breeding in The Origin of Species to demonstrate how evolution gradually occurs by a process of selection. With CRISPR, however, evolution is no longer gradual or subject to chance. It is immediate and under human control.

It is precisely that power that is stirring wide debate and concern over CRISPR. Yet at least some researchers think that gene-edited dogs could put a furry, friendly face on the technology. In an interview this month, George Church, a professor at Harvard University who leads a large effort to employ CRISPR editing, said he thinks it will be possible to augment dogs by using DNA edits to make them live longer or simply make them smarter.

Church said he also believed the alteration of dogs and other large animals could open a path to eventual gene editing of people. “Germline editing of pigs or dogs offers a line into it,” he said. “People might say, ‘Hey, it works.’ ”

In the meantime, Zayner’s ideas are certainly thought provoking. I’m not endorsing either his products or his ideas but it should be noted that early science pioneers such as Humphrey Davy and others experimented on themselves. For anyone unfamiliar with Davy, (from the Humphrey Davy Wikipedia entry; Note: Links have been removed),

Sir Humphry Davy, 1st Baronet PRS MRIA FGS (17 December 1778 – 29 May 1829) was a Cornish chemist and inventor,[1] who is best remembered today for isolating a series of substances for the first time: potassium and sodium in 1807 and calcium, strontium, barium, magnesium and boron the following year, as well as discovering the elemental nature of chlorine and iodine. He also studied the forces involved in these separations, inventing the new field of electrochemistry. Berzelius called Davy’s 1806 Bakerian Lecture On Some Chemical Agencies of Electricity[2] “one of the best memoirs which has ever enriched the theory of chemistry.”[3] He was a Baronet, President of the Royal Society (PRS), Member of the Royal Irish Academy (MRIA), and Fellow of the Geological Society (FGS). He also invented the Davy lamp and a very early form of incandescent light bulb.

Canadian content*

A Nov. 11, 2017 posting on the Canadian Broadcasting Corporation’s (CBC) Quirks and Quarks blog notes that self-experimentation has a long history and goes on to describe Zayner’s and others biohacking exploits before describing the legality of biohacking in Canada,

With biohackers entering into the space traditionally held by scientists and clinicians, it begs questions. Professor Timothy Caulfield, a Canada research chair in health, law and policy at the University of Alberta, says when he hears of somebody giving themselves biohacked gene therapy, he wonders: “Is this legal? Is this safe? And if it’s not safe, is there anything that we can do about regulating it? And to be honest with you that’s a tough question and I think it’s an open question.”

In Canada, Caulfield says, Health Canada focuses on products. “You have to have something that you are going to regulate or you have to have something that’s making health claims. So if there is a product that is saying I can cure X, Y, or Z, Health Canada can say, ‘Well let’s make sure the science really backs up that claim.’ The problem with these do-it-yourself approaches is there isn’t really a product. You know these people are experimenting on themselves with something that may or may not be designed for health purposes.”

According to Caufield, if you could buy a gene therapy kit that was being marketed to you to biohack yourself, that would be different. “Health Canada could jump in. But right here that’s not the case,” he says.

There are places in the world that do regulate biohacking, says Caulfield. “Germany, for example, they have specific laws for it. And here in Canada we do have a regulatory framework that says that you cannot do gene therapy that will alter the germ line. In other words, you can’t do gene therapy or any kind of genetic editing that will create a change that you will pass on to your offspring. So that would be illegal, but that’s not what’s happening here. And I don’t think there’s a regulatory framework that adequately captures it.”

Infectious disease and policy experts aren’t that concerned yet about the possibility of a biohacker unleashing a genetically modified super germ into the population.

“I think in the future that could be a problem,”says Caulfield, “but this isn’t something that would be easy to do in your garage. I think it’s complicated science. But having said that, the science is moving quickly. We need to think about how we are going to control the potential harms.”

You can find out more about the ‘wild’ people (mostly men) of early science in Richard Holmes’ 2008 book, The Age of Wonder: How the Romantic Generation Discovered the Beauty and Terror of Science.

Finally, should you be interested in connecting with synthetic biology enthusiasts, entrepreneurs, and others, SynBioBeta is more than a conference; it’s also an activity hub.

ETA January 25, 2018 (five minutes later): There are some CRISPR/CAS9 events taking place in Toronto, Canada on January 24 and 25, 2018. One is a workshop with Portuguese artist, Marta de Menezes, and the other is a panel discussion. See my January 10, 2018 posting for more details.

*’Segue: There is some Canadian content if you keep reading.’ and ‘Canadian content’ added January 25, 2018 six minutes after first publication.

ETA February 20, 2018: Sarah Zhang’s Feb. 20, 2018 article for The Atlantic revisits Josiah Zayner’s decision to inject himself with CRISPR,

When Josiah Zayner watched a biotech CEO drop his pants at a biohacking conference and inject himself with an untested herpes treatment, he realized things had gone off the rails.

Zayner is no stranger to stunts in biohacking—loosely defined as experiments, often on the self, that take place outside of traditional lab spaces. You might say he invented their latest incarnation: He’s sterilized his body to “transplant” his entire microbiome in front of a reporter. He’s squabbled with the FDA about selling a kit to make glow-in-the-dark beer. He’s extensively documented attempts to genetically engineer the color of his skin. And most notoriously, he injected his arm with DNA encoding for CRISPR that could theoretically enhance his muscles—in between taking swigs of Scotch at a live-streamed event during an October conference. (Experts say—and even Zayner himself in the live-stream conceded—it’s unlikely to work.)

So when Zayner saw Ascendance Biomedical’s CEO injecting himself on a live-stream earlier this month, you might say there was an uneasy flicker of recognition.

“Honestly, I kind of blame myself,” Zayner told me recently. He’s been in a soul-searching mood; he recently had a kid and the backlash to the CRISPR stunt in October [2017] had been getting to him. “There’s no doubt in my mind that somebody is going to end up hurt eventually,” he said.

Yup, it’s one of the reasons for rules; people take things too far. The trick is figuring out how to achieve balance between risk taking and recklessness.