Tag Archives: Hank Greely

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).

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.

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

After giving a basic explanation of the technology and some of the controversies in part 1 and offering more detail about the technology and about the possibility of designer babies in part 2; this part covers public discussion, a call for one and the suggestion that one is taking place in popular culture.

But a discussion does need to happen

In a move that is either an exquisite coincidence or has been carefully orchestrated (I vote for the latter), researchers from the University of Wisconsin-Madison have released a study about attitudes in the US to human genome editing. From an Aug. 11, 2017 University of Wisconsin-Madison news release (also on EurekAllert),

In early August 2017, an international team of scientists announced they had successfully edited the DNA of human embryos. As people process the political, moral and regulatory issues of the technology — which nudges us closer to nonfiction than science fiction — researchers at the University of Wisconsin-Madison and Temple University show the time is now to involve the American public in discussions about human genome editing.

In a study published Aug. 11 in the journal Science, the researchers assessed what people in the United States think about the uses of human genome editing and how their attitudes may drive public discussion. They found a public divided on its uses but united in the importance of moving conversations forward.

“There are several pathways we can go down with gene editing,” says UW-Madison’s Dietram Scheufele, lead author of the study and member of a National Academy of Sciences committee that compiled a report focused on human gene editing earlier this year. “Our study takes an exhaustive look at all of those possible pathways forward and asks where the public stands on each one of them.”

Compared to previous studies on public attitudes about the technology, the new study takes a more nuanced approach, examining public opinion about the use of gene editing for disease therapy versus for human enhancement, and about editing that becomes hereditary versus editing that does not.

The research team, which included Scheufele and Dominique Brossard — both professors of life sciences communication — along with Michael Xenos, professor of communication arts, first surveyed study participants about the use of editing to treat disease (therapy) versus for enhancement (creating so-called “designer babies”). While about two-thirds of respondents expressed at least some support for therapeutic editing, only one-third expressed support for using the technology for enhancement.

Diving even deeper, researchers looked into public attitudes about gene editing on specific cell types — somatic or germline — either for therapy or enhancement. Somatic cells are non-reproductive, so edits made in those cells do not affect future generations. Germline cells, however, are heritable, and changes made in these cells would be passed on to children.

Public support of therapeutic editing was high both in cells that would be inherited and those that would not, with 65 percent of respondents supporting therapy in germline cells and 64 percent supporting therapy in somatic cells. When considering enhancement editing, however, support depended more upon whether the changes would affect future generations. Only 26 percent of people surveyed supported enhancement editing in heritable germline cells and 39 percent supported enhancement of somatic cells that would not be passed on to children.

“A majority of people are saying that germline enhancement is where the technology crosses that invisible line and becomes unacceptable,” says Scheufele. “When it comes to therapy, the public is more open, and that may partly be reflective of how severe some of those genetically inherited diseases are. The potential treatments for those diseases are something the public at least is willing to consider.”

Beyond questions of support, researchers also wanted to understand what was driving public opinions. They found that two factors were related to respondents’ attitudes toward gene editing as well as their attitudes toward the public’s role in its emergence: the level of religious guidance in their lives, and factual knowledge about the technology.

Those with a high level of religious guidance in their daily lives had lower support for human genome editing than those with low religious guidance. Additionally, those with high knowledge of the technology were more supportive of it than those with less knowledge.

While respondents with high religious guidance and those with high knowledge differed on their support for the technology, both groups highly supported public engagement in its development and use. These results suggest broad agreement that the public should be involved in questions of political, regulatory and moral aspects of human genome editing.

“The public may be split along lines of religiosity or knowledge with regard to what they think about the technology and scientific community, but they are united in the idea that this is an issue that requires public involvement,” says Scheufele. “Our findings show very nicely that the public is ready for these discussions and that the time to have the discussions is now, before the science is fully ready and while we have time to carefully think through different options regarding how we want to move forward.”

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

U.S. attitudes on human genome editing by Dietram A. Scheufele, Michael A. Xenos, Emily L. Howell, Kathleen M. Rose, Dominique Brossard1, and Bruce W. Hardy. Science 11 Aug 2017: Vol. 357, Issue 6351, pp. 553-554 DOI: 10.1126/science.aan3708

This paper is behind a paywall.

A couple of final comments

Briefly, I notice that there’s no mention of the ethics of patenting this technology in the news release about the study.

Moving on, it seems surprising that the first team to engage in germline editing in the US is in Oregon; I would have expected the work to come from Massachusetts, California, or Illinois where a lot of bleeding edge medical research is performed. However, given the dearth of financial support from federal funding institutions, it seems likely that only an outsider would dare to engage i the research. Given the timing, Mitalipov’s work was already well underway before the recent about-face from the US National Academy of Sciences (Note: Kaiser’s Feb. 14, 2017 article does note that for some the recent recommendations do not represent any change).

As for discussion on issues such as editing of the germline, I’ve often noted here that popular culture (including advertising with the science fiction and other dramas laid in various media) often provides an informal forum for discussion. Joelle Renstrom in an Aug. 13, 2017 article for slate.com writes that Orphan Black (a BBC America series featuring clones) opened up a series of questions about science and ethics in the guise of a thriller about clones. She offers a précis of the first four seasons (Note: A link has been removed),

If you stopped watching a few seasons back, here’s a brief synopsis of how the mysteries wrap up. Neolution, an organization that seeks to control human evolution through genetic modification, began Project Leda, the cloning program, for two primary reasons: to see whether they could and to experiment with mutations that might allow people (i.e., themselves) to live longer. Neolution partnered with biotech companies such as Dyad, using its big pharma reach and deep pockets to harvest people’s genetic information and to conduct individual and germline (that is, genetic alterations passed down through generations) experiments, including infertility treatments that result in horrifying birth defects and body modification, such as tail-growing.

She then provides the article’s thesis (Note: Links have been removed),

Orphan Black demonstrates Carl Sagan’s warning of a time when “awesome technological powers are in the hands of a very few.” Neolutionists do whatever they want, pausing only to consider whether they’re missing an opportunity to exploit. Their hubris is straight out of Victor Frankenstein’s playbook. Frankenstein wonders whether he ought to first reanimate something “of simpler organisation” than a human, but starting small means waiting for glory. Orphan Black’s evil scientists embody this belief: if they’re going to play God, then they’ll control not just their own destinies, but the clones’ and, ultimately, all of humanity’s. Any sacrifices along the way are for the greater good—reasoning that culminates in Westmoreland’s eugenics fantasy to genetically sterilize 99 percent of the population he doesn’t enhance.

Orphan Black uses sci-fi tropes to explore real-world plausibility. Neolution shares similarities with transhumanism, the belief that humans should use science and technology to take control of their own evolution. While some transhumanists dabble in body modifications, such as microchip implants or night-vision eye drops, others seek to end suffering by curing human illness and aging. But even these goals can be seen as selfish, as access to disease-eradicating or life-extending technologies would be limited to the wealthy. Westmoreland’s goal to “sell Neolution to the 1 percent” seems frighteningly plausible—transhumanists, who statistically tend to be white, well-educated, and male, and their associated organizations raise and spend massive sums of money to help fulfill their goals. …

On Orphan Black, denial of choice is tantamount to imprisonment. That the clones have to earn autonomy underscores the need for ethics in science, especially when it comes to genetics. The show’s message here is timely given the rise of gene-editing techniques such as CRISPR. Recently, the National Academy of Sciences gave germline gene editing the green light, just one year after academy scientists from around the world argued it would be “irresponsible to proceed” without further exploring the implications. Scientists in the United Kingdom and China have already begun human genetic engineering and American scientists recently genetically engineered a human embryo for the first time. The possibility of Project Leda isn’t farfetched. Orphan Black warns us that money, power, and fear of death can corrupt both people and science. Once that happens, loss of humanity—of both the scientists and the subjects—is inevitable.

In Carl Sagan’s dark vision of the future, “people have lost the ability to set their own agendas or knowledgeably question those in authority.” This describes the plight of the clones at the outset of Orphan Black, but as the series continues, they challenge this paradigm by approaching science and scientists with skepticism, ingenuity, and grit. …

I hope there are discussions such as those Scheufele and Brossard are advocating but it might be worth considering that there is already some discussion underway, as informal as it is.

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

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

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

Having included an explanation of CRISPR-CAS9 technology along with the news about the first US team to edit the germline and bits and pieces about ethics and a patent fight (part 1), this part hones in on the details of the work and worries about ‘designer babies’.

The interest flurry

I found three articles addressing the research and all three concur that despite some of the early reporting, this is not the beginning of a ‘designer baby’ generation.

First up was Nick Thieme in a July 28, 2017 article for Slate,

MIT Technology Review reported Thursday that a team of researchers from Portland, Oregon were the first team of U.S.-based scientists to successfully create a genetically modified human embryo. The researchers, led by Shoukhrat Mitalipov of Oregon Health and Science University, changed the DNA of—in MIT Technology Review’s words—“many tens” of genetically-diseased embryos by injecting the host egg with CRISPR, a DNA-based gene editing tool first discovered in bacteria, at the time of fertilization. CRISPR-Cas9, as the full editing system is called, allows scientists to change genes accurately and efficiently. As has happened with research elsewhere, the CRISPR-edited embryos weren’t implanted—they were kept sustained for only a couple of days.

In addition to being the first American team to complete this feat, the researchers also improved upon the work of the three Chinese research teams that beat them to editing embryos with CRISPR: Mitalipov’s team increased the proportion of embryonic cells that received the intended genetic changes, addressing an issue called “mosaicism,” which is when an embryo is comprised of cells with different genetic makeups. Increasing that proportion is essential to CRISPR work in eliminating inherited diseases, to ensure that the CRISPR therapy has the intended result. The Oregon team also reduced the number of genetic errors introduced by CRISPR, reducing the likelihood that a patient would develop cancer elsewhere in the body.

Separate from the scientific advancements, it’s a big deal that this work happened in a country with such intense politicization of embryo research. …

But there are a great number of obstacles between the current research and the future of genetically editing all children to be 12-foot-tall Einsteins.

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.”

Given the persistent confusion around CRISPR and its implications, I’ve laid out exactly what the team did, and what it means.

Who did the experiments?

Shoukhrat Mitalipov is a Kazakhstani-born cell biologist with a history of breakthroughs—and controversy—in the stem cell field. He was the scientist to clone monkeys. He was the first to create human embryos by cloning adult cells—a move that could provide patients with an easy supply of personalized stem cells. He also pioneered a technique for creating embryos with genetic material from three biological parents, as a way of preventing a group of debilitating inherited diseases.

Although MIT Tech Review name-checked Mitalipov alone, the paper splits credit for the research between five collaborating teams—four based in the United States, and one in South Korea.

What did they actually do?

The project effectively began with an elevator conversation between Mitalipov and his colleague Sanjiv Kaul. Mitalipov explained that he wanted to use CRISPR to correct a disease-causing gene in human embryos, and was trying to figure out which disease to focus on. Kaul, a cardiologist, told him about hypertrophic cardiomyopathy (HCM)—an inherited heart disease that’s commonly caused by mutations in a gene called MYBPC3. HCM is surprisingly common, affecting 1 in 500 adults. Many of them lead normal lives, but in some, the walls of their hearts can thicken and suddenly fail. For that reason, HCM is the commonest cause of sudden death in athletes. “There really is no treatment,” says Kaul. “A number of drugs are being evaluated but they are all experimental,” and they merely treat the symptoms. The team wanted to prevent HCM entirely by removing the underlying mutation.

They collected sperm from a man with HCM and used CRISPR to change his mutant gene into its normal healthy version, while simultaneously using the sperm to fertilize eggs that had been donated by female volunteers. In this way, they created embryos that were completely free of the mutation. The procedure was effective, and avoided some of the critical problems that have plagued past attempts to use CRISPR in human embryos.

Wait, other human embryos have been edited before?

There have been three attempts in China. The first two—in 2015 and 2016—used non-viable embryos that could never have resulted in a live birth. The third—announced this March—was the first to use viable embryos that could theoretically have been implanted in a womb. All of these studies showed that CRISPR gene-editing, for all its hype, is still in its infancy.

The editing was imprecise. CRISPR is heralded for its precision, allowing scientists to edit particular genes of choice. But in practice, some of the Chinese researchers found worrying levels of off-target mutations, where CRISPR mistakenly cut other parts of the genome.

The editing was inefficient. The first Chinese team only managed to successfully edit a disease gene in 4 out of 86 embryos, and the second team fared even worse.

The editing was incomplete. Even in the successful cases, each embryo had a mix of modified and unmodified cells. This pattern, known as mosaicism, poses serious safety problems if gene-editing were ever to be used in practice. Doctors could end up implanting women with embryos that they thought were free of a disease-causing mutation, but were only partially free. The resulting person would still have many tissues and organs that carry those mutations, and might go on to develop symptoms.

What did the American team do differently?

The Chinese teams all used CRISPR to edit embryos at early stages of their development. By contrast, the Oregon researchers delivered the CRISPR components at the earliest possible point—minutes before fertilization. That neatly avoids the problem of mosaicism by ensuring that an embryo is edited from the very moment it is created. The team did this with 54 embryos and successfully edited the mutant MYBPC3 gene in 72 percent of them. In the other 28 percent, the editing didn’t work—a high failure rate, but far lower than in previous attempts. Better still, the team found no evidence of off-target mutations.

This is a big deal. Many scientists assumed that they’d have to do something more convoluted to avoid mosaicism. They’d have to collect a patient’s cells, which they’d revert into stem cells, which they’d use to make sperm or eggs, which they’d edit using CRISPR. “That’s a lot of extra steps, with more risks,” says Alta Charo. “If it’s possible to edit the embryo itself, that’s a real advance.” Perhaps for that reason, this is the first study to edit human embryos that was published in a top-tier scientific journal—Nature, which rejected some of the earlier Chinese papers.

Is this kind of research even legal?

Yes. In Western Europe, 15 countries out of 22 ban any attempts to change the human germ line—a term referring to sperm, eggs, and other cells that can transmit genetic information to future generations. No such stance exists in the United States but Congress has banned the Food and Drug Administration from considering research applications that make such modifications. Separately, federal agencies like the National Institutes of Health are banned from funding research that ultimately destroys human embryos. But the Oregon team used non-federal money from their institutions, and donations from several small non-profits. No taxpayer money went into their work. [emphasis mine]

Why would you want to edit embryos at all?

Partly to learn more about ourselves. By using CRISPR to manipulate the genes of embryos, scientists can learn more about the earliest stages of human development, and about problems like infertility and miscarriages. That’s why biologist Kathy Niakan from the Crick Institute in London recently secured a license from a British regulator to use CRISPR on human embryos.

Isn’t this a slippery slope toward making designer babies?

In terms of avoiding genetic diseases, it’s not conceptually different from PGD, which is already widely used. The bigger worry is that gene-editing could be used to make people stronger, smarter, or taller, paving the way for a new eugenics, and widening the already substantial gaps between the wealthy and poor. But many geneticists believe that such a future is fundamentally unlikely because complex traits like height and intelligence are the work of hundreds or thousands of genes, each of which have a tiny effect. The prospect of editing them all is implausible. And since genes are so thoroughly interconnected, it may be impossible to edit one particular trait without also affecting many others.

“There’s the worry that this could be used for enhancement, so society has to draw a line,” says Mitalipov. “But this is pretty complex technology and it wouldn’t be hard to regulate it.”

Does this discovery have any social importance at all?

“It’s not so much about designer babies as it is about geographical location,” says Charo. “It’s happening in the United States, and everything here around embryo research has high sensitivity.” She and others worry that the early report about the study, before the actual details were available for scrutiny, could lead to unnecessary panic. “Panic reactions often lead to panic-driven policy … which is usually bad policy,” wrote Greely [bioethicist Hank Greely].

As I understand it, despite the change in stance, there is no federal funding available for the research performed by Mitalipov and his team.

Finally, University College London (UCL) scientists Joyce Harper and Helen O’Neill wrote about CRISPR, the Oregon team’s work, and the possibilities in an Aug. 3, 2017 essay for The Conversation (Note: Links have been removed),

The genome editing tool used, CRISPR-Cas9, has transformed the field of biology in the short time since its discovery in that it not only promises, but delivers. CRISPR has surpassed all previous efforts to engineer cells and alter genomes at a fraction of the time and cost.

The technology, which works like molecular scissors to cut and paste DNA, is a natural defence system that bacteria use to fend off harmful infections. This system has the ability to recognise invading virus DNA, cut it and integrate this cut sequence into its own genome – allowing the bacterium to render itself immune to future infections of viruses with similar DNA. It is this ability to recognise and cut DNA that has allowed scientists to use it to target and edit specific DNA regions.

When this technology is applied to “germ cells” – the sperm and eggs – or embryos, it changes the germline. That means that any alterations made would be permanent and passed down to future generations. This makes it more ethically complex, but there are strict regulations around human germline genome editing, which is predominantly illegal. The UK received a licence in 2016 to carry out CRISPR on human embryos for research into early development. But edited embryos are not allowed to be inserted into the uterus and develop into a fetus in any country.

Germline genome editing came into the global spotlight when Chinese scientists announced in 2015 that they had used CRISPR to edit non-viable human embryos – cells that could never result in a live birth. They did this to modify the gene responsible for the blood disorder β-thalassaemia. While it was met with some success, it received a lot of criticism because of the premature use of this technology in human embryos. The results showed a high number of potentially dangerous, off-target mutations created in the procedure.

Impressive results

The new study, published in Nature, is different because it deals with viable human embryos and shows that the genome editing can be carried out safely – without creating harmful mutations. The team used CRISPR to correct a mutation in the gene MYBPC3, which accounts for approximately 40% of the myocardial disease hypertrophic cardiomyopathy. This is a dominant disease, so an affected individual only needs one abnormal copy of the gene to be affected.

The researchers used sperm from a patient carrying one copy of the MYBPC3 mutation to create 54 embryos. They edited them using CRISPR-Cas9 to correct the mutation. Without genome editing, approximately 50% of the embryos would carry the patients’ normal gene and 50% would carry his abnormal gene.

After genome editing, the aim would be for 100% of embryos to be normal. In the first round of the experiments, they found that 66.7% of embryos – 36 out of 54 – were normal after being injected with CRIPSR. Of the remaining 18 embryos, five had remained unchanged, suggesting editing had not worked. In 13 embryos, only a portion of cells had been edited.

The level of efficiency is affected by the type of CRISPR machinery used and, critically, the timing in which it is put into the embryo. The researchers therefore also tried injecting the sperm and the CRISPR-Cas9 complex into the egg at the same time, which resulted in more promising results. This was done for 75 mature donated human eggs using a common IVF technique called intracytoplasmic sperm injection. This time, impressively, 72.4% of embryos were normal as a result. The approach also lowered the number of embryos containing a mixture of edited and unedited cells (these embryos are called mosaics).

Finally, the team injected a further 22 embryos which were grown into blastocyst – a later stage of embryo development. These were sequenced and the researchers found that the editing had indeed worked. Importantly, they could show that the level of off-target mutations was low.

A brave new world?

So does this mean we finally have a cure for debilitating, heritable diseases? It’s important to remember that the study did not achieve a 100% success rate. Even the researchers themselves stress that further research is needed in order to fully understand the potential and limitations of the technique.

In our view, it is unlikely that genome editing would be used to treat the majority of inherited conditions anytime soon. We still can’t be sure how a child with a genetically altered genome will develop over a lifetime, so it seems unlikely that couples carrying a genetic disease would embark on gene editing rather than undergoing already available tests – such as preimplantation genetic diagnosis or prenatal diagnosis – where the embryos or fetus are tested for genetic faults.

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As might be expected there is now a call for public discussion about the ethics about this kind of work. See Part 3.

For anyone who started in the middle of this series, here’s Part 1 featuring an introduction to the technology and some of the issues.

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

There’s been a minor flurry of interest in CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats; also known as CRISPR-CAS9), a gene-editing technique, since a team in Oregon announced a paper describing their work editing the germline. Since I’ve been following the CRISPR-CAS9 story for a while this seems like a good juncture for a more in-depth look at the topic. In this first part I’m including an introduction to CRISPR, some information about the latest US work, and some previous writing about ethics issues raised when Chinese scientists first announced their work editing germlines in 2015 and during the patent dispute between the University of California at Berkeley and Harvard University’s Broad Institute.

Introduction to CRISPR

I’ve been searching for a good description of CRISPR and this helped to clear up some questions for me (Thank you to MIT Review),

For anyone who’s been reading about science for a while, this upbeat approach to explaining how a particular technology will solve all sorts of problems will seem quite familiar. It’s not the most hyperbolic piece I’ve seen but it barely mentions any problems associated with research (for some of the problems see: ‘The interest flurry’ later in part 2).

Oregon team

Steve Connor’s July 26, 2017 article for the MIT (Massachusetts Institute of Technology) Technology Review breaks the news (Note: Links have been removed),

The first known attempt at creating genetically modified human embryos in the United States has been carried out by a team of researchers in Portland, Oregon, MIT Technology Review has learned.

The effort, led by Shoukhrat Mitalipov of Oregon Health and Science University, involved changing the DNA of a large number of one-cell embryos with the gene-editing technique CRISPR, according to people familiar with the scientific results.

Until now, American scientists have watched with a combination of awe, envy, and some alarm as scientists elsewhere were first to explore the controversial practice. To date, three previous reports of editing human embryos were all published by scientists in China.

Now Mitalipov is believed to have broken new ground both in the number of embryos experimented upon and by demonstrating that it is possible to safely and efficiently correct defective genes that cause inherited diseases.

Although none of the embryos were allowed to develop for more than a few days—and there was never any intention of implanting them into a womb—the experiments are a milestone on what may prove to be an inevitable journey toward the birth of the first genetically modified humans.

In altering the DNA code of human embryos, the objective of scientists is to show that they can eradicate or correct genes that cause inherited disease, like the blood condition beta-thalassemia. The process is termed “germline engineering” because any genetically modified child would then pass the changes on to subsequent generations via their own germ cells—the egg and sperm.

Some critics say germline experiments could open the floodgates to a brave new world of “designer babies” engineered with genetic enhancements—a prospect bitterly opposed by a range of religious organizations, civil society groups, and biotech companies.

The U.S. intelligence community last year called CRISPR a potential “weapon of mass destruction.”

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

Correction of a pathogenic gene mutation in human embryos by Hong Ma, Nuria Marti-Gutierrez, Sang-Wook Park, Jun Wu, Yeonmi Lee, Keiichiro Suzuki, Amy Koski, Dongmei Ji, Tomonari Hayama, Riffat Ahmed, Hayley Darby, Crystal Van Dyken, Ying Li, Eunju Kang, A.-Reum Park, Daesik Kim, Sang-Tae Kim, Jianhui Gong, Ying Gu, Xun Xu, David Battaglia, Sacha A. Krieg, David M. Lee, Diana H. Wu, Don P. Wolf, Stephen B. Heitner, Juan Carlos Izpisua Belmonte, Paula Amato, Jin-Soo Kim, Sanjiv Kaul, & Shoukhrat Mitalipov. Nature (2017) doi:10.1038/nature23305 Published online 02 August 2017

This paper appears to be open access.

CRISPR Issues: ethics and patents

In my May 14, 2015 posting I mentioned a ‘moratorium’ on germline research, the Chinese research paper, and the stance taken by the US National Institutes of Health (NIH),

The CRISPR technology has reignited a discussion about ethical and moral issues of human genetic engineering some of which is reviewed in an April 7, 2015 posting about a moratorium by Sheila Jasanoff, J. Benjamin Hurlbut and Krishanu Saha for the Guardian science blogs (Note: A link has been removed),

On April 3, 2015, a group of prominent biologists and ethicists writing in Science called for a moratorium on germline gene engineering; modifications to the human genome that will be passed on to future generations. The moratorium would apply to a technology called CRISPR/Cas9, which enables the removal of undesirable genes, insertion of desirable ones, and the broad recoding of nearly any DNA sequence.

Such modifications could affect every cell in an adult human being, including germ cells, and therefore be passed down through the generations. Many organisms across the range of biological complexity have already been edited in this way to generate designer bacteria, plants and primates. There is little reason to believe the same could not be done with human eggs, sperm and embryos. Now that the technology to engineer human germlines is here, the advocates for a moratorium declared, it is time to chart a prudent path forward. They recommend four actions: a hold on clinical applications; creation of expert forums; transparent research; and a globally representative group to recommend policy approaches.

The authors go on to review precedents and reasons for the moratorium while suggesting we need better ways for citizens to engage with and debate these issues,

An effective moratorium must be grounded in the principle that the power to modify the human genome demands serious engagement not only from scientists and ethicists but from all citizens. We need a more complex architecture for public deliberation, built on the recognition that we, as citizens, have a duty to participate in shaping our biotechnological futures, just as governments have a duty to empower us to participate in that process. Decisions such as whether or not to edit human genes should not be left to elite and invisible experts, whether in universities, ad hoc commissions, or parliamentary advisory committees. Nor should public deliberation be temporally limited by the span of a moratorium or narrowed to topics that experts deem reasonable to debate.

I recommend reading the post in its entirety as there are nuances that are best appreciated in the entirety of the piece.

Shortly after this essay was published, Chinese scientists announced they had genetically modified (nonviable) human embryos. From an April 22, 2015 article by David Cyranoski and Sara Reardon in Nature where the research and some of the ethical issues discussed,

In a world first, Chinese scientists have reported editing the genomes of human embryos. The results are published1 in the online journal Protein & Cell and confirm widespread rumours that such experiments had been conducted — rumours that sparked a high-profile debate last month2, 3 about the ethical implications of such work.

In the paper, researchers led by Junjiu Huang, a gene-function researcher at Sun Yat-sen University in Guangzhou, tried to head off such concerns by using ‘non-viable’ embryos, which cannot result in a live birth, that were obtained from local fertility clinics. The team attempted to modify the gene responsible for β-thalassaemia, a potentially fatal blood disorder, using a gene-editing technique known as CRISPR/Cas9. The researchers say that their results reveal serious obstacles to using the method in medical applications.

“I believe this is the first report of CRISPR/Cas9 applied to human pre-implantation embryos and as such the study is a landmark, as well as a cautionary tale,” says George Daley, a stem-cell biologist at Harvard Medical School in Boston, Massachusetts. “Their study should be a stern warning to any practitioner who thinks the technology is ready for testing to eradicate disease genes.”

….

Huang says that the paper was rejected by Nature and Science, in part because of ethical objections; both journals declined to comment on the claim. (Nature’s news team is editorially independent of its research editorial team.)

He adds that critics of the paper have noted that the low efficiencies and high number of off-target mutations could be specific to the abnormal embryos used in the study. Huang acknowledges the critique, but because there are no examples of gene editing in normal embryos he says that there is no way to know if the technique operates differently in them.

Still, he maintains that the embryos allow for a more meaningful model — and one closer to a normal human embryo — than an animal model or one using adult human cells. “We wanted to show our data to the world so people know what really happened with this model, rather than just talking about what would happen without data,” he says.

This, too, is a good and thoughtful read.

There was an official response in the US to the publication of this research, from an April 29, 2015 post by David Bruggeman on his Pasco Phronesis blog (Note: Links have been removed),

In light of Chinese researchers reporting their efforts to edit the genes of ‘non-viable’ human embryos, the National Institutes of Health (NIH) Director Francis Collins issued a statement (H/T Carl Zimmer).

“NIH will not fund any use of gene-editing technologies in human embryos. The concept of altering the human germline in embryos for clinical purposes has been debated over many years from many different perspectives, and has been viewed almost universally as a line that should not be crossed. Advances in technology have given us an elegant new way of carrying out genome editing, but the strong arguments against engaging in this activity remain. These include the serious and unquantifiable safety issues, ethical issues presented by altering the germline in a way that affects the next generation without their consent, and a current lack of compelling medical applications justifying the use of CRISPR/Cas9 in embryos.” …

The US has modified its stance according to a February 14, 2017 article by Jocelyn Kaiser for Science Magazine (Note: Links have been removed),

Editing the DNA of a human embryo to prevent a disease in a baby could be ethically allowable one day—but only in rare circumstances and with safeguards in place, says a widely anticipated report released today.

The report from an international committee convened by the U.S. National Academy of Sciences (NAS) and the National Academy of Medicine in Washington, D.C., concludes that such a clinical trial “might be permitted, but only following much more research” on risks and benefits, and “only for compelling reasons and under strict oversight.” Those situations could be limited to couples who both have a serious genetic disease and for whom embryo editing is “really the last reasonable option” if they want to have a healthy biological child, says committee co-chair Alta Charo, a bioethicist at the University of Wisconsin in Madison.

Some researchers are pleased with the report, saying it is consistent with previous conclusions that safely altering the DNA of human eggs, sperm, or early embryos—known as germline editing—to create a baby could be possible eventually. “They have closed the door to the vast majority of germline applications and left it open for a very small, well-defined subset. That’s not unreasonable in my opinion,” says genome researcher Eric Lander of the Broad Institute in Cambridge, Massachusetts. Lander was among the organizers of an international summit at NAS in December 2015 who called for more discussion before proceeding with embryo editing.

But others see the report as lowering the bar for such experiments because it does not explicitly say they should be prohibited for now. “It changes the tone to an affirmative position in the absence of the broad public debate this report calls for,” says Edward Lanphier, chairman of the DNA editing company Sangamo Therapeutics in Richmond, California. Two years ago, he co-authored a Nature commentary calling for a moratorium on clinical embryo editing.

One advocacy group opposed to embryo editing goes further. “We’re very disappointed with the report. It’s really a pretty dramatic shift from the existing and widespread agreement globally that human germline editing should be prohibited,” says Marcy Darnovsky, executive director of the Center for Genetics and Society in Berkeley, California.

Interestingly, this change of stance occurred just prior to a CRISPR patent decision (from my March 15, 2017 posting),

I have written about the CRISPR patent tussle (Harvard & MIT’s [Massachusetts Institute of Technology] Broad Institute vs the University of California at Berkeley) previously in a Jan. 6, 2015 posting and in a more detailed May 14, 2015 posting. I also mentioned (in a Jan. 17, 2017 posting) CRISPR and its patent issues in the context of a posting about a Slate.com series on Frankenstein and the novel’s applicability to our own time. This patent fight is being bitterly fought as fortunes are at stake.

It seems a decision has been made regarding the CRISPR patent claims. From a Feb. 17, 2017 article by Charmaine Distor for The Science Times,

After an intense court battle, the US Patent and Trademark Office (USPTO) released its ruling on February 15 [2017]. The rights for the CRISPR-Cas9 gene editing technology was handed over to the Broad Institute of Harvard University and the Massachusetts Institute of Technology (MIT).

According to an article in Nature, the said court battle was between the Broad Institute and the University of California. The two institutions are fighting over the intellectual property right for the CRISPR patent. The case between the two started when the patent was first awarded to the Broad Institute despite having the University of California apply first for the CRISPR patent.

Heidi Ledford’s Feb. 17, 2017 article for Nature provides more insight into the situation (Note: Links have been removed),

It [USPTO] ruled that the Broad Institute of Harvard and MIT in Cambridge could keep its patents on using CRISPR–Cas9 in eukaryotic cells. That was a blow to the University of California in Berkeley, which had filed its own patents and had hoped to have the Broad’s thrown out.

The fight goes back to 2012, when Jennifer Doudna at Berkeley, Emmanuelle Charpentier, then at the University of Vienna, and their colleagues outlined how CRISPR–Cas9 could be used to precisely cut isolated DNA1. In 2013, Feng Zhang at the Broad and his colleagues — and other teams — showed2 how it could be adapted to edit DNA in eukaryotic cells such as plants, livestock and humans.

Berkeley filed for a patent earlier, but the USPTO granted the Broad’s patents first — and this week upheld them. There are high stakes involved in the ruling. The holder of key patents could make millions of dollars from CRISPR–Cas9’s applications in industry: already, the technique has sped up genetic research, and scientists are using it to develop disease-resistant livestock and treatments for human diseases.

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I also noted this eyebrow-lifting statistic,  “As for Ledford’s 3rd point, there are an estimated 763 patent families (groups of related patents) claiming CAS9 leading to the distinct possibility that the Broad Institute will be fighting many patent claims in the future.)

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Part 2 covers three critical responses to the reporting and between them describe the technology in more detail and the possibility of ‘designer babies’.  CRISPR and editing the germline in the US (part 2 of 3): ‘designer babies’?

Part 3 is all about public discussion or, rather, the lack of and need for according to a couple of social scientists. Informally, there is some discussion via pop culture and Joelle Renstrom notes although she is focused on the larger issues touched on by the television series, Orphan Black and as I touch on in my final comments. CRISPR and editing the germline in the US (part 3 of 3): public discussions and pop culture