Tag Archives: gene editing

Gold nanoparticle loaded with CRISPR used to edit genes

CRISPR (clustered regularly interspaced short palindromic repeats) gene editing is usually paired with a virus (9, 12a, etc.) but this time scientists are using a gold nanoparticle. From a May 27, 2019 news item on Nanowerk (Note: Links have been removed),

Scientists at Fred Hutchinson Cancer Research Center took a step toward making gene therapy more practical by simplifying the way gene-editing instructions are delivered to cells. Using a gold nanoparticle instead of an inactivated virus, they safely delivered gene-editing tools in lab models of HIV and inherited blood disorders, as reported in Nature Materials (“Targeted homology-directed repair in blood stem and progenitor cells with CRISPR nanoformulations”).

A May 27, 2019 Fred Hutchinson Cancer Research Center news release (also on EurekAlert) by Jake Siegel, which originated the news item, expands on the theme, provides more detail,

It’s the first time that a gold nanoparticle loaded with CRISPR has been used to edit genes in a rare but powerful subset of blood stem cells, the source of all blood cells. The CRISPR-carrying gold nanoparticle led to successful gene editing in blood stem cells with no toxic effects.

“As gene therapies make their way through clinical trials and become available to patients, we need a more practical approach,” said senior author Dr. Jennifer Adair, an assistant member of the Clinical Research Division at Fred Hutch, adding that current methods of performing gene therapy are inaccessible to millions of people around the world. “I wanted to find something simpler, something that would passively deliver gene editing to blood stem cells.”

While CRISPR has made it faster and easier to precisely deliver genetic modifications to the genome, it still has challenges. Getting cells to accept CRISPR gene-editing tools involves a small electric shock that can damage and even kill the cells. And if precise gene edits are required, then additional molecules must be engineered to deliver them –adding cost and time.

Gold nanoparticles are a promising alternative because the surface of these tiny spheres (around 1 billionth the size of a grain of table salt) allows other molecules to easily stick to them and stay adhered.

“We engineered the gold nanoparticles to quickly cross the cell membrane, dodge cell organelles that seek to destroy them and go right to the cell nucleus to edit genes,” said Dr. Reza Shahbazi, a Fred Hutch postdoctoral researcher who has worked with gold nanoparticles for drug and gene delivery for seven years.

Shahbazi made the gold particles from laboratory-grade gold that is purified and comes as a liquid in a small lab bottle. He mixed the purified gold into a solution that causes the individual gold ions to form tiny particles, which the researchers then measured for size.

They found that a particular size – 19 nanometers wide – was the best for being big and sticky enough to add gene-editing materials to the surface of the particles, while still being small enough for cells to absorb them.

Packed onto the gold particles, the Fred Hutch team added these gene-editing components (diagram available [see below]):

A type of molecular guide called crRNA acts as a genetic GPS to show the CRISPR complex where in the genome to make the cut.

CRISPR nuclease protein, often called “genetic scissors,” makes the cut in the DNA. The CRISPR nuclease protein most often used is Cas9. But the Fred Hutch researchers also studied Cas12a (formerly called Cpf1) because Cas12a makes a staggered cut in DNA. The researchers hoped this would allow the cells to more efficiently repair the cut and while so doing embed the new genetic instructions into the cell. Another advantage of Cas12a over Cas9 is that it only requires one molecular guide, which is important because of space constraints on the nanoparticles. Cas9 requires two molecular guides.

Instructions for what genetic changes to make (“ssDNA”). The Fred Hutch team chose two inherited genetic changes that bestow protection from disease: CCR5, which protects against HIV, and gamma hemoglobin, which protects against blood disorders such as sickle cell disease and thalassemia.

A coating of a polyethylenimine swarms the surface of the particles to give them a more positive charge, which enables them to more readily be absorbed into cells. This is an improvement over another method of getting cells to take up gene editing tools, called electroporation, which involves lightly shocking the cells to get them to open and allow the genetic instructions to enter.

Then the researchers isolated blood stem cells with a protein marker on their surface called CD34. These CD34-positive cells contain the blood-making progenitor cells that give rise to the entire blood and immune system.

“These cells replenish blood in the body every day, making them a good candidate for one-time gene therapy because it will last a lifetime as the cells replace themselves,” Adair said.

Observing human blood stem cells in a lab dish, the researchers found that their fully loaded gold nanoparticles were taken up naturally by cells within six hours of being added and within 24 to 48 hours they could see gene editing happening. They observed that the Cas12a CRISPR protein partner was better at delivering very precise genetic edits to the cells than the more commonly used cas9 protein partner.

The gene-editing effect reached a peak eight weeks after the researchers injected the cells into mouse models; 22 weeks after injection the edited cells were still there. The Fred Hutch researchers also found edited cells in the bone marrow, spleen and thymus of the mouse models, a sign that the dividing blood cells in those organs could carry on the treatment without the mice having to be treated again.

“We believe we have a good candidate for two diseases — HIV and hemoglobinopathies — though we are also evaluating other disease targets where small genetic changes can have a big impact, as well as ways to make bigger genetic changes,” Adair said. “The next step is to increase how much gene editing happens in each cell, which is definitely doable. That will make it closer to being an effective therapy.”

In the study, the researchers report 10 to 20 percent of cells took on the gene edits, which is a promising start, but the researchers would like to aim for 50% or more of the cells being edited, which they believe will have a good chance of combatting these diseases.

###

Adair and Shahbazi are looking for commercial partners to develop the technology into therapies for people. They hope to begin clinical trials within a few years.

Here’s the diagram of a gold nanoparticle loaded with CRISPR,

Caption: Graphic of a fully loaded gold nanoparticle with CRISPR and other gene editing tools. Credit: Image courtesy of the Adair lab at Fred Hutch.

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

Targeted homology-directed repair in blood stem and progenitor cells with CRISPR nanoformulations by Reza Shahbazi, Gabriella Sghia-Hughes, Jack L. Reid, Sara Kubek, Kevin G. Haworth, Olivier Humbert, Hans-Peter Kiem & Jennifer E. Adair. Nature Materials (2019) DOI https://doi.org/10.1038/s41563-019-0385-5Published 27 May 2019

This paper is behind a paywall.

October 2019 science and art/science events in Vancouver and other parts of Canada

This is a scattering of events, which I’m sure will be augmented as we properly start the month of October 2019.

October 2, 2019 in Waterloo, Canada (Perimeter Institute)

If you want to be close enough to press the sacred flesh (Sir Martin Rees), you’re out of luck. However, there are still options ranging from watching a live webcast from the comfort of your home to watching the lecture via closed circuit television with other devoted fans at a licensed bistro located on site at the Perimeter Institute (PI) to catching the lecture at a later date via YouTube.

That said, here’s why you might be interested,

Here’s more from a September 11, 2019 Perimeter Institute (PI) announcement received via email,

Surviving the Century
MOVING TOWARD A POST-HUMAN FUTURE
Martin Rees, UK Astronomer Royal
Wednesday, Oct. 2 at 7:00 PM ET

Advances in technology and space exploration could, if applied wisely, allow a bright future for the 10 billion people living on earth by the end of the century.

But there are dystopian risks we ignore at our peril: our collective “footprint” on our home planet, as well as the creation and use of technologies so powerful that even small groups could cause a global catastrophe.

Martin Rees, the UK Astronomer Royal, will explore this unprecedented moment in human history during his lecture on October 2, 2019. A former president of the Royal Society and master of Trinity College, Cambridge, Rees is a cosmologist whose work also explores the interfaces between science, ethics, and politics. Read More.

Mark your calendar! Tickets will be available on Monday, Sept. 16 at 9 AM ET

Didn’t get tickets for the lecture? We’ve got more ways to watch.
Join us at Perimeter on lecture night to watch live in the Black Hole Bistro.
Catch the live stream on Inside the Perimeter or watch it on Youtube the next day
Become a member of our donor thank you program! Learn more.

It took me a while to locate an address for PI venue since I expect that information to be part of the announcement. (insert cranky emoticon here) Here’s the address: Perimeter Institute, Mike Lazaridis Theatre of Ideas, 31 Caroline St. N., Waterloo, ON

Before moving onto the next event, I’m including a paragraph from the event description that was not included in the announcement (from the PI Outreach Surviving the Century webpage),

In his October 2 [2019] talk – which kicks off the 2019/20 season of the Perimeter Institute Public Lecture Series – Rees will discuss the outlook for humans (or their robotic envoys) venturing to other planets. Humans, Rees argues, will be ill-adapted to new habitats beyond Earth, and will use genetic and cyborg technology to transform into a “post-human” species.

I first covered Sir Martin Rees and his concerns about technology (robots and cyborgs run amok) in this November 26, 2012 posting about existential risk. He and his colleagues at Cambridge University, UK, proposed a Centre for the Study of Existential Risk, which opened in 2015.

Straddling Sept. and Oct. at the movies in Vancouver

The Vancouver International Film Festival (VIFF) opened today, September 26, 2019. During its run to October 11, 2019 there’ll be a number of documentaries that touch on science. Here are three of the documentaries most closely adhere to the topics I’m most likely to address on this blog. There is a fourth documentary included here as it touches on ecology in a more hopeful fashion than is the current trend.

Human Nature

From the VIFF 2019 film description and ticket page,

One of the most significant scientific breakthroughs in history, the discovery of CRISPR has made it possible to manipulate human DNA, paving the path to a future of great possibilities.

The implications of this could mean the eradication of disease or, more controversially, the possibility of genetically pre-programmed children.

Breaking away from scientific jargon, Human Nature pieces together a complex account of bio-research for the layperson as compelling as a work of science-fiction. But whether the gene-editing powers of CRISPR (described as “a word processor for DNA”) are used for good or evil, they’re reshaping the world as we know it. As we push past the boundaries of what it means to be human, Adam Bolt’s stunning work of science journalism reaches out to scientists, engineers, and people whose lives could benefit from CRISPR technology, and offers a wide-ranging look at the pros and cons of designing our futures.

Tickets
Friday, September 27, 2019 at 11:45 AM
Vancity Theatre

Saturday, September 28, 2019 at 11:15 AM
International Village 10

Thursday, October 10, 2019 at 6:45 PM
SFU Goldcorp

According to VIFF, the tickets for the Sept. 27, 2019 show are going fast.

Resistance Fighters

From the VIFF 2019 film description and ticket page,

Since mass-production in the 1940s, antibiotics have been nothing less than miraculous, saving countless lives and revolutionizing modern medicine. It’s virtually impossible to imagine hospitals or healthcare without them. But after years of abuse and mismanagement by the medical and agricultural communities, superbugs resistant to antibiotics are reaching apocalyptic proportions. The ongoing rise in multi-resistant bacteria – unvanquishable microbes, currently responsible for 700,000 deaths per year and projected to kill 10 million yearly by 2050 if nothing changes – and the people who fight them are the subjects of Michael Wech’s stunning “science-thriller.”

Peeling back the carefully constructed veneer of the medical corporate establishment’s greed and complacency to reveal the world on the cusp of a potential crisis, Resistance Fighters sounds a clarion call of urgency. It’s an all-out war, one which most of us never knew we were fighting, to avoid “Pharmageddon.” Doctors, researchers, patients, and diplomats testify about shortsighted medical and economic practices, while Wech offers refreshingly original perspectives on environment, ecology, and (animal) life in general. As alarming as it is informative, this is a wake-up call the world needs to hear.

Sunday, October 6, 2019 at 5:45 PM
International Village 8

Thursday, October 10, 2019 at 2:15 PM
SFU Goldcorp

According to VIFF, the tickets for the Oct. 6, 2019 show are going fast.

Trust Machine: The Story of Blockchain

Strictly speaking this is more of a technology story than science story but I have written about blockchain and cryptocurrencies before so I’m including this. From the VIFF 2019 film description and ticket page,

For anyone who has questions about cryptocurrencies like Bitcoin (and who doesn’t?), Alex Winter’s thorough documentary is an excellent introduction to the blockchain phenomenon. Trust Machine offers a wide range of expert testimony and a variety of perspectives that explicate the promises and the risks inherent in this new manifestation of high-tech wizardry. And it’s not just money that blockchains threaten to disrupt: innovators as diverse as UNICEF and Imogen Heap make spirited arguments that the industries of energy, music, humanitarianism, and more are headed for revolutionary change.

A propulsive and subversive overview of this little-understood phenomenon, Trust Machine crafts a powerful and accessible case that a technologically decentralized economy is more than just a fad. As the aforementioned experts – tech wizards, underground activists, and even some establishment figures – argue persuasively for an embrace of the possibilities offered by blockchains, others criticize its bubble-like markets and inefficiencies. Either way, Winter’s film suggests a whole new epoch may be just around the corner, whether the powers that be like it or not.

Tuesday, October 1, 2019 at 11:00 AM
Vancity Theatre

Thursday, October 3, 2019 at 9:00 PM
Vancity Theatre

Monday, October 7, 2019 at 1:15 PM
International Village 8

According to VIFF, tickets for all three shows are going fast

The Great Green Wall

For a little bit of hope, From the VIFF 2019 film description and ticket page,

“We must dare to invent the future.” In 2007, the African Union officially began a massively ambitious environmental project planned since the 1970s. Stretching through 11 countries and 8,000 km across the desertified Sahel region, on the southern edges of the Sahara, The Great Green Wall – once completed, a mosaic of restored, fertile land – would be the largest living structure on Earth.

Malian musician-activist Inna Modja embarks on an expedition through Senegal, Mali, Nigeria, Niger, and Ethiopia, gathering an ensemble of musicians and artists to celebrate the pan-African dream of realizing The Great Green Wall. Her journey is accompanied by a dazzling array of musical diversity, celebrating local cultures and traditions as they come together into a community to stand against the challenges of desertification, drought, migration, and violent conflict.

An unforgettable, beautiful exploration of a modern marvel of ecological restoration, and so much more than a passive source of information, The Great Green Wall is a powerful call to take action and help reshape the world.

Sunday, September 29, 2019 at 11:15 AM
International Village 10

Wednesday, October 2, 2019 at 6:00 PM
International Village 8
Standby – advance tickets are sold out but a limited number are likely to be released at the door

Wednesday, October 9, 2019 at 11:00 AM
International Village 9

As you can see, one show is already offering standby tickets only and the other two are selling quickly.

For venue locations, information about what ‘standby’ means and much more go here and click on the Festival tab. As for more information the individual films, you’ll links to trailers, running times, and more on the pages for which I’ve supplied links.

Brain Talks on October 16, 2019 in Vancouver

From time to time I get notices about a series titled Brain Talks from the Dept. of Psychiatry at the University of British Columbia. A September 11, 2019 announcement (received via email) focuses attention on the ‘guts of the matter’,

YOU ARE INVITED TO ATTEND:

BRAINTALKS: THE BRAIN AND THE GUT

WEDNESDAY, OCTOBER 16TH, 2019 FROM 6:00 PM – 8:00 PM

Join us on Wednesday October 16th [2019] for a series of talks exploring the
relationship between the brain, microbes, mental health, diet and the
gut. We are honored to host three phenomenal presenters for the evening:
Dr. Brett Finlay, Dr. Leslie Wicholas, and Thara Vayali, ND.

DR. BRETT FINLAY [2] is a Professor in the Michael Smith Laboratories at
the University of British Columbia. Dr. Finlay’s  research interests are
focused on host-microbe interactions at the molecular level,
specializing in Cellular Microbiology. He has published over 500 papers
and has been inducted into the Canadian  Medical Hall of Fame. He is the
co-author of the  books: Let Them Eat Dirt and The Whole Body
Microbiome.

DR. LESLIE WICHOLAS [3]  is a psychiatrist with an expertise in the
clinical understanding of the gut-brain axis. She has become
increasingly involved in the emerging field of Nutritional Psychiatry,
exploring connections between diet, nutrition, and mental health.
Currently, Dr. Wicholas is the director of the Food as Medicine program
at the Mood Disorder Association of BC.

THARA VAYALI, ND [4] holds a BSc in Nutritional Sciences and a MA in
Education and Communications. She has trained in naturopathic medicine
and advocates for awareness about women’s physiology and body literacy.
Ms. Vayali is a frequent speaker and columnist that prioritizes
engagement, understanding, and community as pivotal pillars for change.

Our event on Wednesday, October 16th [2019] will start with presentations from
each of the three speakers, and end with a panel discussion inspired by
audience questions. After the talks, at 7:30 pm, we host a social
gathering with a rich spread of catered healthy food and non-alcoholic
drinks. We look forward to seeing you there!

Paetzhold Theater

Vancouver General Hospital; Jim Pattison Pavilion, Vancouver, BC

Attend Event

That’s it for now.

Detecting off-target effects of CRISPR gene-editing

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

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

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

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

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

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

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

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

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

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

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

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

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

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

###

About the Study

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

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

About the Gladstone Institute

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

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

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

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

This paper is behind a paywall.

Money

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

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

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

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

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

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

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

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

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

Anand Giridharadas‏Verified account @AnandWrites



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

7:34 PM – 8 Jul 2019

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

AstraZeneca

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

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

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

Controversies

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

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

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

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

Innovative Genomics Institute (IGI)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Gladstone Institutes

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Final comments

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

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

Greater mortality for the CRISPR twins Lulu and Nana?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Mutation prevents HIV infection

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

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

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

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

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

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

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

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

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

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

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

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

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

This paper is behind a paywall.

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

Lifesaving moths and nanomagnets

Rice University bioengineers use a magnetic field to activate nanoparticle-attached baculoviruses in a tissue. The viruses, which normally infect alfalfa looper moths, are modified to deliver gene-editing DNA code only to cells that are targeted with magnetic field-induced local transduction. Courtesy of the Laboratory of Biomolecular Engineering and Nanomedicine

Kudos to whomever put that diagram together! That’s a lot of well conveyed information.

Now for the details about how this technology might save lives. From a November 13, 2018 news item on Nanowerk,

A new technology that relies on a moth-infecting virus and nanomagnets could be used to edit defective genes that give rise to diseases like sickle cell, muscular dystrophy and cystic fibrosis.

Rice University bioengineer Gang Bao has combined magnetic nanoparticles with a viral container drawn from a particular species of moth to deliver CRISPR/Cas9 payloads that modify genes in a specific tissue or organ with spatial control.

A November 12, 2018 Rice University news release (also on EurekAlert published on November 13, 2018), which originated the news item, provides detail,

Because magnetic fields are simple to manipulate and, unlike light, pass easily through tissue, Bao and his colleagues want to use them to control the expression of viral payloads in target tissues by activating the virus that is otherwise inactivated in blood.

The research appears in Nature Biomedical Engineering. In nature, CRISPR/Cas9 bolsters microbes’ immune systems by recording the DNA of invaders. That gives microbes the ability to recognize and attack returning invaders, but scientists have been racing to adapt CRISPR/Cas9 to repair mutations that cause genetic diseases and to manipulate DNA in laboratory experiments.

CRISPR/Cas9 has the potential to halt hereditary disease – if scientists can get the genome-editing machinery to the right cells inside the body. But roadblocks remain, especially in delivering the gene-editing payloads with high efficiency.

Bao said it will be necessary to edit cells in the body to treat many diseases. “But efficiently delivering genome-editing machinery into target tissue in the body with spatial control remains a major challenge,” Bao said. “Even if you inject the viral vector locally, it can leak to other tissues and organs, and that could be dangerous.”

The delivery vehicle developed by Bao’s group is based on a virus that infects Autographa californica, aka the alfalfa looper, a moth native to North America. The cylindrical baculovirus vector (BV), the payload-carrying part of the virus, is considered large at up to 60 nanometers in diameter and 200-300 nanometers in length. That’s big enough to transport more than 38,000 base pairs of DNA, which is enough to supply multiple gene-editing units to a target cell, Bao said.

He said the inspiration to combine BV and magnetic nanoparticles came from discussions with Rice postdoctoral researcher and co-lead author Haibao Zhu, who learned about the virus during a postdoctoral stint in Singapore but knew nothing about magnetic nanoparticles until he joined the Bao lab. The Rice team had previous experience using iron oxide nanoparticles and an applied magnetic field to open blood vessel walls just enough to let large-molecule drugs pass through.

“We really didn’t know if this would work for gene editing or not, but we thought, ‘worth a shot,'” Bao said.

The researchers use the magnetic nanoparticles to activate BV and deliver gene-editing payloads only where they’re needed. To do this, they take advantage of an immune-system protein called C3 that normally inactivates baculoviruses.

“If we combine BV with magnetic nanoparticles, we can overcome this deactivation by applying the magnetic field,” Bao said. “The beauty is that when we deliver it, gene editing occurs only at the tissue, or the part of the tissue, where we apply the magnetic field.”

Application of the magnetic field allows BV transduction, the payload-delivery process that introduces gene-editing cargo into the target cell. The payload is also DNA, which encodes both a reporter gene and the CRISPR/Cas9 system.

In tests, the BV was loaded with green fluorescent proteins or firefly luciferase. Cells with the protein glowed brightly under a microscope, and experiments showed the magnets were highly effective at targeted delivery of BV cargoes in both cell cultures and lab animals.

Bao noted his and other labs are working on the delivery of CRISPR/Cas9 with adeno-associated viruses (AAV), but he said BV’s capacity for therapeutic cargo is roughly eight times larger. “However, it is necessary to make BV transduction into target cells more efficient,” he said.

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

Spatial control of in vivo CRISPR–Cas9 genome editing via nanomagnets by Haibao Zhu, Linlin Zhang, Sheng Tong, Ciaran M. Lee, Harshavardhan Deshmukh, & Gang Bao. Nature Biomedical Engineering (2018) DOI: https://doi.org/10.1038/s41551-018-0318-7 Published: 12 November 2018

This paper is behind a paywall.

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

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

Introduction to the Chinese CRISPR twins

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

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

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

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

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

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

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

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

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

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

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

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

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

..

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

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

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

But genetics is rarely that simple.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The ethics of not saying anything

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

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

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

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

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

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

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

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

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

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

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

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

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

CCR5 and freedom from HIV

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

A big question: are genes what we thought?

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

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

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

We have reached peak gene, and passed it.

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

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

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

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

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

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

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


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

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

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

Transgenic monkeys and human intelligence

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

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

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

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

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

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

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

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

This appears to be an open access paper,

Transgenic monkeys and an ethical uproar

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

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

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

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

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

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

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

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

….

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

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

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

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

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

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

Global plea for moratorium on heritable genome editing

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

This Comment in Nature is open access.

World Health Organization (WHO) chimes in

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

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

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

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

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

Slow science from Canada

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

Naughty (or Haughty, if you prefer) scientists

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

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

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

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

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

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

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

Parents, children, competition

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Scientists under pressure

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

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

Some thoughts

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

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

Back to the regular programme

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

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

Teaching molecular and synthetic biology in grades K-12

This* story actually started in 2018 with an August 1, 2018 Harvard University news release (h/t Aug. 1, 2018 news item on phys.org) by Leslie Brownell announcing molecular and synthetic biology educational kits that been tested in the classroom. (In 2019, a new kit was released but more about that later.)

As biologists have probed deeper into the molecular and genetic underpinnings of life, K-12 schools have struggled to provide a curriculum that reflects those advances. Hands-on learning is known to be more engaging and effective for teaching science to students, but even the most basic molecular and synthetic biology experiments require equipment far beyond an average classroom’s budget, and often involve the use of bacteria and other substances that can be difficult to manage outside a controlled lab setting.

Now, a collaboration between the Wyss Institute at Harvard University, MIT [Massachusetts Institute of Technology], and Northwestern University has developed BioBits, new educational biology kits that use freeze-dried cell-free (FD-CF) reactions to enable students to perform a range of simple, hands-on biological experiments. The BioBits kits introduce molecular and synthetic biology concepts without the need for specialized lab equipment, at a fraction of the cost of current standard experimental designs. The kits are described in two papers published in Science Advances [2018].

“The main motivation in developing these kits was to give students fun activities that allow them to actually see, smell, and touch the outcomes of the biological reactions they’re doing at the molecular level,” said Ally Huang, a co-first author on both papers who is an MIT graduate student in the lab of Wyss Founding Core Faculty member Jim Collins, Ph.D. “My hope is that they will inspire more kids to consider a career in STEM [science, technology, engineering, and math] and, more generally, give all students a basic understanding of how biology works, because they may one day have to make personal or policy decisions based on modern science.”

Synthetic and molecular biology frequently make use of the cellular machinery found in E. coli bacteria to produce a desired protein. But this system requires that the bacteria be kept alive and contained for an extended period of time, and involves several complicated preparation and processing steps. The FD-CF reactions pioneered in Collins’ lab for molecular manufacturing, when combined with innovations from the lab of Michael Jewett, Ph.D. at Northwestern University, offer a solution to this problem by removing bacteria from the equation altogether.

“You can think of it like opening the hood of a car and taking the engine out: we’ve taken the ‘engine’ that drives protein production out of a bacterial cell and given it the fuel it needs, including ribosomes and amino acids, to create proteins from DNA outside of the bacteria itself,” explained Jewett, who is the Charles Deering McCormick Professor of Teaching Excellence at Northwestern University’s McCormick School of Engineering and co-director of Northwestern’s Center for Synthetic Biology, and co-corresponding author of both papers. This collection of molecular machinery is then freeze-dried into pellets so that it becomes shelf-stable at room temperature. To initiate the transcription of DNA into RNA and the translation of that RNA into a protein, a student just needs to add the desired DNA and water to the freeze-dried pellets.

The researchers designed a range of molecular experiments that can be performed using this system, and coupled each of them to a signal that the students can easily detect with their sense of sight, smell, or touch. The first, called BioBits Bright, contains six different freeze-dried DNA templates that each encode a protein that fluoresces a different color when illuminated with blue light. To produce the proteins, students simply add these DNA templates and water to the FD-CF machinery and put the reactions in an inexpensive incubator (~$30) for several hours, and then view them with a blue light illuminator (~$15). The students can also design their own experiments to produce a desired collection of colors that they can then arrange into a visual image, a bit like using a Light Brite ©. “Challenging the students to build their own in vitro synthetic programs also allows educators to start to talk about how synthetic biologists might control biology to make important products, such as medicines or chemicals,” explained Jessica Stark, an NSF Graduate Research Fellow in the Jewett lab at Northwestern University who is co-first author on both papers.

An expansion of the BioBits Bright kit, called BioBits Explorer, includes experiments that engage the senses of smell and touch and allow students to probe their environment using designer synthetic biosensors. In the first experiment, the FD-CF reaction pellets contain a gene that drives the conversion of isoamyl alcohol to isoamyl acetate, a compound that produces a strong banana odor. In the second experiment, the FD-CF reactions contain a gene coding for the enzyme sortase, which recognizes and links specific segments of proteins in a liquid solution together to form a squishy, semi-solid hydrogel, which the students can touch and manipulate. The third module uses another Wyss technology, the toehold switch sensor, to identify DNA extracted from a banana or a kiwi. The sensors are hairpin-shaped RNA molecules designed such that when they bind to a “trigger” RNA, they spring open and reveal a genetic sequence that produces a fluorescent protein. When fruit DNA is added to the sensor-containing FD-CF pellets, only the sensors that are designed to open in the presence of each fruit’s RNA will produce the fluorescent protein.

The researchers tested their BioBits kits in the Chicago Public School system, and demonstrated that students and teachers were able to perform the experiments in the kits with the same success as trained synthetic biology researchers. In addition to refining the kits’ design so that they can one day provide them to classrooms around the world, the authors hope to create an open-source online database where teachers and students can share their results and ideas for ways to modify the kits to explore different biological questions.

“Synthetic biology is going to be one of the defining technologies of the century, and yet it has been challenging to teach the fundamental concepts of the field in K-12 classrooms given that such efforts often require expensive, complicated equipment,” said Collins, who is a co-corresponding author of both papers and also the Termeer Professor of Medical Engineering & Science at MIT. “We show that it is possible to use freeze-dried, cell-free extracts along with freeze-dried synthetic biology components to conduct innovative educational experiments in classrooms and other low-resource settings. The BioBits kits enable us to expose young kids, older kids, and even adults to the wonders of synthetic biology and, as a result, are poised to transform science education and society.

“All scientists are passionate about what they do, and we are frustrated by the difficulty our educational system has had in inciting a similar level of passion in young people. This BioBits project demonstrates the kind of out-of-the-box thinking and refusal to accept the status quo that we value and cultivate at the Wyss Institute, and we all hope it will stimulate young people to be intrigued by science,” said Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School (HMS) and the Vascular Biology Program at Boston Children’s Hospital, as well as Professor of Bioengineering at Harvard’s John A. Paulson School of Engineering and Applied Sciences (SEAS). “It’s exciting to see this project move forward and become available to biology classrooms worldwide and, hopefully some of these students will pursue a path in science because of their experience.”

Additional authors of the papers include Peter Nguyen, Ph.D., Nina Donghia, and Tom Ferrante from the Wyss Institute; Melissa Takahashi, Ph.D. and Aaron Dy from MIT; Karen Hsu and Rachel Dubner from Northwestern University; Keith Pardee, Ph.D., Assistant Professor at the University of Toronto; and a number of teachers and students in the Chicago school system including: Mary Anderson, Ada Kanapskyte, Quinn Mucha, Jessica Packett, Palak Patel, Richa Patel, Deema Qaq, Tyler Zondor, Julie Burke, Tom Martinez, Ashlee Miller-Berry, Aparna Puppala, Kara Reichert, Miriam Schmid, Lance Brand, Lander Hill, Jemima Chellaswamy, Nuhie Faheem, Suzanne Fetherling, Elissa Gong, Eddie Marie Gonzales, Teresa Granito, Jenna Koritsaris, Binh Nguyen, Sujud Ottman, Christina Palffy, Angela Patel, Sheila Skweres, Adriane Slaton, and TaRhonda Woods.

This research was supported by the Army Research Office, the National Science Foundation, the Air Force Research Laboratory Center of Excellence Grant, The Defense Threat Reduction Agency Grant, the David and Lucile Packard Foundation, the Camille Dreyfus Teacher-Scholar Program, the Wyss Institute at Harvard University, the Paul G. Allen Frontiers Group, The Air Force Office of Scientific Research, and the Natural Sciences and Engineering Council of Canada. [emphases mine]

Well, that list of funding agencies is quite interesting. The US Army and Air Force but not the Navy? As for what the Natural Sciences and Engineering Council of Canada is doing on that list, I can only imagine why.

This is what they were doing in 2018,

Now for the latest update, a May 7, 2019 news item on phys.org announces the BioBits Kits have been expanded,

How can high school students learn about a technology as complex and abstract as CRISPR? It’s simple: just add water.

A Northwestern University-led team has developed BioBits, a suite of hands-on educational kits that enable students to perform a range of biological experiments by adding water and simple reagents to freeze-dried cell-free reactions. The kits link complex biological concepts to visual, fluorescent readouts, so students know—after a few hours and with a single glance—the results of their experiments.

A May 7, 2019 Northwestern University news release (also on EurekAlert and received via email) by Amanda Morris, which originated the news item, provides more details,

After launching BioBits last summer, the researchers are now expanding the kit to include modules for CRISPR [clustered regularly interspaced short palindromic repeats] and antibiotic resistance. A small group of Chicago-area teachers and high school students just completed the first pilot study for these new modules, which include interactive experiments and supplementary materials exploring ethics and strategies.

“After we unveiled the first kits, we next wanted to tackle current topics that are important for society,” said Northwestern’s Michael Jewett, principal investigator of the study. “That led us to two areas: antibiotic resistance and gene editing.”

Called BioBits Health, the new kits and pilot study are detailed in a paper published today (May 7 [2019]) in the journal ACS Synthetic Biology.

Jewett is a professor of chemical and biological engineering in Northwestern’s McCormick School of Engineering and co-director of Northwestern’s Center for Synthetic Biology. Jessica Stark, a graduate student in Jewett’s laboratory, led the study.

Test in a tube

Instead of using live cells, the BioBits team removed the essential cellular machinery from inside the cells and freeze-dried them for shelf stability. Keeping cells alive and contained for an extended period of time involves several complicated, time-consuming preparation and processing steps as well as expensive equipment. Freeze-dried cell-free reactions bypass those complications and costs.

“These are essentially test-tube biological reactions,” said Stark, a National Science Foundation graduate research fellow. “We break the cells open and use their guts, which still contain all of the necessary biological machinery to carry out a reaction. We no longer need living cells to demonstrate biology.”

This method to harness biological systems without intact, living cells became possible over the last two decades thanks to multiple innovations, including many in cell-free synthetic biology by Jewett’s lab. Not only are these experiments doable in the classroom, they also only cost pennies compared to standard high-tech experimental designs.

“I’m hopeful that students get excited about engineering biology and want to learn more,” Jewett said.

Conquering CRISPR

One of the biggest scientific breakthroughs of the past decade, CRISPR (pronounced “crisper”) stands for Clustered Regularly Interspaced Short Palindromic Repeats. The powerful gene-editing technology uses enzymes to cut DNA in precise locations to turn off or edit targeted genes. It could be used to halt genetic diseases, develop new medicines, make food more nutritious and much more.

BioBits Health uses three components required for CRISPR: an enzyme called the Cas9 protein, a target DNA sequence encoding a fluorescent protein and an RNA molecule that targets the fluorescent protein gene. When students add all three components — and water — to the freeze-dried cell-free system, it creates a reaction that edits, or cuts, the DNA for the fluorescent protein. If the DNA is cut, the system does not glow. If the DNA is not cut, the fluorescent protein is made, and the system glows fluorescent.

“We have linked this abstract, really advanced biological concept to the presence or absence of a fluorescent protein,” Stark said. “It’s something students can see, something they can visually understand.”

The curriculum also includes activities that challenge students to consider the ethical questions and dilemmas surrounding the use of gene-editing technologies.

“There is a lot of excitement about being able to edit genomes with these technologies,” Jewett said. “BioBits Health calls attention to a lot of important questions — not only about how CRISPR technology works but about ethics that society should be thinking about. We hope that this promotes a conversation and dialogue about such technologies.”

Reducing resistance

Jewett and Stark are both troubled by a prediction that, by the year 2050, drug-resistant bacterial infections could outpace cancer as a leading cause of death. This motivated them to help educate the future generation of scientists about how antibiotic resistance emerges and inspire them to take actions that could help limit the emergence of resistant bacteria.
In this module, students run two sets of reactions to produce a glowing fluorescent protein — one set with an antibiotic resistance gene and one set without. Students then add antibiotics. If the experiment glows, the fluorescent protein has been made, and the reaction has become resistant to antibiotics. If the experiment does not glow, then the antibiotic has worked.

“Because we’re using cell-free systems rather than organisms, we can demonstrate drug resistance in a way that doesn’t create drug-resistant bacteria,” Stark explained. “We can demonstrate these concepts without the risks.”

A supporting curriculum piece challenges students to brainstorm and research strategies for slowing the rate of emerging antibiotic resistant strains.

Part of something cool

After BioBits was launched in summer 2018, 330 schools from around the globe requested prototype kits for their science labs. The research team, which includes members from Northwestern and MIT, has received encouraging feedback from teachers, students and parents.

“The students felt like scientists and doctors by touching and using the laboratory materials provided during the demo,” one teacher said. “Even the students who didn’t seem engaged were secretly paying attention and wanted to take their turn pipetting. They knew they were part of something really cool, so we were able to connect with them in a way that was new to them.”

“My favorite part was using the equipment,” a student said. “It was a fun activity that immerses you into what top scientists are currently doing.”

###

The study, “BioBits Health: Classroom activities exploring engineering, biology and human health with fluorescent readouts,” was supported by the Army Research Office (award number W911NF-16-1-0372), the National Science Foundation (grant numbers MCB-1413563 and MCB-1716766), the Air Force Research Laboratory Center of Excellence (grant number FA8650-15-2-5518), the Defense Threat Reduction Agency (grant number HDTRA1-15-10052/P00001), the Department of Energy (grant number DE-SC0018249), the Human Frontiers Science Program (grant number RGP0015/2017), the David and Lucile Packard Foundation, the Office of Energy Efficiency and Renewable Energy (grant number DE-EE008343) and the Camille Dreyfus Teacher-Scholar Program. [emphases mine]

This is an image you’ll find in the abstract for the 2019 paper,

[downloaded from https://pubs.acs.org/doi/10.1021/acssynbio.8b00381]

Here are links and citations for the 2018 papers and the 2019 paper,

BioBits™ Explorer: A modular synthetic biology education kit by Ally Huang, Peter Q. Nguyen, Jessica C. Stark, Melissa K. Takahashi, Nina Donghia, Tom Ferrante, Aaron J. Dy, Karen J. Hsu, Rachel S. Dubner, Keith Pardee, Michael C. Jewett, and James J. Collins. Science Advances 01 Aug 2018: Vol. 4, no. 8, eaat5105 DOI: 10.1126/sciadv.aat5105

BioBits™ Bright: A fluorescent synthetic biology education kit by Jessica C. Stark, Ally Huang, Peter Q. Nguyen, Rachel S. Dubner, Karen J. Hsu, Thomas C. Ferrante, Mary Anderson, Ada Kanapskyte, Quinn Mucha, Jessica S. Packett, Palak Patel, Richa Patel, Deema Qaq, Tyler Zondor, Julie Burke, Thomas Martinez, Ashlee Miller-Berry, Aparna Puppala, Kara Reichert, Miriam Schmid, Lance Brand, Lander R. Hill, Jemima F. Chellaswamy, Nuhie Faheem, Suzanne Fetherling, Elissa Gong, Eddie Marie Gonzalzles, Teresa Granito, Jenna Koritsaris, Binh Nguyen, Sujud Ottman, Christina Palffy, Angela Patel, Sheila Skweres, Adriane Slaton, TaRhonda Woods, Nina Donghia, Keith Pardee, James J. Collins, and Michael C. Jewett. Science Advances 01 Aug 2018: Vol. 4, no. 8, eaat5107 DOI: 10.1126/sciadv.aat5107

BioBits Health: Classroom Activities Exploring Engineering, Biology, and Human Health with Fluorescent Readouts by Jessica C. Stark, Ally Huang, Karen J. Hsu, Rachel S. Dubner, Jason Forbrook, Suzanne Marshalla, Faith Rodriguez, Mechelle Washington, Grant A. Rybnicky, Peter Q. Nguyen, Brenna Hasselbacher, Ramah Jabri, Rijha Kamran, Veronica Koralewski, Will Wightkin, Thomas Martinez, and Michael C. Jewett. ACS Synth. Biol., Article ASAP
DOI: 10.1021/acssynbio.8b00381 Publication Date (Web): March 29, 2019

Copyright © 2019 American Chemical Society

Both of the 2018 papers appear to be open access while the 2019 paper is behind a paywall.

Should you be interested in acquiring a BioBits kit, you can check out the BioBits website. As for ‘conguering’ CRISPR, do we really need to look at it that way? Maybe a more humble appraoch could work just as well or even better, eh?

*’is’ removed from sentence on May 9, 2019.

Gene editing and personalized medicine: Canada

Back in the fall of 2018 I came across one of those overexcited pieces about personalized medicine and gene editing tha are out there. This one came from an unexpected source, an author who is a “PhD Scientist in Medical Science (Blood and Vasculature” (from Rick Gierczak’s LinkedIn profile).

It starts our promisingly enough although I’m beginning to dread the use of the word ‘precise’  where medicine is concerned, (from a September 17, 2018 posting on the Science Borealis blog by Rick Gierczak (Note: Links have been removed),

CRISPR-Cas9 technology was accidentally discovered in the 1980s when scientists were researching how bacteria defend themselves against viral infection. While studying bacterial DNA called clustered regularly interspaced short palindromic repeats (CRISPR), they identified additional CRISPR-associated (Cas) protein molecules. Together, CRISPR and one of those protein molecules, termed Cas9, can locate and cut precise regions of bacterial DNA. By 2012, researchers understood that the technology could be modified and used more generally to edit the DNA of any plant or animal. In 2015, the American Association for the Advancement of Science chose CRISPR-Cas9 as science’s “Breakthrough of the Year”.

Today, CRISPR-Cas9 is a powerful and precise gene-editing tool [emphasis mine] made of two molecules: a protein that cuts DNA (Cas9) and a custom-made length of RNA that works like a GPS for locating the exact spot that needs to be edited (CRISPR). Once inside the target cell nucleus, these two molecules begin editing the DNA. After the desired changes are made, they use a repair mechanism to stitch the new DNA into place. Cas9 never changes, but the CRISPR molecule must be tailored for each new target — a relatively easy process in the lab. However, it’s not perfect, and occasionally the wrong DNA is altered [emphasis mine].

Note that Gierczak makes a point of mentioning that CRISPR/Cas9 is “not perfect.” And then, he gets excited (Note: Links have been removed),

CRISPR-Cas9 has the potential to treat serious human diseases, many of which are caused by a single “letter” mutation in the genetic code (A, C, T, or G) that could be corrected by precise editing. [emphasis mine] Some companies are taking notice of the technology. A case in point is CRISPR Therapeutics, which recently developed a treatment for sickle cell disease, a blood disorder that causes a decrease in oxygen transport in the body. The therapy targets a special gene called fetal hemoglobin that’s switched off a few months after birth. Treatment involves removing stem cells from the patient’s bone marrow and editing the gene to turn it back on using CRISPR-Cas9. These new stem cells are returned to the patient ready to produce normal red blood cells. In this case, the risk of error is eliminated because the new cells are screened for the correct edit before use.

The breakthroughs shown by companies like CRISPR Therapeutics are evidence that personalized medicine has arrived. [emphasis mine] However, these discoveries will require government regulatory approval from the countries where the treatment is going to be used. In the US, the Food and Drug Administration (FDA) has developed new regulations allowing somatic (i.e., non-germ) cell editing and clinical trials to proceed. [emphasis mine]

The potential treatment for sickle cell disease is exciting but Gierczak offers no evidence that this treatment or any unnamed others constitute proof that “personalized medicine has arrived.” In fact, Goldman Sachs, a US-based investment bank, makes the case that it never will .

Cost/benefit analysis

Edward Abrahams, president of the Personalized Medicine Coalition (US-based), advocates for personalized medicine while noting in passing, market forces as represented by Goldman Sachs in his May 23, 2018 piece for statnews.com (Note: A link has been removed),

One of every four new drugs approved by the Food and Drug Administration over the last four years was designed to become a personalized (or “targeted”) therapy that zeros in on the subset of patients likely to respond positively to it. That’s a sea change from the way drugs were developed and marketed 10 years ago.

Some of these new treatments have extraordinarily high list prices. But focusing solely on the cost of these therapies rather than on the value they provide threatens the future of personalized medicine.

… most policymakers are not asking the right questions about the benefits of these treatments for patients and society. Influenced by cost concerns, they assume that prices for personalized tests and treatments cannot be justified even if they make the health system more efficient and effective by delivering superior, longer-lasting clinical outcomes and increasing the percentage of patients who benefit from prescribed treatments.

Goldman Sachs, for example, issued a report titled “The Genome Revolution.” It argues that while “genome medicine” offers “tremendous value for patients and society,” curing patients may not be “a sustainable business model.” [emphasis mine] The analysis underlines that the health system is not set up to reap the benefits of new scientific discoveries and technologies. Just as we are on the precipice of an era in which gene therapies, gene-editing, and immunotherapies promise to address the root causes of disease, Goldman Sachs says that these therapies have a “very different outlook with regard to recurring revenue versus chronic therapies.”

Let’s just chew on this one (contemplate)  for a minute”curing patients may not be ‘sustainable business model’!”

Coming down to earth: policy

While I find Gierczak to be over-enthused, he, like Abrahams, emphasizes the importance of new policy, in his case, the focus is Canadian policy. From Gierczak’s September 17, 2018 posting (Note: Links have been removed),

In Canada, companies need approval from Health Canada. But a 2004 law called the Assisted Human Reproduction Act (AHR Act) states that it’s a criminal offence “to alter the genome of a human cell, or in vitroembryo, that is capable of being transmitted to descendants”. The Actis so broadly written that Canadian scientists are prohibited from using the CRISPR-Cas9 technology on even somatic cells. Today, Canada is one of the few countries in the world where treating a disease with CRISPR-Cas9 is a crime.

On the other hand, some countries provide little regulatory oversight for editing either germ or somatic cells. In China, a company often only needs to satisfy the requirements of the local hospital where the treatment is being performed. And, if germ-cell editing goes wrong, there is little recourse for the future generations affected.

The AHR Act was introduced to regulate the use of reproductive technologies like in vitrofertilization and research related to cloning human embryos during the 1980s and 1990s. Today, we live in a time when medical science, and its role in Canadian society, is rapidly changing. CRISPR-Cas9 is a powerful tool, and there are aspects of the technology that aren’t well understood and could potentially put patients at risk if we move ahead too quickly. But the potential benefits are significant. Updated legislation that acknowledges both the risks and current realities of genomic engineering [emphasis mine] would relieve the current obstacles and support a path toward the introduction of safe new therapies.

Criminal ban on human gene-editing of inheritable cells (in Canada)

I had no idea there was a criminal ban on the practice until reading this January 2017 editorial by Bartha Maria Knoppers, Rosario Isasi, Timothy Caulfield, Erika Kleiderman, Patrick Bedford, Judy Illes, Ubaka Ogbogu, Vardit Ravitsky, & Michael Rudnicki for (Nature) npj Regenerative Medicine (Note: Links have been removed),

Driven by the rapid evolution of gene editing technologies, international policy is examining which regulatory models can address the ensuing scientific, socio-ethical and legal challenges for regenerative and personalised medicine.1 Emerging gene editing technologies, including the CRISPR/Cas9 2015 scientific breakthrough,2 are powerful, relatively inexpensive, accurate, and broadly accessible research tools.3 Moreover, they are being utilised throughout the world in a wide range of research initiatives with a clear eye on potential clinical applications. Considering the implications of human gene editing for selection, modification and enhancement, it is time to re-examine policy in Canada relevant to these important advances in the history of medicine and science, and the legislative and regulatory frameworks that govern them. Given the potential human reproductive applications of these technologies, careful consideration of these possibilities, as well as ethical and regulatory scrutiny must be a priority.4

With the advent of human embryonic stem cell research in 1978, the birth of Dolly (the cloned sheep) in 1996 and the Raelian cloning hoax in 2003, the environment surrounding the enactment of Canada’s 2004 Assisted Human Reproduction Act (AHRA) was the result of a decade of polarised debate,5 fuelled by dystopian and utopian visions for future applications. Rightly or not, this led to the AHRA prohibition on a wide range of activities, including the creation of embryos (s. 5(1)(b)) or chimeras (s. 5(1)(i)) for research and in vitro and in vivo germ line alterations (s. 5(1)(f)). Sanctions range from a fine (up to $500,000) to imprisonment (up to 10 years) (s. 60 AHRA).

In Canada, the criminal ban on gene editing appears clear, the Act states that “No person shall knowingly […] alter the genome of a cell of a human being or in vitro embryo such that the alteration is capable of being transmitted to descendants;” [emphases mine] (s. 5(1)(f) AHRA). This approach is not shared worldwide as other countries such as the United Kingdom, take a more regulatory approach to gene editing research.1 Indeed, as noted by the Law Reform Commission of Canada in 1982, criminal law should be ‘an instrument of last resort’ used solely for “conduct which is culpable, seriously harmful, and generally conceived of as deserving of punishment”.6 A criminal ban is a suboptimal policy tool for science as it is inflexible, stifles public debate, and hinders responsiveness to the evolving nature of science and societal attitudes.7 In contrast, a moratorium such as the self-imposed research moratorium on human germ line editing called for by scientists in December 20158 can at least allow for a time limited pause. But like bans, they may offer the illusion of finality and safety while halting research required to move forward and validate innovation.

On October 1st, 2016, Health Canada issued a Notice of Intent to develop regulations under the AHRA but this effort is limited to safety and payment issues (i.e. gamete donation). Today, there is a need for Canada to revisit the laws and policies that address the ethical, legal and social implications of human gene editing. The goal of such a critical move in Canada’s scientific and legal history would be a discussion of the right of Canadians to benefit from the advancement of science and its applications as promulgated in article 27 of the Universal Declaration of Human Rights9 and article 15(b) of the International Covenant on Economic, Social and Cultural Rights,10 which Canada has signed and ratified. Such an approach would further ensure the freedom of scientific endeavour both as a principle of a liberal democracy and as a social good, while allowing Canada to be engaged with the international scientific community.

Even though it’s a bit old, I still recommend reading the open access editorial in full, if you have the time.

One last thing abut the paper, the acknowledgements,

Sponsored by Canada’s Stem Cell Network, the Centre of Genomics and Policy of McGill University convened a ‘think tank’ on the future of human gene editing in Canada with legal and ethics experts as well as representatives and observers from government in Ottawa (August 31, 2016). The experts were Patrick Bedford, Janetta Bijl, Timothy Caulfield, Judy Illes, Rosario Isasi, Jonathan Kimmelman, Erika Kleiderman, Bartha Maria Knoppers, Eric Meslin, Cate Murray, Ubaka Ogbogu, Vardit Ravitsky, Michael Rudnicki, Stephen Strauss, Philip Welford, and Susan Zimmerman. The observers were Geneviève Dubois-Flynn, Danika Goosney, Peter Monette, Kyle Norrie, and Anthony Ridgway.

Competing interests

The authors declare no competing interests.

Both McGill and the Stem Cell Network pop up again. A November 8, 2017 article about the need for new Canadian gene-editing policies by Tom Blackwell for the National Post features some familiar names (Did someone have a budget for public relations and promotion?),

It’s one of the most exciting, and controversial, areas of health science today: new technology that can alter the genetic content of cells, potentially preventing inherited disease — or creating genetically enhanced humans.

But Canada is among the few countries in the world where working with the CRISPR gene-editing system on cells whose DNA can be passed down to future generations is a criminal offence, with penalties of up to 10 years in jail.

This week, one major science group announced it wants that changed, calling on the federal government to lift the prohibition and allow researchers to alter the genome of inheritable “germ” cells and embryos.

The potential of the technology is huge and the theoretical risks like eugenics or cloning are overplayed, argued a panel of the Stem Cell Network.

The step would be a “game-changer,” said Bartha Knoppers, a health-policy expert at McGill University, in a presentation to the annual Till & McCulloch Meetings of stem-cell and regenerative-medicine researchers [These meetings were originally known as the Stem Cell Network’s Annual General Meeting {AGM}]. [emphases mine]

“I’m completely against any modification of the human genome,” said the unidentified meeting attendee. “If you open this door, you won’t ever be able to close it again.”

If the ban is kept in place, however, Canadian scientists will fall further behind colleagues in other countries, say the experts behind the statement say; they argue possible abuses can be prevented with good ethical oversight.

“It’s a human-reproduction law, it was never meant to ban and slow down and restrict research,” said Vardit Ravitsky, a University of Montreal bioethicist who was part of the panel. “It’s a sort of historical accident … and now our hands are tied.”

There are fears, as well, that CRISPR could be used to create improved humans who are genetically programmed to have certain facial or other features, or that the editing could have harmful side effects. Regardless, none of it is happening in Canada, good or bad.

In fact, the Stem Cell Network panel is arguably skirting around the most contentious applications of the technology. It says it is asking the government merely to legalize research for its own sake on embryos and germ cells — those in eggs and sperm — not genetic editing of embryos used to actually get women pregnant.

The highlighted portions in the last two paragraphs of the excerpt were written one year prior to the claims by a Chinese scientist that he had run a clinical trial resulting in gene-edited twins, Lulu and Nana. (See my my November 28, 2018 posting for a comprehensive overview of the original furor). I have yet to publish a followup posting featuring the news that the CRISPR twins may have been ‘improved’ more extensively than originally realized. The initial reports about the twins focused on an illness-related reason (making them HIV ‘immune’) but made no mention of enhanced cognitive skills a side effect of eliminating the gene that would make them HIV ‘immune’. To date, the researcher has not made the bulk of his data available for an in-depth analysis to support his claim that he successfully gene-edited the twins. As well, there were apparently seven other pregnancies coming to term as part of the researcher’s clinical trial and there has been no news about those births.

Risk analysis innovation

Before moving onto the innovation of risk analysis, I want to focus a little more on at least one of the risks that gene-editing might present. Gierczak noted that CRISPR/Cas9 is “not perfect,” which acknowledges the truth but doesn’t convey all that much information.

While the terms ‘precision’ and ‘scissors’ are used frequently when describing the CRISPR technique, scientists actually mean that the technique is significantly ‘more precise’ than other techniques but they are not referencing an engineering level of precision. As for the ‘scissors’, it’s an analogy scientists like to use but in fact CRISPR is not as efficient and precise as a pair of scissors.

Michael Le Page in a July 16, 2018 article for New Scientist lays out some of the issues (Note: A link has been removed),

A study of CRIPSR suggests we shouldn’t rush into trying out CRISPR genome editing inside people’s bodies just yet. The technique can cause big deletions or rearrangements of DNA [emphasis mine], says Allan Bradley of the Wellcome Sanger Institute in the UK, meaning some therapies based on CRISPR may not be quite as safe as we thought.

The CRISPR genome editing technique is revolutionising biology, enabling us to create new varieties of plants and animals and develop treatments for a wide range of diseases.

The CRISPR Cas9 protein works by cutting the DNA of a cell in a specific place. When the cell repairs the damage, a few DNA letters get changed at this spot – an effect that can be exploited to disable genes.

At least, that’s how it is supposed to work. But in studies of mice and human cells, Bradley’s team has found that in around a fifth of cells, CRISPR causes deletions or rearrangements more than 100 DNA letters long. These surprising changes are sometimes thousands of letters long.

“I do believe the findings are robust,” says Gaetan Burgio of the Australian National University, an expert on CRISPR who has debunked previous studies questioning the method’s safety. “This is a well-performed study and fairly significant.”

I covered the Bradley paper and the concerns in a July 17, 2018 posting ‘The CRISPR ((clustered regularly interspaced short palindromic repeats)-CAS9 gene-editing technique may cause new genetic damage kerfuffle‘. (The ‘kerfufle’ was in reference to a report that the CRISPR market was affected by the publication of Bradley’s paper.)

Despite Health Canada not moving swiftly enough for some researchers, they have nonetheless managed to release an ‘outcome’ report about a consultation/analysis started in October 2016. Before getting to the consultation’s outcome, it’s interesting to look at how the consultation’s call for response was described (from Health Canada’s Toward a strengthened Assisted Human Reproduction Act ; A Consultation with Canadians on Key Policy Proposals webpage),

In October 2016, recognizing the need to strengthen the regulatory framework governing assisted human reproduction in Canada, Health Canada announced its intention to bring into force the dormant sections of the Assisted Human Reproduction Act  and to develop the necessary supporting regulations.

This consultation document provides an overview of the key policy proposals that will help inform the development of regulations to support bringing into force Section 10, Section 12 and Sections 45-58 of the Act. Specifically, the policy proposals describe the Department’s position on the following:

Section 10: Safety of Donor Sperm and Ova

  • Scope and application
  • Regulated parties and their regulatory obligations
  • Processing requirements, including donor suitability assessment
  • Record-keeping and traceability

Section 12: Reimbursement

  • Expenditures that may be reimbursed
  • Process for reimbursement
  • Creation and maintenance of records

Sections 45-58: Administration and Enforcement

  • Scope of the administration and enforcement framework
  • Role of inspectors designated under the Act

The purpose of the document is to provide Canadians with an opportunity to review the policy proposals and to provide feedback [emphasis mine] prior to the Department finalizing policy decisions and developing the regulations. In addition to requesting stakeholders’ general feedback on the policy proposals, the Department is also seeking input on specific questions, which are included throughout the document.

It took me a while to find the relevant section (in particular, take note of ‘Federal Regulatory Oversight’),

3.2. AHR in Canada Today

Today, an increasing number of Canadians are turning to AHR technologies to grow or build their families. A 2012 Canadian studyFootnote 1 found that infertility is on the rise in Canada, with roughly 16% of heterosexual couples experiencing infertility. In addition to rising infertility, the trend of delaying marriage and parenthood, scientific advances in cryopreserving ova, and the increasing use of AHR by LGBTQ2 couples and single parents to build a family are all contributing to an increase in the use of AHR technologies.

The growing use of reproductive technologies by Canadians to help build their families underscores the need to strengthen the AHR Act. While the approach to regulating AHR varies from country to country, Health Canada has considered international best practices and the need for regulatory alignment when developing the proposed policies set out in this document. …

3.2.1 Federal Regulatory Oversight

Although the scope of the AHR Act was significantly reduced in 2012 and some of the remaining sections have not yet been brought into force, there are many important sections of the Act that are currently administered and enforced by Health Canada, as summarized generally below:

Section 5: Prohibited Scientific and Research Procedures
Section 5 prohibits certain types of scientific research and clinical procedures that are deemed unacceptable, including: human cloning, the creation of an embryo for non-reproductive purposes, maintaining an embryo outside the human body beyond the fourteenth day, sex selection for non-medical reasons, altering the genome in a way that could be transmitted to descendants, and creating a chimera or a hybrid. [emphasis mine]

….

It almost seems as if the they were hiding the section that broached the human gene-editing question. It doesn’t seem to have worked as it appears, there are some very motivated parties determined to reframe the discussion. Health Canada’s ‘outocme’ report, published March 2019, What we heard: A summary of scanning and consultations on what’s next for health product regulation reflects the success of those efforts,

1.0 Introduction and Context

Scientific and technological advances are accelerating the pace of innovation. These advances are increasingly leading to the development of health products that are better able to predict, define, treat, and even cure human diseases. Globally, many factors are driving regulators to think about how to enable health innovation. To this end, Health Canada has been expanding beyond existing partnerships and engaging both domestically and internationally. This expanding landscape of products and services comes with a range of new challenges and opportunities.

In keeping up to date with emerging technologies and working collaboratively through strategic partnerships, Health Canada seeks to position itself as a regulator at the forefront of health innovation. Following the targeted sectoral review of the Health and Biosciences Sector Regulatory Review consultation by the Treasury Board Secretariat, Health Canada held a number of targeted meetings with a broad range of stakeholders.

This report outlines the methodologies used to look ahead at the emerging health technology environment, [emphasis mine] the potential areas of focus that resulted, and the key findings from consultations.

… the Department identified the following key drivers that are expected to shape the future of health innovation:

  1. The use of “big data” to inform decision-making: Health systems are generating more data, and becoming reliant on this data. The increasing accuracy, types, and volume of data available in real time enable automation and machine learning that can forecast activity, behaviour, or trends to support decision-making.
  2. Greater demand for citizen agency: Canadians increasingly want and have access to more information, resources, options, and platforms to manage their own health (e.g., mobile apps, direct-to-consumer services, decentralization of care).
  3. Increased precision and personalization in health care delivery: Diagnostic tools and therapies are increasingly able to target individual patients with customized therapies (e.g., individual gene therapy).
  4. Increased product complexity: Increasingly complex products do not fit well within conventional product classifications and standards (e.g., 3D printing).
  5. Evolving methods for production and distribution: In some cases, manufacturers and supply chains are becoming more distributed, challenging the current framework governing production and distribution of health products.
  6. The ways in which evidence is collected and used are changing: The processes around new drug innovation, research and development, and designing clinical trials are evolving in ways that are more flexible and adaptive.

With these key drivers in mind, the Department selected the following six emerging technologies for further investigation to better understand how the health product space is evolving:

  1. Artificial intelligence, including activities such as machine learning, neural networks, natural language processing, and robotics.
  2. Advanced cell therapies, such as individualized cell therapies tailor-made to address specific patient needs.
  3. Big data, from sources such as sensors, genetic information, and social media that are increasingly used to inform patient and health care practitioner decisions.
  4. 3D printing of health products (e.g., implants, prosthetics, cells, tissues).
  5. New ways of delivering drugs that bring together different product lines and methods (e.g., nano-carriers, implantable devices).
  6. Gene editing, including individualized gene therapies that can assist in preventing and treating certain diseases.

Next, to test the drivers identified and further investigate emerging technologies, the Department consulted key organizations and thought leaders across the country with expertise in health innovation. To this end, Health Canada held seven workshops with over 140 representatives from industry associations, small-to-medium sized enterprises and start-ups, larger multinational companies, investors, researchers, and clinicians in Ottawa, Toronto, Montreal, and Vancouver. [emphases mine]

The ‘outocme’ report, ‘What we heard …’, is well worth reading in its entirety; it’s about 9 pp.

I have one comment, ‘stakeholders’ don’t seem to include anyone who isn’t “from industry associations, small-to-medium sized enterprises and start-ups, larger multinational companies, investors, researchers, and clinician” or from “Ottawa, Toronto, Montreal, and Vancouver.” Aren’t the rest of us stakeholders?

Innovating risk analysis

This line in the report caught my eye (from Health Canada’s Toward a strengthened Assisted Human Reproduction Act ; A Consultation with Canadians on Key Policy Proposals webpage),

There is increasing need to enable innovation in a flexible, risk-based way, with appropriate oversight to ensure safety, quality, and efficacy. [emphases mine]

It reminded me of the 2019 federal budget (from my March 22, 2019 posting). One comment before proceeding, regulation and risk are tightly linked and, so, by innovating regulation they are by exttension alos innovating risk analysis,

… Budget 2019 introduces the first three “Regulatory Roadmaps” to specifically address stakeholder issues and irritants in these sectors, informed by over 140 responses [emphasis mine] from businesses and Canadians across the country, as well as recommendations from the Economic Strategy Tables.

Introducing Regulatory Roadmaps

These Roadmaps lay out the Government’s plans to modernize regulatory frameworks, without compromising our strong health, safety, and environmental protections. They contain proposals for legislative and regulatory amendments as well as novel regulatory approaches to accommodate emerging technologies, including the use of regulatory sandboxes and pilot projects—better aligning our regulatory frameworks with industry realities.

Budget 2019 proposes the necessary funding and legislative revisions so that regulatory departments and agencies can move forward on the Roadmaps, including providing the Canadian Food Inspection Agency, Health Canada and Transport Canada with up to $219.1 million over five years, starting in 2019–20, (with $0.5 million in remaining amortization), and $3.1 million per year on an ongoing basis.

In the coming weeks, the Government will be releasing the full Regulatory Roadmaps for each of the reviews, as well as timelines for enacting specific initiatives, which can be grouped in the following three main areas:

What Is a Regulatory Sandbox? Regulatory sandboxes are controlled “safe spaces” in which innovative products, services, business models and delivery mechanisms can be tested without immediately being subject to all of the regulatory requirements.
– European Banking Authority, 2017

Establishing a regulatory sandbox for new and innovative medical products
The regulatory approval system has not kept up with new medical technologies and processes. Health Canada proposes to modernize regulations to put in place a regulatory sandbox for new and innovative products, such as tissues developed through 3D printing, artificial intelligence, and gene therapies targeted to specific individuals. [emphasis mine]

Modernizing the regulation of clinical trials
Industry and academics have expressed concerns that regulations related to clinical trials are overly prescriptive and inconsistent. Health Canada proposes to implement a risk-based approach [emphasis mine] to clinical trials to reduce costs to industry and academics by removing unnecessary requirements for low-risk drugs and trials. The regulations will also provide the agri-food industry with the ability to carry out clinical trials within Canada on products such as food for special dietary use and novel foods.

Does the government always get 140 responses from a consultation process? Moving on, I agree with finding new approaches to regulatory processes and oversight and, by extension, new approaches to risk analysis.

Earlier in this post, I asked if someone had a budget for public relations/promotion. I wasn’t joking. My March 22, 2019 posting also included these line items in the proposed 2019 budget,

Budget 2019 proposes to make additional investments in support of the following organizations:
Stem Cell Network: Stem cell research—pioneered by two Canadians in the 1960s [James Till and Ernest McCulloch]—holds great promise for new therapies and medical treatments for respiratory and heart diseases, spinal cord injury, cancer, and many other diseases and disorders. The Stem Cell Network is a national not-for-profit organization that helps translate stem cell research into clinical applications and commercial products. To support this important work and foster Canada’s leadership in stem cell research, Budget 2019 proposes to provide the Stem Cell Network with renewed funding of $18 million over three years, starting in 2019–20.

Genome Canada: The insights derived from genomics—the study of the entire genetic information of living things encoded in their DNA and related molecules and proteins—hold the potential for breakthroughs that can improve the lives of Canadians and drive innovation and economic growth. Genome Canada is a not-for-profit organization dedicated to advancing genomics science and technology in order to create economic and social benefits for Canadians. To support Genome Canada’s operations, Budget 2019 proposes to provide Genome Canada with $100.5 million over five years, starting in 2020–21. This investment will also enable Genome Canada to launch new large-scale research competitions and projects, in collaboration with external partners, ensuring that Canada’s research community continues to have access to the resources needed to make transformative scientific breakthroughs and translate these discoveries into real-world applications.

Years ago, I managed to find a webpage with all of the proposals various organizations were submitting to a government budget committee. It was eye-opening. You can tell which organizations were able to hire someone who knew the current government buzzwords and the things that a government bureaucrat would want to hear and the organizations that didn’t.

Of course, if the government of the day is adamantly against or uninterested, no amount of persusasion will work to get your organization more money in the budget.

Finally

Reluctantly, I am inclined to explore the topic of emerging technologies such as gene-editing not only in the field of agriculture (for gene-editing of plants, fish, and animals see my November 28, 2018 posting) but also with humans. At the very least, it needs to be discussed whether we choose to participate or not.

If you are interested in the arguments against changing Canada’s prohibition against gene-editing of humans, there’s an Ocotber 2, 2017 posting on Impact Ethics by Françoise Baylis, Professor and Canada Research Chair in Bioethics and Philosophy at Dalhousie University, and Alana Cattapan, Johnson Shoyama Graduate School of Public Policy at the University of Saskatchewan, which makes some compelling arguments. Of course, it was written before the CRISPR twins (my November 28, 2018 posting).

Recaliing CRISPR Therapeutics (mentioned by Gierczak), the company received permission to run clinical trials in the US in October 2018 after the FDA (US Food and Drug Administration) lifted an earlier ban on their trials according to an Oct. 10, 2018 article by Frank Vinhuan for exome,

The partners also noted that their therapy is making progress outside of the U.S. They announced that they have received regulatory clearance in “multiple countries” to begin tests of the experimental treatment in both sickle cell disease and beta thalassemia, …

It seems to me that the quotes around “multiple countries” are meant to suggest doubt of some kind. Generally speaking, company representatives make those kinds of generalizations when they’re trying to pump up their copy. E.g., 50% increase in attendance  but no whole numbers to tell you what that means. It could mean two people attended the first year and then brought a friend the next year or 100 people attended and the next year there were 150.

Despite attempts to declare personalized medicine as having arrived, I think everything is still in flux with no preordained outcome. The future has yet to be determined but it will be and I , for one, would like to have some say in the matter.

Call for abstracts: Seventh annual conference on governance of emerging technologies & science (GETS)

The conference itself will be held from May 22 – 24, 2019 at Arizona State University (ASU) and the deadline for abstracts is January 31, 2019. Here’s the news straight from the January 8, 2019 email announcement,

The Seventh Annual Conference on Governance of Emerging Technologies & Science (GETS)

May 22-24, 2019 / ASU / Sandra Day O’Connor College of Law
111 E. Taylor St., Phoenix, AZ
 
The conference will consist of plenary and session presentations and discussions on regulatory, governance, legal, policy, social and ethical aspects of emerging technologies, including nanotechnology, synthetic biology, gene editing, biotechnology, genomics, personalized medicine, digital health, human enhancement, artificial intelligence, virtual reality, internet of things (IoT), blockchain and much, much more!
 
Submit Your Abstract Here: 2019 Abstract
or
Conference Website
 
Call for abstracts:
 
The co-sponsors invite submission of abstracts for proposed presentations. Submitters of abstracts need not provide a written paper, although provision will be made for posting and possible post-conference publication of papers for those who are interested. 
Abstracts are invited for any aspect or topic relating to the governance of emerging technologies, including any of the technologies listed above.
 
·         Abstracts should not exceed 500 words and must contain your name and email address.
·         Abstracts must be submitted by January 31, 2019 to be considered. 
·         The sponsors will pay for the conference registration (including all conference meals and events) for one presenter for each accepted abstract. In addition, we will have limited funds available for travel subsidies (application included in submission form).
For more informationcontact our Executive Director Josh Abbott at Josh.Abbott@asu.edu.

Good luck on your submission!

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.