from the baby-steps dept.
U.S. scientists have genetically modified human embyros using CRISPR and have apparently avoided the worst of the off-target effects that have plagued previous efforts. The results are unpublished and the team is not commenting yet:
The first known attempt at creating genetically modified human embryos in the United States has been carried out by a team of researchers in Portland, Oregon, Technology Review has learned.
The effort, led by Shoukhrat Mitalipov of Oregon Health and Science University, involved changing the DNA of a large number of one-cell embryos with the gene-editing technique CRISPR, according to people familiar with the scientific results.
Until now, American scientists have watched with a combination of awe, envy, and some alarm as scientists elsewhere were first to explore the controversial practice. To date, three previous reports of editing human embryos were all published by scientists in China.
Now Mitalipov is believed to have broken new ground both in the number of embryos experimented upon and by demonstrating that it is possible to safely and efficiently correct defective genes that cause inherited diseases.
Although none of the embryos were allowed to develop for more than a few days—and there was never any intention of implanting them into a womb—the experiments are a milestone on what may prove to be an inevitable journey toward the birth of the first genetically modified humans.
Also at STAT News.
Previously: Chinese Scientists Have Genetically Modified Human Embryos
NIH Won't Fund Human Germline Modification
Group of Scientists and Bioethicists Back Genetic Modification of Human Embryos
The International Summit on Human Gene Editing
UK Scientist Makes the Case for Editing Human Embryos
Second Chinese Team Reports Gene Editing in Human Embryos
Scientists Keep Human Embryos Alive Longer Outside of the Womb
Francis Collins Retains Position as Director of the National Institutes of Health
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A team of researchers led by Junjiu Huang at the Sun Yat-sen University in Guangzhou have reported human germline modification using CRISPR:
In a world first, Chinese scientists have reported editing the genomes of human embryos. The results are published in the online journal Protein & Cell and confirm widespread rumours that such experiments had been conducted — rumours that sparked a high-profile debate last month about the ethical implications of such work.
In the paper, researchers led by Junjiu Huang, a gene-function researcher at Sun Yat-sen University in Guangzhou, tried to head off such concerns by using 'non-viable' embryos, which cannot result in a live birth, that were obtained from local fertility clinics. The team attempted to modify the gene responsible for β-thalassaemia, a potentially fatal blood disorder, using a gene-editing technique known as CRISPR/Cas9. The researchers say that their results reveal serious obstacles to using the method in medical applications.
[...] A Chinese source familiar with developments in the field said that at least four groups in China are pursuing gene editing in human embryos.
While some embryos were successfully edited, the use of CRISPR/Cas9 was not nearly as reliable as desired:
The team injected 86 embryos and then waited 48 hours, enough time for the CRISPR/Cas9 system and the molecules that replace the missing DNA to act — and for the embryos to grow to about eight cells each. Of the 71 embryos that survived, 54 were genetically tested. This revealed that just 28 were successfully spliced, and that only a fraction of those contained the replacement genetic material. "If you want to do it in normal embryos, you need to be close to 100%," Huang says. "That's why we stopped. We still think it's too immature."
A week after a Chinese team reported semi-successful modification of human embryos, Dr. Francis Collins, director of the National Institutes of Health, has said in a statement that his agency will not fund any research involving human germline modification:
The concept of altering the human germline in embryos for clinical purposes has been debated over many years from many different perspectives, and has been viewed almost universally as a line that should not be crossed. Advances in technology have given us an elegant new way of carrying out genome editing, but the strong arguments against engaging in this activity remain. These include the serious and unquantifiable safety issues, ethical issues presented by altering the germline in a way that affects the next generation without their consent, and a current lack of compelling medical applications justifying the use of CRISPR/Cas9 in embryos.
Practically, there are multiple existing legislative and regulatory prohibitions against this kind of work. The Dickey-Wicker amendment prohibits the use of appropriated funds for the creation of human embryos for research purposes or for research in which human embryos are destroyed (H.R. 2880, Sec. 128). Furthermore, the NIH Guidelines state that the Recombinant DNA Advisory Committee, "...will not at present entertain proposals for germ line alteration". It is also important to note the role of the U.S. Food and Drug Administration (FDA) in this arena, which applies not only to federally funded research, but to any research in the U.S. The Public Health Service Act and the Federal Food, Drug, and Cosmetic Act give the FDA the authority to regulate cell and gene therapy products as biological products and/or drugs, which would include oversight of human germline modification. During development, biological products may be used in humans only if an investigational new drug application is in effect (21 CFR Part 312).
However, some scientists aren't joining the chorus of "universal" criticism:
George Church, a geneticist at Harvard Medical School in Boston, Massachusetts, disagrees that the technology is so immature. He says that the researchers did not use the most up-to-date CRISPR/Cas9 methods and that many of the researchers' problems could have been avoided or lessened if they had.
Although researchers agree that a moratorium on clinical applications is needed while the ethical and safety concerns of human-embryo editing are worked out, many see no problem with the type of research that Huang's team did, in part because the embryos could not have led to a live birth. "It's no worse than what happens in IVF all the time, which is that non-viable embryos are discarded," says John Harris, a bioethicist at the University of Manchester, UK. "I don't see any justification for a moratorium on research," he adds. Church, meanwhile, notes that many of the earliest experiments with CRISPR/Cas9 were developed in human induced pluripotent stem cells, adult cells that have been reprogrammed to have the ability to turn into any cell type, including sperm and eggs. He questions whether Huang's experiments are any more intrinsically problematic.
Following a September 3-4 meeting in Manchester, England, the Hinxton Group, "a global network of stem cell researchers, bioethicists, and experts on policy and scientific publishing" has published a statement backing the genetic modification of human embryos, with caveats:
It is "essential" that the genetic modification of human embryos is allowed, says a group of scientists, ethicists and policy experts. A Hinxton Group report says editing the genetic code of early stage embryos is of "tremendous value" to research. It adds although GM babies should not be allowed to be born at the moment, it may be "morally acceptable" under some circumstances in the future. The US refuses to fund research involving the gene editing of embryos. The global Hinxton Group met in response to the phenomenal advances taking place in the field of genetics.
From the statement:
Genome editing has tremendous value as a tool to address fundamental questions of human and non-human animal biology and their similarities and differences. There are at least four categories of basic research involving genome editing technology that can be distinguished: 1) research to understand and improve the technique of genome editing itself; 2) genome editing used as a tool to address fundamental questions of human and non-human animal biology; 3) research to generate preliminary data for the development of human somatic applications; and 4) research to inform the plausibility of developing safe human reproductive applications. These distinctions are important to make clear that, even if one opposes human genome editing for clinical reproductive purposes, there is important research to be done that does not serve that end. That said, we appreciate that there are even categories of basic research involving this technology that some may find morally troubling. Nevertheless, it is our conviction that concerns about human genome editing for clinical reproductive purposes should not halt or hamper application to scientifically defensible basic research.
BBC has this beginner's guide to the designer baby debate.
George Church is one of the biologists who attended the International Summit on Human Gene Editing, held from December 1-3 in Washington D.C. He believes that human aging could be cured in the near future. From the Washington Post:
Church thinks that one of the ailments he can cure is aging. When I met him early this year, in his laboratory at Harvard Medical School, where he is professor of genetics, he expressed confidence that in just five or six years he will be able to reverse the aging process in human beings. "A scenario is, everyone takes gene therapy — not just curing rare diseases like cystic fibrosis, but diseases that everyone has, like aging," he said. He noted that mice die after 2.5 years but bowhead whales can live to be 180 or 200.
So on Tuesday, I asked him if he was still on track to reversing the aging process in the next five years or so. He said yes — and that it's already happening in mice in the laboratory. The best way to predict the future, he said, is to predict things that have already happened.
For most of us lay people, what's striking here is not the way that scientists fiddle with the code of life but the mere fact that they do it at all. Awed though we may be by the skills of the experimenters, we naturally question whether this is a good idea. That's the whole point of the gene-editing summit: To find a path forward that fosters innovation but avoids crossing into ethically dubious territory. Gene-editing could be a tool for eliminating heritable diseases. But it just as easily could be used for purely cosmetic enhancements, or for something smacking of eugenics. The gravest concern is that CRISPR enables germline edits that get passed on to future generations. You're permanently changing the human species when you do that. Who calls the shots here?
Contrast Church's position with that of another biotech heavyweight, Craig Venter. Venter is focused on a "higher-quality life span" and recently said that billionaires extending their own lifespans would be "socially irresponsible". FightAging has additional discussion of the Washington Post article.
[More after the break.]
Dr. Kathy Niakan from the Francis Crick Institute is seeking approval from the UK's Human Fertilisation and Embryology Authority in order to genetically modify human embryos:
A scientist has been making her case to be the first in the UK to be allowed to genetically modify human embryos. Dr Kathy Niakan said the experiments would provide a deeper understanding of the earliest moments of human life and could reduce miscarriages. The regulator, the Human Fertilisation and Embryology Authority (HFEA), will consider her application on Thursday. If Dr Niakan is given approval then the first such embryos could be created by the summer.
[...] Dr Niakan, from the Francis Crick Institute, said: "We would really like to understand the genes needed for a human embryo to develop successfully into a healthy baby. The reason why it is so important is because miscarriages and infertility are extremely common, but they're not very well understood."
Of 100 fertilised eggs, fewer than 50 reach the blastocyst stage, 25 implant into the womb and only 13 develop beyond three months. She says that understanding what is supposed to happen and what can go wrong could improve IVF. "We believe that this research could really lead to improvements in infertility treatment and ultimately provide us with a deeper understanding of the earliest stages of human life."
However, she says the only way to do this is to edit human embryos. Many of the genes which become active in the week after fertilisation are unique to humans, so they cannot be studied in animal experiments. "The only way we can understand human biology at this early stage is by further studying human embryos directly," Dr Niakan said. Her intention is to use one of the most exciting recent scientific breakthroughs - Crispr gene editing - to turn off genes at the single-cell stage and see what happens. [...] She aims to start with the gene Oct4 which appears to have a crucial role.
Second Paper to Show Human Embryo Editing
Researchers in China have reported editing the genes of human embryos to try to make them resistant to HIV infection. Their paper — which used CRISPR-editing tools in non-viable embryos that were destroyed after three days — is only the second published claim of gene editing in human embryos.
The mutation that was introduced is the naturally occurring variant in the CCR5 gene seen in some people resistant to AIDS progression.
Introducing precise genetic modifications into human 3PN embryos by CRISPR/Cas-mediated genome editing (DOI: 10.1007/s10815-016-0710-8)
Chinese Team Uses CRISPR to Genetically Modify Human Embryo
In this latest effort, the Chinese team reports that they obtained 213 fertilized eggs from a fertility clinic, which had been deemed unsuitable for in vitro therapy. The women who had donated the eggs all gave permission for the embryos to be used for genetic research, on condition that the embryos would not be allowed to mature into a human being. The team used the CRISPR technique to edit genes, adding a mutation that causes damage to an immune cell gene called CCR5—such cells that are damaged naturally have been found to lead to HIV resistance. Thus the point of the research was to learn more about the possibility of producing human babies that would be immune to HIV. The team reports that just 4 out of 26 of the embryos that were edited were modified successfully—some still contained genes that had not been modified, and others had resulted in unexpected gene mutations. All of the embryos were destroyed after three days. Due to the results, it is not clear what has been learned from the experiments, except that some groups, particularly in China, are willing to conduct such research despite international condemnation.
Scientists have developed a way to keep embyros alive outside of a womb for days longer than before, by using a mix of amino acids, hormones, and growth factors:
Zernicka-Goetz says being able to go past the previous limit is "extremely important" from a scientific point of view. That's because the seventh day of development is the time when the human embryo becomes embedded within the body of the mother — when it becomes implanted in the womb. Scientists had thought embryos could only keep developing if they were safely in the womb and receiving instructions from the mother's body.
But the embryos in the studies implanted in the dish like they they would in the womb. Then they started organizing themselves into the very early stages of different complex organs and tissues and structures in the body, the researchers report.
A commentary accompanying the research urges regulators to revisit the "14-day rule":
In principle, these two lines of research could lead to scientists being able to study all aspects of early human development with unprecedented precision. Yet these advances also put human developmental biology on a collision course with the '14-day rule' — a legal and regulatory line in the sand that has for decades limited in vitro human-embryo research to the period before the 'primitive streak' appears. This is a faint band of cells marking the beginning of an embryo's head-to-tail axis. The 14-day rule has been effective for permitting embryo research within strict constraints — partly because it has been technologically challenging for scientists to break it. Now that the culturing of human embryos beyond 14 days seems feasible, more clarity as to how the rule applies to different types of embryo research in different jurisdictions is crucial. Moreover, in light of the evolving science and its potential benefits, it is important that regulators and concerned citizens reflect on the nature of the restriction and re-evaluate its pros and cons.
Self-organization of the in vitro attached human embryo (DOI: 10.1038/nature17948)
Self-organization of the human embryo in the absence of maternal tissues (DOI: 10.1038/ncb3347)
Ending weeks of speculation, President-elect Donald Trump has asked National Institutes of Health (NIH) Director Francis Collins to remain in his position. It is not clear for how long. "We just learned that Dr. Collins has been held over by the Trump administration," an NIH spokesperson said in a statement. "We have no additional details at this time."
Collins, a geneticist who has headed the $32 billion NIH for the past 8 years, has been campaigning to keep his job and met with Trump last week. On Wednesday, he told a reporter at the World Economic Forum in Davos, Switzerland, that he still didn't know what his fate would be. But although Collins had the support of key Republicans in Congress, he has been one of several candidates for the NIH post, including Representative Andy Harris (R–MD).
Related: NIH Won't Fund Human Germline Modification
Group of Scientists and Bioethicists Back Genetic Modification of Human Embryos
Human-Animal Chimeras are Gestating on U.S. Research Farms
NIH Plans To Lift Ban On Research Funds For Human-Animal Chimera Embryos
Neuroscientists Stand Up for Basic Cell Biology Research
Major Biomedical Research Funding Bill Sails Through US House
The human embryo editing study first reported by MIT Technology Review last week has been published in Nature. Scientists led by the Oregon Health & Science University's Shoukhrat Mitalipov edited human embryos to remove the MYBPC3 mutation associated with hypertrophic cardiomyopathy:
The experiment corrected the defect in nearly two-thirds of several dozen embryos, without causing potentially dangerous mutations elsewhere in the DNA.
None of the embryos were used to try to create a baby. But if future experiments confirm the techniques are safe and effective, the scientists say the same approach could be used to prevent a long list of inheritable diseases. "Potentially, we're talking about thousands of genes and thousands of patients," says Paula Amato, an associate professor of obstetrics and gynecology at Oregon Health & Science University in Portland. She was a member of the scientific team from the U.S., China and South Korea.
[...] Amato and others stress that their work is aimed at preventing terrible diseases, not creating genetically enhanced people. And they note that much more research is needed to confirm the technique is safe and effective before anyone tries to make a baby this way. But scientists hoping to continue the work in the U.S. face many regulatory obstacles. The National Institutes of Health will not fund any research involving human embryos (the new work was funded by Oregon Health & Science University). And the Food and Drug Administration is prohibited by Congress from considering any experiments that involve genetically modified human embryos.
Nevertheless, the researchers say they're hopeful about continuing the work, perhaps in Britain. The United Kingdom has permitted genetic experiments involving human embryos forbidden in the United States. "If other countries would be interested, we would be happy to work with their regulatory bodies," says Shoukhrat Mitalipov, director of the Oregon Health & Science University's Center for Embryonic Cell and Gene Therapy.
Correction of a pathogenic gene mutation in human embryos (open, DOI: 10.1038/nature23305) (DX)
When the first U.S. team to edit human embryos with CRISPR revealed their success earlier this month, the field reeled with the possibility that the gene-editing technique might soon produce children free of their parents' genetic defects. But the way CRISPR repaired the paternal mutation targeted in the embryos was also a surprise. Instead of replacing the gene defect with strands of DNA that the researchers inserted, the embryos appeared to use the mother's healthy gene as a template for repairing the cut made by CRISPR's enzyme.
But such a feat has not been observed in previous CRISPR experiments, and some scientists are now questioning whether the repairs really happened that way. In a paper published online this week on the preprint server bioRxiv, a group of six geneticists, developmental biologists, and stem cell researchers offers alternative explanations for the results. And uncertainty about exactly how the embryos' DNA changed after editing leaves many questions about the technique's safety, they argue. (The authors declined to discuss the paper while it's being reviewed for publication.)
Embryologist Shoukhrat Mitalipov of Oregon Health and Science University in Portland, who led the now-disputed experiments, released a statement saying that his team stands by its explanation. "We based our finding and conclusions on careful experimental design involving hundreds of human embryos," it says.
[...] Although the researchers inserted short strands of DNA as templates for repair, the cells didn't seem to take them up; those specific sequences were absent from the embryos. The cells must have relied instead on the nonmutated sequence in the egg donor's DNA when making the repairs, the team concluded.
The bioRxiv response, led by developmental biologist Maria Jasin of Memorial Sloan Kettering Cancer Center in New York City and Columbia University stem cell biologist Dieter Egli, challenges that interpretation. The authors, which also include well-known CRISPR researcher and Harvard University geneticist George Church, say that the Nature paper goes against conventional wisdom about how embryos are organized early in development. Right after an egg is fertilized, the DNA from the sperm and the egg aren't believed to be in close enough proximity to interact or share genes, they explain.
Study in question: Correction of a pathogenic gene mutation in human embryos (open, DOI: 10.1038/nature23305) (DX)