Posted on by Dr. Francis Collins
We stand at a critical juncture in the history of science. CRISPR and other innovative genome editing systems have given researchers the ability to make very precise changes in the sequence, or spelling, of the human DNA instruction book. If these tools are used to make non-heritable edits in only relevant tissues, they hold enormous potential to treat or even cure a wide range of devastating disorders, such as sickle cell disease, inherited neurologic conditions, and muscular dystrophy. But profound safety, ethical, and philosophical concerns surround the use of such technologies to make heritable changes in the human genome—changes that can be passed on to offspring and have consequences for future generations of humankind.
Such concerns are not hypothetical. Two years ago, a researcher in China took it upon himself to cross this ethical red line and conduct heritable genome editing experiments in human embryos with the aim of protecting the resulting babies against HIV infection. The medical justification was indefensible, the safety issues were inadequately considered, and the consent process was woefully inadequate. In response to this epic scientific calamity, NIH supported a call by prominent scientists for an international moratorium on human heritable, or germline, genome editing for clinical purposes.
Following on the heels of this unprecedented ethical breach, the U.S. National Academy of Sciences, U.S. National Academy of Medicine, and the U.K. Royal Society convened an international commission, sponsored by NIH, to conduct a comprehensive review of the clinical use of human germline genome editing. The 18-member panel, which represented 10 nations and four continents, included experts in genome editing technology; human genetics and genomics; psychology; reproductive, pediatric, and adult medicine; regulatory science; bioethics; and international law. Earlier this month, this commission issued its consensus study report, entitled Heritable Human Genome Editing .
The commission was designed to bring together thought leaders around the globe to engage in serious discussions about this highly controversial use of genome-editing technology. Among the concerns expressed by many of us was that if heritable genome editing were allowed to proceed without careful deliberation, the enormous potential of non-heritable genome editing for prevention and treatment of disease could become overshadowed by justifiable public outrage, fear, and disgust.
I’m gratified to say that in its new report, the expert panel closely examined the scientific and ethical issues, and concluded that heritable human genome editing is too technologically unreliable and unsafe to risk testing it for any clinical application in humans at the present time. The report cited the potential for unintended off-target DNA edits, which could have harmful health effects, such as cancer, later in life. Also noted was the risk of producing so-called mosaic embryos, in which the edits occur in only a subset of an embryo’s cells. This would make it very difficult for researchers to predict the clinical effects of heritable genome editing in human beings.
Among the many questions that the panel was asked to consider was: should society ever decide that heritable gene editing might be acceptable, what would be a viable framework for scientists, clinicians, and regulatory authorities to assess the potential clinical applications?
In response to that question, the experts replied: heritable gene editing, if ever permitted, should be limited initially to serious diseases that result from the mutation of one or both copies of a single gene. The first uses of these technologies should proceed incrementally and with extreme caution. Their potential medical benefits and harms should also be carefully evaluated before proceeding.
The commission went on to stress that before such an option could be on the table, all other viable reproductive possibilities to produce an embryo without a disease-causing alteration must be exhausted. That would essentially limit heritable gene editing to the exceedingly rare instance in which both parents have two copies of a recessive, disease-causing gene variant. Or another quite rare instance in which one parent has two copies of an altered gene for a dominant genetic disorder, such as Huntington’s disease.
Recognizing how unusual both scenarios would be, the commission held out the possibility that some would-be parents with less serious conditions might qualify if 25 percent or less of their embryos are free of the disease-causing gene variant. A possible example is familial hypercholesterolemia (FH), in which people carrying a mutation in the LDL receptor gene have unusually high levels of cholesterol in their blood. If both members of a couple are affected, only 25 percent of their biological children would be unaffected. FH can lead to early heart disease and death, but drug treatment is available and improving all the time, which makes this a less compelling example. Also, the commission again indicated that such individuals would need to have already traveled down all other possible reproductive avenues before considering heritable gene editing.
A thorny ethical question that was only briefly addressed in the commission’s report is the overall value to be attached to a couple’s desire to have a biological child. That desire is certainly understandable, although other options, such an adoption or in vitro fertilization with donor sperm, are available. This seems like a classic example of the tension between individual desires and societal concerns. Is the drive for a biological child in very high-risk situations such a compelling circumstance that it justifies asking society to start down a path towards modifying human germline DNA?
The commission recommended establishing an international scientific advisory board to monitor the rapidly evolving state of genome editing technologies. The board would serve as an access point for scientists, legislators, and the public to access credible information to weigh the latest progress against the concerns associated with clinical use of heritable human genome editing.
The National Academies/Royal Society report has been sent along to the World Health Organization (WHO), where it will serve as a resource for its expert advisory committee on human genome editing. The WHO committee is currently developing recommendations for appropriate governance mechanisms for both heritable and non-heritable human genome editing research and their clinical uses. That panel could issue its guidance later this year, which is sure to continue this very important conversation.
 Heritable Human Genome Editing, Report Summary, National Academy of Sciences, September 2020.
“Heritable Genome Editing Not Yet Ready to Be Tried Safely and Effectively in Humans,” National Academies of Sciences, Engineering, and Medicine news release, Sep. 3, 2020.
International Commission on the Clinical Use of Human Germline Genome Editing (National Academies of Sciences, Engineering, and Medicine/Washington, D.C.)
Video: Report Release Webinar , International Commission on the Clinical Use of Human Germline Genome Editing (National Academies of Sciences, Engineering, and Medicine)
National Academy of Sciences (Washington, D.C.)
National Academy of Medicine (Washington, D.C.)
The Royal Society (London)
Posted on by Dr. Francis Collins
In seeking the biological answer to the question of what it means to be human, the brain’s cerebral cortex is a good place to start. This densely folded, outer layer of grey matter, which is vastly larger in Homo sapiens than in other primates, plays an essential role in human consciousness, language, and reasoning.
Now, an NIH-funded team has pinpointed a key set of genes—found only in humans—that may help explain why our species possesses such a large cerebral cortex. Experimental evidence shows these genes prolong the development of stem cells that generate neurons in the cerebral cortex, which in turn enables the human brain to produce more mature cortical neurons and, thus, build a bigger cerebral cortex than our fellow primates.
That sounds like a great advantage for humans! But there’s a downside. Researchers found the same genomic changes that facilitated the expansion of the human cortex may also render our species more susceptible to certain rare neurodevelopmental disorders.
Posted on by Dr. Francis Collins
Over the past couple of weeks, we’ve lost two legendary scientists who made major contributions to our world: Sir John Sulston and Stephen Hawking. Although they worked in very different areas of science—biology and physics—both have left us with an enduring legacy through their brilliant work that unlocked fundamental mysteries of life and the universe.
I had the privilege of working closely with John as part of the international Human Genome Project (HGP), a historic endeavor that successfully produced the first reference sequence of the human genetic blueprint nearly 15 years ago, in April 2003. As founding director of the Sanger Centre (now the Sanger Institute) in Cambridge, England, John oversaw the British contributions to this publicly funded effort. Throughout our many planning meetings and sometimes stormy weekly conference calls about progress of this intense and all-consuming enterprise, John stood out for his keen intellect and high ethical standards.
Posted on by Dr. Francis Collins
It’s hard to believe, but it’s been almost 15 years since we successfully completed the Human Genome Project, ahead of schedule and under budget. I was proud to stand with my international colleagues in a celebration at the Library of Congress on April 14, 2003 (which happens to be my birthday), to announce that we had stitched together the very first reference sequence of the human genome at a total cost of about $400 million. As remarkable as that achievement was, it was just the beginning of our ongoing effort to understand the human genome, and to use that understanding to improve human health.
That first reference human genome was sequenced using automated machines that were the size of small phone booths. Since then, breathtaking progress has been made in developing innovative technologies that have made DNA sequencing far easier, faster, and more affordable. Now, a report in Nature Biotechnology highlights the latest advance: the sequencing and assembly of a human genome using a pocket-sized device . It was generated using several “nanopore” devices that can be purchased online with a “starter kit” for just $1,000. In fact, this new genome sequence—completed in a matter of weeks—includes some notoriously hard-to-sequence stretches of DNA, filling several key gaps in our original reference genome.
Posted on by Dr. Francis Collins
The human genome contains more than 20,000 protein-coding genes, which carry the instructions for proteins essential to the structure and function of our cells, tissues and organs. Some of these genes are very similar to each other because, as the genomes of humans and other mammals evolve, glitches in DNA replication sometimes result in extra copies of a gene being made. Those duplicates can be passed along to subsequent generations and, on very rare occasions, usually at a much later point in time, acquire additional modifications that may enable them to serve new biological functions. By starting with a protein shape that has already been fine-tuned for one function, evolution can produce a new function more rapidly than starting from scratch.
Pretty cool! But it leads to a question that’s long perplexed evolutionary biologists: Why don’t duplicate genes vanish from the gene pool almost as soon as they appear? After all, instantly doubling the amount of protein produced in an organism is usually a recipe for disaster—just think what might happen to a human baby born with twice as much insulin or clotting factor as normal. At the very least, duplicate genes should be unnecessary and therefore vulnerable to being degraded into functionless pseudogenes as new mutations arise over time
An NIH-supported team offers a possible answer to this question in a study published in the journal Science. Based on their analysis of duplicate gene pairs in the human and mouse genomes, the researchers suggest that extra genes persist in the genome because of rapid changes in gene activity. Instead of the original gene producing 100 percent of a protein in the body, the gene duo quickly divvies up the job . For instance, the original gene might produce roughly 50 percent and its duplicate the other 50 percent. Most importantly, organisms find the right balance and the duplicate genes can easily survive to be passed along to their offspring, providing fodder for continued evolution.