Much going on about heritable genome editing

The first meeting of the International Commission on the Clinical Use of Human Germline Genome Editing was held in Washington, DC on August 13.  This is a US/UK commission convened by the UK Royal Society, the US National Academy of Medicine, and the US National Academy of the Sciences.  Space for in-person attendance at these meetings appears limited, but information is freely accessible on the internet.  For example, the meeting materials and videos from the August 13 can be accessed here, and one can register to be on the Commission’s mailing list at this link. 

It is challenging for anyone with a “day job” whose work is not dedicated to the field of gene editing to try to keep up with developments, so the open access to information is welcome.  The August 13 meeting included numerous basic science discussions as well as some from biotechnology companies seeking to develop gene editing approaches.  As discussed often on this blog and elsewhere, so-called “somatic” gene editing—that is, gene therapy of fully-formed individuals by editing an undesirable gene such as one known to cause disease–appears generally to fall within the existing regime of human research ethics and regulation and pose relatively few unique ethical issues.   The day included industry presentations regarding somatic gene editing, either “in vivo”—involving injecting the gene editor into a person—or “ex vivo”—involving removing cells from a person, editing the cells in the medical lab, then re-injecting the gene-edited cells into the person’s body as a form of treatment.  In neither case is the editing inherited across generations, avoiding the larger issues of manipulating human beings more fundamentally, and, as your present correspondent has consistently argued, unacceptably.

Even for somatic gene editing, however, “getting it right” in the form of editing the genes intended, and only those, and developing approaches to assess and control for longer-term or unintended risks is still a substantial set of tasks, as was described in a presentation by an official from the FDA.

The day also included a presentation from the separate World Health Organization multidisciplinary advisory panel, which held its first meeting in March 2019 with another one having been due this week in Geneva, Switzerland.  At the March meeting, the WHO panel adopted three main recommendations for developing oversight of human genome editing:

  • Establish a structured mechanism for collecting and curating details about proposed and ongoing research;
  • “it would be irresponsible at this time for anyone to proceed with clinical applications [they mean trying to establish a pregnancy or birth] of human germline genome editing”
  • Establish approaches to obtain input from the “broadest possible range of stakeholders” and “explore opportunities for an open, online mechanism for seeking input.”

All that said, the Salk Institute in San Diego is working on a new technique of editing, called SATI (short for intercellular linearized Single homology Arm donor mediated intron-Targeting Integration [say THAT three times fast!], which is expected to be more versatile than the current “preferred” technique called CRISPR-Cas9.  Biologic details between the two differ, but the ethical issues mainly apply to applications, and are therefore the same for both.  But don’t be surprised if you hear about “SATI” for 5-10 minutes in the news sometime.

And scientists at Cornell Medical Center in New York City are trying to gene-edit human sperm to alter the characteristics of children conceived using them.  Pressing ahead with getting ready for the WHO panel’s “clinical applications.”

Mildred Solomon of the Hastings Center has recently added her voice to those pointing out that whether heritable human genome editing should ever be done is not just a matter of weighing benefits vs risks, but involves much more momentous possibilities that should give us pause.  The key graphs:

“Even as [the WHO and US/UK commissions] regroup to produce clearer guidance, however, I sense a shift in the debate. For a very long time, the scientific and bioethical consensus was that we must not do human germ-line modifications—that we should not change gametes and embryos in ways that would be permanent, affecting all future generations. In contrast, somatic modifications, which affect only the person in whom the edits are made, have been mainly uncontroversial.

But that border between germ-line and somatic genome modification is blurring; the zeitgeist feels different. There is a growing sense of inevitability that we will eventually do human germ-line modification and that our only obligation is to wait until it is safe. When that day comes, we may want to make permanent heritable changes to the human species to eradicate otherwise intractable diseases. We should, however, enter this discussion with eyes wide open, considering each application on its own merits and anticipating a wide range of issues that go well beyond safety. Many of these issues are explored in Human Flourishing in an Age of Gene Editing, which will be published by Oxford University Press on August 28, 2019.”

I’m willing to forgive the plug for a book from people at Dr. Solomon’s institution, which is where the editors of the book in question work.  It looks worth checking out.  In the meantime, the US/UK commission has called for “expert evidence” to assist them in the task “to develop a framework for considering technical, scientific, medical, regulatory, and ethical requirements for human germline genome editing, should society conclude such applications are acceptable.”  Follow this link to have a look at their questions.

Contraception, Climate, and Population Control

This week’s New England Journal of Medicine (NEJM) carries an opinion piece (subscription required) pressing the concern that human-caused climate change should prompt a concerted effort to develop new methods of contraception and increase the ready availability of all forms of contraception worldwide.  About 222 million women in the lowest-income countries need family planning services, the author says.  About 40% of pregnancies (80 million out of a worldwide annual total of 210 million) are unintended, with similar rates in higher- and lower-income nations, it is said.  Past Malthusian fears about overpopulation had subsided with improved agriculture and a leveling, or even declining, fertility rate in many countries, but that appears now to have created a false sense of security, because the world’s population continues to grow, global warming and resource depletion are threatening sustainability of the ecosystem, and “naturalists” warn that half of all species living today may be extinct by 2100 because of human activity.  While the number of people the earth can support has been estimated at between 2 and 100 billion, the author prefers a more conservative “modern estimate” of 1.5 to 5 billion, as opposed to the current 7.7 billion.

Leaving aside the question of why the earth’s carrying capacity is a proper topic within the purview of the NEJM, the author says that currently available contraception is inadequate.  Sterilization “is not suitable” for people who want to have children, hormonal methods have side effects, and barrier methods are not reliably used.  (In case the reader wonders, abortion is not listed.)  Moreover, side effects notwithstanding, needing a prescription for much contraception limits availability and increases costs.  Development of newer methods, including some that would also protect against sexually transmitted diseases, could meet a large need, limit population “growth,” and have the further advantage of giving people more choices.

Unless one is fundamentally opposed to contraception on moral grounds, these suggestions may seem attractive on the surface.  Better, effective, preferably reversible, affordable, widely available, low-risk contraception would be welcomed by most people.  But the primary aim of this particular piece does not seem to be the well-being of individuals, but limiting the number of them overall.  One might object that pursuing limits on population is an invitation to tyranny, just in more sophisticated forms than one-child policies or forced sterilization.  One could not trust full reproductive freedom to “limit the excess population,” as Ebenezer Scrooge famously advocated.  Rather, controls would have to be instituted on who could have children, how many, and under what circumstances, not to mention trying to control what sort of people are brought into the world.  I do not think this is a farfetched concern.  After all, the NEJM writer thinks there are too many people already.  Might not someone (someone else, not the writer of the piece in question) think that some culling would be for the good of the ecosphere overall?  Getting back down to 5 billion from 7.7 billion would be a reduction of about 35%–an apocalyptic figure, to be sure.  I must confess that it would not entirely surprise me to see a future NEJM piece addressing population reduction.

Promoting vaccination with a not-too-heavy hand

This week’s Nature has a worthwhile read, “Mandate Vaccination with Care.”    The recent rise in the number of cases of measles is well-documented in the general press, and there is a strong argument that it is a social good that sufficient numbers of children be vaccinated for a range of infectious diseases.  Your correspondent considers it unfortunate, to put it mildly, that there is a persistent belief that vaccines for the standard childhood diseases are harmful.  Although some cases of vaccine harm occur, they are rare—rarer than many in the general public believe—and the cost of under-vaccination is great.  I, for one, never want to see an infant with pertussis (whooping cough) again, and, although I recall having had measles and chicken pox when I was a kid, it’s best to prevent them.  Some can even be eradicated (see: smallpox—which we should fervently hope is never purposely re-introduced, now that we don’t routinely vaccinate for it). 

In brief, the authors in this case argue for promoting vaccination in the public with such steps as ensuring supply and access, providing information and allowing public forums, monitoring safety carefully, and tracking vaccination rates.  They argue, reasonably, that mandatory vaccination that carries the wrong kind of penalties—such as, fines or even jail sentences imposed in some countries—for non-compliance actually can harm poorer, medically underserved people, and as such be counterproductive and, frankly, unfair.  They comment that harsh mandates can unnecessarily prompt a backlash, with increased resistance.

They say, further, that if mandates are deemed “politically appropriate,” then the procedures should be just, with constraints on choice as limited as possible; any penalties must be proportionate; those who do suffer complications should be adequately compensated.   They speak favorably of creating administrative hurdles to getting exemptions from mandates.  They also argue against governments mandating only some vaccines while excluding others.  They claim that making some vaccines only “recommended” can limit the uptake of all. 

This last point may be the most questionable of all in this article.  It is easier to justify mandating vaccination for highly contagious diseases that can have devastating effect (e.g. measles, rubella, diptheria, and others), than, for example, vaccination for human papilloma virus (HPV), infection with which predisposes to certain kinds of cancer but transmission of which is through sexual activity.  In this last case, the argument for a mandate is substantially weaker; vaccination at a fairly young age might be wise, but one might still reasonably accept, for oneself or one’s child, the less certain and more remote risks of the consequences of infection, and therefore reasonably object to mandated vaccination.

Again, a worthwhile read. >

“Safe” gene editing

The New England Journal of Medicine carries a brief article about “Controlling CRISPR-Cas9 Gene Editing” (subscription required).  The upshot: RNA used as a medicine, as in the case of “CRISPR” to edit genes, can hang around well after administration, and alter genes other than the ones intended to be altered.  These “off-target” effects could lead to unwanted clinical side effects.  You’d like to be able to shut the RNA medicine off.  Pharmaceutical companies that make and develop medicines from short RNA sequences have been doing just that—creating “antidotes,” if you’ll pardon the expression (bad use of the word, really—an antidote is to a poison, and the medicines are not poisons)—to reverse unwanted off-target effects of their medicines, should such effects occur.

Using CRISPR for gene editing to treat known genetic disease raises a similar concern, and the NEJM article cites a recent experiment indicating that such a “reversing agent” for CRISPR, if needed, might indeed be feasible.  So, suppose you are trying to treat someone with genetically-caused blindness, and there’s a risk that other genes might be affected.  You could give the “reversing agent” to block that.  Cool.  You’d want to get it into the right tissues—the right parts of the body—but the work described in NEJM suggests that might all be reality eventually. 

One challenge is: these RNA-based agents don’t always get into the parts of the body, or into cells, all that well.  The NEJM writer says that this new work into “controlling” CRISPR-based gene editing “of course, depends on the [reversing agent] delivery problem being solved, but that is a topic for another day.”

It’s been some time since your correspondent worked for a drug company making RNA-based drugs, and I’m not close to the work these days, but I would say that is most definitely a topic for another day.

So, why bring this up in a bioethics forum?  Because it’s one more matter that would need to be considered and addressed before charging into gene editing that can be inherited from generation to generation.  This, as the present writer has repeatedly held, is something that that the human race should never do.

But it’s bowling along.  The latest reports are that attempts to edit genes babies of deaf couples to prevent them from being born with genetic deafness are nigh in Russia.  Understandable, laudable goal, but we should not think that control of the process is nigh.   edium

Technical steps to gene-edited babies

This blog has carried several comments about the prospect of heritable human gene editing.  While nearly no one currently supports bringing such babies to birth—and condemns those who would rush ahead to do so—it appears a distinct minority think that we the human race should, if we could, agree never to do such a thing.  The most cautious perspective is to advocate a moratorium.  Others in favor of proceeding argue that, in essence, with the technologic genie (my term, not necessarily theirs) out of the box, a moratorium, much less a ban, is futile; the “rogues” will press ahead, casting off restraint. 

Advocates of research in this area have argued that a clear, careful, regulated pathway is needed to guide the work through necessary laboratory experiments that should be done first, before making a woman pregnant with a gene-edited embryo, in an attempt to be sure that the process is safe and highly likely to yield the intended result.  Even a moratorium would be, by definition, temporary, leaving the question, “when we will know to remove the moratorium?” to be answered.

A feature article in Nature, accessible without a paid subscription, asks “When will the world be ready” for gene-edited babies.  It walks through scientists’ understanding of what the technical issues are.  It is longer than a blog post, so I can only list key points here.  It is worth a reading by anyone interested, and it is written in sufficiently non-technical language that it’s accessible to the general, non-scientist public.

Key concerns are:

  • How would we be sure that genes that were NOT intended to be edited, in fact were not?
  • How would we be sure that genes that ARE intended to be edited are edited correctly?

These two matters have been addressed to some degree, or could be, in animals, but that would be faster and easier than in human egg cells or human embryos, and the results in animals may be different from what is found in the embryos.  (A further question is how many embryos, observed for how long, would need to be studied to support confidence.)

  • Even if the intended gene edit is made, is it clear that doing so is safe and does not induce other health risks? 

This blog recently reported the UK study that suggested that changes in the gene edited in the twin girls born in China last year might eventually reduce life span.  A criterion promulgated in 2017 by the National Academies of Sciences, Engineering, and Medicine was that the edited gene should be common in the population and carry no known risk (including, presumably, no increased risk) of disease.  Such knowledge is lacking for human populations, and what is believed known about the association of genes with risk of future disease has often been developed in Western populations, and may not apply to, for example, Africans.

  • At least some embryos would include some edited and some non-edited cells.  It would not easily be possible, if possible at all, to tell how many of which were present, or needed to be for the editing to work and not cause risks to the embryo’s development into a baby and beyond.  And what answers were obtained would require manipulating healthy embryos after in vitro fertilization.  The outcomes could not be predicted from first principles.
  • What should a clinical trial look like?  How many edited children would have to be born, and their health (and, most likely, the health of their progeny) observed for how long to get provisional answers before practicing the technique more widely?  Or, would the work proceed as IVF did—with dissemination in the general public, and no regulated research?

A US and UK committee is planned to address these questions, with the intent of proposing guidelines in 2020.  This will be important to follow, but with no chance to affect.  Most of us will just be watching, which leads to the last concern:

  • Is the world ready?

If that means, is there an international, or even a national, consensus, then the answer is clearly “no.”  That almost certainly remains “no” if one asks whether there is a future prospect for consensus.  It’s hard to envision something other than different groups and nations holding different judgments, and, most likely, remaining in some degree of irresolvable conflict.

More gene-edited babies on the way

It is reported this week that a Russian scientist plans to edit the genes of more human embryos intending to bring gene-edited babies to birth.  As with the case in China last year, the intent is to edit a gene called CCR5 that is responsible for a receptor that facilitates initiation of HIV infection.  The stated reason is to prevent transmission of infection from the mother, not the father, as in the Chinese case.  Maternal transmission of HIV is a real risk, but there are other ways to prevent it, with medications.  And, as recently reported on this blog, the risks of editing this gene are not understood, nor are the long-term risks of heritable genome editing.

The science press is saying that someone should put a stop, now, to bringing edited embryos to pregnancy and birth.  But it is unlikely that effective action can be taken.  The public will has not been engaged, necessary medical research controls are not in place, and no one can say just who would have the authority to take what sort of action.

So for the moment there is little else to say.  We will hear of more cases.  We will find out later how we will respond.  Clarity and consistency of that response seem unlikely. https:/

Pragmatism and principle regarding human gene editing

You may have seen in the general press that the gene-edited twin girls born in China last year may have had their life expectancies shortened in the bargain.  The doctor who edited the babies’ genes specifically edited one gene, that is associated with susceptibility to HIV infection.  Their father is HIV positive, but that does not put the babies at any health risk.  Further, the gene editing potentially could have increased their future risk for other infections.  Now, a group in the United Kingdom have analyzed mortality data for about 400,000 people who volunteered to have their genetic information placed in a data bank.  They reported that people who have a gene mutation similar—but apparently not identical—to the change made in the Chinese babies had a 21% lower chance of living to age 76 than people without the mutation.  Now, the average age of the people who volunteered their information for the data bank is said to be 56.5 years, so the implication is that there is a shortening of life expectancy after middle age, for people who have lived at least that long. 

One should interpret the U.K. analysis with caution, but the argument seems to be, “see, we don’t know the risks of human gene editing, so we shouldn’t be doing it.”  And indeed we do not know the risks.  But the argument in fact is, “…we shoudn’t be doing this—at least not yet.”  As Joy Riley pointed out on this blog a few days ago, the goal of a moratorium on human genome editing appears to be to allow the scientists working on the technology to take time to build public trust and consensus for it.  “We shouldn’t be doing this, ever” does not appear to be an option.  Long-term readers of this blog may recall numerous posts over the last few years describing this process of gradual acceptance in the scientific community.  The scientists draw an analogy to the 1975 Asilomar conference on recombinant DNA work, which established guard rails around that work.  But the analogy is flawed.  The risks of the work addressed at Asilomar were more readily defined, with shorter time frames to results, than can be addressed with genome editing.  400,000 middle-aged people’s mortality due to any (unspecified) cause over the ensuing quarter-century?  How many edited people, studied for how long, over how many generations, with what consent process, to determine the risks?  There can be no acceptable definition of the risks prior to actually assuming them.  “The babies are the experiment.”

The correct conceptual framework for human genome editing is not benefit-risk analysis, it is deeper reflection on where we should not let engineering encroach on the human organism.  “Keep your ambition off our bodies,” I suppose.  And when we think in those terms, we should quickly recognize territory where we fear to tread at all, not just slow down.

Emerging attempts to control gene editing

Recently, it was reported that the panel convened by the World Health Organization (WHO) to develop standards and guidelines for gene editing will ask the WHO to establish a registry for any projects on heritable human gene editing.  The idea is that, to get research funding, a project would have to be registered, and there would be a required review in order to get on the registry in the first place.  The net effect would be to control the flow of money to such projects.

Also, according to Nature, the Chinese government is looking at amending its civil code, effective March 2020, to in essence make a gene editor liable for health outcomes by declaring that “experiments on genes in adults or embryos that endanger human health or violate ethical norms can accordingly be seen as a violation of a person’s fundamental rights.”  The idea here appears to be to make gene editors think twice about whether they are sure enough of their work to accept essentially a permanent risk of being sued for all they are worth if anything goes wrong in the future.  Your correspondent knows nothing about Chinese civil procedure, but in the litigious U.S., the risk of really big, unpredictable lawsuits at some entirely unpredictable time in the future, with no limit, can make even big companies shy to pursue something. 

So maybe these approaches, by “following the money,” as it were, would at least slow down heritable genome editing, short of a ban.  Skeptics of the utility or wisdom of a ban argue that the “rogues” will just find work-arounds anyway, and that entire states can “go rogue,” limiting the effects of the ban to only the nations willing to enact and enforce it.

That’s a reasonable argument, but it still seems that, by only requiring a registry—with noncompliance always a risk—or trying to up the ante in court—a risk that some entities might take if the perceived reward is big enough to warrant it, and they can hire enough expansive lawyers to limit the risk—there is an admission that heritable genome editing is going to go forward.  And, indeed, maybe there’s no stopping it.  But it seems like promoting a stance toward human life that refuses to accept heritable gene editing is still something we should do.

Brain resuscitation (?) in pigs

The latest mind-blowing (seriously, no pun intended) report from the science literature is that a team of scientists at Yale Medical School have been able to use an artificial preservative solution to recover electrical activity in some of the cells of the brains from the severed heads of pigs that had been slaughtered for food.  This is absolutely stunning because the understanding—so widely accepted that the term “conventional wisdom” is trite in this case—that the brain’s need for oxygen, nutrients, and the blood flow that provides them is so massive, so constant that an interruption of even a few minutes means irreversible death of brain tissue.  This can be in part of the brain (as in a stroke), or the whole brain (as in brain death).  Your correspondent is not a neuroscientist, but understands that recent research is showing the human brain, anyway, to be more adaptable than historically understood, meaning that after an event like a stroke, function can be restored over time with rehabilitative efforts that support the remaining, undamaged brain tissue adapting to the damage.

In this case, it was four hours after the pigs’ deaths that the researchers isolated their brains and put them into the solutions.  Besides the electrical activity in some nerve cells, the researchers also found evidence that blood vessels could support circulation, and that there was metabolic (energy-using) activity in the isolated brains.  Evidence that the whole brain was working, and able to, for example, “feel” pain or detect stimuli, was not evident, but the researchers were not trying to do that.  Their immediate goal was apparently to understand how long brain cell function might be preserved.

Before we rush to invoke the immortal Viktor Frankenstein, it should be said that the researchers in this case appear to have carefully followed existing ethical guidelines for the research use of animals.  And it is tempting to speculate about this work leading to new treatments for brain injury.

Still, many ethical issues are raised.  What constraints should proper ethics of experimentation on animals put on future, similar experiments?  Is it acceptable to pursue a model for whole animal or even human brains preserved outside the body to study preservation and restoration of function, perhaps even to the point of trying to “jump start” the whole brain, as the current researchers speculate might be necessary.  Or, such a recovery might be impossible; they say they might just be observing an evitable process of brain death and decay.  Maybe it takes rather longer than previously appreciated.

That last point raises further concerns about how we understand when death has occurred.  Do current approaches toward harvesting human organs for transplantation, that may require that blood flow to the brain be interrupted for only a matter of minutes before declaring death of the donor, effectively jump the gun?  Might some people who are thought brain dead in fact have better chance of recovery than appreciated?  These questions already trouble ethicists thinking about how to determine when a person has died.

These are only a few of the concerns, and some authors this week are calling for an international review of the ethics of this work, before proceeding further with research on mammals—never mind humans, that’s not in view, yet.

A summary of the work for the non-specialist is openly available.  Summaries of related ethical issues, also openly available, can be found here and here.  The full scientific report in Nature requires subscription or purchase.

Human brain genes in monkeys

By Jon Holmlund

This week’s news is that a group of Chinese researchers have birthed and studied a small number of rhesus monkeys that were “transgenic” for a human gene associated with brain development.  In this work, monkey eggs (oocytes) were altered by adding the human form of a gene that is believed important to the development of the brain.  This gene is one of the relative few that is different between humans and primates (monkeys, as in the work described here, or apes, such as chimpanzees or gorillas).  That gene is abnormal in cases of human babies with small heads and brains, making it a good candidate for a gene that is critical to normal human brain development.

The gene was added to the monkeys’ egg cells using a viral delivery mechanism.  The monkey genes were not, in this case, “edited” to the human form using CRISPR/Cas9.  (Presumably, that experiment is coming.)  Using the altered eggs, 8 monkey embryos were then conceived and implanted in females.  Six of these survived to birth, and 5 of them lived long enough to do tests on their brains.  These monkeys’ brains looked, on imaging studies and under the microscope, more like human brains than normal monkey brains do, and these monkeys’ brains developed more slowly than normal, mimicking the human situation, in which brain development occurs largely in late pregnancy and then a lot more in infancy and childhood.  The five surviving monkeys also did better on some short-term memory tests than did “natural” monkeys given the same tests side-by-side.  How strong this finding is appears debatable; the number of monkeys tested was small, and your correspondent cannot say how useful the tests are.

The scientists also took sperm from these transgenic monkeys and conceived three other monkeys (again, using IVF, they apparently did not try to breed the animals), all of which were sacrificed before birth, and whose brains apparently showed some of the same features as their “parents'” brains.

Genetically modifying non-human primates is generally frowned upon in the West, largely on grounds of the animals’ welfare, but in China, it’s full-speed ahead.  The Chinese scientists apparently agree with Western scientists that the brains of apes (chimpanzees) should not be genetically altered because they are too much like us humans for comfort.  Monkeys are not so close, in the Darwinian schema.

The investigators in this case think they are learning important lessons about the genetics of human brain development in a model that is enough like humans to be informative.  They also think they are shedding light on human evolution (assuming that the evolutionary model is correct).  Those conclusions seem to be a reach.  The gene in question had already been identified as a candidate of interest, and its association with brain development arguably could be studied in other ways, within the ethical bounds of human subject research.  And it seems unlikely that a creature such as created in this work would ever have arisen from random mutation.  Rather, these transgenic monkeys seem to be an artifact of the investigators’ design, with uncertain relevance.

In any event—off to the races.  Anticipate more work to alter monkeys’, if not eventually apes’, brains genetically.  They might get something really interesting—and hard to know quite what to do with.

Another example of work that seems unethical on its face, done not because they should, but because they could.  The full paper can be found here.  A description for general readership is here.