Heritable genome editing: a too-short list of 12 questions

Last week, I discussed efforts by a US/UK commission formed to recommend a framework for regulating and monitoring heritable human gene editing.  This 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.”  The deadline is September 27, 2019 to make recommendations.  The website to do so appears open to the public. 

Now, I suppose the commission will ultimately decide who qualifies as an “expert,” and several of the questions are decidedly technical.  But I submit that many who read this blog qualify as experts in bioethics or in some aspect of biomedicine, and will be able to offer considered responses to at least some of the questions.  So I encourage readers of this blog to access the link and weigh in.

I have yet to complete my effort.  I started last week, then pulled back in the middle.  Responses to each question appear to be submitted in real time, and the possibility to save work (there are ‘”back” and “next” buttons) for future editing seemed unclear.  And these questions merit careful responses.  So I decided to wait for another day—before the September 27 deadline!

If you would like to mull over possible responses in advance of trying to offer them online, I have copied them here, for advance thinking before submitting at the online portal, or to inform reflection and discussion otherwise:

  1. Which diseases and conditions, if any, do you see as appropriate for human germline genome editing?
  2. If there were to be an appropriate use case for human germline genome editing, what evidence would be needed to proceed to first in human use?
  3. What is the status of editing mechanisms for early stage human embryos (e.g., using different editing techniques, improving homology directed repair, etc.)? What are the factors that predict whether single nucleotide changes or other intended modifications in human embryos will be correct? To what extent will genome editing affect the viability of embryos?
  4. What is the status of the technology for validating that a correct edit (on target characterization) has been made and that unintended edits (e.g., off target effects, mosaicism, etc.) have not occurred in a range of cell and tissue types? If possible, please provide evidence drawn from work on induced pluripotent stem cells, embryonic stem cells, and/or early stage human embryos.
  5. What is the status of generating cell lines from human and non-human germline stem cells?
  6. How might animal models inform the editing in human embryos (inclusive of analysis of phenotypic correction)?
  7. To what extent do different genetic backgrounds affect success and phenotypic outcomes after genome editing?
  8. What is the success rate of full-term pregnancies following pre-implantation genetic diagnosis? What affects this (e.g., age, number of oocytes harvested, technique used, etc.)?
  9. What are the appropriate mechanisms for obtaining informed consent, long-term monitoring of the future children, assessing potential effects in subsequent generations, and addressing untoward effects? Are there best practices from: a) assisted reproductive technologies; b) pre-implantation genetic diagnosis; c) gene transfer research for children; d) mitochondrial replacement therapy; and e) somatic genome editing?
  10. How should we think about the inter-generational medical (e.g., genetic changes to the genome) and ethical implications of human germline genome editing (e.g., potential harms and benefits)? How should the rights of future generations and the wider human population be taken into account?
  11. What international oversight structures would need to be in place to facilitate, in a responsible way, a path forward for germline genome editing?
  12. Are there any topics or issues that are not covered by the above questions that you think the Commission should attend to during its deliberations?

This last question, of course, is the most pregnant of all.  The list of questions is so technical, so question-begging about whether heritable gene editing should be done at all, that the commission should receive carefully-considered reflections on the meaning of the potential enterprise, how the future practice of heritable genome editing should not be a foregone conclusion, and how and why the right answer to “when should we edit human genes heritably” might well be “never.”

By all means, reader of this blog, go online and offer what you reasonably can to this important discussion!

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.

“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.

Proposed moratorium on human germline: Asilomar analogue?

The Editorial Board of The Washington Post (WaPo) recently published their opinion  on regulation of heritable genetic changes in human eggs, sperm, and embryos. The authors expressed some measure of relief that organizations such as the National Academies in the U.S., the Royal Society in Britain, and the World Health Organization are beginning to consider the daunting topic of human heritable genetic changes. The board advised, “The goal must be a framework that will enable genuine scientific advancement but avoid reckless fiddling with the source code of life.”

The WaPo editorial board further recommended “something of similar scope and power” to that of the Asilomar Conference on Recombinant DNA Molecules, held in February 1975. Asilomar, as that conference came to be called, was convened to evaluate the risks posed by the novel technology of genetically modifying organisms. The public perception of Asilomar has been primarily one of scientists shouldering the “social responsibility of science.”

Further, the WaPo article pointed out that one of the authors of the March 2019 Nature commentary calling for a “global, temporary moratorium on clinical uses of human germline editing” was Paul Berg, a Nobel laureate, and one of the organizers of the Asilomar conference. The Nature commentary, authored by Eric Lander, Françoise Baylis, Feng Zhang, Emmanuelle Charpentier, and Paul Berg, described the consensus for a moratorium thusly:

The 18 signatories of this call include scientists and ethicists who are citizens of 7 countries. Many of us have been involved in the gene-editing field by developing and applying the technology, organizing and speaking at international summits, serving on national advisory committees and studying the ethical issues raised.

This description appears to differ substantively from one Berg gave of the Asilomar analogue. In an 18 June 2011 video interview by Larry Goldstein, Berg had this to say about the success of Asilomar:

We made some decisions that were smart in retrospect. For example, one of the things we did not do – and did not include in any way in the agenda was the ethics. We didn’t talk about genetic testing… we talked about real experiments, and what the impact of those experiments would be in the field (10:40-10:58)

Of the five authors calling for a moratorium on human heritable genetic changes, only Françoise Baylis is an ethicist. A 2004 article penned by Baylis and Jason Scott Robert, “The Inevitability of Genetic Enhancement Technologies,” gives insight to her views. The paper concludes with

. . . we maintain that accepting the inevitability of genetic enhancement technologies is an important and necessary step forward in the ethical debate about the development and use of such technologies. We need to change the lens through which we perceive, and therefore approach, the prospect of enhancing humans genetically. In recognising the futility of trying to stop these technologies, we can usefully direct our energies to a systematic analysis of the appropriate scope of their use. The goal of such a project would be to influence how the technologies will be developed, and the individual, social, cultural, political, economic, ecological, and evolutionary ends the technologies should serve. It is to these tasks that bioethical attention must now fully turn.

It appears that 1) Paul Berg’s previous concerns about “ethics” being involved is not a problem to date in this enterprise; and 2) the called-for moratorium is truly only a “speed bump” on the road to converting future generations into our own laboratory experiments. The “individual” ends such experiments will serve are likely to be the individuals who are paid handsomely to do such experiments or who hold the patents to the processes utilized – not the individuals formed. Despite the extensive embrace of heritable human genome editing by the principals cited here, we need to remember that this is not a road that we must travel. Future generations are not our playground. We need to rethink this “moratorium”:  It should be an outright ban.

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.

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. 

The (at least, an) other side of the argument about heritable human gene editing

By Jon Holmlund

Last week’s New England Journal of Medicine (subscription required) included four articles addressing heritable human gene editing (HHGE, if you’ll allow the acronym).  All assumed that it would or should go forward, under oversight, rather than seeking a moratorium.  One took the position that a moratorium is a bad idea, because the “rogues” would press ahead anyway, and the opportunity to create meaningful partial barriers to at least slow down what could easily be a runaway train.

This week, a group of prominent scientists in the field, representing seven nations, take the other side in Nature.  They call for an international moratorium on HHGE.  This is not a permanent ban, nor is it an international treaty banning HHGE until a subsequent action removed the ban.  Rather, they propose that for a fixed time (they suggest 5 years), nations as a group agree to block, and scientists and clinicians agree to abstain from, any attempt to bring a gene-edited baby to pregnancy or birth.  The scientists writing this week would allow research on human embryos to proceed, as part of a broader effort to define the reliability and safety of the editing—something they say has clearly not yet been established. 

During the moratorium, hard work would need to be done for societies to define what people should be edited.  The scientists suggest that HHGE would rightly be limited, pretty strictly, to “genetic correction,” meaning cases in which a defect of a single gene known to cause, or almost certainly to cause, a serious disease would be corrected.  They would not permit genetic enhancement absent “extensive study” into long term and unintended effects, and even then, they say, “substantial uncertainty would probably remain.”  Genetic enhancement, in their view, would include altering genes that increase the risk of diseases.  They don’t cite examples, but it appears that abnormalities like BRCA1 mutations that increase cancer risk are in view here.  Further, which medical conditions would have no alternative to HHGE must be determined.  In most cases, IVF and preimplantation genetic diagnosis would likely suffice, obviating the need to take the profound additional step of HHGE (whatever one may think of the moral status of the human embryo).  The cases eligible for HHGE, they suggest, would be “exceedingly rare,” limited to essentially unavoidable situations for which a “small minority” of genetic diseases is caused by a genetic abnormality that is frequent in the population.  (It seems like such situations would be rare indeed.)  In such cases, they say, “legitimate needs” of couples seeking to have unaffected, biologically related offspring would need to be weighed against “other issues at stake.”

Most critically—and, hardest to achieve—the scientists envision a broad, intensive effort, that is not limited to or driven by scientists and physicians, and that goes beyond current regulatory regimes to include all aspects of society in an effort to achieve broad consensus—neither simple majority nor unanimity, but a situation in which the clear, large majority opinion exists on when and how HHGE should be countenanced.

Whether these tasks could be pulled off in five short years is something to wonder about, and even allowing planning for HHGE under these constricted circumstances raises questions about how we understand our humanity, whether embryos should be treated as raw materials in development of new treatments, and other matters that go deeper than discussions of medical, scientific, and population risks and benefits.  Were the tasks achieved under a moratorium, the authors envision that individual nations would be sovereignly free to go separate ways, with some allowing HHGE, but perhaps others not.

The editors of Nature, without taking a side about a moratorium per se, call for rules to be set, broad societal conversations to take place, research to be carefully overseen to be sure it is on a “safe and sensible” path and to identify and stop the “rogues,” and journals to refuse to publish work that transgresses limits in place at the time.

With something this big, a “presumption to forebear,” rather than a proactive drive to progress, should be the dominating sentiment.  The details are too complex to address in a few articles, a few short blog posts, a few minutes on cable news, or a few passing conversations wedged into the cracks of busy lives.  We should slow down.  We should ALL call for a moratorium. b