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.

Then a Miracle Occurs…

If a picture is worth a thousand words, then a single-paneled comic is worth a thousand more. Sydney Harris is a famous cartoonist who has the gift of poking fun at science, causing scientists (and the rest of us) to take a second look at what they are doing. My favorite of his cartoons shows two curmudgeonly scientists at the chalkboard, the second scrutinizing the equations of the first. On the left side of the chalkboard is the starting equation demanding a solution. On the right is the elegant solution. In the middle, the first scientist has written: “Then a Miracle Occurs”. The second scientist then suggests to his colleague: “I think you should be more explicit here in step two” (the cartoon is obviously better).

Recently, in my usual scavenging around the internet for interesting articles on artificial intelligence (AI), I came across a Wired magazine article by Mark Harris describing a Silicon Valley robotics expert named Anthony Levandowski who is in the process of starting a church based on AI called Way of the Future. If their website is any indication, Way of the Future Church is still very much “in progress”. Still, the website does offer some information on what their worldview may look like in a section called Things we believe. They believe intelligence is “not rooted in biology” and that the “creation of ‘super intelligence’ is inevitable”. They believe that “just like animals have rights, our creation(s) (‘machines’ or whatever we call them) should have rights too when they show signs of intelligence (still to be defined of course).” And finally:

“We believe in science (the universe came into existence 13.7 billion years ago and if you can’t re-create/test something it doesn’t exist). There is no such thing as “supernatural” powers. Extraordinary claims require extraordinary evidence.”

This is all a lot to unpack – too much for this humble blog space. Here, we are interested in the impact such a religion may or may not have on bioethics. Since one’s worldview influences how one views bioethical dilemmas, how would a worldview that considered AI divine or worthy of worship deal with future challenges between humans and computers? There is a suggestion on their website that the Way of the Future Church views the future AI “entity” as potentially viewing some of humanity as “unfriendly” towards itself. Does this imply a future problem with equal distribution of justice? One commentator has pointed out “our digital deity may end up bringing about our doom rather than our salvation.” (The Matrix or Terminator, anyone?)

I have no doubt that AI will continue to improve to the point where computers (really, the software that controls them) will be able to do some very remarkable things. Computers are already assisting us in virtually all aspects of our daily lives, and we will undoubtedly continue to rely on computers more and more. Presently, all of this occurs because some very smart humans have written some very complex software that appears to behave, well, intelligently. But appearing intelligent or, ultimately, self-aware, is a far cry from actually being intelligent and, ultimately, self-aware. Just because the present trajectory and pace of computer design and programming continues to accelerate doesn’t guarantee that computers will ever reach Kurzweil’s Singularity Point or Way of the Future Church’s Divinity Point.

For now, since Way of the Future Church doesn’t believe in the supernatural, they will need to be more explicit in Step Two.

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

One side of the argument about heritable human gene editing

The current issue of the New England Journal of Medicine (subscription required) includes four new articles addressing heritable human gene editing.

George Daley (who was also discussed in a post on this blog last December 6) argues that work must proceed to find a responsible way of editing the human germline for people with genetic diseases that are devastating, untreatable, and largely unavoidable unless affected people forego having children.  This would be a limited use of heritable gene editing, he holds, although it may ultimately become attractive to the 1-4% of offspring of unrelated people who have genetic diseases, who seek to eliminate risk of passing on those diseases, or risk of them, to future generations.  He thinks that “our ignorance” regarding genetic complexity will ultimately prevent attempts at begetting genetically enhanced, “designer” children.

Matthew Porteus reviews “the new class of medicines” becoming possible due to DNA editing.  These include genetically modified cells as drugs, other attempts to treat existing people with known genetic disease by editing genes in part of their bodies, and, eventually, editing humans so that the genes they transmit to future generations are permanently altered. 

Lisa Rosenbaum reviews several of the objections to heritable gene editing that can stand in the way of scientific and social consensus.  Among these, she points out that people with disabilities often live very fruitful lives—lives that may never have come to be if their parents had the chance to edit their genomes, or not brought them to birth in favor of another embryo selected, without editing, through preimplantation genetic diagnosis.  But some disabilities are too severe to allow fruitful lives.  In such cases, she asks, “who is qualified to decide whether it is ethical to alter these children’s fate?”  If you think you can edit a baby destined to suffer severe genetic disease, are you obligated to try?  In that case, there’s “no such thing as an ‘informed decision’…you can’t know until you know.”

Alta Charo, who has co-led several recent prominent international conferences on human gene editing, argues that the “rogues” will proceed to edit people irresponsibly, even—and perhaps especially—in the face of a moratorium.  A more effect approach would be an “ecosystem” of restrictions, including formal regulation, restriction on supplies of raw materials (that is, human eggs, sperm, and embryos) for experimentation, patent and licensing restrictions, health insurance policies, liability for lawsuits, and the like.  Broad, international consensus is an unlikely prospect, she argues, but individual nations may enact their own regimes.  Whether this would really stop a black market is questionable, and heritable editing would become the province of favored entities (government or industry), I suppose—perhaps slowing the whole process down but leaving objections to the practice unsatisfied.

Each of these authors condemns He Jiankui’s claimed editing of Chinese twin girls who were born late last year.  Each of them also clearly takes the position that human gene editing should be regulated, either because it should proceed or because it will, inevitably, proceed. 

None of the authors suggests that heritable human gene editing should “never” be done, the position Francis Collins, the head of the US National Institutes of Health, took on Gerry Baker’s WSJ at Large on the Fox Business Network on Feb 22, 2019.  (I would link it but it appears that the clip has not been preserved on the network’s website.)

This blog recently recounted some reasons why heritable human gene editing should not be pursued.  But the train appears to have left the station.

The new WHO advisory panel on human gene editing

By Jon Holmlund

The World Health Organization (WHO) has empaneled an expert advisory committee to propose standards for governance and oversight of human gene editing.

This group is to meet in Geneva on March 18 and 19 to review the state of the field, broadly, and formulate a plan for its work, over the ensuing 12-18 months.  Sounds like your basic organizational meeting. 

The WHO website does not specify a more detailed charge for the committee, which no doubt will determine its goals.  It is said to have been formed “after an open call for members,” implying, I suppose, that the members volunteered, as opposed to being invited or otherwise prevailed upon.

The co-chairs are Edwin Cameron, former Justice of South Africa’s Constitutional Court, and Margaret Hamburg, who, among her other positions, was FDA Commissioner under Barack Obama.

A review of the full list of biographical sketches for the members shows that they are a truly international group, representing nations from the developed and developing world, and from all continents (except Antarctica, of course).  They are a mix of physicians, biologists, and ethicists.  None appears immediately recognizable from the recent media coverage of human gene editing.  If there are members with a specific interest in promoting technology, that is not obvious from the list, which WHO further says was limited to people screened carefully for conflicts of interest.

One can tell but little from such bio sketches, but in this case it at least appears that a broad range of cultural perspectives will be represented.

There is no clear representation for a theistic or religious perspective.  Also, because the work of such a group naturally draws and involves scientific specialists, the broader, non-scientific, “lay” public is not represented.

Past work by these members addressing gene editing will be of interest to review, which your present correspondent has not, yet.

One hopes that this group will offer wise counsel that, as discussed in prior posts to this blog and elsewhere, goes beyond the usual, limited “benefit-risk” estimates that characterize Western bioethics.

But it will unavoidably not constitute the broad, cosmopolitan, multinational and multiethnic, naturalistic and theistic dialogue that is hoped for—probably too much to hope for, too much to ask of a group of 18 people—in advance of broad adoption of heritable human gene editing, which appears inexorable.

Godspeed and best of success to this group—follow its work as closely as possible. ity51 \lsdl

Informed Consent and Genetic Germline Engineering

By Mark McQuain

I recently read, with admittedly initial amusement, an article from The Daily Mail that described a young man of Indian decent who was intending to sue his parents for giving birth to him “without his consent.” Raphael Samuel, a 27 year-old who is originally from Mumbai, is part of a growing movement of “anti-natalists”, who claim it “is wrong to put an unwilling child through the ‘rigmarole’ of life for the pleasure of its parents.” While he claims he loves his parents and says they have a “great relationship”, he is bothered by the injustice of putting another person through the struggles of life “when they didn’t ask to exist.”

While I was amused at the absurdity of asking a non-existent entity for permission to do anything, I began to wonder whether my position against germline genetic engineering should continue to include the lack of informed consent by the progeny of the individuals whose germline we are editing.

I have made the claim on this blog previously that one of my arguments against germline genetic engineering is that it fails to obtain the permission of the future individuals directly affected by the genetic engineering. Ethical human experimentation always requires obtaining permission (informed consent) of the subject prior to the experiment. This goes beyond any legal issue as many would consider Autonomy the most important principle of Beauchamp and Childress’s “Principles of Biomedical Ethics”. Informed consent is obviously not possible for germline genetic engineering as the future subjects of the current experiment are presently non-existent at the time of the experiment. While I believe there are many other valid reasons not to experiment on the human genetic germline, should the lack of informed consent continue to be one of them?

In short, if I am amused at the absurdity of Mr. Samuel’s demand that parents first obtain their children’s permission to be conceived prior to their conception, is it not equally absurd to use the lack of informed consent by the progeny of individuals whose germline we are editing as an additional reason to argue against genetic germline engineering?

Summarizing ethical issues with heritable human gene editing

By Jon Holmlund

A brief recap of reasons why we should not pursue heritable human gene editing:

It seems unlikely that risks to immediately-treated generations can be predicted with the accuracy we currently and reasonably expect from human subject research and medical practice.

Risks to later generations, that is, to the descendants of edited people, would be incalculable, and the informed consent of those later generations would be unobtainable.

To allow heritable gene editing even in the uncommon cases of untreatable, devastating genetic illness is to place too much faith in the ability of human providence to identify, and human behavior to observe, firm boundaries on its eventual use. 

Eventual use will become unavoidably subject to a eugenic approach in which the key decision will be what sort of people do we want, what sort of people should be allowed to receive life.

There will be no end to the disagreement over what edits should be permitted, and to the vilification of those considered to have been illegitimately edited, from those who object to their existence, perceived unfair advantage, or other characteristic.

Human populations will become stratified into the “edited” and the natural, introducing deep new justice concerns.  The main issue will be not will humans be gene-edited, but what should be the social status of those who are. 

To reduce heritable human gene editing to a reliable practice requires submitting it to the paradigm of manufacturing, as in drug development, with children seen as quality-controlled products of choice, not gifts of procreation.   To develop the practice, a “translational model,” again analogous to drug development, is necessary, with human embryos serving as raw materials, and, of necessity, a large, indeterminate number created and destroyed solely for development purposes, for the benefit of other humans yet to be born, and of those who would raise them.

Quite possibly, the translational model will demand great license on the extent to which embryos and fetuses may be experimented on; to wit, longer and longer gestations, followed by abortion of later and later stage, to further verify the success of the editing process.

In the extreme situation, the degree of editing may change the human organism in ways that will create a “successor” species to homo sapiens whose nature and desirability cannot be reasonably envisioned at this time.  In the extreme situation.

Even granting that this last scenario may never really arrive in ways that fiction writers can easily imagine, the other reasons should be enough that we simply don’t move heritable gene editing forward.

National Public Radio recently reported on the gene editing of human embryos—one day old—in the laboratory, in an attempt to correct and eliminate the inherited cause of blindness, retinitis pigmentosa.  The end is laudable.  The means is not.  We should not race ahead without considering why, first.  Then, we should not move ahead, but seek alternate means to the medical ends.

Edited embryos should not be created and brought to term—certainly not now, and I would say, not ever.  To be outraged over the former but not the laboratory creation of edited embryos is insufficient.  Both are outrages, although outrage over the recently-claimed birthing of edited babies in China is real, not “faux,” as one reaction held.  Still, the authors of that reaction are correct that one’s condemnation of the China event somehow justifies the laboratory work.  It does not. One last point: The Economist carried an essay decrying the birth of the edited twins in China as a case of “ethical dumping,” the practice of carrying out human subject research that would be disallowed in the West in other, perhaps less advanced (although China is certainly not backward), nations with fewer ethical scruples.  A valid point—but not one to cloak oneself in, while trying to justify the efforts to edit humans in ways that can be passed on from generation to generation.

Cyborg Society

By Mark McQuain

A cybernetic organism, or cyborg, is an organism that is part human and part machine. My favorite TV show in the mid 1970’s was “Six Million Dollar Man”, the story of an injured test pilot who lost both of his legs, his right arm and his left eye. His doctors made him “better than he was” by replacing his injured limbs and eye with artificial parts that actually enhanced his functional ability. Technology in the 1970’s was completely inadequate to accomplish those tasks and even now still lags far behind that TV show.

Perhaps the closest that any single person has come to becoming a cyborg is Steven Mann, an electrical engineering professor at the University of Toronto who, beginning in the 1980’s, literally began attaching various computers and cameras to his body and wearing them regularly to the point where, he argued, the equipment became part of him and he felt somewhat “unplugged” if he wasn’t wearing his equipment. The early equipment was so bulky, that in retrospect, he looked frankly ridiculous. As computers advanced, it became more difficult to recognize the equipment. The following photo shows that progression.

Steven Mann

Now most of the rest of us do not imagine that we are anything like Professor Mann. But I think we are more like him than we realize. Consider this – how many of you have a sense of disconnected-ness if you can’t find your smartphone? I would argue that most of us feel “unplugged” when we are without our phones. That certainly seems to be the case with anyone younger than 30. Your calendar, to-do lists, contact information, credit cards, airline or movie tickets are all stored on your phone. In that sense, part of your identity is in your phone. My wife and I joke that our children would not regularly communicate with us absent the ability to text.

Issues of faulty child-rearing aside, my point is not just our dependence on technology, and not just the nearness and intimacy of that technology. We have become dependent upon other artificial tools and parts such as walkers, hearing aides, prosthetics, pacemakers and insulin pumps, which are not just intimate but, in some cases, actually vital. But none of those machines affects our thinking or changes how we interact with one another.

Consider two new exercise systems popular this Christmas – Peloton and the Mirror (Disclaimer – I am not encouraging another Christmas gift). Both use smartphone technology to augment the exercise experience, allowing an individual to access what appears to be unlimited options in coaches, resources and locations. Notice the ads. They seem to elegantly emphasize both virtual community and individual physical isolation. And, while this technology is not cybernetically attached to us (yet), it, like the smartphone technology upon which it is based, appears to be detaching us from one another.

From a bioethics standpoint, I wonder whether, in augmenting our reality via our cyborg progression, we aren’t also becoming isolated from that reality as we become more dependent on the very technology we use to connect with one another.

Will a cyborg society make us more or less connected within that society?

#HappyNewYear