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

“The Babies are the Experiment”

By Jon Holmlund

 

The Thursday, Dec 13 edition of the Wall Street Journal carries this headline:  “Doubts Arise Over Gene-Editing Claim.”  The work behind the recent report that the world’s first two gene-edited babies had been born has been publicly discussed, but the details have not yet been published for full scientific review.  Apparently scientists in the gene-editing field are reviewing the public presentation and finding it lacking:

  • Some, but not all, of the cells in the children may have been edited. One would expect changes in all of the cells, and this should be necessary for the overall stated medical goal (protection from HIV infection) to have a chance of having been met.

The edited babies may have variants of the edited gene that have not been fully studied and could have unforeseen health consequences.

The technique used to confirm the gene changes may not be sensitive enough to detect whether other, unintended and potentially undesirable gene changes had been made.

And perhaps most notably, the studies done in mice to demonstrate the feasibility of the technique, before editing the embryos that grew into the full-term babies, involve a different change in the target gene in mice than the change sought in the children. In other words, the animal studies appear not to be representative of the human situation.

This is a common problem for development of new treatments for cancer and other diseases.  Tests are initially done in animals—usually mice—to determine whether the putative new treatment appears to be working.  The animal models used never entirely reflect the human disease.  Some come closer than others.  But the way of handling that uncertainty is to define and limit the risks to people who subsequently have the new treatment tested on them in clinical trials.

In the case of the gene-edited babies, there’s really no way to limit the potential risks, at least not yet, if ever.  Ultimately, one has to strike out and make changes that could backfire for the recipient humans, or be propagated into their descendants with unpredictable effects. 

Accordingly, without good animal models, and appropriately extensive testing in them, then, as professor Sean Ryder of the University of Massachusetts Medical School is quoted as saying, “the babies are the experiment.”  Ultimately, heritable gene editing may just require a leap of biomedical faith.

We should just say, “no, we shall not.”

Gene editing for genetic enhancement

By Steve Phillips

I appreciate the prior posts by Jon Holmlund and Mark McQuain regarding the recent announcement of the birth of genetically modified twins in China. Much has been written about why this should not have been done, but something very significant has been left out of most of those responses. They have failed to mention that the scientist who created the genetically altered twins was doing a form of genetic enhancement. As I have noted before, the only real reason for anyone to do research on the genetic modification of human embryos is to enable the possibility of human genetic enhancement. The scientist involved in this situation has recognized that and directly pursued it. I suspect that his open pursuit of enhancement is one of the reasons why he has received such a negative response from those who otherwise support the permissibility of using human embryos for experimentation on germline genetic modification.

The primary argument presented for why this was wrong is that he has subjected two healthy human infants to the unknown risks of genetic modification without any corresponding medical benefit to the infants. The modification was disabling the gene that codes for a cell membrane receptor that the HIV virus commonly uses to gain entry into cells it infects. The hope was that these infants would have enhanced resistance to HIV infection, although not complete immunity to such infection. The infants themselves would not have been at increased risk for HIV without the modification, but the parents had a desire to have children with increased resistance because their father has HIV and is aware of the difficulty of living with the disease. Thus, the modification was being done to provide an enhancement desired by the parents and was not being done to infants would have otherwise suffered from a genetic disorder.

Most who support current research to develop effective techniques for human germline genetic modification take the position that the safety of doing this has not been established well enough to use the technique to create infants and that when the research does reach the point that genetically modified human infants are created it should only be in situations in which those infants would otherwise have had serious genetic disorders. They are correct that this technique is currently unsafe but fail to realize that we will probably never be able to establish the safety of this type of genetic modification, because that would require safety data from multiple generations of these infants’ offspring. The idea of restricting this technique to infants who would have been born with serious genetic disorders and the idea that this technique could be used to rid the world of these genetic disorders does not make sense. If a couple desires to have children and know that they are at risk to have a child with a serious genetic disorder and have no moral concerns about the destruction of human embryos involved in such things as genetic modification, they can pursue selection of an unaffected embryo using PGD and have no need to take on the additional risks of genetic modification. Using genetic modification to eliminate genetic diseases would require a Brave New World scenario in which all human beings are artificially conceived and natural conception is prohibited. Therefore, the only reason to pursue the genetic modification of human embryos is for the purpose of human enhancement.

Let me be clear that I agree that what the scientist has done is wrong because he has subjected these two infants to significant risk without any significant medical benefit. That is always wrong. However, the strength of the negative response from those who generally support research to develop human germline genetic modification is likely due to the fact that he has opened up to public scrutiny the real purpose of such research. He has also shown that it is not true that we can ignore ethical concerns about enhancement because we could regulate the use of genetic modification so that would not occur. Enhancement was the goal of the very first use of this technique to produce human infants.

The Genetic Singularity Point has Arrived

By Mark McQuain

November 2018 will go down as one of the most pivotal points in human history. Jon Holmlund covered the facts in his last blog entry. Regardless of what you think about the ethics of He Jiankui’s recent use of CRISPR to alter the human genomes of IVF embryos and his decision to intentionally bring those genetically altered twin girls to full term, one thing is perfectly clear – we humans are in charge now. Whether you believe in God or Nature as the Entity or Force that previously determined the arrangement of our genes, humans now sit at the adult table and will be gradually (rapidly?) making more of those genetic decisions. Like Kurzweil’s upcoming Singularity Point when computers develop sufficient artificial intelligence to design the next computer, humans have now reached the point where we can and are willing to design the next human.

The Genetic Singularity point has arrived.

While there are some scientists who are frustrated that our Institutional Review Boards and ethics committees have held us back this long, most of the rest of us are frankly stunned and uneasy that we have reached this point. But anyone who thinks our stunned uneasiness will prevent a repeat of this experiment or prevent a push to alter increasing portions of our human genome to change other genetic sequences will simply remain more frequently stunned and persistently uneasy, ethical arguments notwithstanding.

My reason for expecting this to be the case is I believe we will hear increasing demands of the form that now that we have the ability to change our genome, we have the responsibility to change our genome. In fact, it would not surprise me to see, in the not-to-distant future, insurance companies paying for the cost of IVF/CRISPR to modify your child’s genome to prevent disease/condition X to avoid paying for the later treatment of disease/condition X. Oh, you won’t be forced to do this. But, if you choose to rely on God or Nature for your baby’s genetic pattern, “we” won’t be responsible for his or her care. And, if big data can eventually be married to IVF/CRISPR to statistically improve one’s chances of having a smart/beautiful/athletic/successful baby, wouldn’t you want the same for your child? Since it will be our responsibility, how could a parent not choose to make their child the best that they could be?

This will be Gattaca writ large.

Being at the Genetic Singularity point, by definition, means we humans choose our next step. We have reached the point where we believe we are ready to select our future direction. It is up to us now to chart our own course. Our genetic trajectory is our responsibility. Our success or failure, or more broadly, our future good or bad, is finally ours to determine – really ours to assign.

So Man created mankind in his own image, in the image of Man he created them…And Man saw everything he had made, and behold, it was very good…

Approaching Immortality?

By Neil Skjoldal

With the death of President George H. W. Bush this past weekend, the country seems united in eulogizing him for, among other things,  having lived “a well-lived life,” because amidst his accomplishments, he was able to reach 94 years of age.  This brought to mind a recent article published in The NY Times, “How Long Can People Live?”  In it, health writer Nicholas Bakalar observes, “There is considerable dispute, however, over how long humans might live under optimal circumstances.”

The brief article discusses the possibility of drug therapies designed to kill old cells, while leaving young cells in place.  Apparently many are working on research projects to see what may be possible.  Even the well-known drug metformin will be tested to see its effectiveness against age-related diseases.   Bakalar is not overly optimistic.  He clearly states, “No serious scientist believes in immortality.”   Rather the goal is to assure a “healthier old age than ever before.”

I find Bakalar to be reasonable in his assessment.  Of course, one can question whether trying to extend life past 100 years is the best use of limited resources when there are so many other health issues with which to contend.  However, perhaps a ‘healthier old age’ could reduce some of those very high medical costs at the end of life which seem to plague our health care system.

I do not anticipate that I will be jumping out of an airplane at an advanced age like President Bush, but I am interested to see if any of the health issues related to old age can be addressed in a meaningful way.