Promoting vaccination with a not-too-heavy hand

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

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

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

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

Again, a worthwhile read. >

“Safe” gene editing

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

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

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

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

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

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

Technical steps to gene-edited babies

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

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

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

Key concerns are:

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

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

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

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

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

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

  • Is the world ready?

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

More gene-edited babies on the way

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

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

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

Pragmatism and principle regarding human gene editing

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

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

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

Emerging attempts to control gene editing

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

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

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

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

Brain resuscitation (?) in pigs

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

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

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

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

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

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

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

Human brain genes in monkeys

By Jon Holmlund

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

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

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

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

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

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

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

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.