Raiding the CRISPR

A couple of gene-editing news items from this week’s science literature:

First, Nature reports that a group in my “back yard,” at the University of California San Diego, has tested gene editing using the CRISPR approach in mice.  Recall that CRISPR is an acronym for a particular molecular mechanism, first discovered in bacteria, that is particularly efficient—though not perfectly so!—at editing genes.  The idea is to find a “bad” gene that you’d like to replace, for example to prevent or treat a disease, and edit it to be the normal version of that gene.

The kicker in this particular case in mice is that it tested something called “gene drive.”  In classical genetics, humans (and other higher organisms) have two copies of each gene.  In sexual reproduction each parent passes one copy of the gene to offspring, so the chance of a particular gene being handed down is 50%.

“Gene drive” is a technique designed to change those odds, and make a particular gene “selfish,” and much more likely to be passed on.  In fact, the idea is that transmission would be 100%, or nearly so.  If that worked, then a new gene would soon take over a population of organisms, and every member would, in a few generations, have that gene.

Why might that be a good thing?  Suppose you are interested in pest control, and you could use the technique to make, say, mosquitoes infertile.  Then they would soon all die off.  Or if you had some other “desirable” characteristic, you could make it so all members of a species (rodents?  Cattle?  People?) have that characteristic.  Assuming it’s determined by one gene, that is.

And assuming that the technique works.  In the mouse experiment, efficiency was only 73%.

That’s probably good news.   This is one of those techniques that could have serious unintended consequences if tried in the field.  Scientists have been warning about that.  It looks like it’s a way off, but something else to fret about.

The second item involves a clinical trial to treat sickle cell anemia.  In this one, blood stem cells from a person with the disease are removed from the bloodstream and gene-edited outside the body to make hemoglobin that is not as damaged as in the disease (SCA is an inherited disease in which the red blood cells have abnormal hemoglobin that doesn’t carry oxygen well).  Then the altered cells become the therapy, and are given back to the patient.

The FDA has put a “clinical hold” on this clinical trial.  Exactly why has not been publicly disclosed (it doesn’t have to be), and it sounds like the trial itself hadn’t started yet, but that the company developing it was getting ready to start.  This is, in my view, an approach to gene editing that does not pose special or particularly worrisome ethical issues, because the genetic changes are done on “adult” stem cells to treat an existing individual with a disease in a way that would not entail transmission of altered genes to future generations.

And, probably, it’s a case of “this too shall pass,” and the FDA’s concerns will be answered and the trial will proceed.

But check out the sidebar reporting this in Nature Biotechnology.  If you follow the link you will probably get a prompt asking for payment but I was able to sneak a free read on my screen.  If you go there, read below the separate quote (itself picked up from The New York Times) from Dr. George Church of Harvard:  “Anyone who does synthetic biology [engineering of biological organisms] should be under surveillance, and anyone who does it without a license should be suspect.”  Apparently he said that in response to “the publication of an experiment recreating a virus that has engendered fears that such information could be used to create a bioweapon. ”

The old “dual use problem,” eh?  We should really fret about that.

Labs are growing human embryos for longer than ever before

That’s only a slight paraphrase of a news feature article this week in Nature.  The clearly-written article is devoid of scientific jargon, with helpful illustrations, open-access online, and readily accessible to the non-specialist.  Check it out.

Key points include:

  • Scientists who do not find it ethically unacceptable to create and destroy human embryos solely for research purposes continue to follow the so-called “14-day rule,” by which such experimentation is limited to the first 14 days after fertilization. At that point, the human nervous system starts to form and the time for twinning is past.
  • The 14-day rule is law in some nations, but until now has not been a practical issue because scientists have been unable to grow human embryos that long in the laboratory.
  • That technical limit has been sufficiently overcome that embryos are now surviving for almost 14 days. Scientists have not directly challenged the 14-day rule yet, but might, and would like to revisit it.
  • Experiments on human embryos in that time have included editing of critical genes to see what happens (sometimes they stop growing), and making hybrids of animal embryos with human cells whose purpose is to “organize” embryonic development rather than remain part of the developing individual.
  • Embryo-like structures, referred to as “embryoids” in the article, and sounding similar to “SHEEFs” (“synthetic human entities with embryo-like features”) are also being created. These entities don’t necessarily develop nervous systems in the same way as a natural embryo, prompting questions of just how much they are like natural embryos, whether the 14-day rule applies, and whether they raise other ethical concerns.

The last paragraph of the article, reproduced here with emphases added, is striking and more than a little ironic in light of arguments that embryos are “just a clump of cells”:

As the results of this research accumulate, the technical advances are inspiring a mixture of fascination and unease among scientists. Both are valuable reactions, says [Josephine] Johnston [bioethicist from the Hastings Center]. “That feeling of wonder and awe reminds us that this is the earliest version of human beings and that’s why so many people have moral misgivings,” she says. “It reminds us that this is not just a couple of cells in a dish.”

The essence of humanity

Over the past few days I have been reflecting on this year’s CBHD conference which was titled Bioethics and Being Human. In reviewing all the thought-provoking presentations and discussions, I think the opening address by Dennis Hollinger impacted me the most. His talk was entitled Why Humanness Is the Key to Bioethics. He began by saying that in the culture around us the focus has shifted from concept of human dignity to the concept of humanness or what it means to be human. He suggested the technology which is developing artificial intelligence that may be able to reason and robots that take on roles that we have traditionally considered to be human raises questions about what counts as a human being.

The core of what he said related to the idea that there has been a shift in how the culture around us thinks about these things. Our surrounding culture now questions whether there can be an essence of realities. If the existentialist assertion that existence precedes essence is true and there is nothing outside the self to define the self, all our concepts, including our understanding of humanness, become subjective.

Those of us who see the world from a biblical Christian viewpoint understand that there are objective realities in the world. We see that human beings do have a nature, a humanness, that is not subjectively defined, but it is an objective reality that exists due to how we have been created by God. We find that objective understanding of what it means to be human represented in the ultimate human being, Jesus.

But how do we express this understanding of an objective reality of humanness to people in a culture that believes that everything is subjective? I think Hollinger suggested a strategy when he identified the ironies of our surrounding culture’s thinking. He said that the surrounding culture rejects humanness, but longs for relationship; rejects intrinsic moral norms, but longs to be treated justly and honestly; and rejects human meaning, but longs for something beyond. We live within a culture that leaves people without a solid foundation for meaning, relationship, and values. That foundation is available in the God who created us and in his Son, who became one of us, died for us, and rose again to redeem us. He is the essence of humanity and we can share Him with those around us who are deeply in need of the hope that He can provide.

A Supreme Court of One

Like Neil Skjoldal in yesterday’s blog entry, I, too, am a Supreme Court watcher and enjoy reading their decisions as some might enjoy watching a good sports match or listening to a beautiful symphony. Nerd that I am, I find a well-articulated argument a beautiful thing to behold, even when it runs counter to my bioethics, as it can be a learning experience to help me sharpen my counter argument. My counter argument becomes moot if five or more Justices concur with that original argument, as it is rare, though not impossible, for the Court to completely reverse itself.

Last week, the legal landscape suffered the equivalent of a San Andreas-like major tremor along its political fault-line with the announced retirement of Associate Supreme Court Justice Anthony Kennedy. Justice Kennedy has generally been considered the political center of the Court, the all-important tiebreaker, if you will, on controversial bioethical issues related to abortion, gay marriage and the death penalty. Presently, we give 9 Justices the authority to be the final interpreters of our laws, including those that determine our collective bioethics. Amazingly, we will accept a majority rule 5-4 split decision as being just as acceptable as a 9-0 unanimous decision when validating or invalidating our laws. Being the tiebreaker on previous controversial issues effectively made Justice Kennedy what I call “a Supreme Court of One”. And that is exactly how both political parties are treating the selection of Justice Kennedy’s replacement.

And they should.

In a past blog entry, I tried to make the case that it vitally matters who is interpreting our Constitution, as those individuals are grounding our secular bioethics. Allowing one tie-breaker to decide these important issues is too much power and responsibility in one individual but that has been the reality in our presently divided Court.

My favorite legal philosopher is the late Yale Law School professor Arthur Leff. He gave a lecture at the Duke University Law School in the late 1970s called “Unspeakable Ethics, Unnatural Law”. He made the case that if our source of right and wrong is anything other than a transcendental (unnatural) source, then the resulting ethics/law is always open to challenge. The U.S. Constitution is an example of a natural source of law, perhaps the best that mankind can create for itself, but, since it was created by us, it is therefore always open to challenge by us. Given its internal checks and balances, as long as “We the People” continue to agree to be governed by the Constitution (and this is by no means a permanent agreement), rulings by the Supreme Court essentially function as our collective approval of laws that determine our national bioethics.

I have shared the following quote from Leff’s lecture before but it again seems appropriate:

As long as the Constitution is accepted, or at least not overthrown, it successfully functions as a God would in a valid ethical system: its restrictions and accommodations govern. They could be other than they are, but they are what they are, and that is that. There will be, as with all divine pronouncements, a continuous controversy over what God says, but whatever the practical importance of the power to determine those questions, they are theoretically unthreatening. It is only when the Constitution ceases to be seen as fulfilling God’s normative role, ceases, that is, to be outside the normative system it totally constitutes, or when, as is impossible with a real God, it is seen to have “gaps,” that a crisis comes to exist. What “wins” when the Constitution will not say, or says two things at the same time?

Presently, the Supreme Court interprets those gaps and decides what wins and what loses in our national bioethics debates. Given our present evenly split Court, picking the next Supreme Court of One can literally make all the bioethical difference in the world.

Goodbye, Korematsu

Supreme Court watchers always eagerly anticipate the last week of June because that is when the highest court in the land usually reaches decisions in its most controversial cases.  Last week did not disappoint — several of the decisions were reached by the slimmest of majorities (the infamous 5-4 vote). Then, to add to the excitement, one of the longest serving justices, Anthony Kennedy, announced his retirement, giving the talking heads of cable news seemingly endless fodder for roundtable discussions.

In the midst of the frenzy, a few observers noted the words of Chief Justice John Roberts at the end of his Trump v. Hawaii opinion.  The dissent in the case brought up Korematsu, the decision from the 1940s which concluded that the internment of American citizens of Japanese descent was constitutional.  Roberts disagreed with the dissent, but offered this assessment of Korematsu:

“The dissent’s reference to Korematsu, however, affords this Court the opportunity to make express what is al­ready obvious: Korematsu was gravely wrong the day it was decided, has been overruled in the court of history, and—to be clear—‘has no place in law under the Constitu­tion.’ 323 U. S., at 248 (Jackson, J., dissenting).”

Bioethics should affirm the basic dignity of all humanity.  It reacts strongly to governments using people for experimentation against their will, or to the preferential treatment of one people group over another, or any number of other abuses that have arisen over the years.  Those from the Judeo-Christian perspective often link this to the biblical teaching of the image of God (see the powerful book by John Kilner, Dignity and Destiny).  From my perspective, it means hearing the voice of those who do not normally have a voice and affirming the rights of those whom society so casually overlooks.

Looking back seventy-plus years, Chief Justice Roberts sees the issues of Korematsu clearly.  Sadly, for the many American citizens of Japanese descent interred during the Second World War, there were only three Supreme Court justices who stood with them against such horrific treatment.   Korematsu is a sobering reminder of what can happen when the powerful trample the powerless.  During this Fourth of July week, I will celebrate that this decision has been placed in its rightful place, the ash heap of history.




Vaccines: Modern Trolley Car Dilemmas

The Trolley Car dilemma is back in bioethics news. For those unfamiliar with the trolley car dilemma, you alone are responsible to operate a trolley track switch to divert an out-of-control trolley car away from five workers on one section of track only to cause the death of a lone worker on the only alternate section of track. The dilemma: someone is going to die, and you get to decide who. In a recent editorial in the June 13th New England Journal of Medicine, Dr. Lisa Rosenbaum nicely describes the utilitarian dilemma surrounding the public health risks and benefits associated with a vaccine for the dengue virus, a mosquito-borne virus that annually causes significant severe illness and death worldwide. The dengue vaccine, Dengvaxia, is a real-world trolley car dilemma. Dengvaxia presently can protect large numbers of patients from this deadly virus, but at the expense of causing severe illness and death in a much smaller number of patients, mostly children.

Dr. Rosenbaum describes our response to utilitarian thinking, correctly I think. We don’t mind utilitarian rules that negatively affect others, particularly when the rules tend to confer benefit to our group as a whole (the very definition of utilitarianism) but we resist utilitarian thinking when it threatens to affect us negatively as an individual despite overall benefit to the rest of our group. Healthy self-interest often conflicts with the utilitarian calculus that purports to determine the overall benefit to the group. In the case of Dengvaxia, if the deaths caused by the vaccine only occurred in people who would have died from the natural dengue virus anyway, there would be no problem. In other words, by golly, you all were going to die from the widespread disease anyway, and since the vaccine did save some of you from dying, there is really no new or additional loss. Net positive outcome, right?

Sadly, vaccines do not work that way. With Dengvaxia, it may be possible to create a pre-vaccine test for seropositivity for the virus. This would mean determining whether a person previously had a very mild case of the virus such that they would not suffer a catastrophic outcome from receiving the vaccine, thereby allowing them to safely receive the vaccine to prevent a more severe case of dengue in the future. Such a screening test may be possible but it would cost some unknown amount of additional money and would still not be 100% accurate. Even so, no vaccine is 100% safe.

How many lives would need to be saved and at what cost before we are satisfied with the cost/benefit ratio of Dengvaxia (or any vaccine for that matter)? Presently the World Health Organization is recommending a pre-vaccination test be developed and only vaccinate those who test positive for prior exposure. This is effectively saying that the vaccination is not only not required but not even presently recommended in endemic regions, this despite the fact that Dengvaxia clearly significantly reduces overall mortality and morbidity. If the disease were more contagious and more lethal than dengue, at what point does the vaccine, however imperfect, become mandatory? This is the ultimate trolley car switch for public health officials.

Aren’t trolley car dilemmas fun?

A safety concern with gene editing

Hat-tip to Dr. Joe Kelley for bring this to my attention…

As readers of this blog will recall, there is keen interest in exploiting recent discoveries in genetic engineering to “edit” disease-causing gene mutations and develop treatments for various diseases.  Initially, such treatments would likely use a patient’s own cells—removed from the body, edited to change the cells’ genes in a potentially therapeutic way, then return the altered cells to the patient’s bloodstream to find their way to the appropriate place and work to treat the disease.  How that would work could differ—make the cells do something they wouldn’t normally do, or make them do something better than they otherwise do (as in altering immune cells to treat cancer); or maybe make them work normally so that the normal function would replace the patient’s diseased function (as in altering blood cells for people with sickle cell anemia so that the altered cells make normal hemoglobin to replace the person’s diseased hemoglobin).

Or maybe we could even edit out a gene that causes disease (sickle cell anemia, Huntington’s disease) or increases the risk of disease (e.g., BRCA and cancer) so that future generations wouldn’t inherit it.  Or maybe we could edit genes to enhance certain health-promoting or other desirable qualities.

The recent scientific enthusiasm for gene editing is fueled by the discovery of the relatively slick and easy-to-use (if you’re a scientist, anyway) CRISPR-Cas9 system, which is a sort of immune system for bacteria but can be used to edit/alter genes in a lot of different kinds of cells.

It turns out that cells’ normal system to repair gene damage can and does thwart this, reducing the efficiency of the process.  The key component to this is something called p53, a critical protein that, if abnormal, may not do its repair job so well.  When that happens, the risk of cancer increases, often dramatically.  In cancer research, abnormal p53 is high on the list of culprits to look out for.

Two groups of scientists, one from the drug company Novartis and one from the Karolinska Institute in Sweden, have published on this.  P53’s thwarting of gene editing is particularly active in pluripotent stem cells, that are some, but not the only, candidate cells to be edited to create treatments.  These cells are also constituent cells of human embryos.  If the CRISPR-Cas9 process is used on these cells, p53 usually kills them off—unless it’s lacking or deficient, in which case it doesn’t, but also in which case it means that the altered cells could themselves become cancers, later on.

This is something that has to be monitored carefully in developing cells as medicines, so to speak, with genetic editing.  One does not want the patient to appear to be healed, only to develop a cancer, or a new cancer, later on.  One certainly would want to know the risk of that before editing an embryo—an unborn human, a future baby if placed in the right environment—to create a gene-edited human being.

Yet, as I’ve written here in the past, it appears that experimentation in heritable gene editing is pressing on.  I’ve argued, and continue to argue, that heritable human gene editing is a line that must not be crossed, that would place too much trust in the providence of the scientists/technologists who are the “actors” exerting power over fellow humans who become “subjects” in a deep sense of the term; that the risks to the subjects are undefinable; that it would enable perception of humans as “engineering projects”; that the gift of life would tend to be replaced by seeking to limit birth to “the people we want”; that the people acted upon are unable to provide consent or know what risks have been chosen for them by others, even before birth.  Rather than press ahead, we in the human race should exercise a “presumption to forbear.”

A counter argument is that, in limited cases where the genetic defect is limited and known, the disease is terrible, treatment alternatives are few or none, that the risks are worth it.  The recent papers seem to expose that line as a bit too facile.  How many embryos created (and destroyed) to develop the technique before “taking it live?”  Could we work things out in animals—monkeys, maybe?  How many generations to alter, create, and follow to be sure that a late risk—such as cancer—does not emerge?  Or maybe our animal rights sensibilities stop us from putting monkeys at such risk—maybe mice will do?

The new papers are dense science.  Frankly, I can grasp the topline story but have trouble digesting all the details.  More sophisticated readers will not be so impaired.  The news report, in the English of the general public, can be read here, the Novartis and Karolinska reports read (but not downloaded or printed) here and here, respectively.

More on physician-assisted suicide

Recently, Dr. Arthur Caplan of NYU, on the Medscape service (subscription required), took on the question of whether physician-assisted suicide (PAS) should be allowed for old folks just because they are old, or because they want to die together.  There have been reports of just that.  While he supports PAS for terminal illness but objects that PAS for “suffering” in general is just too fuzzy, and therefore rejects broadening it.  An accompanying poll of doctors reported:  64-36% against PAS for old age, but 69-31% in favor of PAS for terminal illness.  As some advocates of PAS, like the editors of The Economist, have pointed out in the past, however, this distinction is highly difficult to sustain:  if someone is suffering “intolerably,” who are we to overrule that person’s wishes based on a diagnosis of the cause of said suffering?

Better is to recognize, as Neil Skojdlal noted this week, that real palliative care is not PAS, but is the ethical alternative.  And as Mark McQuain noted this week, changing the terminology confuses, rather than clarifies, the issues.  At least Dr. Lo, whose New England Journal of Medicine editorial Mark reviewed, accepted that not all physicians will accept PAS or be willing to offer it or refer for it.  He seemed to make room for that—unlike some advocates.

In a related item, Hastings center president Mildred Solomon “Calls for ‘Moral Leadership’ to Improve End-of-Life Care.”  In essence, she argues that over-emphasis on “autonomy” can be a way for doctors to abdicate their responsibility, and leave patients out to dry without guidance in end of life decision making.  She argues for a more relational approach, rethinking social supports to provide people with broader help in late life.  Makes sense.  She doesn’t address PAS in the brief piece I’m citing here, but I would certainly leave that out of the list of recommendations.

A Rose By Any Other Name…

Dr. Bernard Lo, professor emeritus at the University of California, San Francisco and present President and CEO of the Greenwall Foundation, a foundation that sponsors bioethics research, wrote one of the lead editorials in the May 31st NEJM entitled Beyond Legalization – Dilemmas Physicians Confront Regarding Aid in Dying. His main point was that regardless of the physician’s position, given the increasing number of jurisdictions where “Physician Aid in Dying” (his term, hereafter PAD) is now legal, at some point the physician will probably be asked about the process, as well as their position, and whether or not they are willing to participate, so it is better for physicians to have answers to those questions prior to that doctor-patient discussion. I think it is perhaps more important to understand the terminology in which these issues are presently being discussed so I encourage your review of the short editorial in the link before considering my following concerns.

I believe the lumping of all terminal care into the moniker PAD confuses the issue. Physicians have always participated in their patient’s care, including the death of their patients. What is novel is the expectation that physicians will hasten the death itself. A physician treating a dying patient has always been legal. What is becoming legal is physician-assisted suicide (PAS), specifically causing the death via suicide that the terminal illness has, at that point, failed to accomplish. A physician directly administering an agent with the intent to cause death should be physician homicide (PH) or at least physician manslaughter (PM), though it is unclear why the adjective “physician” should change the criminality of the event.

At one point, Dr. Lo appears to include Palliative Care within PAD but later clearly identifies them as distinct and separate options in his provision for patients with terminal illness. This is especially so given his statement that “perceived loss of autonomy and dignity is now a more common reason for requesting PAD than inadequate pain control.” If PAD simply was the preferred term for general end-of-life care then palliative care would obviously be one component. Since it is not, then Dr. Lo is really talking about PAS and he should use the term PAS rather than PAD and be honest about it.

Finally, Dr. Lo discusses the need to consider adverse outcomes “such as deciding whether to call 911 if distressing symptoms develop after lethal medications are ingested.” What does he expect 911 to do? I am assuming he wants their assistance in stopping the suicide process, nevermind that it was physician assisted. If a growing number of physicians are henceforth going to be expected to actively kill their patients, surely we can all agree to keep 911 as an emergency response unit of healthcare providers unambiguously dedicated to keeping their patients alive? A call to 911 seems a tacit admission that supporters of PAS aren’t exactly certain or in common agreement as to what euthanasia (“a good death”) or “Death with Dignity” is supposed to look like, and, perhaps more importantly, an admission that no one can control the dying process as well as they may believe they can. By the way, what does Dr. Lo mean by “distressing symptoms”? I thought the reason for providing PAS was that the original terminal process wasn’t going as desired and this was causing “distressing symptoms”. If the addition of PAS can cause more distressing symptoms, what has been gained through PAS? Certainly not euthanasia or “Death with Dignity”.

Discussing whether or not a physician should hasten their patient’s death for any reason is unfortunately a necessary debate given the present diversity of world views in our society. Describing that process in less specific terms such as “Physician Aid in Dying” does nothing to help that discussion. Like Neil Skjoldal said in yesterday’s blog entry, I also will “continue to advocate strongly against PAS, affirming God’s gift of life whenever and wherever I can.”

Physician Assisted Suicide, Again

Last month, I sat through a presentation on the ethics of Physician Assisted Suicide (PAS) in a local hospital.  I attended the presentation, not because I am unfamiliar with the arguments on the subject and ambivalent about my feelings on it, but because I wanted to observe how it was presented, what the reaction of the audience was to the presentation, and how it might affect my work as a hospital chaplain.

For some context, the state where I reside, Florida, does not have a PAS law on the books, nor, according to the “Death with Dignity” website, is it even considering one.

I found the presentation to be disappointing, in part because the participants talked past each other as if they were on a cable news program, repeating the typical talking points that have become so common over the years.  It was also disappointing because it used the classic example of a sad, horrible death story to advocate the use of PAS with the highly manipulative question, “You wouldn’t want your loved one to experience this, would you?”  No one ever seems to respond that we cannot build a law out of such experiences because hard cases make bad law, nor does anyone ever take the time to wonder what else could have been done to make the suffering patient more comfortable.  It simply is an elevation of human autonomy to a staggering height.

At the end of the presentation, the PAS advocate asked for a show of hands on people’s support/non-support of PAS.  I didn’t have the heart to count the hands, but the speakers said it was about 65%-35% in favor of PAS.  My worst fears had been confirmed.  After what I witnessed in that presentation, I have no doubt that we are headed full-speed ahead towards a civilization that will in some way systematically encourage its elderly, its weak, its sick, and its disabled citizens to make a “compassionate choice” and choose “death with dignity.”  Those of us who think otherwise are firmly entrenched in the minority.

I understand that I am not the first person to have had this experience, and in some ways I have anticipated this day for some time, but because I saw it so close to home, it still was somewhat shocking to me.   When filling out the seminar evaluation, I found the question, “How will apply what you have learned today to your current practice?”  I’m not sure what the reviewers thought, but my response was simple: “I will continue to advocate strongly against PAS, affirming God’s gift of life whenever and wherever I can.”