Bioethicist Arthur Caplan comments on Pinker piece claims

In the Steve Pinker interview that I posted this morning he was highly critical of noted bioethicist Dr. Arthur CaplanArthur Caplan. I contacted Dr. Caplan out of fairness and balance to invite him to do a post/ask for any comment, etc. for this blog.

Here is what he wrote:

“Steven Pinker says;

“But Arthur Caplan, the country’s most famous bioethicist, argued that the parents of such infants would be so consumed with grief that they could not truly give consent—the kind of paternalistic argument that is all too common in this field—and that an 18-year-old with a mild form of the disease, who technically could give consent, should be enrolled instead. A strained interpretation of the magic word “consent” was allowed to trump expected harm and benefit, and the result was tragedy.”

If this is the level of Professor Pinker’s commentary on bioethics I think it fair to say his insights on the value of bioethics are sorely lacking and can be dismissed out of hand.  His comments on the Gelsinger case are apparently drawn from reading the newspapers, rather than trying to find out what actually happened.  If you are going to limit your critical insights to newspaper quotes you will surely produce lousy assessments of bioethics.  Pinker has.  For someone so self-avowedly concerned about the deleterious impact of bioethics on biomedicine past and future one would expect much much better.”

Steven Pinker interview: case against bioethocrats & CRISPR germline ban

CRISPR-Cas9 gene editing technology is red-hot right now.

It has great power for research in the lab and there are hypothetical transformative clinical applications of CRISPR too. The latter efforts could include experimental attempts at reversal of disease-causing mutations in one-cell embryos with the hope that they then grow into full-fledged, healthy human beings. Hypothetically CRISPR could also be used for pursuing human enhancement via germline genetic modification.

As a tool CRISPR is exciting and my own lab is using it for genetic studies, but from a technical perspective it’s not perfect. It can introduce a range of types of errors into the genome, with largely unknown biological consequences. To date, the first and only report of CRISPR-based modification of human embryos was arguably most notable for the problems encountered including genetic errors. However, suboptimal CRISPR methods were used so better design would almost certainly reduce risks of errors.

CRISPR raises a number of questions and has sparked many discussions. How should we handle a cutting edge biotechnology of this kind as a community of scientists? What if anything should be the appropriate role of others in such considerations including bioethicists? Should there be a temporary moratorium on clinical use of CRISPR? I tackled some of these issues in my own past piece Practical Plan for Managing Human Germline Genetic Modification. Others advocate for a more liberal perspective on the road to possible clinical use of CRISPR, focusing on the potential for great benefits.

Overall, this all might be summed up as follows: how do we balance the gas pedal and the brakes on CRISPR’s use in humans to aim for the greatest overall net benefit?

Steven PinkerProfessor Steven Pinker of Harvard has been one of the most outspoken advocates for more gas and less brakes here. Both in writing and in talks he has expressed the view that we should move forward without substantial impediments to CRISPR-Cas9. For instance, Pinker’s “get out of the way” editorial last week in The Boston Globe on CRISPR was very critical of bioethics and advocated an expeditious path forward for the research without constraints. It sparked wide-ranging discussions and even some anger from bioethicists. Update: see also this brief reply to Pinker’s interview from noted bioethicist, Art Caplan.

A few days ago I reached out to Dr. Pinker to do an interview to learn more of the specifics about his views with a goal toward increasing dialogue. For instance, I wondered if he really felt that strongly about the harms caused by bioethics that were suggested in his editorial. I want to thank him for taking the time to provide such detailed answers that make the full depth of his views on these issues far clearer here than in the past.

Knoepfler. 1. Related to your talk at BEINGS and your more recent editorial, what do you see as the appropriate role for bioethics and bioethicists in the life sciences? “Get out of the way” seems rather absolute. Can you help us understand the nuances there in your view of bioethics if any?

Pinker: There’s a difference between ethics, on the one hand, and “bioethics” and “bioethicists,” on the other. Of course everything a scientist does—everything a human being does—ought to be ethically guided. But bioethics has become a professional guild that all too often impedes sound ethical concerns rather than advancing them. Many moral philosophers—the scholars who specialize in evaluating the soundness of ethical arguments—believe that mainstream bioethics commonly trades in confused claims based on emotion and woolly thinking (see these articles by Julian Savulescu, Sally Satel, and me for examples).

Take the very foundation of ethics. You’d think it would be an obvious ethical principle that life is better than death, health is better than disease, and vigor is better than disability. But, astonishingly, so-called bioethicists have repeatedly denied these truisms, either explicitly (in the case of the country’s former bioethicist-in-chief, Leon Kass, who argued that the desire to extend life is a sign of shallowness and immaturity), or implicitly, by fetishizing sweeping rubrics such as dignity, equity, social justice, sacredness, privacy, and consent at the expense of the health and lives of actual people.

It’s not just that many bioethicists practice bad moral philosophy. It’s that they are entangled in a conflict of interest. Institutionalized bioethics has become an academic and bureaucratic industry, and they need to rationalize their existence. You hardly need a bioethicist to tell you that it’s wrong to inject typhus into twins or to withhold antibiotics from syphilis patients. But to come up with an abstruse argument as to why a parent should be prohibited from saving the life of her infant by donating a part of her liver—for that you need a “bioethicist.”

Regarding my advice to “get out of the way,” the nuances were stated, albeit tersely, in the article. The first is that a truly ethical bioethics must weigh the benefits of any restriction on research against the harm that will be caused to the vast number of people who would benefit if the research proceeded expeditiously. Savulescu puts it starkly: “To delay by 1 year the development of a treatment that cures a lethal disease that kills 100,000 people per year is to be responsible for the deaths of those 100,000 people, even if you never see them.”

The second is that a truly ethical bioethics should justify any restrictions on research with rigorous, defensible arguments about benefit and harm, not with moralistic grandstanding, science fiction dystopias, perverse analogies to Nazis and nuclear weapons, esoteric theories pulled out of the air, or freak-show scenarios like armies of cloned Hitlers, people selling their eyeballs on eBay, or warehouses of zombies to supply people with spare organs—all of which I’ve heard in these debates.

And as I wrote, no one questions the need to protect patients and research subjects from exploitation or harm. If there are flaws in the existing safeguards, as, for example, Alice Dreger argues, the safeguards should be fine-tuned or re-engineered. This is not the same as giving more power to the bioethocrats. A great deal of bioethical argumentation has nothing to do with protecting people. It rather cooks up reasons why consenting adults should be prohibited from doing things that help them or others while harming no one—a prominent example being recipient-solicited or incentivized organ and tissue donation. And establishment bioethics has caused preventable harm. Most infamous is the case of Jesse Gelsinger, the young man who died in a Phase-1 trial of gene therapy in 1999. Common sense would say that the experimental therapy should have been tested for safety on infants with a severe form of the disease who would have died anyway. But Arthur Caplan, the country’s most famous bioethicist, argued that the parents of such infants would be so consumed with grief that they could not truly give consent—the kind of paternalistic argument that is all too common in this field—and that an 18-year-old with a mild form of the disease, who technically could give consent, should be enrolled instead. A strained interpretation of the magic word “consent” was allowed to trump expected harm and benefit, and the result was tragedy.

Today mainstream bioethics gets in the way on a massive scale. The most obvious example is Institutional Review Boards. They are blatant abridgments of free speech, convenient weapons for fanatics to wield against people whose opinions they don’t like, and high-volume red-tape dispensers which bog down research while being unnecessary or even harmful to the protection of patients and research subjects. (See the Illinois White Paper and American Association of University Professors reports on IRB mission creep, David Hyman’s “The Pathologies of Institutional Review Boards,” and the new books The Ethics Police by Robert Klitzman and The Censor’s Hand by Carl Schneider). Regulations on confidentiality and consent to use data and tissues have also gone way overboard. The future of medicine hinges on the use of massive, open-access datasets to find signals in the noise. If every byte has to be multiply certified for consent and privacy, or even destroyed after a few years, no matter how inconsequential to the person who contributed it, then huge numbers of future patients will suffer or will fail to be helped by our faulty knowledge of the real effects of treatments.

There is, to be sure, an important role for bioethics. Satel puts it well: bioethicists at their best are “scholars who study the intellectual and social history of value controversies in medicine and biotechnology. They can teach us about the technical and cultural antecedents of modern debates and show us how to engage in disciplined moral inquiry.  They are skilled at drawing conceptual maps of the dilemma at hand while enumerating various ways to resolve it.”

Knoepfler. 2. Forgetting bioethicists entirely for the moment, prominent scientists such as Jennifer Doudna, David Baltimore, and others have publicly called in unambiguous terms for at least a temporary moratorium on clinical applications of human germline editing technology. Do you disagree or agree? Why?

Pinker: Disagree. The specific harms they warn against, such as inducing cancer, mutations, or birth defects in the unborn child are already ruled out by a plethora of existing regulations and norms. Obviously we shouldn’t mess around with embryos in ways that have a significant probability of producing a sick or deformed child with no compensating benefit. But why do we need a new, across-the-board ban on an entire method to rule out what’s already ruled out on the uncontroversial grounds of protecting individuals against foreseeable harm? The authors seem to be acquiescing to the yuck-factor that surrounds the very idea of germline modification, if for no other reason than to draw a firewall around their own research programs, which are restricted to the genetic modification of somatic cells. But scientists should work to dismantle irrational taboos, not indulge them.

First, the idea that there is some sacrosanct entity called “the human germline,” such that deliberately manipulating it would violate this sanctity, or restrict the freedom of future generations, or alter the species in unprecedented and frightening ways, is biological nonsense. No two people, not even monozygotic twins, have the same germline. Each of us introduces dozens of random mutations into our germlines, often multiplied by voluntary choices such as exposing ourselves to mutagens like tobacco smoke or fathering a child in middle age. And we affect the genetic makeup of our offspring, and the species, every time we choose to have unprotected sex with one partner rather than another. So even if it did come to pass that some people edited out disease genes, or (far less likely—see below) edited in enhancement genes, it would be a droplet in the maelstrom of naturally churning genomes.

Second, a ban or moratorium would only reinforce the pernicious aura of dread that surrounds genomic modifications. This is the dread that incites across-the-board opposition to genetically modified organisms and that underpins the bogus moral arguments against cytoplasmic donation for mitochondrial disease (the so-called three-parent babies—another case in which so-called bioethical concerns increase rather than decrease death and suffering). And the spurious ideal of germline sacredness could compromise the treatment of disease in other ways. Though lots of things went wrong in the Gelsinger case, one complication was the decision to administer massive doses of the viral vector directly to his liver, with the risk of lethal inflammation, rather than systemically, out of the fear that (God forbid!) it might introduce the needed gene into his sperm-forming cells. That’s probably not what killed Gelsinger, but it did kill a monkey in a safety trial, and this germlinophobia could certainly endanger gene-therapy patients in the future.

Third, germline editing could have direct benefits in a number of scenarios: to parents with disease genes who don’t produce enough viable embryos for preimplantation genetic diagnosis (especially when more than one such gene is involved, which multiplies the number of necessary embryos); to parents who both are homozygous for some recessive disease gene (not far-fetched given how often people meet each other through support groups); if future data were to show that PGD babies have compromised longevity or health; and in other scenarios that perhaps we can’t imagine. For these reasons Savulescu, with Chris Gyngell, and Henry Miller with Drew Kershen argue that research on germline editing is not only morally permissible but morally imperative.

Knoepfler. 3. You appear relatively confident in future benefits of new biotechnology such as CRISPR to millions of people, but you seem very skeptical of the risk predictions that you described as “speculative harms”. What makes you so confident of benefit and at the same time so skeptical of risks? If us humans struggle generally at accurately predicting outcomes of biomedical science, why should there be a more accurate expectation of benefits as opposed to risks?

Pinker: No, this is wrong. Though it’s certain that the biomedical research enterprise as a whole will deliver benefits to billions of people, we can have no such confidence in particular technologies. That’s why we need a diversified research portfolio, without arbitrary bans. If you ban something, the probability that people will benefit is zero. If you don’t ban it, the probability is greater than zero.

As for the potential harms, they are far too nebulous to justify a ban or moratorium. Far from being confident in the power of gene editing, I’m on the record as being skeptical that we’ll ever see genetic enhancement of babies—the outcome that the prohibitionists and moratoristas dread and that many bioethicists blithely assume is inevitable. (For example, in 1999 Caplan announced that before the end of this century “We will see many children made by the artificial creation of embryos…This prediction is 100 percent certain.”) The prophesy of designer babies ought to be a relic of the early 1990s, when people thought there was “A Gene For” this or that talent. We now know that heritable psychological traits such as intelligence and personality are the product of hundreds or thousands of genes, each with a tiny effect, many of which may have harmful effects as well, such as an increased risk of neurological disease or cancer. With each enhancement gene providing a nugatory benefit and a non-negligible risk, and with the editing process itself imposing risks, it’s unlikely that today’s morbidly risk-averse helicopter parents will take a chance at enhancing a child—they won’t even feed their babies genetically modified applesauce! And that’s assuming that such a procedure ever got to the point of clearing conventional safety hurdles, which is far from likely. Add these risks to the fantastic expense and tribulation of IVF compared to good old-fashioned sex, and one should conclude that widespread genetic enhancement is too unlikely a possibility to worry about. And that’s assuming we should worry at all. There is, in addition, the argument (from Savulescu, the transhumanists, and others) that if enhancement were ever feasible it would be a good thing, not a bad thing—or at least a matter of individual freedom rather than government coercion.

Now, the story is different for editing out disease genes. There are more ways that a complex system can break down than that it can work better, and it’s easier to fix a defect than engineer in an improvement. Also, the benefits are very different for preventing death and disease (huge) than for implementing an enhancement (minor). So the possibility that germ-line editing might prevent disease in the future is well worth exploring.

Knoepfler. 4. Congress recently held a public hearing on human germline modification and is considering a legal provision to block editing of human embryos. What do you think of having such a hearing and the possibility of a restrictive legal provision? You said to bioethics, “get out of the way”. Should we scientists say the same thing to lawmakers? Why?

Knoepfler. 5. There is likely to be a NAS meeting sometime late this year on human germline modification by such technology as CRISPR-Cas9 and mitochondrial transfer (3-person IVF) in the spirit of the 1975 Asilomar meeting. Do you think this new meeting will achieve positive outcomes such as a white paper that appropriately has a vision for the future? What if the consensus is for a moratorium? Could you support that?

Pinker: I’ll answer these together. I think that scientists should reiterate the principle that no experiment should be permitted which imposes an unreasonable risk of an illness or birth defect on an individual. But no, I don’t think that scientists should support a ban or moratorium on germline genetic editing, for the reasons I set out in my answers to questions 2 and 3. Though the Asilomar recommendations have long been a source of self-congratulation among scientists, they were opposed by a number of geneticists at the time, who correctly argued that they were an overreaction which would needlessly encumber and delay important research. And the journalist Victor McElheny reminds us that the recommendations sowed a panic which came perilously close to shutting down some of the nation’s major laboratories, a danger he argues we are now in danger of repeating.

That having been said, I recognize that the political arena follows different rules than scientific and intellectual discourse. The scientists who lead major research institutions and deal with politicians and other public figures have to master the arts of compromise, tact, euphemism, and strategic deal-cutting. That’s how democracy works, and I’m grateful to the scientific leaders who carve out a space in which the rest of us can flourish. There are things they may believe but can’t say. But it’s important that someone says them, and that’s how I see my role in these debates.

As iPS cell studies in humans approach, accessible relevant pre-clinical data remains minimal

When are iPS cell-based therapies ready to be tested in actual people?

It’s the million or perhaps even billion dollar question of today in the stem cell field.

I realize that perhaps it is also a dangerous question, politically-speaking, for me to ask in a public forum, but patient lives as well as potentially the progress of the entire iPS cell field are at stake.

So someone needs to start an open discussion about this topic. People are certainly talking about it behind the scenes asking questions such as:

  • Are iPS cells being raced too fast to the clinic?
  • Who will be the “winner” in terms of commercializing iPS cells?
  • Will the iPS cell field find itself in a gene-therapy, Jesse Gelsinger kind of situation soon?

Tragically, Gelsinger and a few other patients died from what one might say was a gene therapy treatment that was not ready for prime time and from a side effect not anticipated by researchers based on animal studies. The gene therapy field was crippled for two decades.

Masayo Takahashi ISSCR talk

We all want to get stem cell-based medicines to patients who need them as soon as possible, but there is such a thing as going too quickly.

There are quite a number of teams around the world working to make iPS cell-based therapies a reality in humans, but the team at the forefront is in Japan led by Dr. Masayo Takahashi.

How strong are the Japanese team’s pre-clinical data on the iPS cell-based retinal pigmented epithelial cell (RPE) therapy for macular degeneration (MD), the leading cause of blindness in the world?

No data has been published so it is a tough question to answer.

Six months ago I asked whether things were moving too fast on moving iPS cells into people? 

It is an even more apt question today in April 2013 as the first ever transplantation of the first iPS cell therapy into human patients seems ever more imminent in Japan. The proposed study has already been approved by some regulators and is awaiting approval from one last regulatory body in Japan.

Even though the pre-clinical data have not been published on this study so far, there is at least a small window into that world.

Takahashi gave a lecture at the ISSCR 2012 Annual Meeting on her lab’s pre-clinical work on iPS cell-derived RPEs for treating MD. ISSCR made the video of Takahashi’s very important talk available on the web here, but only to ISSCR members. Fortunately I watched it before its run was supposed to end.

The talk was outstanding, just not enough to support in human iPS cell studies in the near future to my way of thinking.

As mentioned above, none of the data have been published yet as well. Interestingly, three leaders in the stem cell field that I queried all essentially told me the same thing when I mentioned the lack of published pre-clinical data on safety of transplanted iPS cell-based therapies using clinically relevant transplantation paradigms:

“They do not have to publish their data and in fact why would they when that would give their competitors an advantage?”

There is a dilemma here. On the one hand, data are viewed by for-profit companies and scientists as proprietary and valuable assets. In the iPS cell field those assets could be measured in billions of dollars. On the other hand, openness protects patients and the field more generally. How do we find the right balance?

One other earlier published study by a different team was encouraging on safety based on studies in mice, but far from strong enough to support studies in humans.

Of course prior publication of pre-clinical data is not specifically required for regulatory approval to start a clinical study, but given the historic nature of what could be the first ever in human iPS cell study, it would be extremely wise in my opinion for teams to publish their work first.

Since the data is in fact not published yet, how strong were the data in Takahashi’s talk?

In her ISSCR seminar given 10 months ago, Takahashi presented some safety data from mice on the RPEs, but not from larger animals such as monkeys. To be clear, larger animal studies are not also not required, but this is an important distinction since larger animals are sometimes better models for humans and also because there were some anecdotal reports that said she had in fact presented larger animal pre-clinical safety data at the ISSCR meeting.

The only large animal data I saw in the web-broadcast of her talk was that an autologous iPS cell-based transplant into monkeys survived and there was no inflammation, but I believe that she later mentioned that this was only done on 1 monkey. Allogeneic iPS cell-based transplant in a monkey was rejected.

From murine safety studies of the iPS cell-derived, purified RPE, Takahashi reported that no tumors were observed using RPE made from 3 different human iPS cell lines. There are some major limitations to how far one can go with this data though.

Three key limitations of these safety studies come to mind:

  • The studies were relatively short-term, only going out to ~6 months.
  • The data presented were only on 5-7 mice, a very low number per parental iPS cell line.
  • The safety testing that was presented consisted only of subcutaneous teratoma assays (assuming I understood this correctly from the talk) and not eye transplant safety data.

My understanding from Geron’s and ACT’s experience at the FDA here in the US is that the short-term nature of this iPS cell safety data along with very low animal numbers and lack of a clinically-relevant transplantation paradigm would be far from satisfying regulators here in the US that human studies should begin. Geron used thousands of rodents, while ACT used hundreds. Follow up was far longer than 6 months in some studies. Both teratoma studies as well as studies using the relevant transplantation modality (e.g. in the eye and spinal cord) were conducted.

Of course the proposed study would not take place in the US so the point is moot from a regulatory standpoint, but it still is illustrative of how minimal the data supporting the study seems to be at least from what is publicly available.

Much more data might and probably does exist, but remain private. 

Indeed, it is probable that the Takahashi team and/or affiliated for-profit teams (the latter being a key point and more on that in future posts) have more data now and/or beyond what was presented at ISSCR 10 months ago. That is my hope. If so, I encourage them to publish it all. It does not have to go into Nature or Cell Stem Cell. Just get the data out there. It is certain to be a high-impact paper regardless of the journal.

Unless there are a lot more, longer-term studies (e.g. 1 year or even longer) done on many more animals (e.g. 100s) yielding equally encouraging safety results specifically on transplants in the retina (not just sub-Q teratoma assays), I am deeply concerned as to whether the field is really ready to make the jump to transplanting iPS cell-based therapies into people any time soon.

I realize that the regulatory system in Japan is different in terms of the process for studying potential medical therapies. Takahashi is proposing a clinical study, which is perhaps more akin to a Phase 0 here in the US and to be distinguished in Japan from a clinical trial, which might come later.

But in any case the bottom line is that  patients (and the field) would be put at risk unless there is far more rigorous pre-clinical animal data.

The field has to hope that the data presented at ISSCR 2012 were just the tip of the iceberg and that much more thorough and compelling data exists below the surface. Further, it is not just the Japanese team, but also many others that are moving quickly to get iPS cell-based therapies into humans for a variety of conditions…..how strong are pre-clinical data?

Who knows. They remain generally unpublished and unavailable for informed review by anyone but regulators.

I hope the iPS cell-based therapies come to fruition as safe and effective for blindness and other diseases, which would be tremendous advances for medicine, but let’s not kid ourselves: the risks are substantial and a lack openness just increases risk further in my opinion.