Neanderthal Research Subjects?

If we could clone Neanderthals, should we? Why or why not? What would the ethical pitfalls be? Would the consequences of doing of it be the problem, or would the research leading to the cloning be problematic in its own right?

Here's the article inspiring the questions, by Zach Zorich, in Archaeology, Should We Clone Neanderthals?

If Neanderthals ever walk the earth again, the primordial ooze from which they will rise is an emulsion of oil, water, and DNA capture beads engineered in the laboratory of 454 Life Sciences in Branford, Connecticut. Over the past 4 years those beads have been gathering tiny fragments of DNA from samples of dissolved organic materials, including pieces of Neanderthal bone....

There are still technical obstacles, but soon it could be possible to use that long-extinct genome to safely create a healthy, living Neanderthal clone. Should it be done?....

Two main thoughts occurred to me, reading this article.

1) Do (or would) Neanderthals fall, as a matter of jurisdiction, into the domain of regulations established to protect human research subjects? Whether Neanderthals ought to count as human is controversial among scientists (according to the Wikipedia page on Neanderthals, "Neanderthals are either classified as a subspecies of humans (Homo sapiens neanderthalensis) or as a separate species (Homo neanderthalensis)." Given such scientific controversy, it's at least not obvious that laws & guidelines set up to protect specifically human research subjects would apply. Research on non-human research subjects is covered by the laws & guidelines for animal research.

Now, the article has some interesting stuff about human rights law, which suggests that interpretation of the term "human" in that regard might be broad enough to include Neanderthals. But then, it might not — depending on the jurisdiction and the decision-maker. Also, it's not clear that the standard applied under human rights law would automatically be the standard taken up by those who administer the rules of research ethics. And even if it were, that leaves open interesting questions about just how far from homo sapiens you have to stray before you leave the domain of "human" research, for either ethical or regulatory purposes.

2) The article points to a number of technical obstacles to cloning a Neanderthal. It points out, for example, that getting Neanderthal DNA isn't enough — the DNA needs to be formed into chromosomes and situated inside an egg, for starters. But the article leaves out one other, ethically crucial part of the equation: Mom. To create a living, breathing Neanderthal, you'd need not just an egg loaded with Neanderthal DNA, you need to implant that egg in the uterus of a female of a closely-related species. In other words, a woman. So, even setting aside the question of whether a genetically-Neanderthal fetus would be a "human fetus", such an experiment would still clearly fall into the category of research on human subjects. Would an ethics board approve it?

Fitter, Faster and Stronger: Olympics Athletes as Research Subjects

While the Olympics don't officially start until tomorrow, the "anti-doping" investigation clinics are open and working well before the games begin. But this year, those who test athletes for "doping" are faced with another possible way for athletes to enhance performance: gene therapy.

Here is a link to the story, from CBC news: Gene Doping Risky for Athletes

"Some athletes and coaches will be tempted, prematurely and unwisely, to take advantage of results packaged by some as performance-enhancement 'breakthroughs,' even if they are untested in humans and the only 'breakthrough' is faster or stronger mice," the researchers wrote. The article says gene therapy has complicated international competitions like the Olympics. Online marketing campaigns target athletes with ads focusing on how treatments can "alter muscle genes … activating your genetic machinery."

Already, scientists doing experiments in lab animals have been approached by athletes volunteering themselves as human test subjects. The athletes want to be like the "Schwarzenegger mice" that have an extra copy of a gene that led the critters to become 30 per cent stronger.

Gene therapy isn't new. It's been used in a number of therapeutic ways, but in many contexts, it remains highly experimental. As a performance-enhancing agent, gene therapy has been used in animal experiments with baboons and the famous "Schwarzenegger mice" but has yet to be safely or thoroughly tested on humans.

The risk to athletes is considered potentially deadly. One of the most interesting aspects of this kind of performance-enhancing gene therapy is also the most lethal: the kinds of physiological processes that are "turned on" when this kind of gene product is injected into a person can't be simply turned off. This lack of control over the physiological processes can lead to deadly consequences, clearly demonstrated in animal studies.

A few thoughts:

In terms of gene therapy, science is moving quickly. However, not quickly enough, it seems. The vision and hope for the science are racing ahead of even the most efficient research. And this clearly can lead to unethical and, in this case, potentially deadly consequences as athletes are being used as research subjects exposed to very high-risk experimentation.

The potential for profit creates even more pressure to use the products of scientific inquiry prematurely. The interest in using experimental gene-based enhancements on athletes is quickly growing. As noted in the CBC report, an article that will appear in Science on Feb 12 will cite an Associated Press report that gene therapy products were being surreptitiously offered to athletes at the 2008 Beijing Olympics.

One of the take-away messages here is that potential profit and great hope for a product of research creates pressure to advance the science as quickly as possible, often, much too quickly. Earlier this month, we blogged about the
Wakefield case. While this is very different, there is one similarity. The strong desire for a quick answer to the question What causes autism? and the possibility for profit from such an answer meant that unethical and unsafe science was advanced overzealously, resulting in significant harm to many. In this case, the hope to make athletes as fit, fast and strong as possible (and the subsequent potential for profit from their achievements) is driving the science of gene therapy much faster than any safe, ethical lab or researcher.

[Chris has also written about this over on the Biotech Ethics Blog
- I highly recommend reading his analysis as well]

The Tragedy of the Wakefield Case

Here's an update to a troubling story I published here almost a year ago. Dr. Andrew Wakefield was a senior lecturer in the Departments of Medicine and Histopathology at The Royal Free Hospital (a teaching hospital in London) and a consultant in experimental Gastroenterology. Last year, when I published the original blog entry, Dr. Wakefield was in the midst of being investigated for medical misconduct, in a "fitness to practice" panel hearing of The General Medical Council in the UK. The hearing was centered around a Feb 1998 Lancet article in which Wakefield made various claims about autism, the MMR vaccine and inflammatory bowel diseases. Since the publication of that Lancet article (which, as of today, has been retracted by the journal), vaccination rates in the UK have plummeted and Wakefield has been viewed as the scientist "poster-boy" of sorts for the supposed link between autism and vaccination. You can read more about it in my initial blog entry here.

The longest medical misconduct inquiry ever conducted by the General Medical Council has now come to an end, and as Brian Deer of the Sunday Times reports, they confirmed more than 30 charges against Wakefield.

Here is a link to the Sunday Times story: ‘Callous, unethical and dishonest’: Dr Andrew Wakefield

The panel’s findings were astounding, both in their number and substance. More than 30 charges were found proven against Wakefield. For him alone they ran across 52 pages. Embracing four counts of dishonesty — including money, research and public statements — they painted a picture of a man not to be trusted. Other proven charges included nine of mistreating developmentally challenged children: causing invasive “high-risk” research to be carried out without ethical approval and against their best clinical interests.

The panel ruled that Wakefield caused three children to undergo lumbar punctures without clinical reason. Three more rulings said he had breached his employment contract at the hospital’s medical school which forbade him from involvement in patient care. He was also found to have shown “a callous disregard” for the “distress and pain” of children to whom he paid £5 in return for blood samples at his son’s fifth birthday party.

This is arguably one of the "worst case scenarios" we imagine in the field of research ethics. While we're appropriately concerned with a myriad of ethical problems such as ghostwriting, undeclared conflicts of interest, breaches of confidentiality and the like, conducting research on vulnerable children without ethics approval is clearly one of the worst and most tragic cases we can think of. The resultant harm in this case, however, is not limited to the children and families Wakefield used in his "research". I'm thinking of two additional harms that may well have resulted, surely in part, from the Wakefield case.

First, there is the societal effect that the condemned research has had. Vaccination rates in the UK (and other countries) have significantly decreased. The lack of clarity about this issue has polarized communities of parents with autistic children, creating "us" and "them" camps of parents and families. Serious misunderstandings abound, both about autism and about vaccination. As I said in my original posting last year, it's difficult to hold Wakefield solely responsible for these problems. However, in part, his research spearheaded this movement for many (especially in the UK) and he has continued to promote his findings, despite considerable objections and serious questions from the scientific community.

The second kind of harm I'm thinking of is harm to the research community in general. It's challenging enough for highly trained researchers and clinicians to sort through the vast collection of research articles and findings on this topic, that range from high-quality, valid, reliable and trustworthy to questionable, unreliable, invalid and simply untrue. For a lay person or concerned parent to try to sort through this topic and figure out what constitutes "good" versus "bad" data is beyond challenging. Now, this case may result in discredit and distrust of researchers, thus further "muddying the waters" for lay persons trying to figure out whose data to trust and whose to dismiss.

Privacy of Data is an Ongoing Concern

This week, just outside of Toronto, an unencrypted USB key was lost that contained the names, government-issued ID numbers and personal health information of more than 80,000 patients who visited a local H1N1 vaccine clinic.

Here's the story from CBC News:
Ont. privacy commissioner orders 'strong encryption' of health records

In December the Durham health authority, which is responsible for a large area east of Toronto, announced it had lost the medical records of thousands people after a nurse misplaced a USB key at Durham region's headquarters in Whitby, Ont. The information on the USB key, also known as a memory stick, was not encrypted. The device contained data collected from more than 83,000 patients during H1N1 flu vaccination clinics in the region between Oct. 23 and Dec. 15.

On Thursday, Ontario privacy commissioner Ann Cavoukian said Durham must ensure the safety of patient records and ordered it "to immediately implement procedures to ensure that any personal health information stored on any mobile devices [laptops, memory sticks, etc] is strongly encrypted." Cavoukian made clear in her report that she expects every health authority in the province — not just Durham — to follow suit.

As Cavoukian notes, personal health information must be kept confidential. This includes (although Cavoukian doesn't explicitly say this) personal health information that is part of research data. The safeguard that she is urging all health authorities to implement (encryption) is something that ethics review boards should be urging researchers to use in order to protect the confidentiality of research data. And this, of course, doesn't just apply to personal health information, but any research data about which a promise has been made to maintain confidentiality. We have become much more sensitive to the careful protection of health information (although this story indicates otherwise!) but there is a great deal of research that has nothing to do with health in which careful consideration must be taken to protecting confidential data or identities, as promised in many processes of consent.

Simply advising researchers to encrypt electronic data isn't enough. Granted, it's better than just protecting your data with a password. But there are more things that researchers who use electronic data must be thinking about.

There are two questions related to electronic data storage and security that ethics review boards must ask researchers to also think about if they haven't already. collection.

The first question is, where are the data being stored? Best case scenario is always to store data locally, i.e. on secure servers that never requires the data to be "moved" anywhere. Many hospitals and academic centres now have these and issue staff passwords and "space" on the servers so that data can be stored locally. Once you transport data electronically even just to a non-local server, you increase the risk of that data being lost, manipulated, leaked or corrupted. This is something that is particularly worth keeping in mind when research projects involve electronic surveys. Many electronic survey tools store data remotely, even outside of the country where the research is being conducted. Case in point: Survey Monkey. Survey Monkey has long been the choice of many researchers to collect information easily using an electronic survey. However, the fact data are stored on servers within the USA and are therefore subject to the USA PATRIOT Act means that many non-USA researchers are now choosing Canadian-based, local survey tools.

The second question is how are the data being stored? If the data are stored on a local server accessible only to the researcher and research team via a password-protected desktop computer in a securely locked office, that's a very good start. The data doesn't have to be "transported" anywhere so it's difficult to lose it and it's reasonably inaccessible to others. If, however, the data is being stored on any kind of portable device such as a laptop or memory key — as data often are — then the data must be encrypted.

It's very easy to now buy a USB key that uses encryption to store data. If you happen to lose it, the data is virtually useless to others. They're much cheaper now and hold large amounts of data.

One final strategy is to always require that researchers store identifiable information separately from other kinds of data. Coding lists, consent forms and raw data should always be stored securely and separately.

Hopefully none of these safeguards is news to most researchers and ethics review board members. They are, for the most part, not burdensome or time-consuming for the researcher. However, clearly, as the above story demonstrates, many are not paying attention to these quite easy-to-implement safeguards, resulting in deleterious effects: loss of trust, breaking promises of confidentiality, and the potential for significant harm.

Journal Editors and Conflicts of Interest

A recent story in the Milwaukee-Wisconsin Journal Sentinel points to what seems like a new kind of potential conflict of interest in medicine. We've published various stories on conflicts of interest in medicine and research before more than once — stories about ghostwriting, asking authors to declare potential conflicts of interest, about med schools tightening up their conflict of interest policies, a story on how personal relationships between drug reps and physicians and most recently, a story the appointment of a Pfizer VP to CIHR's Governing Council. But this time, the story focuses on someone in a different role with a clear conflict of interest — a journal editor.

Thomas Zdeblick, a University of Wisconsin orthopedic surgeon, took over as editor-in-chief of The Journal of Spinal Disorders and Techniques in 2002 while he was working with Medtronic (which he continued to do) in developing, researching and patenting spinal implants. And making millions of dollars in royalties for the patented spinal implants that he then wrote about and published in a number of articles over the last seven years, all published in his own journal.

Here's a link to the story, in the Milwaukee Sentinel: Journal editor gets royalties as articles favor devices

It would be the beginning of a beautiful friendship.

In the years to come, Zdeblick would receive more than $20 million in patent royalties from Medtronic for spinal implants sold by the company. And the medical journal he edited would become a conduit for positive research articles involving Medtronic spinal products, a Journal Sentinel analysis found.

Dozens of studies that mentioned Medtronic products have been published while Zdeblick has been editor. But in issue after issue, readers of the journal were not told that he was receiving millions of dollars in royalty payments from Medtronic at the same time.

Most of the time the articles, including some co-authored by Zdeblick himself about devices for which he gets royalties, had good things to say about the Medtronic products. Only on a small number of occasions did the articles find major problems with Medtronic devices.

It's clear that Zdeblick had a conflict of interest and that he was not forthright with readers about this conflict, both in his role as author and his role as editor — according to the article, his relationship with Medtronic was not disclosed in any articles or editorials. Certainly, journals do and should ask authors to declare any potential conflict of interest. And it's obvious that having a vested financial interest in the success of a device should put up a red flag for anyone assessing the author's ability to be objective about such a device. But that role — assessing the author's objectivity and asking questions about relationships — is really the role of an editor along with an editorial board and assigned reviewers. But according to the Sentinel, Zdeblick never declared his relationship with Medtronic and it seems, until now, no one asked.

While there has been plenty of discussion over potential conflicts of interest for authors and researchers, little attention has been paid to editors of journals who have a great deal of control over what research gets published. The representative for Wolters Kluwer (who publishes the journal) and the rep for Medtronic, both cited in the article, feel that there is no need for concern though. Their reassurance, however, is based on the claim that the journal is "independent and peer reviewed" through "strict processes". Processes which are controlled by the editor-in-chief, who also happens to have co-authored a number of the articles, etc. etc.

Unfortunately, it seems like it's hardly news anymore when a conflict like this is revealed. In this case, while it seems unique as we're highlighting a journal editor instead of say, a researcher or an author, it's the same theme time and time again. Lack of transparency and accountability. No one asking the obvious questions. In this case, one is left wondering about the roles of the editorial board and the reviewers who would have encountered and reviewed article after article, co-authored by the editor-in-chief, about Medtronic spinal implants. It seems like no one had any backbone, until now, to ask questions about this.

As of today, Zdeblick is still listed as editor-in-chief of the journal. We'll keep you updated on this story as it develops.

Conflict of Interest at Med Schools (podcast)

A couple of weeks ago, I was interviewed on Yoni Freedhoff's excellent Weighty Matters blog. The blog entry and podcast are here: Milk, conflicts of interest, and med-school profs.

Here's a bit from the blog, setting up the issue:

...should University professors disclose their potential conflicts of interest before lecturing students? I certainly don't remember any professors disclosing their ties to anyone during my medical school days at the University of Toronto yet it's an obligatory practice for those same professors to do so at conferences and in journal articles.

To me this seems like a dangerous double standard as one might argue that students are far more vulnerable than full fledged physicians and researchers in critically appraising data. Given the incredible power differential between professor and student and the intrinsic trust one places in the purveyors of their education I wondered about the ethics of such a lack of disclosure and so I contacted Dr. Chris MacDonald to chat about this further....

The direct link to the audio podcast is here: MacDonald on Conflict of Interest.

(We've blogged before about this issue. See: Harvard Med School Students Push for Stricter Conflict of Interest Policy.)

Should Pfizer VP Sit on CIHR's Governing Council?

Controversy has arisen over the appointment of one of Pfizer's VPs to the governing council of the Canadian Institutes of Health Research (CIHR). (For those who don't know, CIHR is the Canadian government's main agency for funding research in the area of health.)

Here's the story, as reported by the CBC: Appointment of Pfizer exec to health funding body criticized

Prominent bioethicists have expressed alarm at the recent appointment of a senior pharmaceutical executive to the Canadian Institutes of Health Research (CIHR), the government's funding arm for medical research.

They hope to have their concerns about the three-year appointment of Dr. Bernard Prigent, vice-president and medical director of Pfizer Canada, to the governing council of the CIHR addressed at a parliamentary meeting Monday....

The CBC story also refers to a petition recently begun, in opposition to Prigent's appointment. Here it is: Petition Against the Appointment of the VP of Pfizer Canada to CIHR Governing Council.

The main worry here is conflict of interest. Perception plays a big role in conflict of interest. In this regard, both the government and their critics are wrong. It's not a matter of whether Prigent will be able to avoid letting his obligations to his shareholders affect his obligations as a member of the Council. The problem is whether his job at Pfizer will jeopardize the reputation of CIHR (and more particularly its governing council) by rendering its judgment suspect. I don't know anything about Dr. Prigent & he may well be an individual of outstanding integrity. The point is, that doesn't matter. Even if he does exercise his best, publicly-minded judgment on behalf of CIHR, his presence could still render the governing council's judgment suspect.

It's also worth noting that opposition to this appointment involves 2 separable issues. One is the appointment of someone from the pharmaceutical industry to CIHR's governing council. The other is the appointment of someone from Pfizer, in particular.

So one issue is Pfizer's less-than-stellar reputation. As the CBC story notes, Pfizer recently paid a record-breaking $2.3 billion fraud settlement. And I've also blogged about just a handful of the many cases of wrongdoing at Pfizer, including here and here and here. And because of Pfizer's poor reputation, I think the petition-writers are right that Prigent is a bad choice to be on CIHR's governing council. Pfizer's reputation is not good, and so many people will justifiably be suspicious of the intentions and judgment of its senior executives. That's crucial to the worry about conflict of interest.

The other issue is whether anyone from the pharmaceutical industry could ever be on CIHR's governing council, and that I think is a harder issue, one on which the writers of the petition have overreached. I for one would need to know much more about the governing council, its mandate, and its operations, to know whether an executive from a small or mid-sized pharmaceutical company with a good reputation could be valuable in that role. "Divergence of interests" between a company's shareholders and the public isn't sufficient reason to exclude executives from that company. Nobody's interests are perfectly aligned with the public's. What matters is whether the divergence is sufficient to render an individual's advice suspect in a way that cannot be remedied through standard mechanisms used to mitigate the effects of conflict of interest (mechanisms such as disclosure and recusal). So simply working for industry doesn't strike me as an insurmountable flaw, particularly if (if!) the governing council's role makes an intimate understanding of the drug industry useful.

But the main point remains: it's very hard to support the inclusion of an executive from this pharmaceutical company on the governing council of Canada's most important health-research-funding organization.