Too much optimism at NIH: Opinion
One researcher's reservations about Francis Collins's nomination as head of the agency
I am not celebrating the nomination of Francis Collins to head the National Institutes of Health (NIH). My modest level of enthusiasm does not stem from concerns relating to his scientific accomplishments, administrative talent, political astuteness, or ability to communicate with average citizens, all of which are impressive. Nor do my reservations primarily follow from his religious commitments, although I disagree with a number of his assertions regarding the relationship between science and religion as well as some of his claims about the relative merits of evolution-related science versus non-scientific belief systems in explaining human behavior.
My concern about Dr. Collins assuming the leadership of the NIH relates principally to the content of his claims for the medical promise of genomics, especially pertaining to therapy, and his assertions regarding the coming era of personalized medicine, which have included a promise of what he termed "medical nirvana" in responding to one radio interviewer. Where some see his enthusiasm for genomics as merely linkurl:"irrepressible optimism";http://www.sciencemag.org/cgi/content/full/324/5934/1504 (1), I see insufficient concern with informing the public about biomedical realities -- specifically, this should be done in a more balanced manner, preserving hope while not generating unrealizable expectations. As Gardiner Harris put it in linkurl:The New York Times;http://www.nytimes.com/2009/07/09/health/policy/09nih.html?ref=health of July 9 (presumably conveying the views of scientists not willing to be identified), "Dr. Collins cannot be blamed for the unexpected scientific hurdles facing genetic research, but he played an important role in raising expectations impossibly high" (2).
So, before Dr. Collins takes the reins of the NIH, I would want to receive, and our representatives in Congress should demand, satisfactory explanations for many statements such as the following from an article he co-authored in the December 1999 Scientific American (3):
"Within 20 years, novel drugs will be available that derive from a detailed molecular understanding of common illnesses such as diabetes and high blood pressure. The drugs will target molecules logically and therefore be potent without significant side effects" [emphasis added].
This statement is surprising, and was so at its publication, regardless of the effectiveness of genomics in identifying genes associated with diseases. The notion of drugs without side-effects (even a single drug!), is scientifically dubious if not preposterous. Molecules can never be absolutely specific for other molecules (4) and even if molecular interactions were absolutely precise, the inhibition or activation of one cellular or physiological process frequently affects functionally linked processes not intentionally targeted by the therapy. Even those with no special training in or knowledge of biology or medicine should be skeptical of such a prediction if only because every drug they have ever taken or heard about has been associated with significant side effects at some doses in some people.
Consider the experience already in hand for drugs that target specific molecules "logically." While Vioxx worked as intended to inhibit a particular enzyme involved in inflammation, linkurl:cyclooxygenase-2,;http://www.rxlist.com/script/main/art.asp?articlekey=31218 it had a very long list of side effects including, most importantly for the lawsuits it engendered, increased risk for heart attack and stroke (5, 6). Epogen, an enormously profitable drug that effectively binds to a particular blood cell receptor, nevertheless has serious side effects, such as enhanced tumor growth in some cancer patients, some of which took years to fully appreciate (7).
Quoting further from the same paragraph quoted above:
"Drugs such as those for cancer will routinely be matched to a patient's likely response, as predicted by molecular fingerprinting. ... When people become sick, gene therapies and drug therapies will home in on individual genes, as they exist in individual people, making for precise, customized treatment."
Collins's enthusiastic pitch for the notion that in the future drugs will be matched to the genotypes of individual patients is supported by some current examples in which particular treatments are avoided for patients possessing particular genes or are varied in dosage as a function of genotype at one or a few loci. However, he tends not to acknowledge the limitations of even these examples.
An illustrative case is provided by the anti-retroviral drug, abacavir, used to treat AIDS. Abacavir causes a dangerous hypersensitivity reaction in patients with a particular gene involved in immune responses. However, based on recent studies, only about 55% of the individuals with the relevant gene are expected to exhibit the undesirable response on exposure to the drug (8, 9). Therefore, as many as 40-45% of those testing positive for the gene, and who could potentially use the drug safely, will receive an alternative agent. In other clinical situations, there may not be so many alternative agents of comparable effectiveness so that the inefficiency in such a genetic test, even if justified on balance, could incur its own costs in non-optimal treatment.
The bolder implication of pharmacogenomics hinted at in the above quote, that everyone will receive genotype-based customization of treatment for whatever ails them, is problematic in at least two fundamental respects. Scientifically, it is doubtful that safe and effective genotype-specific drugs will be found to meet every need. Financially, it is difficult to imagine that pharmaceutical companies will be willing to invest the massive sums required to create such drugs for ever smaller genetically-constrained markets.
Another disturbing aspect of Collins's genomic advocacy is his tendency, shared with some other proponents of genomics, to attribute to recent studies of human (or other) genomes insights that were in fact already arrived at through earlier genetics research. Consider the following quote from an article in The New Republic in 2001 (10): "Fortunately, ten years of intensive study of the human genome have provided ample evidence that these fears of genetic determinism are unwarranted." Anyone familiar with the term "genetic determinism" may have encountered one of the many articles or books (e.g., 11-13) that significantly predated the conclusion of the Human Genome Project and that were devoted to documenting the potentially complex relationships between genotypes and phenotypes.
Collins and his co-authors admit as much in what follows, but the statement quoted above will conceivably cause unwary readers to credit our understanding of the subsequently described instances of "genes not being everything" to the power of genomics. For example, the authors of the article note that sickle cell disease, initially regarded as a so-called single-gene defect, can vary in severity even though the same disease-associated alleles at the hemoglobin beta-chain locus are present (in two copies) in the individuals with the clinically more and less severe forms of the condition. This interesting and important insight can be traced back to a study from 1978 (14).
So, while Dr. Collins has many impressive credentials, talents, and skills relevant to directing the NIH, his tendency to make dubious claims for the future benefits of genomics is unsettling. The director of NIH should be a reliable and realistic source of medical information if the entire biomedical research enterprise is to remain credible. Therefore, in the future, Dr. Collins should harness his intellect to control his enthusiasm so that he is more realistic in his public pronouncements regarding improvements in medical care that will undoubtedly develop in part from new insights into human genetics and genomics.
linkurl:Neil Greenspan;http://path-www.path.cwru.edu/information6.php?info_id=22 is an immunologist and professor of pathology at the Case Western Reserve University School of Medicine and director of the Histocompatibility and Immunogenetics Laboratory of University Hospitals Case Medical Center. The opinions expressed above are solely his own and do not reflect official views of the institutions with which he is affiliated.
1. J. Couzin-Frankel, "The promise of a cure: 20 years and counting," Science, 324:1504-07, 2009.
2. G. Harris, "Pick to lead health agency draws praise and some concern," The New York Times, July 9, 2009.
3. F.S. Collins and K.G. Jegalian, "Deciphering the code of life," Scientific American, 281:86-91, 1999.
4. B. Alberts et al., Molecular Biology of the Cell, Second Edition, Garland Publishing, Inc., New York & London, 1989, p. 94.
5. R.S. Bresalier et al., "Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial," N Engl J Med, 352:1092-102, 2005. Erratum in: N Engl J Med, 355:221, 2006.
6. L.E. Levesque et al., "Time variations in the risk of myocardial infarction among elderly users of COX-2 inhibitors," CMAJ, 174:1563-69, 2006.
7. M. Henke et al., "Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial," Lancet, 362:1255-60, 2003.
8. S. Mallal et al., "HLA-B 5701 screening for abacavir hypersensitivity," N Engl J Med, 358:568-79, 2008.
9. Personal communication, Simon Mallal, March 31, 2009.
10. F.S. Collins, L. Weiss, and K. Hudson, "Have no fear. Genes aren't everything," The New Republic, June 25, 2001.
11. R. Hubbard and E. Wald, Exploding the Gene Myth: How Genetic Information Is Produced and Manipulated by Scientists, Physicians, Employers, Insurance Companies, Educators, and Law Enforcers, Beacon Press, Boston, 1993.
12. R. Lewontin, Biology as Ideology: The Doctrine of DNA, HarperPerennial, New York, 1991.
13. R. Lewontin, The Triple Helix: Gene, Organism, Environment, Harvard University Press, Cambridge, MA, 2000.
14. R.P. Perrine et al., "Natural history of sickle cell anemia in Saudi Arabs. A study of 270 subjects," Ann Intern Med, 88:1-6, 1978.
**__Related stories:__***linkurl:Collins seen as boon to NIH;https://www.the-scientist.com/blog/display/55820/
[9th July 2009]*linkurl:The Human Genome Project +5;https://www.the-scientist.com/article/display/23065/
July 22, 2009
\nI appreciate the author?s alert on Dr Collins?s tendency to overstate his enthusiasm when it comes to potential outcomes of genomics. I was not aware since I have not followed Dr Collins?s endeavors.\n\n Giving hope to patients and families is, in my view, part of what medicine is about , as well as an expression of the scientific community?s commitment to understanding disease and finding solutions. But giving false expectations is not fair to the patient, to the families and to the scientific community itself\n\nI entirely support the author?s plea and hope that, if confirmed, Dr Collins makes an effort in correcting himself of this tendency.\n\n
July 22, 2009
I agree very much with what Dr. Greenspan's concern. However, in terms of the possibilities of "personalized medicine", this is not a new idea nor a new practice. "Personalized medicine" has been practiced thousands of years in traditional Chinese herbal medicine. The doctor would order various combinations of herbs depending on each individual's condition. "Not all the headaches are the same". Of course, each diagnosis and each medicine preparation would take much longer time than our western medicine's going through the clinics or pharmacy windows. Can "personalized medicine" be done based on individual's genetic makeover? Possible. Does the big Pharma need to cater to "individual medicine"? Not necessary. As long as each individual component (medicine) can be measured at the pharmacy in a variable fashion (e.g. like "powdered" medicine being measured in variable quantity and mixed carefully), that is a possible way to apply "personalized medicine". Of course, this wild idea will have to be accepted by common people who are willing to take "powder" instead of pills. Or, the pills will be made in various quantities---e.g. Aspirin from 50, 100, ...250 mg, so the doctors can perscribe in "combo" of medication depending on each individual's illness/health to avoid severe side effects and to gain the best treatment. Just two-cents worth of thought here.
July 22, 2009
I agree with the problems of overstating the promises of medical research. But, why are you picking on FC? Seems to me that most "big name" scientists overstate the case for their research. I have been hearing promises about that a vaccine for AIDS is just 10 years away for 25 years.\n\nOr that Stem Cells will cure Parkinson's Disease and let the lame walk.\n\nOr that monoclonal antibodies will cure Cancer (well we do have one or 2 I guess for very specific cancers)...\n\nI can't imagine NIH getting getting significant increases in its budget by telling Congress...Give us lots of money and we can study exciting projects that will probably never help a single American citizen in our lifetimes. \n\nIf anyone should be an overly optimistic booster of science it should be the NIH and Institute Directors.\n
July 22, 2009
It sounds like the Perfect NIH Director for Dr. Greenspan would be the teacher played by Ben Stein in Ferris Bueller's Day off.\n\nBueller?... Bueller?... Bueller?
July 22, 2009
\n\nI think that\n\n1) the fact that "big names have overstated the case for their research" does not justify that Dr Collins follow their example.\n\n2) Being a greatly optimistic booster of science is compatible with seemingly great realism on the steps and progress we are making in our research at any time in point.
July 22, 2009
Rafaela,\n That might work in a grant app renewal or a key note speech at a major meeting. But, we are talking getting Congress to cough up big dollars.\n\nThey want to hear about roads that will be built, fighter jets purchased and diseases that will be cured.\n\nOne of the NIH Director's major jobs is getting dollars from Congress. If you want big new money for stem cell research you better promise amazing breakthroughs. Most of Congress is not impressed by the discovery of an exciting new protein even if it leads to a Nobel Prize. They want results. Or at least promises of amazing results. \n\nI am usually disgusted by the overselling of science too. But, if anyone should be doing it it is the NIH and IC Directors.
July 22, 2009
\nThanks anonymous. I don?t have experience with Congress at all but it seems to me that when Congressmen do not deliver in their promises, the public is reluctant to re-elect them and even develop cynicism on the truthfulness of their representatives and the political process itself.\n\nI am all for the biggest possible investment in science because this is what I think the country needs. But we?d better make sure that we deliver on the promises we make. I would hate having the public disengaged and questioning along the road on the use of investing in science. It?s just a concern. I understand and take your point since you appear to be talking from experience. \n\nThanks again.\n\n
July 22, 2009
dr. greenspan almost sounds like a luddite to me. not that he shuns technological advances per se but his doubt in their impact on medicine. i would say dr. collins' main error is probably in his timeframe--the pharmacogenetic revolution will take more than another 10 years. my guess is it will take 100 years for it to predominate medicine. however, to deny that it will happen at all is the preposterous assertion. it already is happening in many instances with cancer, antithrombotic and many other therapies. and to think that pharmaceutical companies would be unwilling to participate in this is naive.\n\nfurthermore, cox-2 inhibitors are a pretty weak example of what dr. collins is talking about. we are in a nanotechnology revolution with targeted drug therapies in minuscule doses. cox-2's were probably a first step. and please don't misquote dr. collins--he said no "significant" side effects, not no side effects at all. i live near georgia tech which has a large nanotech program so i would urge you to look into the projects in the medical realm that institutions like this are involved in. personalized medicine is the future as collins rightly predicts. it is just going to take much longer.
July 22, 2009
Each of us can come up with anecdotes where broad simplified claims are irritating to us 'experts' (except of course when we make the claims). All of us, Dr. Collins included, should be aware of the nuances but find those nuances difficult to communicate in a sound-bite to the general audience. \n\nYes, many of Dr. Collin's claims cited in the article may be overly rosy. But one has to consider the audience. Does he overpromise? Certainly sometimes, as we all do. But I really don't know which claims will ultimately prove to be right or wrong. I have seen enough over the years to accept that I don't have a crystal ball. When leaps happen, advances occur with breathtaking speed. Honestly, a good dose of optimism is what the culture of the NIH needs to inspire the innovations that lead to those breakthroughs.\n\nOn the whole, Dr. Collins is a proven, capable researcher and administrator with a vision for the future of biomedical research. I'll take that over a cautious beaurocrat hedging his/her bets in order to adhere to the middle of the road. Since I see nothing in Dr. Collin's optimisim that that tip my opinion of him to reckless, I believe Dr. Collins will be a strong leader. I wish him the best of luck.
July 23, 2009
While everybody is or should be entitled to his or her personal beliefs, there are limits. I seriously question the intelligence and abilities of a scientist with Collins' religious beliefs.\n\nI would not take a physicist who believes in magic carpets particularly seriously. For the same reasons, I question Francis Collins.\n\nHe is living proof that academic degrees have no intrinsic value.\n\nHis optimism is ridiculous at best. DNA is a recipe for proteins. It does make sense that some predictions can be made from intimate knowledge of someone's genetic material. However, because of the evolved nature of humans, making precise and reliable predictions about how a particular human will react to a particular therapy is essentially science fiction. Maybe, just maybe, this may become possible one day. However, it is extremely unlikely that this will happen within the lifetime of anybody alive today.\n\nThink about it: we are not even able to create computer operating systems that don't crash, and that don't make errors. The human biological system is so much more complicated than even our most sophisticated computer systems. There is just no rational basis for Collins' assertions.\n\nCollins may be a good administrator, but I do question his abilities as a scientist.\n\nAs for the reason to single out Francis Collins: he is going to head the NIH. That puts him in the spotlight and rightfully so, since his influence can be tremendous in that position.
July 23, 2009
Enthusiasm and modesty are not incompatible. What surprises me is that someone of Collins's religious turn of mind would display such hubris. Scientific triumphalism and scientific millenialism went out of fashion about a century ago. What separates science from religion is not rationalism, but empiricism. Rational drug design was being touted as The Answer twenty years ago. In spite of a few notable successes, it's been almost as big a disappointment as gene therapy. A lot of people in drug discovery have thrown in the towel and gone back to the more empirical approach of shotgun screening.
July 24, 2009
How did Dr. Collins respond when you expressed these reservations to him? I prefer speaking to someone first rather than speaking about him behind his back. More polite, and also more constructive and efficient. \n\nI also prefer giving someone a chance to benefit from constructive criticism, rather than automatically not hiring him (or firing him!) when one has a concern.
July 24, 2009
I think that having reservations is part of the inquisitive human process. \n\nI also believe that having reservations is a necessary control when looking for maximizing optimal function. \n\nWho has not ever had reservations about her own experimental designs ?. Is it going to work?. Am I missing something here?.\n\nI love children. Some months ago, I was playing puzzles with a beautiful 4-yr-old girl. Her parents just brought her a huge puzzle that, in my view, was very hard and overpassed the abstraction?s abilities of children of her age.\n\nShe started putting it together and was hesitant as to how to proceed. I said: ?Lily, perhaps we should look at the model that is depicted on the box. That way we might do faster?.\n\nShe looked at me and said: ?How do you know that the model on the box is right ?. Sometimes boxes have wrong things?.\n\nLily had reservations. I did have reservations too on her success because the puzzle was very hard.\n\nIn spite of my reservations, Lily put the puzzle together beautifully.\n\n
July 24, 2009
"Personalized medicine" is not new. Real personalized medicine is traditionally Chinese Medicine, which emphasizes ?personalization?, "integrity" and targeting both ?cause? and ?symptom? rather than ?symptom? only. Therefore, each patient with the same disease might be subjected to totally different therapeutic modes. Genomic signature might strengthen ?personalized medicine? with respect to modern medicine. However the theory of TCM represents real ?Personalized Medicine?.
July 24, 2009
I don't believe that Dr. Collin's enthusiasm for the future should have any bearing on whether or not he should lead the NIH. Sure, he may be making some unrealistic expectations, but why not set the bar high? It may take more like 50 years for personalized medicine to grab a foothold and become something that more and more patients are exposed to, rather than his 20, but the enthusiasm of a leader is something that is needed.\n\nPeople will look to Dr. Collin's and think 'wow, if hes so enthused about this, maybe it can be done'. I think its an admirable trait rather than one to be admonished. Like they say, aim for the moon and at the least, you'll land among the stars.\n\n
July 27, 2009
I don't know if the author, Neil Greenspan, is related to the former Federal Reserve Chair, Alan Greenspan, who coined the title of my post. It seems to me that over-enthusiasm can lead to media hype and unrealistic expectations from the public. The Human Genome Project has identified the blueprint of the body, but it will take major breakthroughs to figure out how epigenetics actually makes it work. Meanwhile, Congress wants to spend millions on clinical trials, despite statistics that show 8-9 out of 10 of them fail to produce useful results.
August 14, 2009
Futuristic opinions always had a major role in scientific achievement from past to present\n\nHowever, Francis Collins, is known as a scientist who has a strong relationship with church, provide lots of feasibilities for scientific investigations via this privileged situation. No one could contradicts his actions.
August 17, 2009
\n\n?Futuristic opinions always had a major role in scientific achievement from past to present.\nHowever, Francis Collins, is known as a scientist who has a strong relationship with church, provide lots of feasibilities for scientific investigations via this privileged situation. No one could contradicts his actions.?\n\nDear anonymous,\n\nI don?t know if The Scientist does not allow you for clarity in your posting. I do know that The Scientist is concerned about giving out information that could be considered libel. \n\nI think that for the sake of a productive discourse you should be permitted explaining a little bit more on ?? provide lots of feasibilities for scientific investigations via this privileged situation ?, as well as that of ? no one could contradict his actions ?.\n\nThank you\n
August 18, 2009
"...we are in a nanotechnology revolution with targeted drug therapies..."\n\nis precisely the sort of statements that Francis Collins made and got pulled up for now. So it surely doesn't help to make more statements like these to defend him!\n\nI wonder how many millions of dollars 'nanotech' will gobble up before declaring itself for what it truly is.
August 18, 2009
Dr. Greenspan's discomfiture at the Obama administration's choice of Francis Collins to run the National Institutes of Health is puzzling to anyone who has been paying attention since January 20th.\n\nOnce again, as with the Obama administration's choice of Leon Panetta to run the Central Intelligence Agency and Hillary Clinton as Secretary of State, we got a talking head and a political operator to do a job calling for someone with a more highly developed sense of intellectual honesty.\n\nWas Greenspan actually expecting something else to happen?
August 20, 2009
Thank you, Neil Greenspan, for your commentary. I have other reservations concerning Dr. Collins' fitness for the NIH Directorship, but yours are VERY IMPORTANT indeed. \n\nActually, your words suggest a disturbing answer to a concern that I have often wondered about -- just how broad, and just how deep, are Dr. Collins' scientific and biomedical backgrounds and knowledge? Is his knowledge base sufficient to prepare him for his new role? Your words suggest that the answer is no.\n\nA different concern that I have is his lack of appreciation of (and lack of ability to recognize) creative breakthroughs and how truly creative science works. This concern stems from his infamous historical resistance to Craig Venter's ideas. The head of NIH needs to understand that "creativity" and the path to truly paradigm-shattering breakthroughs does not emanate from incremental research activities. I am concerned that Dr. Collins has not learned his lessons. \n\nThis is not to detract from your concerns, which are enormously important.
August 22, 2009
\n\nDoes NIH equals Francis Collins?. No, in my view.\n\n\nSince his nomination, NIH, the entire scientific community and the public at large have had the opportunity to express concerns, reservations and expectations. Now, he is the confirmed leader of NIH. I believe that is high time to move on the issues that are at the heart of NIH itself: better science and medicine for the benefit of the nation and the world.\n\nNIH does not equal Francis Collins. I assume that the Director of NIH exercises his leadership in collegiality with Deputy Directors, Directors of NIH Institutes/Centers, multiple and diverse Advisory Councils, as well as in direct communication with the scientific community and science and health international organizations. The idea of a monolithic leader on whom load all responsibilities and, therefore, privileges is not conceptually found in any democratic society. It is up to us to make a true leadership happens from now on. It appears as if Francis Collins has assumed his leadership with that concept in mind. In his first day as NIH Director, he stated:\n\n?The greatest asset NIH possesses is not its physical facilities, its high tech equipment, or its $30 billion budget. It is the people of NIH: the staff who work in our intramural and extramural programs, and the grantees that we support. In the coming years I hope to encourage you, learn from you, and be inspired by you?and I promise to devote every bit of my energies to our shared goals of advancing biomedical research, to the benefit of humankind?\n\nI assume that we will be allowed to communicate, freely and openly, to NIH our understanding of what are ?creative breakthroughs and how truly creative science works?. \n\nI had the privilege to watch direct in C-SPAN the presentation of Craig Venter : ?A life decoded, my genome, my life?. I loved it and bought the book that same day. Yesterday, I went back through the pages where Venter describes interactions with Francis Collins. I agree that is hard to come up to terms with ?stranged? interactions that do not appear to be based on what science is all about: promote creativity and discoveries for the benefit of the public. On the other hand, we only know Venter?s version of the facts and a full evaluation would require, in my view, all sides?s versions. Different people have different views, as well as goals and approaches.\n\nAgain, It is up to us now to make sure that the NIH leadership serves the interests of science for the American public and the world at large.\n\n\n\n