Optimism for science in 2009 (and two budget-saving ideas)

As 2008 ends, I’m feeling very optimistic about the new year, principally because we here in the U.S. have elected Barack Obama, a new President who represents a dramatic change away from the policies of the past eight years. In the scientific arena, the Bush administration has been a disaster in more ways than I care to list. Not only have the Bushies politicized many, many areas of science, but their political views have almost always hindered or reversed progress in important scientific areas. But let’s look forward to the new year and to a new, re-invigorated U.S. science program.

Of course, the Bushies have also saddled us with an enormous debt burden, over $10 trillion dollars by one recent estimate (Harper’s magazine, December 2008). That number is so stunningly large that it might seem to leave no room for optimism – with such a gigantic debt, how can we hope for progress in anything, much less “discretionary” areas like scientific research?

Well, I’m still optimistic, but I know we’ll see little or no increase in the budgets of the U.S.’s top scientific agencies, including NIH, NSF, NASA, NOAA, and others. So here are two constructive suggestions for how to save significant funds at one agency, NIH, without adversely affecting scientific progress.

1. Get rid of the security fence and all the additional pointless security operations at NIH headquarters in Bethesda, Maryland. For those who haven’t visited NIH in the past few years, there is now a high metal fence (operational since 2005) surrounding the entire campus, and an elaborate security screening operation that every visitor must go through. Getting a car onto campus is now nearly impossible – every car has to be searched – and visitors have to plan for at least 20 minutes of extra time to get to their destination. This makes it much more difficult for NIH scientists to have visitors or to host conferences on the NIH campus – and it’s an utter waste of money.

Over at scienceblogs.com, there was an entertaining post on this topic last month by Mark Hoofnagle, who offered the opinion that “NIH security is run by paranoid idiots.” While I can’t say I agree with that sentiment, I share his feeling when he writes, “I hope in the next administration the first thing they do is tear down that stupid fence and treat the NIH like any other academic medical campus.” And if they get rid of all the accompanying security – which is really just “security theater”, as a writer in The Atlantic recently opined – they can save millions (probably tens of millions) of dollars per year.

2. Readers of my blog will probably guess my second cost-cutting suggestion for NIH: eliminate the National Center for Complementary and Alternative Medicine (NCCAM). This center was created at the behest of Iowa Senator Tom Harkin in 1992, not for any scientific reason, but because he personally believed in the efficacy of bee pollen as a medical treatment (see this NY Times article). There was never any need for this – any promising therapy can be studied in one of the existing Institutes, as has happened many times in the past. NCCAM has become a center for a raft of poorly-designed studies that would not pass review at the other institutes. Furthermore, in its 16 years of existence, NCCAM has failed to show that any “alternative” treatment works – the best that I can say about it is that some of its studies have showed that some pseudo-scientific treatments don’t work.

Like many government projects, though, part of NCCAM’s mission now is to perpetuate itself. So one of its major activities is to fund training centers that will educate health professionals in CAM treatments – even though its own studies have failed to show that those treatments work. This is how a government agency perpetuates itself. NCCAM is hopeless: its advisory council is required to include at least half its members from CAM disciplines such as “chiropractic, acupuncture and Oriental medicine. naturopathic medicine and massage therapy” – and when the board recently dropped below that percentage, CAM advocacy groups such as he Integrated Healthcare Policy Consortium and Academic Consortium for Complementary and Alternative Health Care wrote to NIH to complain. These groups are very active in promoting NCCAM, and they will continue to be as long as they make money by offering their various (and ineffective) alternative therapies.

Let’s get rid of NCCAM entirely before it’s too late. Former NIH Director Harold Varmus tried to put more scientific controls on the original CAM office, and Harkin responded with legislation that made NCCAM into a much-larger Center, with a budget that now exceeds $200 million. These funds could be put to far better use elsewhere in NIH. So without increasing the NIH budget, we could effectively increase the funds available for research by eliminating NCCAM.
(Note that others have suggested eliminating NCCAM too – see the excellent article by Wallace Sampson at Quackwatch).

I know that both these suggestions – modest as they are – are unlikely to be followed any time soon. But I will remain stubbornly optimistic that the Obama administration will choose a new NIH Director who has a strong, positive vision for the future of biomedical research, and who will be willing to take on anti-science interest groups – including Senators who want to promote pseudoscience – and start reversing the last eight years of policies. A few weeks ago the Obama administration announced that Varmus will be co-chair of its scientific advisory committee, and Varmus has shown in the past that he’s willing to take on NCCAM. Perhaps with stronger support from the President this time, he and others who agree with him will succeed.

Astonishingly stupid pseudoscience claim of the week

This week’s Parade magazine, distributed to millions of U.S. households in their Sunday newspaper, contains an article called “Alternative therapies that really work,” by Mark Liponis, an M.D. who’s promoting his books on how to live longer. I haven’t read his books, and based on this article, I certainly wouldn’t recommend them. He claims that he's found 3 alternative therapies that “have scientific backing and have passed the litmus test of rigorous medical inquiry” (Parade, Dec 14, 2008): acupuncture, meditation, and biofeedback. Let me just address the first one.

According to Dr. Liponis, “stimulating an acupuncture point in the toe may even help to correct the breech position of babies in the last trimester and allow more women to avoid C-sections, according to a study in the Journal of the American Medical Association.” This is so astonishingly stupid that I had to look it up. Is there really an article in JAMA that supports this?

Well, sort of. The study that Liponis refers to – I don’t know if he read it – is an old 1998 study by F. Cardini and H. Weixin (JAMA 1998;280:1580-1584). It’s a poorly done study, without placebo controls and without blinding (meaning the patients knew if they were in the “treatment” or “control” group), and it was done in a Chinese hospital.

What did they do? They burned the herb Artemisia vulgaris (mugwort) to stimulate acupuncture point BL 67, located beside the outer corner of the fifth toenail. Why? Because “traditional Chinese medicine” claims that this will encourage fetuses in breech presentation (feet down) to turn around so that they will be born normally; i.e., head first. Crazy, right?

Well, the 1998 study claimed that the treatment worked, although it was a small study and the authors admitted that there were methodological problems. To the lead author’s credit (but not to Dr. Liponis's), he conducted a follow-up study much more recently, this time in Italy, and reported on it in April 2005 in the British Journal of Obstetrics and Gynaecology (Cardini et al., BJOG 112(6): 743-747). This time none of the women were Chinese. And this time, there was no positive effect from this bizarre therapy. As the authors wrote, “The results of this study do not confirm those of the original study.”

So no, Dr. Liponis, stimulating an acupuncture point in the toe does not correct the breech position of babies in pregnant women. If you were even the slightest bit skeptical, you’d never have reported this in your article in Parade. It didn’t take me long at all to find the followup study. And the claim itself is so laughably stupid that it’s hard to see how an intelligent person could repeat it without embarrassment. But it’s clear from your article that you believe this nonsense.

I’ll bet that the Parade article – written by someone with the title “Dr.”, after all - convinces at least some pregnant women to seek acupuncture. Liponis should be embarrassed, but somehow I doubt that he is.

I'm thinking of making "astonishingly stupid quack claim of the week" into a recurring blog topic - the popular press seems to provide plenty of material for me.

Top 10 genome papers of all time

It’s December, and that means “top 10” lists are starting to appear for the year. I’ve put together a top 10 list, but it’s not just for the year 2008. The genome era is far enough along that we can now ask the question, “what are the top 10 genome papers to date?” The first complete genome of a free-living organism was published in 1995 (Haemophilus influenzae) and literally hundreds of genomes have appeared since then - thousands, if you count virus genomes.

How does one measure the importance of a genome to science? Of course I could give you my subjective list, but I was looking for an objective measurement, one that anyone would have to admit is reasonable. The one I chose – the obvious one, really – is the number of scientific citations that the original genome paper has collected. This measure has a bias towards older papers, because newer papers haven’t yet had time to accumulate as many citations, but all of the papers on the Top 10 Genomes list are at least 6 years old. I will revise this list in the future to accommodate updates in the citation counts.

The other question is how to count citations. After looking at several sources, I chose ISI’s Web of Science citation index. Google Scholar is another option, and I used it as well, but I found that Google is less accurate – it uses a heuristic method to collect citations, and it frequently double-counts references, especially for papers with large numbers of authors. I listed both counts in the Top 10 list, but the ranking follows ISI where there’s a disagreement.

So here they are! The Top 10 Genome Papers include 5 bacteria, 3 model organisms, and the two human genome papers right at the top. Not surprisingly, all 10 appear in Nature or Science (5 in each journal). All of the first authors are different, and three were authored by consortia without a traditional first author. And for those who want to argue about which of the two human papers deserves #1, ISI gives a clear edge to the publicly-funded effort, while Google Scholar, curiously, ranks the Celera Genomics effort (which I was part of) well ahead of the public project. My subjective list would have included the malaria genome paper (MJ Gardner et al, Nature 2002) – TB and malaria are the two greatest infectious disease killers of humans – but it came in at #12 using citation criteria. But it’s much newer than #9 and #10, so I'm betting it will move up in the future – stay tuned.

[Note that I’ve also created a separate web page for this list.]

Top 10 genome papers of all time

Criteria for inclusion: a paper must be the first description of the complete or near-complete genome of a species, and it must describe the DNA sequence as well as relevant sequencing methods and biological discoveries revealed by the initial sequencing of the genome. Rankings are based on citation counts, with the ISI Web of Science taking priority over Google Scholar, which is less accurate as it uses heuristic rules to gather citations. Counts from both databases are provided. Citation counts are current as of December 2008.

1. Initial sequencing and analysis of the human genome
International Human Genome Sequencing Consortium
Nature 409:6822 (15 Feb 2001), 860-921.
Times Cited: 6,416
Google Scholar: 5,542

2. The sequence of the human genome
JC Venter, MD Adams, EW Myers, et al. (274 authors)
Science (16 Feb 2001), 1304-1351.
Times Cited: 4,588
Google Scholar: 6,502 [Note that Google places this paper at #1]

3. The Complete Genome Sequence of Escherichia coli K-12
FR Blattner, G Plunkett, CA Bloch, et al.
Science 277:5331 (5 Sept 1997), 1453-1462.
Times Cited: 3,327
Google Scholar: 3,625

4. Whole-genome random sequencing and assembly of Haemophilus influenzae RD
RD Fleischmann, MD Adams, O White, et al.
Science 269:5223 (28 July 1995), 496-512.
Times Cited: 3,075
Google Scholar: 2,651

5. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence
ST Cole, R Brosch, J Parkhill, et al.
Nature 393:6685 (11 June 1998), 537-544.
Times Cited: 2,858
Google Scholar: 3,163 [Note that Google places this paper at #4]

6. Analysis of the genome sequence of the flowering plant Arabidopsis thaliana
The Arabidopsis Genome Initiative (143 authors)
Nature 408:6814 (14 Dec 2000), 796-815.
Times Cited: 2,689
Google Scholar: 1,728 (Google has real trouble tracking this "group author" name)

7. The genome sequence of Drosophila melanogaster
MD Adams, SE Celniker, RA Holt, et al.
Science 287:5461 (24 Mar 2000), 2185-2195.
Times Cited: 2,632
Google Scholar: 3,002

8. Initial sequencing and comparative analysis of the mouse genome
Mouse Genome Sequencing Consortium
Nature 420:6915 (5 Dec 2002), 520-562.
Times Cited: 2,188
Google Scholar: 1,763

9. The complete genome sequence of the gastric pathogen Helicobacter pylori
JF Tomb, O White, AR Kerlavage, et al.
Nature 388:6642 (7 Aug 1997), 539-547.
Times Cited: 1,960
Google Scholar: 1,325

10. Complete genome sequence of the methanogenic archaeon, Methanococcus jannaschii
CJ Bult, O White, GJ Olsen, et al.
Science 273:5278 (23 Aug 1996), 1058-1073.
Times Cited: 1,811
Google Scholar: 1,425 [Note that Google places this paper at #9]

Autism's false theories

The St. Petersburg (Florida) Times last week ran a feature story on the controversy surrounding autism and vaccines. I’ve written about this before and you can found many blogs and websites devoted entirely to autism - some good, some bad. The “controversy” is due to some people’s belief that autism is caused by the measles, mumps, and rubella (MMR) vaccine, which was first proposed in a 1998 article – later revealed to contain fraudulent data – by by Andrew Wakefield and colleagues. (10 of Wakefield’s 12 co-authors retracted their findings and repudiated the study.)

The St. Pete Times article does a better-than-average job at presenting the issue, although its title - “Debate rages over need for vaccines” – is very misleading, and I worry that the title alone will make some parents withhold vaccines from their children. But if you read the article, the reporter (Lisa Greene) does point out clearly that:

“Since then, the study [by Wakefield and colleagues] has been harshly criticized. Most of the researchers involved have retracted their results. In September, researchers who conducted a similar study said they found no link between measles virus and autism.”

Vaccines do not cause autism. After >20 studies, some of them quite large, there is no serious scientific debate over this question. But Greene makes an interesting point when she writes: “This is no longer principally a debate about science. The real question is whether Americans still believe in science — or at least, in the nation's scientists.”

That’s a good question. The anti-vaccine camp often uses conspiracy-theory arguments to make their case, as in “the government is hiding the truth” or “big pharma” doesn’t want us to know that vaccines are harmful. If you want to read some really extreme conspiracy-theory arguments, just look at what Robert F. Kennedy Jr. has been saying about thimerosal and vaccines. (And it worries me that his name is being floated for possible high-level positions in the Obama administration.) These arguments are indeed an effort to convince people (not just Americans, of course) not to believe scientists, but instead to believe, well, non-scientists, who make all sorts of other claims, ranging from the merely ignorant to the outright fraudulent. These frauds include people such as Mark and David Geier, who offer testosterone-reduction and chelation drugs to autistic children and claim that these treatments work, despite evidence that they don't - and that they might even cause serious harm.

Why do people prefer to trust quacks rather than science? Neurologist and skeptic Steven Novella has one explanation: “I know that when you are a parent of a sick child the gears of science may grind maddeningly slowly” and science hasn’t yet determined the cause, or a cure, for autism. So when someone comes along, perhaps someone with seemingly respectable credentials (but not always), and says he knows the answer, parents understandably want to believe it.

The St. Pete Times article includes a very interesting set of tables and charts (as a special supplement, not in the main article, alas) with real numbers showing the dramatic reductions over the years in the prevalence of measles and other diseases as vaccines were introduced. The press rarely does enough to point out what a major public health benefit vaccines represent, so kudos to SPT for their special report. As the Vaccine Ethics site at U. Penn says, “Vaccines are credited with having saved more lives than any medical treatment ever developed.”

Note: the title of this posting is a reference to Paul Offit’s outstanding new book, Autism’s False Prophets. I highly recommend it – Offit is a terrific writer who knows the science and the history of research on autism as well as anyone I've ever read.

Serious doubts about new study of statins and heart disease

The news this past week was filled with reports of a new study in the New England Journal of Medicine (NEJM), which reported a “dramatic risk reduction” in heart attack risk for men using Crestor, a statin drug made by AstraZeneca. This was all over the news, getting headlines on the Sunday (Nov 9) major TV networks and front page reports Monday in The New York Times, the Washington Post, and other major papers. What was striking about this study was that it claimed that people with normal cholesterol levels could get significant health benefits. If true, this new study implies that millions more people should start taking statins to protect themselves against heart attacks.

Wow. Should we all rush out and get some statins? Should we all buy AstraZeneca stock (which went up 20% on the news of this report)? Both?

Hold on a minute. This new finding is rife with problems, despite the breathless news reporting about it. Actually, there are two studies: one published in NEJM, and the second published in Circulation. I’ve read them both. Study 1, in NEJM, got most of the headlines. Study 2 reports on a new diagnostic test that looks at levels of C-reactive protein (CRP), a marker of inflammation. Study 2 found that use of a test called hsCRP – for high-sensitivity C-reactive protein – improved the predictions of cardiovascular risk in men. In other words, the study said, using this test would let you predict more accurately who’s going to have heart problems. Let’s go over the problems one by one. (This is a long blog post, so if you want to know the REAL problem with the study, scroll down to Problem 5 below.)

Problem 1 (raise an eyebrow): Both studies were funded by AstraZeneca, the drug company that sells Crestor. Obviously, AstraZeneca must be pleased that the results suggest that millions more people – those currently considered at low risk for heart disease – should start taking Crestor. However, the funding was disclosed in the reports, and AstraZeneca did not interfere in the analysis, so the funding source does not invalidate the results – not at all. It just makes me a bit more skeptical.

Robert Bazell, a journalist at NBC, was much more credulous. He reported that the study was “squeaky clean.” Well, it’s awfully nice of Mr. Bazell to give his stamp of approval, but disclosure alone does not mean the study had no bias. We’ll get to that in a minute.

Problem 2 (raise the other eyebrow): Both studies also say that high levels of C-reactive protein (CRP) are linked to heart disease, even in men with normal cholesterol levels. The lead author of both studies was Paul Ridker. Paul Ridker owns the patent on the hsCRP test for CRP. Another consequence of these studies is that millions of people are now likely to get tested for CRP, using Ridker’s test. Clearly, Ridker has an interest in the results coming out the way they did. NBC’s Bazell gives him a pass: “As for Dr. Ridker, he says flat out that the financial interest in the test had no effect on the outcome. I certainly believe that. Dr. Ridker has spent most of career working on c-RP and this study validates all his work.”

So let me get this straight: because Ridker has spent his career working on CRP and this study validates his work, we shouldn’t question it? I don’t think so. What this meant to me was that the parties conducting and funding both studies had a very strong interest in the results coming out the way they did. That doesn't mean the results are wrong - again, it just makes me more skeptical. But that’s why we have placebo-controlled trials: to eliminate the effect of bias. So I read the papers, carefully, to see what the data actually said.

Problem 3: the Circulation study didn’t report separately on the effect of CRP and family history of heart disease. In this study, Ridker and colleagues looked at 10,724 men retrospectively (over a 10-year time period), and used a “traditional” model to predict the risk of heart disease. The traditional model had 5 variables: age, blood pressure, smoking status, total cholesterol, and HDL cholesterol. They then added two more variables to the model: (a) the hsCRP test and (b) family history of a heart attack before the age of 60. The report shows that the new, 7-variable model is somewhat more accurate. The study has several methodological problems that I won’t try to describe here, but the biggest problem is that the fail to report the separate effects of the two new variables. In other words, they report only that both variables should be used to measure risk, which means (of course) that patients should be getting the hsCRP test. But what if the entire effect of the study is due to the family history of heart disease? The study doesn’t say. We simply can't tell if the hsCRP test has added value or not. And the leader of this study - Ridker - has the patent on the hsCRP test.

Problem 4: the NEJM study actually reports a very small benefit. All the glowing press reports emphasized the “44% reduction in risk” in those taking Crestor, making it sound very dramatic, but they neglected to report the absolute risk. What I mean here is that if the risk is very, very small, then a relative reduction of 44% is not so significant. Here are the actual numbers: this was a large study, with 17,802 subjects, 8901 getting Crestor and 8901 getting a placebo. The placebo group suffered 251 “events” (one of five cardiac problems, including heart attack), and the Crestor group had 142 events.

This looks pretty significant – and statistically speaking, it is. But the clinical significance is different: you’d have to treat 95 people for 2 years with statins to prevent 1 heart attack. Is that worth it? And if we put millions of people on statins for the rest of their life, which might indeed prevent some heart attacks, will there be other consequences that we can’t yet foresee?
Having an NNT (number needed to treat) of 95 might not sound so bad, but that’s a very high number. An article in Business Week a few years ago pointed out that such high NNT numbers might just represent statistical noise. That article quoted Dr. Nortin M. Hadler, professor of medicine at the University of North Carolina, who said, "Anything over an NNT of 50 is worse than a lottery ticket; there may be no winners.” The article goes on to point out that “an estimated 10% to 15% of statin users suffer side effects, including muscle pain, cognitive impairments, and sexual dysfunction.” Furthermore, it is highly likely that lifestyle changes – getting more exercise, for example – will have a better NNT than 95. So rather than prescribing Crestor, perhaps physicians should explain the greater benefits – possibly much greater - that patients will have from changes in diet and exercise.

Problem 5: This one is the biggest problem of all. The patients in the NEJM study were randomly divided into two groups, treatment (Crestor) and placebo. Table 1 in the paper describes the groups according to a long list of features, and the groups are virtually indistinguishable for most of these – average age, blood pressure, LDL cholesterol levels, body mass index, etc. However, there are 3 critical variables where the two groups are not identical. Presumably this happened by chance, but when you have such a small effect as the one found in this study, small differences can have huge consequences. Let’s look at these 3 variables and at the number of patients in each group (Crestor vs. placebo) with these factors:

Numbers of subjects in Crestor vs. placebo groups

Treatment group:	Crestor	Placebo
Current smoker	1400	1420
Family history of premature CHD	997	1048
Metabolic syndrome	3652	3723

Notice that the Placebo number is higher in all 3 cases. There were 20 more smokers in the placebo group, 51 more people with a family history of CHD (coronary heart disease), and 71 more with metabolic syndrome. All 3 of these variables are risk factors for heart disease – in fact, 2 of them were used by Ridker in his Circulation paper as part of a test to predict risk!

Even if these differences are accidental, all 3 of them put the placebo group at higher risk of heart disease. We don’t know if these totals represent separate people (one person might be a smoker and have a family history of CHD), but if they were, we have as many as 142 more “at risk” people in the placebo group.

Remember, the total number of excess events in the placebo group was only 109 (252 events versus 141 in the placebo group). How many of those events occurred in people with the 3 “bad” variables above? It is entirely possible that these differences in the two study groups could dramatically reduce – even eliminate – the supposed benefit observed in the study.

So what does this all mean? Well, I am not convinced that Crestor has a clinically significant benefit for patients with normal cholesterol. My guess is that further studies, if done properly, will show that the benefit is smaller than that reported last week, and perhaps the benefit is nonexistent.

Finally, on a lighter note, I was pleased that one of my favorite “fake news” reporters, Stephen Colbert, wasn’t fooled at all – he made fun of the study on his show (The Colbert Report) on Wed 12 November. (Scott Hensley over at The Wall St. Journal blog has a nice post about this.) Colbert reported the study in his “Cheating Death with Dr. Stephen T. Colbert, D.F.A.”:

“This is a great breakthrough in the battle to find things to prescribe to people who don’t need them. True, the drug costs $100 a month, but that is a small price to pay to not have the heart attack that there’s no way of knowing if you would have had it.”

Colbert then showed a video clip of Stanford cardiologist Mark Hlatky. Hlatky was interviewed on PBS, where he said “we need to be cautious before we expand the numbers of patients so drastically.” Colbert responded: “sounds like someone hasn’t gotten enough free Crestor pens.”

I guess I haven’t gotten enough free Crestor pens either.

Johns Hopkins University offers quack medicine as "herbal consultations"

Well, it's sad to see, but one of the top medical research institutions in the world, Johns Hopkins University, is now offering - and advertising - a quack treatment for its students. This comes as part of its new "Integrative Medical Center", where "Integrative" is a code word for quackery. Oh, I'm sorry, that's not what JHU calls it: they say "integrative medicine refers to the practice of combining Western treatments such as pills and vaccinations with the traditional treatments of the East. It holds that curing a disease means treating the whole patient, not just the patient's illness."
Sorry, JHU, but there's only one kind of medicine: treatments that work. Using words such as "traditional," "integrative," and "alternative" is little more than marketing hype to disguise the fact that none of these treatments actually cure anything.

Having JHU endorse this nonsense is a big coup for proponents of these bogus treatments. But I should point out that many - I would venture to bet most - JHU medical researchers and physicians don't support this apparent endorsement by their institution. I was a professor at JHU myself not long ago, and I have many good friends and colleagues there who don't buy into quackery.

So just for entertainment, let's look at what JHU's own newsletter says about the new "herbal consultations":

"Allegra Hamman, CRNP, clinical herbalist and wellness consultant, will be administering the new services for the SHWC. Over the past three years, she has studied herbal medicine at the Tai Sophia Institute, where she received her master's degree in June. As part of her studies, Hamman spent a year and a half treating patients using herbal remedies."

Great! The Tai Sophia Institute is a hotbed of quack treatments, including homoepathy, Qi Gong, and acupuncture. Their own website says their "values" include:

- Operate from an acknowledgement and declaration of Oneness.
- Use nature and the rhythms of the earth as a guide in teaching our students and one another.

This is New Age gobbledegook, not medicine. Gee, it's a good thing that Hopkins has a nurse who trained at Tai Sophia! I wonder how much they're paying for these valuable services.

By the way, the University of Pennsylvania Medical School started a joint master's degree program with Tai Sophia in 2005, but they came to their senses shortly thereafter and severed the relationship. Before they did, though, they were fiercely criticized by skeptics such as David Colquhoun:

"What on earth was the University of Pennsylvania thinking about when it associated itself with such pathetic twaddle [as Tai Sophia]? Is it that their senior people are so in the grip of the delusional age that they no longer care what's true and what isn't? Or did they just spot a good chance to make money from the gullible public?"

Too bad JHU didn't talk to UPenn before they went down this path. Here's more from nurse Hamman about her new herbal consulting practice: "From the point of view of the medical community, I function as a bridge," she said. "I can speak the language of herbs, and I can speak the language of medicine." The language of herbs? What? Is that supposed to mean something, or is it just more New Age nonsense?

She goes on: "Herbalists would say that there's an enormous written record: thousands of years of information about herbal medicines. Traditional use counts for a lot."

Actually, Ms. Hamman: no, it doesn't. What counts is scientific evidence that we can gather through proper studies. Some plant products do indeed have great benefit - take aspirin, for example - but before we can offer them as medicine, we need to show that they work. (Not to mention we need to understand how to identify the active ingredients and how to provide a controlled dose.)

The JHU Newsletter also published an Editorial on this article in which they expressed mild criticism of the move: "While a clinical herbalist may provide an alternative option that appeals to students who do not wish to undergo conventional treatments, the addition of a general practitioner rather than a specialist should be prioritized. Yet, if the University were to hire specialists, there are others who would better serve the needs of the student body, such as a gynecologist or dentist, whose availability should take precedence over the option of an alternative medicine practitioner."

The Editorial misses the main point entirely, though, when it endorses alternative medicine: "Alternative medicine has been proven to be a safe and effective form of treatment for some conditions, and the attractiveness of this more natural form of medicine has propelled it into the realm of mainstream Western medicine including at Hopkins's own Hospital and medical school." And they also say "we supported the Hospital in taking the progressive step of creating a branch for alternative medicine." Sorry, Newsletter editorial staff, but you're wrong. You've been sold by the marketing hype of quack practitioners. "Alternative" medicine has not been proven to be safe and effective for anything, and I challenge you to provide examples. There's only one kind of medicine - the kind that works - and we don't label it "alternative."

Surprisingly, the JHU Newsletter includes a skeptical comment from a student, junior Rick Carrick: "I think that Health and Wellness has some issues just servicing people with regular medicine," he said. "I think that they should focus on getting people the treatment they need normally before they focus on any sort of essentially fake medicine."

Bravo! At least some of the students are too smart to be fooled by this nonsense. Now if only JHU would listen to its own students - and doctors.

Patent dispute costs Robert Gallo the Nobel Prize

I've written before about how I'm opposed to patents, particularly software patents,
but also patents on biological discoveries. And pro-patent attornies and scientists have argued against me, here on this blog and elsewhere.

But this year's Nobel Prize in Medicine illustrates another peril of patenting, one that I'd never thought of: it can cost you the Nobel Prize.

How is that possible? The 2008 Nobel Prize in Medicine went to 3 scientists, Luc Montagnier and Francoise Barre-Sinoussi for their discovery of HIV, the virus that causes AIDS, and Harald zur Hausen for his discovery that human papilloma virus causes cervical cancer. Notably missing from the prize list was Robert Gallo, who many people believe deserves joint credit with Montagnier for discovering HIV. Montagnier himself commented, after learning that he was awarded the Nobel, that "it is certain that he [Gallo] deserved this as much as us two."

The history of the discovery of HIV has been documented in great detail elsewhere - including a 1993 movie, "And the Band Played On," that I highly recommend. But briefly: in the early 1980s, both Montagnier and Gallo were racing to discover the cause of AIDS. Montagnier is now widely acknowledged as having found it first, although Gallo announced his discovery soon after. The two viruses identified by the scientists were later determined to be the same, but Gallo was, for a while, credited with independently finding the virus. [The Nobel committee, in announcing the prize, said that there was "no dispute" that the French duo had discovered HIV first.] It was only much later - in 1991 - that independent NIH scientists determined that Gallo had, in fact, grown the French strain of HIV, which he had obtained from Montagnier and which had contaminated some of his own samples.

Gallo is, however, given credit for proving that HIV is indeed the causative agent of AIDS. The Nobel committee's press release acknowledges this: "several groups contributed to the definitive demonstration of HIV as the cause of acquired human immunodeficiency syndrome (AIDS)." Although their press release never mentions Gallo by name, many scientists thought (and still think) that this contribution by Gallo, along with his other groundbreaking AIDS work, would justify him jointly receiving the Nobel.

Now for the patent story: both Gallo and Montagnier filed for patents on a blood test for the AIDS virus. This spawned a huge controversy, in part because Gallo applied first, and also because Gallo's claim excluded Montagnier. The Pasteur Institute (Montagnier's employer at the time) sued the U.S. government in 1985 in an effort to share in the patent royalties. After two years of fighting, the U.S. and France agreed to share royalties on the patents, and in March 1987 President Ronald Reagan and Prime Minister Jacques Chirac held a joint press conference to announce that Montagnier and Gallo had independently identified the AIDS virus.

It was only after this press conference that scientists discovered that Gallo's virus was actually the same as Montagnier's, and that both must have come from the same patient.

Why did the Nobel committee snub Bob Gallo? Of course, they won't admit that they did any such thing. Gallo and Montagnier themselves have long since repaired their relationship, as indicated by Montagnier's generous comments quoted above. But the patent dispute caused deep and lingering resentment among a much broader community, resentment towards Gallo personally and towards the U.S. and its patent system. As was later revealed in an investigation by the U.S. Congress:

"Just minutes before the press conference, HHS submitted applications for U.S. patents on an HIV antibody blood test and a method of producing the virus. These patent applications contained the seeds of the French/American dispute; they contained fundamental assertions that could not be substantiated. Chief among these was the assertion that, "... we are the original, first and joint inventors ... of the subject matter which is claimed and for which a patent is sought ...." The real inventors of the HIV blood test were the IP [Institute Pasteur] scientists, who had developed and begun to use their blood test the previous Summer (1983). Dr. Gallo knew about the IP blood test. In fact, as early as September 1983, Dr. Gallo and his colleagues actually sent LTCB AIDS patients' samples to Paris to be assayed with the IP blood test.

Dr. Gallo and his colleagues did not disclose to PTO their knowledge and use of the IP blood test, nor did they disclose the IP scientists' considerable body of scientific work on their virus and blood test."

Not surprisingly, the patent application infuriated the Institute Pasteur scientists. NIH didn't behave well either - their response was to defend Gallo's claim uncritically. If Gallo - whose work was all publicly funded by his employer, the NIH - simply hadn't filed for a patent, who knows how things would have turned out?

So here's my advice to scientists with a hot discovery: publish it, and share it freely with the world. Don't apply for a patent on the hope that you will get lucky and cash in - you probably won't. And you never know what kinds of backlash a patent application may cause. You might just cost yourself a Nobel Prize.

Obama for President

In case it isn't obvious, I might as well make it explicity: I support Barack Obama for President. In the scientific community, support for Obama is very strong, so I'm joining with my colleagues on this one. Recently, a group of 63 Nobel Laureates announced their endorsement of Obama, in an open letter you can find here. (Of course I don't consider myself a part of this group - by "colleagues" I mean the broad scientific community.)

It's a short letter, but I'll quote just one sentence: "we support the measures he plans to take – through new initiatives in education and training, expanded research funding, an unbiased process for obtaining scientific advice, and an appropriate balance of basic and applied research – to meet the nation's and the world's most urgent needs." Francis Collins, formerly the Director of NHGRI, also endorsed Obama recently, and although he focused primarily on positive aspects of Obama's plans, he also wrote: "As I have examined the positions taken by the current Presidential candidates on these critical issues, I regret to say that I have found little comfort in Sen. John McCain's plan."

There are many non-scientific reasons to support a candidate, but this is a science-focused blog, so I'll stick with these. On scientific issues, Obama has a far better agenda than McCain.

Debate reveals who will help science funding

The final presidential debate between Obama and McCain had at least one telling moment for U.S.-based scientists who depend on grants for their research. After McCain repeated his promise to immediately freeze all federal funding, Obama pointed out (a bit later) that if you impose a freeze, you can't do new research to discover new cures. They were talking about special-needs children, but the broader implication was clear to me, and it was nice to see Obama point it out.

Yes, I realize I'm speaking as a member of an interest group on this (but who isn't a member of some interest group or other?), but science funding can't just be frozen. A budget freeze is an unthinking administrative step, and it's the coward's way out - it's a way to avoid favoring any one program over any other. Obama pointed out, correctly, that the smarter path is to set priorities and cut some programs, but not others. Admittedly he didn't make it so clear what he would cut either, but at least he said he would pick winners and losers rather than freeze everything. Whenever I hear "across the board freeze" (or "cut"), I know that someone was too chicken to make some tough decisions.

Most people outside academic science don't realize that a "freeze" has real consequences for biomedical and scientific research. New programs cannot get started unless there is new money. Most large scientific programs have multi-year funding, so you can't just cut those off to start new ones. And the costs of doing science increase like everything else, so if you freeze funding, the amount of scientific research steadily declines.

McCain made one other anti-science comment - for the second time in a debate - though many people don't realize it. This is his annoying gripe about the "$3 million overhead projector." It makes a good sound bite, but no one is paying $3 million for an overhead project - that's absurd. The money was for the Adler planetarium in Chicago, a very popular exhibit with children and adults alike. They need a new Zeiss Mark VI star projector to replace their 40-year-old one, and they are trying to raise money for it. Phil Plait (the Bad Astronomer) blogged about this in detail the first time McCain raised it.

So in the last debate, when it came to Science issues, the score in my book was Obama 2, McCain 0.

new members for Vioxx Hall of Shame

Back in May, I created a list of medical researchers who had been paid by Merck to conduct studies of Vioxx (rofecoxib), and who had helped Merck "prove" that Vioxx was safe. It later turned out, as many of us now know, that Vioxx substantially increased the risk of heart attacks in some patients. Unfortunately, this risk wasn't known to the public until multiple patients had died.

What made their behavior particularly egregious was that, in many cases, the doctors hadn't even written the articles - the articles had been written by Merck employees or contractors, and the doctors' names had been added only when the article was submitted for publication. This violates multiple ethical standards for research and scholarship.

Well, my list wasn't complete, and I learned recently of a few additional names that should be added. Chief among them is Marvin Konstam, a Tufts University professor who is also an advisor to the National Heart, Lung, and Blood Institute (NHLBI) at NIH. In addition to his Merck-supported articles on Vioxx (see the list below), he recently wrote an article in support of medical devices produced by a heart device company that he works for. He recently switched his affiliation from NIH to Tufts after he was named in the JAMA article about ghost writing as one of many researchers who allowed his name to be attached to articles that he didn't write.
So here are some additions to the

Vioxx Wall of Shame (Addendum)

Martin Konstam, M.D., Tufts University School of Medicine, Boston
Matthew R. Weir, M.D., University of Maryland Hospital, Baltimore
These two researchers are the first two authors on

"Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib."

Circulation. 2001 Nov 6;104(19):2280-8. They also jointly authored a review paper called "Current perspective on the cardiovascular effects of coxibs," Cleve Clin J Med. 2002;69 Suppl 1:SI47-52.

More recently, Konstam was a co-author of another Vioxx study (Bresalier et al., N Engl J Med. 2005 Mar 17;352(11):1092-102) that reported - somewhat to Dr. Konstam's credit - an increased risk of heart attack associated with Vioxx.

I should add that the original JAMA article included a much longer list than my Wall of Shame. Dr. Konstam's name only came to my attention because of the new controversy, reported in the Boston Globe and elsewhere, over his conflict of interest involving a medical device company.

NIH halts chelation study after patients die

Yet more proof emerged today that "alternative" medicine is not only useless - it can kill. The U.S. government had funded a study to test chelation therapy on heart attack survivors. At least two patients have died already, and the National Institute of Health has now halted the study and launched an investigation. The patients weren't properly informed of the risks - namely, that the treatment could kill you - and there were other serious problems as well.

Kimball Atwood and colleagues published an article in May 2008 (freely available in PubMed) that looked at this study, called TACT (Trial to Assess Chelation Therapy), and wrote:

"We conclude that the TACT is unethical, dangerous, pointless, and wasteful. It should be abandoned."

Wow. It doesn't get much more blunt than this. Nonetheless, the study had already gone on for years, and it was another 4 months (until now) before NIH pulled the plug.

Chelation therapy involves injections of a powerful drug, disodium EDTA, into patients. Proponents claim - with little or no evidence - that disodium EDTA will bind to arterial plaques and help flush them away. Chelation therapy has also been proposed - and used - on autistic children, despite evidence that it carries great risks and despite no evidence that it works.

The just-halted study involves some 1500 patients. The US government approved the study, according to AP reports, because some heart patients were trying chelation therapy anyway, and the study would provide evidence of whether it worked or not. (Note that this is the same argument that NIH recently used when it announced it would study chelation therapy for autistic children.) The argument is bogus. It is a classic example of a logical fallacy, which could be re-stated in this case as "lots of people believe this, so it must be true."

There are (were) multiple problems with this study. The Atwood article states them very bluntly:

We present evidence that chelationists and their organization, the American College for Advancement in Medicine, used political connections to pressure the NIH to fund the TACT. The TACT protocols justified the trial by misrepresenting case series and by ignoring evidence of risks. The trial employs nearly 100 unfit co-investigators. It conflates disodium EDTA and another, somewhat safer drug. It lacks precautions necessary to minimize risks.

Astonishing. And yet, unbelievably, the group of chelation doctors (who should more accurately be called quacks and scam artists), known by the deceptive name American College for Advancement in Medicine (ACAM), are insisting that the allegations of impropriety are "political" and that the trial should resume as soon as these allegations can be dismissed. On ACAM's own website, their president, Jeanne Drisko, says "We call for a swift end to the moratorium and a resumption of the trial."

These chelation practitioners (I can't call them doctors) are deceiving their patients and making money off them by offering harmful therapies. This is, frankly, despicable.

Finally, I have to shine the spotlight of shame on the study's Principal Investigator, Gervasio Lamas of Mt. Sinai Medical Center in Miami Beach. If you know anyone in Miami who needs a cardiologist, stay away from this doctor! Back in 2001, he said of chelation therapy, "It's pretty different - it's cool." I want a doctor who chooses therapies because they work, not because he thinks they're cool.

And finally, which part of NIH funded this study? NCCAM, of course. See my earlier posts on that. This is yet another example of why NCCAM should be shut down.

Knee surgery is a poor choice for arthritis

A report appears today in the New England Journal of Medicine, one of the foremost medical journals, that has a surprising result:

"Arthroscopic surgery for osteoarthritis of the knee provides no additional benefit to optimized physical and medical therapy."

I write "surprising" because this will indeed be surprising to many surgeons, and to their patients who have undergone unnecessary knee surgery. This study is interesting - and important - because it is a negative result, something which is difficult to obtain scientifically. It is also a classic case of a medical treatment that was initiated based on intuition rather than science: orthopaedic surgeons have been telling patients for years that their arthritis could be alleviated by "debridement" of the inside of your knee.

The new study by Kirkley et al. shows that the control group, which received physical therapy and "medical therapy" - ibuprofen, in other words - did just as well as the surgical group. Both groups improved, although neither group improved much. The conclusion: don't get the surgery! There is a huge downside to surgery - not only does it require weeks or months of followup therapy, but there is also the possibility of infection, not to mention the cost.

A friend of mine recently had exactly this surgery - he has arthritis in both knees, and his doctor told him that arthroscopy would smooth out the rough spots, which were causing him pain. This sounded reasonable, so my friend agreed. After months of follow-up therapy, his knee was only slightly improved.

Arthroscopic knee surgery was developed to treat torn cartilege and ligaments, and it works beautifully for these acute injuries. I have personal experience of this - some years ago I tore my cartilege in my left knee, and I couldn't even straighten my leg for a while. I had arthroscopic surgery which removed the torn cartilege and fixed the acute problem - though it left me with much less cartilege. However, treating an acute injury is far different from treating arthritis, which is a chronic, degenerative condition that affects huge numbers of people as they age.

Unfortunately, orthopaedic surgeons are not likely to give up this lucrative procedure so easily. An editorial appears in the same issue of NEJM, written by Robert Marx, a surgeon. He argues - with no scientific evidence to back him up - that some patients have both arthritis and torn cartilege, and that in such cases "it can be difficult to determine which of the two is the major cause" of knee pain. I can hear him already explaining to his patients that he recommends surgery.

Brian Feagan, a co-author of the new study, was clearly disappointed that NEJM printed this editorial, which he said (in today's Washington Post) would result in continued overuse of arthroscopic surgery. The Post points out that a second study in the same issue of NEJM, involving nearly 1000 patients, found that many arthritis patients have small cartilege tears, but that their pain is caused by arthritis, not the tears. "I'm very disappointed by the editorial. I'm not sure who he [Marx] is advocating we should treat," said Feagan.

Arthroscopic knee surgery is performed on hundreds of thousands of patients in the U.S. alone each year, costing about $5000 per operation. This new study shows that many of these operations - perhaps most of them - are unnecessary. I hope that surgeons will pay attention, but Marx's editorial makes it clear that some of them won't. For their patients, only a healthy skepticism - and perhaps a 2nd or 3rd opinion - will save them the pain and expense of unnecessary surgery.

Evolution and the candidates

Well, the election line-up is set. We know all four major-party candidates for president and vice president. And for those of us who believe it is important to teach good science to our children, the choice is pretty clear: the Republican candidates favor the teaching of creationist dogma in the science classroom. The Democrats support the teaching of evolution. On this issue, there is a clear different between the candidates in this election.

Let’s look at a few specifics. On evolution, John McCain has waffled. In 2005, he supported the teaching of creationism in the classroom, in this newspaper interview:

Arizona Daily Star: Should intelligent design be taught in schools?
McCain: I think that there has to be all points of view presented. But they’ve got to be thoroughly presented. So to say that you can only teach one line of thinking I don’t think is - or one belief on how people and the world was created - I think there’s nothing wrong with teaching different schools of thought.
Daily Star: Does it belong in science?
McCain: There’s enough scientists that believe it does. I’m not a scientist. This is something that I think all points of view should be presented.

(By the way, I’m not falling for the ploy by the Discovery Institute and other creationists that “intelligent design” is different from creationism. It’s not, so I will call it what it is.) The following year, in 2006, McCain reversed himself, saying: “I think Americans should be exposed to every point of view. I happen to believe in evolution… I respect those who think the world was created in seven days. Should it be taught as a science class? Probably not.“ And again in 2007, McCain stated explicitly to CNN: “I believe in evolution.”

However, McCain’s VP choice, Sarah Palin, is a firm believer in creationism. She is a fundamentalist Christian who has stated explicitly, when asked if creationism or evolution should be taught in science class:

Palin: Teach both. You know, don’t be afraid of information. Healthy debate is so important and it’s so valuable in our schools. I am a proponent of teaching both. And, you know, I say this, too, as the daughter of a science teacher.

This is the standard “teach the controversy” argument made by creationists. But it’s a bogus argument: within the scientific community, there is no controversy. Evolution has been widely accepted for over one hundred years, and virtually all of modern biology is built upon it. This argument is used merely as a ploy to get creationism into the classroom. It doesn't belong there.

How about the Democrats? Obama has made it clear he supports the teaching of evolution:

Obama: But I also believe our schools are there to teach worldly knowledge and science. I believe in evolution, and I believe there’s a difference between science and faith. That doesn’t make faith any less important than science. It just means they’re two different things. And I think it’s a mistake to try to cloud the teaching of science with theories that frankly don’t hold up to scientific inquiry.“ (from the York, PA Daily Record)

That’s a refreshingly clear statement for a political candidate. And Joe Biden too has said that he strongly opposes teaching creationism alongside evolution.

McCain, as you can see above, has been wishy-washy about this topic, clearly trying to placate the Christian right, who would like to see their religious views on creationism taught in science classes (not to mention all their other views). And by picking an outspoken supporter of creationism who is anti-science in other ways too (Palin doesn’t agree with the scientific consensus on global warming, for example), McCain has placed himself solidly in the pro-Creationism camp, despite his attempts to avoid being pinned down.

This is serious business. Sometimes I feel like politicians treat all these topics as a game, and maybe it is – to them - but it shouldn’t be. If science education is going to be taken over by religious fundamentalists, then we are in big trouble as a country. Our science education is already well behind many other countries, and we are pathetically behind on educating students about evolution. We can’t elect leaders who would put us further behind, but that’s exactly what Sarah Palin would do.

I realize there are many other issues separating the candidates, some of them perhaps more important. But for our long-term future, we need to restore respect for science, not only in our classrooms, but at all levels of government. On this topic, Sarah Palin would be a huge step backwards.

Other blog posts on this topic (a selection among many):
Brian Switek on scienceblogs
Matt Nisbett on scienceblogs
Brandon Keim at Wired
Jonathan Eisen at phylogenomics

T. rex peptides now available to public

I'm pleased to follow-up my August 22 post with a note that John Asara has responded to the calls for him and his colleagues to release the spectra from their study that reported the identification of Tyrannosaurus rex collagen protein isolated from a 68-million-year-old fossil. Pavel Pevzner, Tom Kaye, Mike Buckley, and others have all called this data into question, arguing in 3 separate papers that the protein fragments represent modern contaminents or statistical artifacts, rather than original T. rex proteins.

Pevzner argued forcefully that the only way to validate the claim was to have independent scientists look at all the spectra generated in the original experiment. Asara has now agreed, and has released all the spectra at the PRIDE database. I encourage those with expertise in the analysis of mass spec data to take a look. It will likely take some time for this analysis, but I will follow the developments and report them here.

I should add that although I remain skeptical that original T. rex proteins - even fragments - survived for 68 million years, I find it very plausible that such proteins would indeed be similar to those from modern birds. But the issue of whether proteins could survive for so long is a separate question from their evolutionary relatedness to modern species.

T. rex protein degrades further

An article in Science this week casts fresh doubt on the Tyrannosaurus rex "proteins" that were extracted from a 68-million-year-old fossil. The new report by Pavel Pevzner and colleagues argues that the T. rex peptides (protein fragments) represent statistical artificacts rather than genuine T. rex proteins. The original study by Mary Schweitzer, John Asara, and colleagues, which appeared in Science in 2007, claimed that the authors had discovered 7 peptides from T. rex, all from the collagen protein, which is the most common protein in bone. The story, which received tremendous publicity at the time, has been slowing falling apart ever since. Asara and Schweitzer continue to defend it, including a response in Science this week, but let's look at how the story is collapsing:

1. After the original report, Pevzner (privately) pointed out statistical problems, and the authors revised their findings, admitting in a letter to Science in September 2007 that one of the peptide fragments was a statistical artifact. One down, six remaining.
2. In January 2008, Science published a new Technical Comment in which 27 authors (Buckley et al.) used a standard set of authentication tests developed for ancient DNA, and reported that the T. rex sample failed those tests. (Another sample from mastodon, also reported by Asara but 100 times younger, passed the same tests.)
3. In July 2008, Thomas Kaye and colleagues published a report that re-examined the microscope evidence of the T. rex "soft tissue". The original findings by Schweitzer were based on this soft "tissue" being original T. rex organic material. Kaye et al. report that the soft material was a bacterial biofilm - not original material at all. They also report on carbon dating of the biofilm showing it to be modern, not ancient.
4. Pevzner et al. report this week that the peptide mass spectrometry evidence - which Asara and Schweitzer repeatedly used to defend their results against the earlier criticism - are also flawed. One way to resolve this, Pevzner points out, is to release the mass spec data, which is a common practice in that community. This would allow others to re-interpret the data and test more rigorously for statistical artifacts. However, Asara and Schweitzer refuse to release their data. Instead, they wrote another response which simply gives more details about how they ran the software to search their spectra against a peptide database, but doesn't really answer Pevzner's questions.

This ongoing controversy reveals some of the worst behavior I've seen on the part of Science. (Disclaimer: I've published repeatedly in Science myself.) They published two articles by Schweitzer and Asara, grabbing all the publicity they could, although they knew about the problems. The second article appeared this past spring - long after they received Pevzner's article (which was received on January 7, 2008, according to the Science website) and after they received and published the criticism by Buckley et al. What I find most reprehensible on their part is that they published both the Buckley et al. and the Pevzner et al. critiques as "Technical Comments" - which means they appear online only, not in the print edition. Both the Asara and Schweitzer articles, by contrast, appeared in the print edition, which means they will be read more widely.

If Science truly cared about getting this story right, they would publish the critiques just as prominently as the original article. It seems that Science is eager to get publicity for a "discovery", but not so eager for publicity when it turns out the discovery is false. Yes, it's true that they did publish the critiques, but they should have done better.

Finally, I recommend Rex Dalton's story in Nature on this controversy, which does a good job of summing it up, with links to all the articles. We'll see what happens next, but it appears that Schweitzer and Asara will keep defending their claims. The mounting evidence seems to show that they were wrong - wrong about the soft tissue, wrong about the mass spec identifications, wrong about the age of the sample, and wrong to continue to refuse to release their data.

Associated Press turns a story on critical care into commentary on religion

A news story from the Associated Press (and carried by CNN) illustrates how the media can focus on whatever they want to in a scientific or medical article, and create a headline that doesn't seem to match the article. Here's the CNN headline: "Survey: Many believe in divine intervention". The URL is even more telling: god.vs.doctors. The first sentence reads: "When it comes to saving lives, God trumps doctors for many Americans."

Well, this isn't too surprising - Americans tend to be religious, and the results were gathered by a survey, which might have biases. But the surprising element of this story is what the original article in the journal Archives of Surgery really contains. It is a survey by three doctors titled "Trauma Death: Views of the public and trauma professionals on death and dying from injuries." The main result is that a majority of the public prefer palliative care (i.e., making the patient as comfortable as possible) when "aggressive critical care would not be beneficial in saving their lives." The study also found that most people trust a doctor's recommendation to withdraw treatment when there is no hope for improvement. These findings are presented first.

However, the authors also asked a question about religion in their survey - they asked both the public and trauma professionals if "divine intervention" could save a person after medical professionals determine there is nothing left to do. Not too surprisingly, over half (57.4%) of the respondents from the public said yes, while only 19.5% of professionals did.

I'm not sure why the authors of the study included this question - maybe they knew it would be a "hot button" that would get them headlines. But it seems the point of their study was to educate doctors about what patients think. CNN turned this into a story that claimed "God trumps doctors," although the article didn't say any such thing. The CNN headline suggests that people would prefer "God" to doctors, but in fact the story says that most people trust a doctor's recommendations for treatment.

This is another illustration of how careful scientists and doctors need to be in presenting their work to the public. The reporter in this case (an un-named AP reporter) gathered quotes from a number of medical professionals, none of whom supported the article's lead sentence. Reporters sometimes decide for themselves what the story is - which clearly seems to have happened here - and they are only too happy to "shape" a story from the scientific literature to support their pre-determined conclusions.

Preserved T. rex or bad science?

Science has published several articles in the past year or so, with much publicity, announcing that researchers had found preserved soft tissue from Tyrannosaurus rex that contained fragments of the original collagen proteins from T. rex. The researchers leading the research, J.M Asara and M.H. Schweitzer, claimed (Science 2007 Apr 13;316(5822):280-5) that the T. rex protein fragments were more closely related to birds than to reptiles. Very plausible, of course - and if correct, yet another bit of evidence linking modern birds to dinosaurs.

However, even though birds almost certainly are descended from dinosaurs, this series of articles is a textbook case of how even the best journals - Science, in this case - can publish bad science. The mass spectrometry in the Asara et al. articles was poorly done, and even they had to admit - in a letter published in Science last fall - that at least one of their protein fragments was falsely identified. Despite this admission - and they only had 7 fragments to begin with - Science published a second article this past winter by the same authors. What did that article (Organ et al., Science 2008 Apr 25;320(5875):499) contain? Nothing new about the T. rex material, but instead some additional analysis of crocodile and ostrich proteins and a repeat of the claim that T. rex is closer to birds. The title of the article, though, is "Molecular phylogenetics of mastodon and Tyrannosaurus rex" - astonishing, if you expect Science to publish only the best science. But maybe not so astonishing if seen in the light of the publicity that Science is always hungry for. Still, it's too bad.

But why am I so skeptical? Well, don't take it from me. In a comprehensive examination of the T. rex material and methods, Buckley et al. reported - in Science, no less (2008 Jan 4;319(5859):33) that the "ancient" DNA reported by Asara and colleagues failed all the standard tests for such material. In other words, it's a contaminent.

Now, the most recent news on this story, published in PLoS ONE (Kaye TG, Gaugler G, Sawlowicz Z 2008 Dinosaurian Soft Tissues Interpreted as Bacterial Biofilms. PLoS ONE 3(7): e2808 doi:10.1371/journal.pone.0002808), shows that the most likely source for this DNA is a bacterial biofilm. Not really surprising, but it's great to see this correction of the record. Unfortunately, the Science articles got so much play in the press that they will likely be hard to "erase" from the public's memory. I suspect that far more scientists will have heard of the "T. rex tasted like chicken" stories (yes, that's how some of the press stories were headlined) than the new PLoS ONE article.

For a more detailed discussion of the biofilm story, see Tara Smith's recent blog post on this same topic.

So my conclusion about the original (2007) article in Science: those 7 protein fragments weren't from T. rex at all. They were bacterial contaminents. Asara, Schweitzer, and colleagues were simply wrong - perhaps wishful thinking clouded their vision. The article never should have passed peer review, and Science should make an effort to correct the record. Sometimes even the best journals screw up, and that's what happened here.

Victor McKusick, R.I.P.

The genetics world lost one of its pioneers this week - Victor McKusick died of cancer at age 86, at his home in Baltimore. McKusick was a professor of genetics at Johns Hopkins University for most of his career.

Dr. McKusick was known as the father of medical genetics, and became famous for his tireless efforts, beginning in the 1960's, at cataloging all human genes associated with disease. Eventually he compiled these into a book, Mendelian Inheritance in Man (the first edition appeared in 1966), which later became the widely-referenced database Online Mendelian Inheritance in Man, or just OMIM. OMIM is so central to research that it moved, many years ago now, to NIH's National Center for Biotechnology Information, which also houses GenBank. Over the years, this collection has grown from just a few genes to 18,850 entries today. (Many genes are linked to more than one disease.)

McKusick "retired" from Hopkins in 1985 but continued working, and was a big presence when I joined the faculty there in 1989. I only met him briefly, and I wish I'd had the chance to get to know him. He was a true visionary. I recommend the extensive Wikipedia entry to anyone who wants to know more about Victor McKusick.

Influenza vaccines and free sharing of flu data

I don't usually discuss my day job on this blog, but this week there's some overlap between the two. My comments in this blog back in November 2007 drew the attention of the editors of the journal Nature, and they invited me to write a Commentary for Nature on the flu vaccine and issues surrounding the open exchange of influenza data.

My Commentary appeared this week as part of a special Nature section on "Flu fighting" in the journal. See this link for the Editor's summary of the special section. The summary has links to my article and to other articles included in the special section. If you can't get the articles (a subscription may be required), then you can get a reprint of my article from my home page, under "Editorials and opinion pieces."

Coming soon to this blog: should doctors prescribe statins for overweight children?

And what else is acupuncture good for?

"Unclear whether acupuncture helps fertility"

I love this headline from Yahoo News/Reuters! It just appeared today on the Yahoo News site. So acupuncture doesn't boost pregnancy rates? What a surprise! I can't resist the obvious: acupuncture also doesn't help cure back pain, headaches, infections, depression, or cancer. In fact, the list of conditions that acupuncture doesn't help is endless!

But the Reuters reporter wasn't just making this up - there really was a presentation in London by a researcher, Sesh Sunkara, who conducted a review of 13 other studies (a meta-analysis) and found that "the current available evidence is not conclusive" on acupuncture's benefits on fertility. She apparently reported her results at the conference of the European Society of Human Reproduction and Embryology. The findings were also reported online by reporter Mark Henderson at the Times, under the headline

"Acupuncture has 'no effect' on pregnancy rates following IVF, say experts"

The Times reports that there was a reason for this study, which otherwise might raise eyebrows (why on earth do a study for which there's no plausible reason to find a positive effect?): in England, and maybe elsewhere, "acupuncture has become the most popular complementary therapy" for infertility. A number of hospitals in England have on-site acupuncture services for their patients, charging hundreds of pounds for the sessions.

Dr. Sunkara is quoted in the Times story as saying:

...every day we have patients who ask whether they should have acupuncture to improve their success rate. There have been all sorts of papers saying that sticking pins and needles increases the pregnancy rate, which have been widely reported in the media, and we are looking at women who are very vulnerable, who want to do everything possible to increase their pregnancy chances.

It's sad but true: practitioners of quack medicine - in which I include acupuncture - are quite happy to profit from the desperation of naive people who are looking for medical help. Kudos to Dr. Kundara.

And a big fat raspberry to Paul Robin, the chairman of the British Acupuncture Society, who is shocked, shocked to hear these results: "I've been treating people for 20 years and in my experience treatment does seem to improve their chances of becoming pregnant." Right, Mr. Robin - so will you be finding some other occupation now? Or maybe reducing your fees? Somehow I doubt it.

I invite readers of this forum to suggest other headines on treatments that don't work. How about "Homeopathy doesn't cure common cold"? The possibilities are endless.

NCCAM is funding quack vitamin cures

It's been a while since I looked at what the National Center on Complementary and Alternative Medicine (NCCAM) is spending our tax dollars on, so I took at look and found a newly funded proposal (grant R43AT003025) called "Medical Food Cocktail for Alzheimer's Disease." The title raised suspicions right away - what the heck is a medical food cocktail, and why would it help treat Alzheimer's? Is it some new miracle treatment? I was skeptical - after all, this is NCCAM, the NIH center dedicated to wasting our valuable research funds on bad science.

A second red flag was raised by the official email address of the Principal Investigator (PI), Curt Hendrix - rather than a university or a company, his address is a personal email account. Very strange. So what is the study going to do? From the NIH website, we find that

The overall goal ... is to formulate and conduct initial feasibility tests of a medical food cocktail composed of standardized herbal extracts, vitamins, and minerals that are demonstrated in the basic science and clinical medical literature to impact the biochemical and pathophysiological processes involved in Alzheimer's Disease. The first Specific Aim will be to formulate and standardize the cocktail, which will include extracts of tumeric, green tea, black pepper and vitamins and other nutritive ingredients.

Once they formulate this cocktail, they'll test it on mice. What? Tumeric, green tea, black pepper, and vitamins will cure Alzheimer's? That would be great if it were true, but there's no evidence to support it. (And if it were true, we'd have sub-populations of humans that had very low Alzheimer's rates, since these are common components of many people's diets.)

So who is the company that NCCAM has given this award to? It's Akeso Health Sciences, LLC, in Westlake Village, California. I've never heard of them, so I did some quick checking. It only took a few minutes to find that Akeso is another name (or a front) for a company called Migrelief that sells vitamin supplements: http://www.migrelief.com. ("Migraine relief," get it?) They used to call themselves MigraHealth, and they sell vitamin supplements that they claim help cure migraines.

Akeso Health Sciences is also quoted in a testimonial on a website called The SBIR Coach, a company that helps other companies win NIH grants. Their motto - prominently posted at the top of their website - is "We know this game." That's right, they teach companies how to play the "game" and win small business grants (called SBIRs) from the federal government. So we have one scammer (SBIR Coach) helping out another (Migrelief, also known as Akeso Health Sciences) to get funding from NIH.

How can a purveyor of vitamins for migraines re-brand themselves and get NIH money? That's what happened here: Migrelief used their alter ego, Akeso Health Sciences (sounds like they do science, right?) and wrote a proposal to NCCAM. Because NCCAM has far lower standards than the rest of NIH, and because their mission includes the promotion of pseudoscience, they funded this ridiculous proposal. What a colossal waste of funds. And I can imagine that Migrelief will soon be selling their supplements to Alzheimer's patients, offering them false hope of a cure so they can make a fast buck.

NCCAM should be closed down. Any scientific proposal worthy of funding should have to go through one of the legitimate NIH institutes. And while we're at it, we should shut down the SBIR program too; that'll have to be the subject of a future blog.

Chocolate genome sequenced - verrrry slowly

I read in the Washington Post yesterday - on the front page, no less - that the chocolate genome (the genome of the cacao plant) was going to be sequenced, with most of the funding coming from the Mars chocolate company. But then I saw on CNN the headline "Scientists analyze chocolate genome." Huh? So it's already done? Well, no - this is science by press release (as opposed to real science). No one sequenced the chocolate genome - not even a small part of it. All the news stories are based on press releases from Mars and IBM (which is collaborating with Mars on the project). The NY Times reported it with the headline, "A Genetic Quest for Better Chocolate."

Well, okay, I suppose it's interesting cocktail-party talk that someone is working on the chocolate genome. But all these dramatic news stories don't amount to much news at all, at least not on the scientific front, since nothing has been done yet. I guess the science reporters were too busy to find some real science to report on, and it's so easy to take this press release from Mars, Inc. and turn it into a story. Good job, people!

One strange element is this: "The group anticipates that it will take approximately five years to complete the entire sequencing, assembly, annotation and study of the cocoa genome." What? The genome is only 500 million bases (DNA letters). These days, a genome of that size can easily be sequenced in one year; in fact, I'm working on two species, each twice as large, that we're planning to sequence in less than a year each. This raises suspicions that they will be doing something else with the data during all that time - though they claim they will make the intellectual property freely available through PIPRA, the Public Intellectual Property Resource for Agriculture.

We should keep an eye on this and see if they really deliver. But five years? That is way too long.

Another drug maker paying for scientific articles

About a week ago I saw the full-page ad in the Washington Post by Pfizer for its drug Chantix. The ad didn’t say what Chantix was for (it supposedly helps people quit smoking); instead, it was a statement by Pfizer reassuring patients who take Chantix that everything was okay. There was some verbiage about how careful Pfizer is to ensure the safety of its drugs and that no one need worry. Obviously something wasn’t okay.

A quick web search revealed that Chantix is causing some very bad side effects: heart problems, seizures, diabetes, and over 100 vehicle accidents linked to the drug. (See the Wall St. Journal article by Alicia Mundy and Avery Johnson, May 29, 2008.) After my recent blog on Merck and Vioxx, discussing how Merck paid for scientific articles about Vioxx and then got outside scientists to put their names on them (the Vioxx Wall of Shame) , I wondered if Pfizer had done something similar for Chantix.

Well, they did.

I jumped over to PubMed and searched for articles on varenicline, the generic name for Chantix. I found many articles, some of which were exactly what I suspected: articles promoting the use of Chantix as safe that were paid for by Pfizer, but whose authors were not Pfizer employees. Let’s look at a few:

Nides M, Oncken C, Gonzales D, Rennard S, Watsky EJ, Anziano R, Reeves KR.
Smoking cessation with varenicline, a selective alpha4beta2 nicotinic receptor partial agonist: results from a 7-week, randomized, placebo- and bupropion-controlled trial with 1-year follow-up. Arch Intern Med. 2006 Aug 14-28;166(15):1561-8.

The lead author, Mitchell Nides, works for Los Angeles Clinical Trials, a company that runs trials for a fee. The article discloses at the end that Pfizer paid for the entire trial. Oncken is at the Univ. of Connecticut, Gonzales at the Univ of Oregon, and Rennard at the Univ. of Nebraska. The last 3 authors – Watsky, Anziano, Reeves – are Pfizer employees. All three of the university authors have been paid by Pfizer – as consultants, grantees, and/or speakers. Not surprisingly, this article concludes that “Varenicline was well tolerated and may provide a novel therapy to aid smoking cessation.”

The same issue of Arch Intern Med has another article by many of the same authors, concludes that “Varenicline tartrate is efficacious for smoking cessation.” On this one, Dr. Oncken is now first author, which means Pfizer can say that this study was led by the Univ. of Connecticut:

Cheryl Oncken, D Gonzales, M Nides, S Rennard, E Watsky, CB Billing, R Anziano, K Reeves; for the Varenicline Study Group. Efficacy and Safety of the Novel Selective Nicotinic Acetylcholine Receptor Partial Agonist, Varenicline, for Smoking Cessation. Arch Intern Med, Aug 14/28, 2006; 166: 1571 - 1577.

If you go to the end of the article, you learn that all the authors are in the pocket of Pfizer. Here’s what it says about just the first two authors: “Dr Oncken has received research grants, consulting fees, and honoraria from Pfizer; nicotine replacement and placebo products from GlaxoSmithKline at no cost for smoking cessation studies; and honoraria from Pri-Med. Dr Gonzales has received research contracts, consulting fees, and honoraria from Pfizer.”

Here are two more articles by LA Clinical Trials:

Nides M, Glover ED, Reus VI, Christen AG, Make BJ, Billing CB, Williams KE.
Nides again, and LA Clinical trials. Varenicline Versus Bupropion SR or Placebo for Smoking Cessation: A Pooled Analysis. Am J Health Behav. 2008 Nov-Dec;32(6):664-75.

Mitchell Nides M. Update on pharmacologic options for smoking cessation treatment. Americal Journal of Medicine 2008 Apr;121(4 Suppl 1):S20-31.

They’ve been busy! (Guess how well Chantix/Varenicline fared?) But Pfizer can’t just use this unknown company – they also recruited much more prestigious institutes, such as the Mayo Clinic:

J. Taylor Hays, Jon O. Ebbert, and Amit Sood. Efficacy and Safety of Varenicline for Smoking Cessation. American Journal of Medicine 2008 Apr;121(4 Suppl 1):S32-42.

The lead author – Hays – is at the Mayo Clinic in Rochester, Minnesota. But if you go to the end of the article, you find that “J. Taylor Hays, MD, has served as an unpaid consultant on an advisory board for Pfizer Inc; and has received grant/research support from Pfizer Inc. But get this: “Editorial support was provided by Darlene Benson, BSPharm, of Medesta Publications Group, and funded by Pfizer Inc.” I strongly suspect that Ms. Benson may have written part of this article. Another example of doctors basically selling their names to a drug company for the financial benefit of both. The Mayo clinic should be ashamed.

There are many more, for example this article on Chantix:

D F Heitjan, D A Asch, Riju Ray, M Rukstalis, F Patterson, and C Lerman. Cost-effectiveness of pharmacogenetic testing to tailor smoking-cessation treatment. Pharmacogenomics J. 2008 Mar 18.

These authors are at the University of Pennsylvania, and the senior (last) author was paid by Pfizer: “Dr Lerman has served as a consultant to Glaxo Smith-Kline, who provided bupropion and placebo for the studies described. She has also served as a consultant for Pfizer and has received funding for a project unrelated to the data presented in this paper.”

Pfizer also paid a group at Lund University (Sweden) to show that their drug was better than their competitors:

Kristian Bolina, Ann-Christin Mörk, Stefan Willers, and Björn Lindgren. Varenicline as compared to bupropion in smoking-cessation therapy—Cost–utility results for Sweden 2003. Respiratory Medicine 102:5, May 2008, 699-710.

The paper reveals that “this research was sponsored by Pfizer AB, Sweden. Kristian Bolin, Stefan Willers, and Björn Lindgren [at Lund University], were funded by Pfizer AB, Sweden, in connection with the development of this manuscript. Ann-Christin Mörk is an employee of Pfizer AB, Sollentuna, Sweden.”

There are many more, but I hope this list more than makes my point. Even one bad article pollutes the literature – but the drug companies don’t take chances. They pay for multiple studies that show the results they want. When Pfizer doesn’t pay, you get articles like this one:

Kristensen PL, Pedersen-Bjergaard U, Thorsteinsson B. Varenicline may trigger severe hypoglycaemia in Type 1 diabetes. Diabet Med. 2008 May;25(5):625-6.

The title says enough here – Chantix can be deadly to diabetics.

These are only a small sample – there are many more articles, but my institution (U. Maryland) doesn’t have subscriptions to all these journals, so I’d have to pay to read them. Without paying, I can’t find out the author affiliations and I can’t look at the end of the article to see if they disclosed any financial relationships. But I saw enough: just like Merck’s behavior with Vioxx, Pfizer paid to have articles published in the peer-reviewed literature that demonstrated the results they wanted.

The scientists who put their names on these articles aren’t independent – they are tools of their sponsors, the drug companies. But many of these articles don’t hide the affiliation with Pfizer, so there is more blame to go around. The journals should be held accountable: for example, why is Archives of Internal Medicine publishing studies run by LA Clinical Trials, which apparently is happy to run studies that produce the results a sponsor wants? Archives is a highly reputable journal (or at least I thought so) run by the American Medical Association.

I’m beginning to think that we can’t trust anything we hear about a new drug unless we read the original literature, and scan the literature with a highly critical eye for conflicts of interest. This is truly unfortunate. Most people don’t have the training (or the time!) to read these original articles, and very few non-academics have subscriptions to these journals. Even the experts tend to rely on the short abstracts (which summarize the conclusions), especially in reputable journals, but it appears that we can’t trust those either.

Money seems to have corrupted the biomedical literature, more deeply than I had realized. We need to work to correct this situation, starting by pointing it out wherever we see it. And before taking any new medication, I plan to dig into the literature to find out if the benefits are real, and if there are harmful side effects that the drug manufacturers have attempted to hide. Meanwhile, shame on Pfizer and on all the so-called scientists listed above who took Pfizer’s money to write articles promoting its drug Chantix.