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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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July 1, 2008

The Gates Foundation: Dissatisfied With Results?

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Posted by Derek

Well, since last week around here we were talking about how (and how not to) fund research, I should mention that Bill Gates is currently having some of the same discussions. He’s doing it with real money, though, and plenty of it.

The Bill and Melinda Gates Foundation definitely has that – the question has been how best to spend it. They started out by handing out money to the top academic research organizations in the field, just to prime the pump. Then a few years ago, the focus turned to a set of “Grand Challenges”, fourteen of the biggest public health problems, and the foundation began distributing grant money to fight them. But according to this article, from a fellow who’s writing a book on the topic, Gates hasn’t necessarily been pleased with the results so far:

”. . .Gates expected breakthroughs as he handed out 43 such grants in 2005. He had practically engineered a new stage in the evolution of scientific progress, assembling the best minds in science, equipped with technology of unprecedented power, and working toward starkly-defined objectives on a schedule.

But the breakthroughs are stubbornly failing to appear. More recently, a worried Gates has hedged his bets, not only against his own Grand Challenge projects but against how science has been conducted in health research for much of the last century.”

My first impulse on hearing this news is not, unfortunately, an honorable one. To illustrate: I remember a research program I worked on at the Wonder Drug Factory, one that started with a series of odd little five-membered-ring molecules. Everyone who looked them over had lots of ideas about what should be done with them, and lots of ideas about how to make them. The problem was, the latter set of ideas almost invariably failed to work.

This was a terribly frustrating situation for the chemists on the project, because we kept presenting our progress to various roomfuls of people, and the same questions kept coming up, albeit in increasingly irritated tones. “Why don’t you just. . .” We tried that. “Well, it seems like you could just. . .” It seemed like that to us, too, six months ago. “Haven’t you been able to. . .” No, that doesn’t work, either. I know it looks like it should. But it doesn’t. Progress was slow, and new people kept joining the effort to try to get things moving. They’d come in, rolling up their sleeves and heading for the fume hood, muttering “Geez, do I have to do everything myself?”, and a few weeks later you’d find them frowning at ugly NMR spectra next to flasks of brown gunk, shaking their heads and talking to themselves.

I’d gone through the same stage myself, earlier, so my feelings about the troubles of the later entrants to our wonderful project devolved to schadenfreude which, as mentioned, is not the most honorable of emotions. I have to resist the same tendency when reading about the Gates Foundation – sitting back and saying “Hah! Told you this stuff was hard! Didn’t believe it, did you?” isn’t much help to anyone, satisfying though it might be on one level. I’m cutting Bill Gates more slack than I did Andy Grove of Intel, though, since Gates seems to have taken a longer look at the medical research field before deciding that there’s something wrong with it. I note, though, that we now have well-financed representatives of both the hardware and software industries wondering why their well-honed techniques don’t seem to produce breakthroughs when applied to health care.

Now the Gates people are trying a new tactic. The “Explorations” program, announced a few months ago, is deliberately trying to fund people outside the main track of research in its main areas of focus (infectious disease) in an effort to bring in some new thinking. I’ll let Tadataka Yamata of the Gates Foundation sum it up, from the NEJM earlier this year:

”New ideas should not have to battle so hard for oxygen. Unfortunately, they must often do so. Even if we recognize the need to embrace new thinking — because one never knows when a totally radical idea can help us tackle a problem from a completely different angle — it takes humility to let go of old concepts and familiar methods. We have seemed to lack such humility in the field of global health, where the projects related to diseases, such as HIV, malaria, and tuberculosis, that get the most funding tend to reflect consensus views, avoid controversy, and have a high probability of success, if "success" is defined as the production of a meaningful but limited increase in knowledge. As a result, we gamble that a relatively small number of ideas will solve the world's greatest global health challenges. That's not a bet we can afford to continue making for much longer.”

What’s interesting about this is that the old-fashioned funding that Yamata is talking about is well exemplified by the previous Gates Foundation grants. After last week’s discussion here about “deliverables” in grant awards, it’s interesting to look back at the reaction to the 2003-2005 round of “Grand Challenges” funding:

”Researchers applying for grants had to spell out specific milestones, and they will not receive full funding unless they meet them. "We had lots of pushback from the scientific community, saying you can't have milestones," says Klausner. "We kept saying try it, try it, try it." Applicants also had to develop a "global access plan" that explained how poor countries could afford whatever they developed.

Nobel laureate David Baltimore, who won a $13.9 million award to engineer adult stem cells that produce HIV antibodies not found naturally, was one of the scientists who pushed back. "At first, I thought it was overly bureaucratic and unnecessary," said Baltimore, president of the California Institute of Technology in Pasadena. "But as a discipline, to make sure we knew what we were talking about, it turned out to be interesting. In no other grant do you so precisely lay out what you expect to happen."

I have to think, then, that in no other grant are the chances of any breakthrough result so slim. It would be interesting to know what the Gates people think, behind closed doors, of the return they’ve gotten on the first round of grant money, but perhaps the advent of the Explorations program is already comment enough. (One round of Explorations funding has already taken place, but a second round is coming up this fall. You can start your application process here).

The next question is, naturally, how well the Explorations program might work – but that’s a big enough topic for a post of its own. . .

Comments (28) + TrackBacks (0) | Category: General Scientific News | Who Discovers and Why


1. Haggis on July 1, 2008 8:16 AM writes...

Bill's discovered the science equivalent of the Blue Screen of Death.

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2. CC on July 1, 2008 9:11 AM writes...

New ideas should not have to battle so hard for oxygen. Unfortunately, they must often do so. Even if we recognize the need to embrace new thinking — because one never knows when a totally radical idea can help us tackle a problem from a completely different angle — it takes humility to let go of old concepts and familiar methods.

My impression is that the people you attract with rhetoric like this are mostly useless, expensive, self-promoting gasbags. (And "humility" sure won't be what you get.)

That said, Gates also kicks in the necessary piles of money to enable clinical trials for therapies in unprofitable indications, which I'd say is the single most important thing that can be done, provided someone with a clue is picking the drugs to back.

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3. CC on July 1, 2008 9:13 AM writes...

Incidentally, for everyone else who has been unable to comment here for months: deleting the cookie for this site seems to fix it.

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4. Hap on July 1, 2008 10:28 AM writes...

Do you know how to delete the cookies in IE?

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5. Jennifer on July 1, 2008 11:14 AM writes...

The Gates Foundation is attempting to solve a lot of problems where easy access to good food and clean water might be the solution to the problems. Moreover, if they could intervene in the various unstable political situations, people living there might actually survive to eat the good food and drink the clean water.

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6. The Pharmacoepidemiologist on July 1, 2008 11:20 AM writes...

Rather interesting that Gates funds many of the established leaders in the field--and it turns to those same leaders for advice on its programs. If one wants out of the box thinking, then you need to go to new blood. Unfortunately, in its history, Gates hasn't done that much. Hence, the current "problem" should have been expected. The cancer community has had this problem for almost four decades, and at some point, it will realize that the current approach isn't getting much ROI. So Gates' problem isn't unexpected at all--curious that with all those smart folks running it, they didn't anticipate this problem.

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7. Layman on July 1, 2008 11:56 AM writes...

Would Peter Duesberg's work on aneuploidy qualify ( Is that still controversial and/or relevant?

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8. PharmtoAcademe on July 1, 2008 12:15 PM writes...

"If one wants out of the box thinking, then you need to go to new blood. ... So Gates' problem isn't unexpected at all--curious that with all those smart folks running it, they didn't anticipate this problem."

Well the second paragraph of Yamada's NEJM article (the paragraph just before the one quoted by Derek) does say,

"I must confess to having learned the hard way that embracing new thinking, as difficult as it may be, is crucial for the advancement of science and medicine"

Ultimately, I think the concept of new blood makes perfect sense on paper, but is frustrating in practice. Not every promising scientist is destined for a breakthrough and the impatient and overly-structured culture of large research organizations are not positioned to nurture out-of-the-box thinking. I cannot think of any personal, professional, or academic incentives to go out on a limb in biomedicine. Building more of these -- which is a major cultural change -- might move us towards a more innovative research world.

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9. burt on July 1, 2008 12:36 PM writes...

The Gates Foundation's idea of funding work on 3rd world diseases is laudable and I don't wish to diminish it, but never forget: the whole reason the Foundation exists is to pain Bill as a philanthopist. The DoJ "pre-Bush" was actually interested in anticompetitive behavior and MSFT was actually CONVICTED.

The Foundation also has a dark side-- funding computer access projects and pushing Windows-based solutions.
Wikipedia: "Each year an award of up to US$1 million is given to a public library or similar organization outside the United States that has an innovative program offering the public free access to information technology."

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10. Anonymous on July 1, 2008 2:08 PM writes...

I'm sure any library will happily endure the torture of have Windows 'forced' upon them for a generous $1 million donation....

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11. hibob on July 1, 2008 2:28 PM writes...

do I see some shades of Andy Grove's complaints about the Pharma industry in Gates's frustrations with biomedical research?

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12. MTK on July 1, 2008 3:32 PM writes...

Anon #10: Agreed.

It would be easy to cynically dismiss the Gates Foundation or for that matter any other philanthorpic actions by the filthy rich as nothing more than self-aggrandizing. It may be, but to automatically assume so is ludicrous. Let's take it at face value as someone who has accumulated a vast amount of wealth and would like to see some good come out of it.

Actually the fact that Gates doesn't seem happy with the results to date would seem to indicate that he really wants to solve these problems, not just get some good press here. If that were the case, he'd just throw more money at it.

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13. Mac on July 1, 2008 3:40 PM writes...

Gates is one of the few rich people who is genuinely trying to do something to make things better in the world. So is Warren Buffet.

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14. Curtis on July 1, 2008 4:48 PM writes...

I'm enjoying this discussion very much.

I believe that in order to fund research that is "out of the box" and from "new blood" it is important to fund young investigators. Young investigators are the most likely to think outside of the establishment.

Along with funding young investigators it is important to change the reward structure of biomedical research. Tenure, grants, and almost every other reward to research is only given to successful research. In fact, it can seriously damage a young career to do risky work that does not discover something novel. There is no reward for doing good quality research. Emphasis should be put on funding quality researchers and not necessarily successful projects.

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15. CMC guy on July 1, 2008 9:02 PM writes...

The Grand Challenges are mostly very difficult problems so the Gates Foundation should be applauded for ambitious attempting to address (especially since so few others willing to risk). Perhaps the progress has not been as immediate as desired/projected but trust still could eventually lead to benefits and underlying knowledge for continued pursuits. I don't think it hurts to have outside perspectives brought to bear on issues although most people who have been involved in drug development (& science in general) realize easy answers are rare so can be frustrated by outsiders who don't appreciate complexity.

I like the enthusiasm and even naivety of young investigators can bring however IMO must be coupled with experienced and knowledge mentors to guide and evaluate. One has to avoid replowing too much over the same ground, yet it may not hurt to use some modern tools to perhaps uncover observations missed earlier.

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16. Allchemistry on July 2, 2008 3:24 AM writes...

As Jennifer (#5) pointed out, prevention, rather than cure, is a much cheaper and more effective solution to most health-problems in developing countries. One should not forget that the introduction of sewerage systems, safe drinking water and better nutrition has greatly contributed to the increased life expectancy in Europe in the 19th and 20th century. So in my opinion the main challenge is to achieve an effective and durable implementation of such already existing solutions. I admit that it is scientifically less appealing, but on the other hand, ODA policy makers, which now merely throw money at incapable and corrupt administrations, will far more benefit from out-of-the box thinking than medchemists.

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17. burt on July 2, 2008 7:11 AM writes...

Allchemistry is right. Simple public health solutions work. There are places in India where the water is beyond unclean; it is downright toxic (arsenic). Dengue fever is less prevalent in Texas than neighboring Mexican communities simply because Texans have window screens to keep out mosquitos (or, more likely, keep their windows closed and AC on).

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18. Retread on July 2, 2008 8:30 AM writes...

The Grand Challenges derive from the line of thinking that led to the launching of the "war on cancer' in 1971. Landing a man on the moon back in 1969 impressed everyone. I remember taking our kids out to the back yard the night it happened and telling them that there were now men on it. Since they were 1 and 3 at the time, they were unimpressed. It we could throw men and money at a problem that large, surely the same approach would work for cancer.

Not much progress on cancer has been made -- Science vol. 312 pp. 1162 '06 (Harold Varmus-- former head of the NIH) "The age-adjusted mortality rate for cancer is about the same in the 21st century as it was 50 years ago, whereas the death rates for cardiac, cerebrovascular and infectious diseases have declined by about two-thirds."

Similarly not much progress has been made on Gates challenges. Why" Because the problems are very hard. Unlike the moon shot, cell biology and infectious disease are not basically engineering problems.

They are hard for several reasons. First, because the system we are studying is quite complex. Have a look at the Chemiotics post of 3 April on the Skeptical Chymist web site "Causality in the cell" for what happens just to one type of protein modification inside the cell when you throw only one thing at a cancer cell.

Second, because I don't think we even know all the players at this point. Consider what we knew about cancer biology in '71 and now. Split genes, microRNAs and most of the oncogenes were on the horizon. MicroRNAs have only received attention in the past 5 years. Some bacteria and viruses release microRNAs into the cell for their own purposes. If Breaker's work on riboswitches applies to infections we'll have to consider a host of metabolites as well. And that's what we know about presently. Do you really think we've know all the types of biologic players residing within us?

So it's hard. So what. It's fit work for smart people. Go to it.

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19. MTK on July 2, 2008 8:34 AM writes...

Agreement with those regarding prevention.

The Gates Foundation website lists two main areas of focus:

* Access to existing vaccines, drugs, and other tools to fight diseases common in developing countries

* Research to develop health solutions that are effective, affordable, and practical

I would assume that the first point includes better sanitation, health infrastructure, etc.

From the research end, I think that a mix of government and private foundation money like this is good and that if each uses a different approach , or at least a different % of conservative vs "out of the box" thinking, even better.

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20. Bioorganic Chemist on July 2, 2008 10:31 AM writes...

The Gates Foundation is to be lauded for spending money to attract scientists to work on difficult problems. The mere presence of a different funding source, with different criteria than NIH, is inherently good for science. And I think they've chosen great challenges as well.

But with statements like the following (from the grants page linked at the end of the post), it is essentially impossible to avoid schadenfreude:

"The power of innovation is at work in countless other fields, from space travel to the Internet: now is the time to harness that power to save lives and improve the health of millions of people in the developing world."

Yes, there is no innovative thinking in modern biomedical science...the problem is that we scientists are all a bunch of closed-minded, uninnovative dolts.

Let's consider the industries. In science, it takes a decade or more post-college before you can really find your groove: early assistant professors and freshly starting pharmaceutical/biotech scientists may be exceptionally well-trained, but are incredibly naive. After a few years on the job, things have changed.

In contrast, in software, you can be a college dropout and be incredibly successful.

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21. burt on July 2, 2008 11:34 AM writes...

"In contrast, in software, you can be a college dropout and be incredibly successful."

Particularly if your re-package somebody else's DOS and sell it to a big, lumbering company called "IBM" at the twilight of the mainframe era. A good con artist beats a trained professional any time.

Having said that, maybe I should have spend my college years on "C" instead of "CPK"......

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22. The Pharmacoepidemiologist on July 2, 2008 11:44 AM writes...

Peter Drucker noted many times that the essential characteristic about the Manhattan Project and the Apollo Project was that at the time each was started, all the science needed for their successful completion was known. The scale of each was immense, requiring considerable engineering accomplishment, but the intellectual strides needed were few and far between. Not so with the areas Gates (and even Grove, if you want to go that far) is interested in. The technical/scientific knowledge needed simply isn't there, and one can not simply advance the science by throwing money at it. The same problem has challenged the War on Cancer since it started (never mind the decade in which resources were thrown willy-nilly at viral causes of cancer). Until that recognition of the importance of having all the scientific knowledge available when starting the project is made, funders of such work will likely continue to be frustrated. It's one thing to say, "We're going to distribute birth control pills as a matter of keeping the world's population at sustainable levels" and another to state, "Our concern is population control and developing a scientifically sound way to implement it." The latter is much more where Gates is at, and it's no wonder it hasn't recorded more success. Lots of the problems it wants to address are pharmacoepidemiologic or environmental epidemiologic ones, but there is nary a pharmacoepidemiologist or environmental epidemiologist in its midst. And Bill Foege, as good an epidemiologist as he is, hasn't been in evidence for a while. No surprise then that Bill G is frustrated. He'd be frustrated in his previous position, too, if he asked a bunch of marketing MBAs to write the code for Office 2007 and expected something usable in a product.

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23. burt on July 2, 2008 11:55 AM writes...

"The latter is much more where Gates is at, and it's no wonder it hasn't recorded more success. Lots of the problems it wants to address are pharmacoepidemiologic or environmental epidemiologic ones,"

Yea. And anthropological. You throw a bunch of birth control pills at Zimbabwe or Yemen (or for, that matter, Mississippi) and where's the guarantee they'll be used-- and used correctly?

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24. Anonymous on July 2, 2008 2:47 PM writes...

The majority of health problems can be reduced to a great extent by providing people an easy access to healthy water, food in many African and Asian counties, they say "developing countiries" (don't know how many decades they take to get fully developed!!).
One would think that these countries are lacking resources and are poor. Though I agree these counties are poor, one should not underestimate the money, supplies being donated by WHO and other international charity organizations. But, how much of the help is reaching the poor is a big question (according to some estimates, it is less than 5%).
Corruption and red-tapism at all levels in the administration are the most important culprits hindering the help reaching the poor and the needy. One possible solution to the problem is establishing a parellel organization to take care of the supply system so that the help and supplies from international charities reaches the poor and needy directly. I know this is a huge and gigantic task, but once established it can serve as a supply system for all the charities. Western countries should take care of the administration and running of the organization and should completely remove the local government's influence on the supplies.
Another thing that can be done is increase efforts in improving literacy and make them aware of their health. Literacy also helps in getting good people elected to the offices (wherever democracy exists).
These two things can solve the problems by about 75% and the remaining 25% problems can be solved by investing in the R&D to make new drugs and technologies and see that the technologies reach the poor and the needy.

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25. Bryan on July 5, 2008 8:10 PM writes...

I was just reading this article in the ledger and was reminded of this post. Is it possible that the funding cuts could be backlash signifying the end of a golden era in funding scientific discovery? Biotech was supposed to herald in an revolution in biomedical technology where we would be able to cure and eradicate all disease and correct all inborn errors of metabolism. Could it be that we sold the world really well on an idea that we are now admitting is harder than we had anticipated? Perhaps we just kept our mouths shut when we were told that millions of dollars would be pumped into our programs? I can only hope that by the time I finish my minimum 6 year biomedical PhD and my 5 years of postdoc I might actually have a job.

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26. butch palmer on July 15, 2008 2:03 AM writes...

There are scads of people like me who had fine healthcare insurance a decade ago but now we cannot afford it.
Around age 50 costly diagnostics are necessary for preventive medicine. Is there a way that we might benefit from Mr Gates Foundation ? Microsoft has been a major part of our lives since Windows operating system. We were a chunk of the market. Shouldn't' charity began at home ?

Sincerely, Butch Palmer
Augusta, GA

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27. eugene on July 15, 2008 10:32 AM writes...

Butch, did you use legally licensed versions of Windows during the last 20 years and all related proprietary software? I know I slipped up a few times. You might be ineligible if that is the case. I think I hacked a version of Windows for a 486 back in the 90s, so I don't expect much karma from that.

In all seriousness though, if Mr. Gates paid the insurance costs of every American that wasn't getting proper care, he'd be even more dissatisfied with the results and the money would run out a lot sooner. Coupled with that, the lack of any senior Microsoft folks reading this blog, and you might be better off to take your concerns to our elected representatives. Or moving to a country with a more sane and fair health care system.

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28. eagreenhalgh on October 22, 2008 4:14 PM writes...

Regarding the Challenge Grants of Mr.Gates,1. congratulations to the winners ,but if Mr. Gates really wants answers then I must ask the public to consider the following.Bill Gates is aware thru his association with the University of Waterloo that research of importance to cancer and AIDS was blocked so lies could be covered up so fraud charges would not be laid. For all his talk , for Mr. Gates to go along with this says he is not a brave man and we must also question his own honesty and the honesty of his advisors : allowing researchers to lie is bad!. You are asked to see the 2008 White Section ,the emails to Dr. Faucci, who also claims he wants new people and new ideas, and the research proposals to the Gates foundation. Also you must realize the research is getting ready to prove a direct link between global warming and emerging diseases that could TAG for death 70% of mankind.A Fmr US Surgeon Gen. has regretted my treatment and Noam Chomsky considers my research to be very important , among others.Ask Mr. Gates for his own opinion and note when asked if his own children could be at risk why he didn't respond.Mankind is running out of time , and covering up fraud should not be a priority for people like Mr.Gates. Thank you. E.A.Greenhalgh

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