Maryland Congressman asks the NIH to fund more young scientists

Maryland Congressman Andrew Harris

Now here's something that you don't get to see everyday - a politician taking (the right kind of) interest in the NIH's activities and asking the agency to support the most important ideas in basic biomedical research by funding young scientists. Maryland Congressman Andrew Harrison's thesis is that whatever money the NIH might have left after all the funding cuts is being spent on scientists in their 40s and beyond; he is mostly alluding to the depressing fact that most academic researchers now receive their first big RO1 grant at the age of 42. Harris says this is a mistake.

The problem, as he sees it, is that cutting-edge science is a young man's game, and it is also unlikely to be the game of someone who has already achieved his or her biggest hits:

"Every year the National Institutes of Health receives almost $30 billion in federal funds to invest in biomedical research. The bulk of that money goes to researchers who are in many cases esteemed in their fields — but also, in many cases, beyond the age when most scientists make their most important contributions to their fields.  

A study for the National Bureau of Economic Research from 2005 examined the age at which over 2,000 Nobel Prize winners and other notable scientists in the 20th century came up with the idea that led to their breakthrough. Most were between 35 and 39. Yet the median age of first- time recipients of R01 grants, the most common and sought-after form of N.I.H. funding, is 42, while the median age of all recipients is 52. More people over 65 are funded with research grants than those under age 35."

The Congressman makes another two observations that are cogent; first, that the NIH often funds glamorous research at the expense of more basic research, and second, that the NIH also seems to fund interesting projects that nonetheless seem far less important than research into humanity's most pressing problems like Alzheimer's disease.

"For many fields, particularly those that don’t have immediate commercial applications or sex appeal for grant-making nonprofit groups, the N.I.H. is a vital source of money. We’ll never know what breakthroughs were missed because young investigators were not provided with the resources necessary to pursue unique ideas over the last 15 years. They may have had the idea that would have led to a cure for ovarian cancer, Alzheimer’s disease or pediatric cardiomyopathy. 

...Today we see too many grants going to things like creating a video game for moms to teach them how to get their kids to eat more vegetables, or studying the creation of a social security system in southern Mexico. Such projects may have value to some, but is creating a video game really more important than researching a cure for Alzheimer’s?"

I have no problem seeing where Harris is coming from - the paucity of funds for young scientists is one of the biggest barriers for newly minted PhDs to consider academic research these days - but I am not sure the "young is great" theme applies as much to biomedical researchers as to, say, theoretical physicists. In fact a study which I blogged about a few years ago pointed out that because their work involves raw brain power more than anything else, theoretical physicists are the most likely to produce great breakthroughs in their 20s and early 30s; no wonder that the physics done by young Turks like Paul Dirac and Werner Heisenberg was called 'Knabenphysik' - the physics of youth.

As that study indicated however, with experimental sciences like biomedical research things are different, and many biomedical breakthroughs came from scientists at a relatively advanced age. There has been no synthetic organic chemist winning the Nobel Prize in his or her 20s for instance, and even the great Robert Burns Woodward - widely considered to be a true prodigy in chemistry if there ever was one - had to wait until his 40s to be recognized. When it comes to sciences like organic chemistry or molecular biology it's not a question of raw IQ; it's a question of spending those 10,000 hours to learn the tricks of laboratory manipulation, to assimilate the existing literature and, because of the great complexity of biological systems, to develop a feel for their workings. This inevitably takes time, even for very smart people.

Thus while I think Harris's heart is in the right place and we undoubtedly need more grants for young people, the real strategy should be to fund interesting ideas irrespective of age. I fear that Harris's proposal, if carried out to its logical conclusion, might achieve the opposite effect - it might alienate older researchers who are still very much capable for bright ideas. To fund the best science, all we have to do is to fund the best science.

Note: I did not even notice until much later that the Congressman is Republican. This gives me hope that I haven't turned one hundred percent cynical yet.

John LaMattina on the new NIH drug discovery center

There's a post by ex-Pfizer research chief John LaMattina about the new NIH drug discovery center, and predictably he does not seem too happy about it. While the initial center was supposed to be all about translational research, the latest idea is to use the NIH's resources for "repurposing", or discovering new indications for old drugs.

LaMattina echoes some of the dissatisfaction that a few of us have earlier expressed about this idea. The main point here is that the NIH should not be in the business of discovering new drugs; it should be in the business of doing the basic biological research that may enable such potential discoveries. In fact one might argue that the biggest challenge facing drug discovery today is an incomplete understanding of the complexities of the biology underlying major diseases. Just think of the conflicting data and the complications that have emerged from attacking beta amyloid in Alzheimer's disease for instance. There's hardly any doubt that better treatments can only result from a proper evaluation of the basic biology of disease. And it's also clear that this understanding is not going to come from industry. Only the NIH and academic labs can accomplish this, and spending money on therapies when it could more fruitfully be spent on such fundamental studies seems to be folly. So ironically, funding drug discovery may hinder an understanding of the very foundations that may truly enable it.

Nor is what the NIH doing truly novel. As LaMattina points out, repurposing is an obvious route and an attractive one at that, since finding a novel indication for an old drug means that the drug has already run the gauntlet of FDA approval. So we can bet that industry would have worked on repurposing if they could possibly do it. Now granted, there's always going to be compounds that were dropped for financial or project-related reasons which may be potentially valuable agents for all kinds of conditions. And we can also assume that these numbers might have grown during the last few years when projects have been axed and personnel laid off in increasing numbers. But what are the chances that hidden among those dusty vials on the shelf is the next cure for pancreatic cancer? Of course one may never find out if one does not look, but the NIH's announcements make it sound like there's pure gold among those neglected compounds, waiting to be discovered. The fact is that examples of truly repurposed drugs are quite few; as LaMattina points out, even the two repurposed drugs cited by NIH director Francis Collins are drugs for which the "other" indications were rather obvious based on their mechanism of action. Repurposing by itself is not entirely misguided, but repurposing at the cost of basic biomedical research draws resources away from more worthy endeavors.

Thus, by and large LaMattina's arguments seem to be cogent. Unfortunately the indignation on the other side of the equation is not as justified as it sounds. LaMattina refers to a statement by legendary Merck ex-CEO Roy Vagelos along the lines that if there was real benefit to something that the NIH wants to do, pharma would already be doing it. Sadly this is increasingly not the case. In the last few years pharma has defined "benefit" based on whether something's going to affect the next quarter's profits. Working on Alzheimer's disease and other CNS disorders where the rewards are long-term but undoubtedly stellar is no longer considered a beneficial strategy. So we have a situation here where industry is rightly advising the NIH to work on basic research rather than drug development, but not committing itself to its part of the deal. As well-intended as it may be, the impact of your advice gets blunted a little if you stop looking in the mirror.

A government center for drug discovery?

The New York Times has an article about a new center for drug discovery that the government is going to set up in the face of the declining pace of new drug discovery in the pharmaceutical industry. We all know what's wrong with the industry, with the numero uno factor being the pursuit of short-term profit goals at the expense of basic science and long-term benefit. The question is, can the government make up for this shortfall?

Perhaps, if it's done right. But the vision for the new center does not inspire me with much confidence. The center seems to mainly be a result of NIH director Francis Collins's conviction that gene-based drug discovery is the wave of the future. Collins is disappointed with the fact that Big Pharma has been unsuccessful with "translational genomics" in spite of spending millions of man hours and dollars. He thinks that if done right, this kind of translational approach will result in new drugs. As he makes it clear in his book "The Language of Life", Collins is a longstanding proponent of genomics-based medicine.

But isn't this what everyone has been saying ever since genome sequencing became possible? We all remember the hype about genomics enabling a new generation of 'rational' drugs based on intimate knowledge of genes and their protein products. The fact that this vision has not panned out could partly be ascribed to the lackluster efforts and the constant waves of lay-offs in industry, but maybe there's also a deeper reason why the optimism has hit a wall. Maybe, and experts have been saying this for a while now, it's simply because taking a genomics-based approach to drug discovery ignores all the other complexities of biological systems like signal-transduction and epigenetics. Discovering the gene and protein is one thing, understanding the intricate interactions of the protein as part of a multi-layered cellular communication network is quite another. We are still struggling to understand the very basics of how proteins and genes link up in cells to enable complex physiological and behavioral responses, let alone rationally design drugs to block specific parts of those responses. In the absence of such understanding, simply pinning your hopes on the promise of 'translational genomics' seems to me to be another big sink for money and personnel.

So what else can a government center for drug discovery do which could be more concrete and fruitful? Ironically, the article contains part of the answer when it highlights the complexity of biological systems stated above.

Consider this remarkable fact; in the last century, only two breakthrough treatments for mental illness have been developed, lithium for bipolar illness and chlorpromazine (Thorazine) for schizophrenia. Many other successful antipsychotic drugs were spinoffs of thorazine. Also consider that even today we have little clue about how these drugs work, let alone how to rationally design them. Thorazine likely affects multiple neurotransmitter pathways involving serotonin, norepinephrine, dopamine etc. While we have made great advances in the last fifty years, brain chemistry remains as complex as ever. At a molecular level, the main problem is in understanding the basic mechanisms and specificity through which a molecule as simple as dopamine binds to only certain subtypes of a neurotransmitter receptor, stimulates multiple second-messenger pathways to different extents and elicits a complex behavioral response. In this case we know most of the genes and we know most of the protein products, yet we are light years away from understanding how Thorazine works. Lithium is an even more mysterious substance whose workings are almost akin to black magic. Instead of chasing the genes, thoroughly understand the action of a few of these drugs on a biochemical level and we can make significant inroads into understanding brain chemistry.

So if there's one thing a new government center for drug discovery can do, it should be to focus on these specific problems in the most general way rather than pool together resources for "translational genomics". Doing translational genomics will simply mean advancing work which industry is already involved in; it will largely be more of the same and there's good reasons why it may not work.

Here's what I think instead. If the center truly wants to do something productive that pharmaceutical companies cannot, let it put together a mini Manhattan Project type team focused on understanding a few specific problems, like how lithium works in the brain. The problems should be picked based both on their medical importance and their potential impact in enabling general understanding of the field. Just like the Manhattan Project did, get together the best people in the country from several disciplines who are experts at multidisciplinary thinking and problem solving. If you want to attack the lithium problem for instance, get together chemists, biologists, neuroscientists, pharmacologists, doctors and perhaps even a few physicists, mathematicians and computer scientists. Put them in a couple of large rooms (and maybe even seclude them in the majestic mountains of New Mexico) and give them enough funds. And then most importantly, give them almost complete freedom to brainstorm about specific problems. Let them consider every possible approach, from running basic biophysical experiments to the most advanced neural imaging techniques. Don't limit yourself to any one philosophy like translational genomics or any other currently fashionable mantra. Genomics can certainly be part of the mix but it should not be put on a pedestal. Combine the oldest tools of classical pharmacology with the newest tools of molecular biology. If the industry has been missing one thing, it's been the presence of bright young people who are given complete freedom to focus on their diverse ideas without strings attached and constant fear of unemployment. The government can give these men and women what industry has taken away from them in recent years.

The government has always been good at this kind of free-for-all interaction among talented scientists who are unencumbered by research funds and job insecurity. A new government center for drug discovery could be a great idea, but only if it provides the kind of freedom to operate that brings out the best in creative minds. Focusing on translational genomics to me seems to be another way to repeat what has been done and to waste more funds, time and personnel. Instead, do what the government does best; let them think, and let their minds soar.

Marshall Nirenberg (1927-2010)

In the latest issue of Cell, Edward Scolnick offers a moving and insightful tribute to his former mentor, Marshall Nirenberg. Nirenberg won the Nobel Prize for Medicine along with Har Gobind Khorana and Robert Holley for one of the most important scientific discoveries, the cracking of the genetic code. Scolnick pinpoints the essential nature of the man and his work.

The world of science knows the substance of his work: He opened up the mystery of the genetic code with the poly-U-polyphenylalanine experiment, then with the triplet binding assay with Phil Leder, and finally with the triplet termination assay with Tom Caskey. From UUU to all 64 triplets: the “periodic table” for molecular biology. But how many have read the poly-U paper—I mean, really read it? Marshall’s approach to science comes through, loud and clear. Every possible control is tested. Every method is described so that anyone else can reproduce it. Every piece of data, even imperfect data, is included in the tables and figures. The incorporation of phenylalanine into the product is more than a thousand-fold over background without the poly-U template, and the incorporation of this amino acid is selective for this homopolymer. How many of us would take the care to characterize the actual product to be sure it had the characteristics of polyphenylalanine? Marshall believed deeply in being meticulous and in being certain that one’s data were true, that the results were due to the variables one had manipulated and were not caused by some vagary that had not been thought of or controlled for. He believed that the methods in one’s paper should be so clearly described that any investigator trying to reproduce the results could do so on the very first attempt. Supplementary sections could never be a part of a Nirenberg paper...

Scolnick also ends with an admonition and a wise message that every member of the government should read.

Members of Congress—guardians of taxpayer dollars and decision-makers for NIH funding—often ask themselves whether the funding for science provided to NIH really matters to the health of the nation. We should tell them to think for a moment about the impact of the cracking of the genetic code. If it were not for Marshall Nirenberg’s work, there would be no recombinant DNA technology, which changed life science and medicine. The sequence of the human genome and the era of modern genomics could not have come into being. Protein therapeutics for cancer and autoimmune diseases, drugs for HIV, statins for atherosclerosis, and modern vaccines all ultimately owe their origin to the knowledge of the code. The genetic code is the periodic table for biological science...How can we honor Marshall Nirenberg’s memory? We can remember all the things he stood for: complete truth in science, meticulous attention to detail, passionate love for discovery, thorough training of students, deep values about how science should be carried out. Marshall will never be dead, because what he stood for in science is timeless—bridging generations of scientists, and bridging millennia

How easy is it to forget that the greatest applied scientific breakthroughs and the greatest fundamental discoveries in science have mainly come out of government-funded basic research? Those who forget this will only condemn their own grandchildren to paucity of knowledge and bereave them of that magical horizon of understanding that science reveals. It is up to all of us to ensure that Nirenberg and others live on through a commitment to such basic scientific research.