Field of Science

How to run a world-class lab

One of this year's Nobel laureates in physics, Serge Haroche, has a few words of wisdom for fostering a good research environment.

Our experiments could only have succeeded with the reliable financial support provided by the institutions that govern our laboratory, supplemented by international agencies inside and outside Europe. European mobility programs also opened our laboratory to foreign visitors, bringing expertise and scientific culture to complement our own. During this long adventure in the micro-world, my colleagues and I have retained the freedom to choose our path without having to justify it with the promise of possible applications. 

Unfortunately, the environment from which I benefited is less likely to be found by young scientists embarking on research now, whether in France or elsewhere in Europe. Scarcity of resources due to the economic crisis, combined with the requirement to find scientific solutions to practical problems of health, energy and the environment, tend to favour short-term, goal-oriented projects over long-term basic research. Scientists have to describe in advance all their research steps, to detail milestones and to account for all changes in direction. This approach, if extended too far, is not only detrimental to curiosity-driven research. It is also counterproductive for applied research, as most practical devices come from breakthroughs in basic research and would never have been developed out of the blue.

Haroche’s quip about short-termism being bad even for applied research is especially worth noting, since applied research is supposedly what short-termism seeks to encourage. The point is that the path of science is almost always unexpected and complex, and most applied research is the illegitimate albeit charming and often spectacularly successful offspring of blue-sky basic research. Neglect of this foundation is one major flaw I see with the whole concept of “translational medicine” which seems to lack an accurate appreciation of the haphazard way in which basic scientific principles have actually translated to practical medical therapies. Unless we know the underlying biology of disease, which even now is quite complex for us to grasp, it’s not going to be possible to have scientists sit in a room and think up treatments for Alzheimer’s disease and diabetes.
On a related note, an article in Nature explores the phenomenal success of the MRC’s Laboratory of Molecular Biology at Cambridge which has produced 9 Nobel Laureates, the latest one in 2009. The piece also talks about similar successful experiments, for instance at Justus von Liebig’s laboratory in Germany or Ivan Pavlov’s laboratory in Russia and places a significant share of the productivity in successful labs on the shoulders of their leaders. The MRC’s leaders led less and interacted more. Tea was a daily tradition and Nobel Laureates sat at the same table with graduate students and postdocs during lunch. Everyone was encouraged to speak up and no one was afraid to ask what could be perceived as a stupid question; Tom Steitz who was awarded a prize for work on the ribosome remembers a meeting where director Max Perutz asked about the difference between prokaryotes and eukaryotes. The ideal leader directed less vertically and more horizontally.
Some of the Nobel Laureates at the MRC

A similar tradition was carried out in many other outstanding institutes producing famous scientists; these included the Institute for Advanced Study at Princeton (where Robert Oppenheimer used to say that “tea is where we explain to each other what we don’t understand”), Niels Bohr’s institute in Copenhagen which nurtured the founders of quantum mechanics and the forerunner of the MRC, Ernest Rutherford and Lawrence Bragg’s Cavendish Laboratories which discovered both the neutron and the structure of DNA. The same principle applied to industrial labs like Bell Labs and IBM; as Jon Gertner’s book on Bell Labs chronicles, Bell’s first director Mervin Kelly gave his scientists the same freedom. This freedom manifested itself even in the physical layout of the buildings which featured movable panels that allowed experimental and theoretical sanctums to connect. And it goes without saying that Kelly and most other successful directors were world class scientists themselves or at least people with a considerable scientific background. Contrast that with much of today’s corporate research enterprise where scientific leaders at the top have been replaced with lawyers and MBAs.
It’s also worth noting that these scientific leaders never made the mistake of equating quality with quantity; Rutherford’s lab even had a rule that forbade work after 6 PM except in rare cases. There’s a huge lesson there for professors and departments who insist that their students spend 12 or 14 hour days at the bench. As history has adequately demonstrated, it’s very much possible to work a productive 9 AM – 6 PM workday and still achieve significant results, and I have been told this is the way it still largely works in countries like Germany. The key lies in culture, collaboration and focus, not raw work hours. It’s really not that hard to understand that the best results arise when scientists are supplied with a general overarching plan but are otherwise left free to work out their own details for implementing it. And often the best short-term research is long-term research.
A friend of mine tells the story of her father who was working at a well-known government institution in the US. He quit when they started circulating forms that asked the scientists what they thought they would discover next year. “How the hell should I know what I am going to discover next year?”, wrote my friend’s father on the form before he stormed out.
Image links: 1, 2 

Post first published on the Scientific American blog network.

ChemCoach Carnival: What I do

I am late to the party, but SeeArrOh's ChemCoach Carnival has given me a chance to indulge in some narcissistic self-promotion. There many great entires on his blog so you should take a look. Here's my pitch.

Your current job.

I am an organic chemist turned molecular modeler at a small biotech startup in Cambridge, MA. I spend as much time looking at synthetic strategies, building block procurement, target selection and assays as I spend building models. I also spend a lot of time thinking about how my work fits within the broader boundaries of science.

What you do in a standard "work day."

As a lot of others scientists on this thread have emphasized, one of the great things about our job is that there is no “standard work day”. I am the lone modeler in a small startup so that requires me to wear several hats. I am as involved in discussing synthesis and assays as I am in docking small molecules to proteins or running molecular dynamics simulations. In addition I also need to occasionally look up building block availablity, talk to database and informatics specialists and arrange for presentations from outside vendors. The point is that in drug discovery and especially in a small outfit, you must be adaptable and be able to accomplish multiple, diverse tasks. This kind of capability makes you a valued member of the team, especially in a small company where your voice will be heard by everyone, from the intern to the CEO. It’s also a terrific learning experience in general.

What kind of schooling / training / experience helped you get there?

I have a doctorate in organic chemistry, although frankly that is just the means to an end. I switched from synthesis to modeling because I was clumsy in the lab and because I was interested in many different fields of science. I don’t regret my choice at all. Modeling allowed me to indulge interests in physics, chemistry, computer science and biology. I would say that if you have diverse scientific interests, modeling and simulation in a general sense would excellent career choices for you. If you are planning for a career in drug discovery or biotechnology, I would encourage you to soak up as much knowledge from diverse fields of chemistry and biology as possible. You won’t regret it.

This would also be the place for me to sneak in my favorite pitch regarding the history and philosophy of science. A simple piece of advice: study it. Science is done by fascinating human beings with all their flaws and triumphs. Your experiments are not being done in a vacuum. Reading up on the history of your discipline will give you the feeling of participating in a grand, unbroken thread of discovery going back to the Greeks. Even if you may not be a world-famous scientist or are not doing earth-shattering research, the simple fact that you are exploring the same laws of physics and chemistry that world-famous scientists once did will put you in their league and inspire a feeling of kinship. Studying the history of science will convince you that there are many who empathize and who have shared the same sense of despair and triumph that you do. Study the history of science, and you will know that you are not alone.

How does chemistry inform your work?

It is all-pervasive in my work. When I say I am a “molecular modeler”, I mean that in the broadest sense of the term. For me all of chemistry is largely about models, whether the models consist of structures scribbled on a hood or three-dimensional protein images built on a computer screen. A lot of people think computation in drug discovery is all about building regression models and writing fancy algorithms. But what it’s really about is data interpretation, and pretty much all this data is chemical. I cannot stress how important it is for a molecular modeler to understand chemistry, especially organic and physical chemistry. What has turned out to be an intractable problem has often proved amenable to a solution found in the principles of basic organic chemistry. In addition you have to have a real feel for structure-activity relationships and the basic physiochemical properties of functional groups. Useful numbers from thermodynamics and kinetics should ideally roll off your tongue like French verbs. A knowledge of statistics is also important. My background in organic chemistry is much more important than any facility with programming or knowledge of particular software that I may have picked up on the way. Those things you can learn, but the bedrock of your work will always be chemistry, even when it's operating behind the scenes.

Finally, a unique, interesting, or funny anecdote about your career*

Well, when I said I was clumsy in the lab I was thinking about the time I actually dropped a rotavap on the floor and broke it. My advisor, a generous man, said that maybe I was not quite cut out for working in the lab. It was the only time in my life that an embarrassing accident gently pointed out by a wise future advisor has fortuitously decided the trajectory of my career.

In which the Discovery Institute mocks me and reveals its ignorance...again.

You must be doing something useful if the Discovery Institute, that bastion of intelligent design propaganda, devotes an entire post to your article.

This time it was the piece on junk DNA that I wrote for Scientific American. Here's what the DI folks had to say:

Darwinian "Science" in Action

Evolution News & Views  October 9, 2012 5:53 AM | Permalink

Someone forgot to put Scientific American blogger Ashutosh Jogalekar on the list to get the memo on massaging the ENCODE results. Darwinists used to say a genome scattered with junk is just what you'd expect from natural selection. Now they say the reverse, that a much more fully functional genome is just what you'd expect. (See here for David Klinghoffer's note on Richard Dawkins's remarkable change of heart.)
But in the immediate wake of ENCODE, poor Jogalekar was still carrying on with the old talking point ("Three reasons why junk DNA makes evolutionary sense").
We think his third paragraph is most revealing:
But what I found astonishing was why it's so hard for people to accept that much of DNA must indeed be junk. Even to someone like me who is not an expert, the existence of junk DNA appeared perfectly normal. I think that junk DNA shouldn't shock us at all if we accept the standard evolutionary picture.
In other words, because Darwinism is true, "much of DNA must indeed be junk." Theory trumps evidence. That's Darwinian "science" for you.

As usual, the DI's interpretation is chock full of misleading statements. Let's address the objections in short order:

1. Yes, I was not on the ENCODE memo because the whole point that people like me, Larry Moran and Ryan Gregory were making is that the ENCODE results misrepresented the lack of significance of junk DNA by having their own, very liberal, definition of "functional" DNA sequences. Several posts criticized the widely disseminated impression provided by ENCODE that "80%" of DNA was functional. The DI of course jumped on this bandwagon with alacrity since it fit like a jigsaw puzzle piece into their worldview that most or all of the human genome had to be "designed". As many commentators mentioned, the 80% quip was a PR disaster.

2. The "old talking point" is old precisely because it fits well into standard evolutionary theory. The DI wants to make it sound like scientists were for junk DNA before they were against it before they were for it again. This of course proves that scientists are a confused lot who are not sure about anything...

The truth of course is that "junk DNA" was always a misnomer since we did not know what function, if any, the sequences of DNA regarded as "junk" would turn out to have. Now some of them (but a small percentage) did indeed turn out to be functional in the true sense of being coding or regulatory elements. But the fact is that many of them are still non-functional by these same definitions. 

What scientists were saying is that some DNA which was regarded as "junk" might turn out to be functional, and in fact it has been found to be so. However, there is no reason - based on standard evolutionary interpretations which I explored in my post - to assume that most DNA would have a function. Will we find function for some more DNA in the future? Absolutely. Does that still mean that most DNA is functional? Of course not. Thus, contrary to what the DI would have us think, believing that some junk DNA would turn out to be functional but also believing that most DNA might still be predictably "junk" are not opposed viewpoints. The DI would have us believe that they are and this then becomes a convenient vehicle for them to insinuate that scientists are not sure of anything.

The last statement is just a gross misunderstanding of the scientific method:

In other words, because Darwinism is true, "much of DNA must indeed be junk." Theory trumps evidence. That's Darwinian "science" for you.

No, the accurate way to say this is that "evidence supports theory". The DI wants to give the impression that we "Darwinists" used two sets of evidence, one contradictory to the other, to support our pet theory. But as I have indicated, it's a straw man to proclaim that these two sets are contradictory. Both pieces of evidence are entirely consistent with a standard evolutionary interpretation in which some junk DNA does turn out to be functional without providing any reason to believe that most junk DNA would also be the same.

It's not that hard to understand. At best the confusion is a result of confusing nomenclature and bad PR, not a failure of evolutionary theory that the DI would perpetually have us buy into.

When satire hits home

Fiction indeed mirrors reality more than we would ever want it to...

From The Onion:

Latest Study Finds Cancer Cells Now Cruelly Mocking Researchers

ROCHESTER, MN—Stating that cancer cells are now “laughing in our fucking faces,” a new Mayo Clinic study with widespread implications for the treatment and potential cure of the disease has found that the malignant growths have begun cruelly mocking researchers. 

The findings—published this week in a rambling, expletive-laden 8,000-word article in The Journal Of The American Medical Association—provides the strongest evidence yet that abnormal cells targeted with cutting-edge cancer treatments are basically flipping off scientists left and right, and get a huge kick out of making oncologists feel like a bunch of bumbling dipshit chumps...
..."You can almost hear them cackling at us while they spread to the lymph nodes,” he added.
According to the study, researchers now have a much better sense of the molecular and cellular basis of tumor growth, including the ingrained sense of entitlement that reportedly drives cancer cells to grow irregularly until they become one big fuck-you to scientists.
The report confirmed that while all types of carcinomas are beginning to make researchers feel like garbage, myeloma cancer cells in particular think they’re God’s gift just because they’re resistant to the frontline drug Velcade.
Researchers found that in addition to those toxic cells, basal cell carcinomas also get a “certain sick joy out of smacking researchers around like a bunch of little bitches.”
“Several years ago, when you looked at cancer cells under a microscope, they weren’t such huge jerks,” said Dr. Karen Phillips, an oncologist at Johns Hopkins Medical Center. “But now they are playing with us—taunting us even. For example, one minute, ovarian granulosa cell tumors and other stromal malignancies are being successfully destroyed with a cisplatin and etoposide combination chemotherapy. But the next minute, those shit-eaters are overexpressing the BRCA1 locus protein and triggering the expression of the antiapoptotic protein survivin, thus protecting ovarian cells from cisplatin-induced survivin down-regulation and making them completely chemo-resistant.”

A chestnut so old, it's started stinking

Both Derek and SeeArrOh have nicely weighed in on this Washington Post letter by a disgruntled parent who is demanding to know why his son should be "forced" to study chemistry in high school. He then lists a number of arguments usually offered in favor of teaching and learning chemistry and proceeds to what he thinks are cogent rejoinders. This one in particular sent a giant bee through my bonnet:

Chemistry will teach him analytical skills that he can apply to other fields.

Great. So will a hundred other possible subjects that will be less painful and potentially even more interesting to him. An experimental physicist recently told me that at this phase in chemistry instruction “it’s all about memorization anyway.” There will be no other phases in chemistry instruction for my son. He will forget everything he “learned” a week after the class is over. I can’t remember a thing, and I was a pretty good chemistry student.

Ah, the "math and physics need good problem solving skills while chemistry and biology need a good memory" chestnut again, and SeeArrOh touches on this. I am hazarding a guess that this experimental physicist was jealous of chemists; I am tempted to send a few beakers flying through his office window. I was exposed adequately to this fallacy myself; when I was in high school, apparently all the future engineers were supposed to study physics and math to hone their analytical skills while the future doctors were supposed to study chemistry and biology, since "medicine is all about memorization too". This was nonsense. Chemistry is as useful for future engineers as math is for future doctors.

Obviously our schools are still not doing a good job of driving home the analytical nature of chemical science. Try to memorize every reaction in an organic chemistry textbook and you will indeed not remember any of it within a few months. But try instead to learn a few unifying principles like syn-anti addition, pkA, stereochemistry, acid-base chemistry and resonance and you can make sense of a vast landscape of chemistry which you will likely remember. The best textbooks like the one by Clayden et al. indeed emphasize this unified approach. In addition, learning the subject this way will make chemistry much less painful than memorizing it. 

It's very likely that the letter writer's high school teacher made chemistry all about memorization; if that had been the case then it might have been easy to be good at chemistry in the short-term without really understanding most of it. Unfortunately much of chemistry and biology is still stuck - if not by content, by its mental makeup and by the attitude of its teachers- in the nineteenth century where there was no structural theory and no molecular biology and therefore these sciences did appear like a set of disconnected facts to be memorized. That's also why chemistry makes a convenient target. Math and physics are much more obviously about analytical and logical thinking whereas biology is much more easily seen as essential for things like medicine. Chemistry as usual is the middle child, the one everyone likes to treat with benign neglect. But the fact is that the twentieth century saw both chemistry and biology elevated to the status of conceptual sciences, perhaps not as pristinely analytical as math but enough to be able to take a completely logical approach to the way in which they are taught.

Derek and SeeArrOh cover the other objections thoroughly. Physics, chemistry, biology and math are all part of the world we inhabit. I cannot see how omitting any of these from the school curriculum (along with history, politics, economics and literature) could contribute to an informed citizenry. The writer probably makes a good case that a high school shouldn't "force" students to take chemistry, but that hardly detracts from chemistry's intrinsic value value.

Come on Mr. Bernstein, you should at least have your son take chemistry so he can recognize all those dangerous "chemicals" in food products...

Woodward, and the importance of being born at the right time

Woodward as a freshman at MIT (Image: CHC)
On his blog Derek has a contemplative post on the conditions necessary for seeing titans in particular fields, and whether these conditions can be replicated again. I completely concur with his viewpoint that it’s possible to discover the structure of DNA, or formulate general relativity, or revolutionize organic synthesis, just once.

Putting it another way, the question to ask is whether the general problem has been solved. Woodward is certainly a case in point...

Read the rest of the post on my Scientific American Blog

Crystallography, chemistry and Nobel Prizes: Nothing to complain about

Roger Kornberg, chemist
One reason I have been puzzled and disappointed by the negative response to "biologists winning the chemistry Nobel Prize" is that the biologists who are the target of criticism have almost always been protein crystallographers. It's not like they are handing out chemistry prizes to entomologists or animal behaviorists. 

The response is especially puzzling because there's always been a proud tradition of crystallographers winning the chemistry Nobel Prize. In my reading of Nobel history I haven't really come across someone criticizing this trend; in fact I have seen the complaints emerge roughly in 2006 or so, when Roger Kornberg was recognized for his work on the machinery of transcription. Ironically, Kornberg himself in his Nobel interview praised chemistry as the "queen of the sciences" and even went to the length of saying that if an intelligent person could familiarize himself with just one science, it should be chemistry. Not surprisingly, Kornberg emphatically described himself as a chemist and chemists should proudly count him as one of their own.

And yet the gripes keep coming which is unfortunate. Let's be clear about one thing that Kornberg alluded to. Traditionally, the determination of molecular structure has always been a profoundly important concept in chemical science. Synthesis and function come next, but first one has to know the structure of the substance under investigation. A large part of the history of chemistry thus consists of organic chemists determining the structure of natural products, first through chemical degradation and then through increasingly sophisticated spectroscopic techniques including x-ray diffraction. The ribosome, GPCRs, ion channels and nuclear receptors are giant molecular assemblies, and the meticulous determination of their atomic-level structure is in principle no different from the structure determination of penicillin, aspirin or sodium chloride for that matter.

Largely for my own private elucidation but also to make this point clear, it's worth pointing out the list of crystallographers who have been awarded chemistry Nobel Prizes and their achievements. Most of these prizes have been awarded for specific structures but some have been awarded for methods, thus putting these prizes in the same category as those for NMR and mass spectrometry.

1954: Linus Pauling - Although Pauling is best known as a theoretical chemist, much of his most important work was in crystallography. At the beginning he used electron diffraction to resolve the structures of simple minerals and developed rules to describe their packing. Later he used crystallography to deduce the famous alpha helical and beta pleated sheet secondary structures of proteins.

1962: Max Perutz and John Kendrew - the fathers of modern protein crystallography, awarded the prize for their structure determination of two key proteins, hemoglobin and myoglobin. Perutz labored over the structure for fifteen years before cracking it and set the trend for every persistent crystallographer who was to follow.

1964: Dorothy Hodgkin - for her determination of the structures of important biochemical substances such as vitamin B12 and penicillin. Most chemists even today would place this work in the realm of chemistry.

1982: Aaron Klug - Klug developed crystallographic electron microscopy techniques to study many key biochemical assemblies like the tobacco-mosaic virus and chromatin.

1985: Herbert Hauptman and Jerome Karle - Hauptman and Karle formulated mathematical techniques for the direct interpretation of x-ray diffraction patterns which addressed the notorious "phase problem". This work was very much in the spirit of physics, and was the first prize awarded for diffraction methods. It's again worth noting that similar prizes were awarded for NMR and mass spectrometry methods and there was not a sound from chemists.

1988: Johann Deisenhofer, Robert Huber, Hartmut Michel - This prize was awarded for cracking open the structure of one of the most important proteins on the planet - the photosynthetic reaction center which captures light and performs the initial reactions in photosynthesis. This was also the first integral membrane protein to be crystallized, a huge technical achievement.

1997: Paul Boyer, John Walker and Jens Skou - Again, a prize awarded to an important and truly fascinating protein and the first molecular motor, the Na+ K+ ATPase. This discovery also shed light on the crucial process of ATP synthesis.

2003: Peter Agre and Roderick McKinnon - Another key protein, they just keep on coming. This time it was the potassium ion channel, the nerve center (pun) of ionic conduction, muscle action and neurotransmission among other processes.

2006: Roger Kornberg - Kornberg dissected the fundamental process of DNA to RNA transcription in meticulous detail over two decades. The work involved pinning down the positions of dozens of proteins assembled in a precisely orchestrated circus.

2009: Venki Ramakrishnan, Tom Steitz and Ada Yonath - Another molecular machine of profound importance - the ribosome. Not only did the fearsome structure of this gargantuan assembly of proteins and RNA yield to crystallography but it also validated one of the most startling and significant observations in the history of biochemistry - the ribosome is a ribozyme.

2011: Dan Shechtman - Caused a paradigm shift, albeit not in protein crystallography. Interestingly chemists were lukewarm even about this prize, relegating it to metallurgy or even physics rather than chemistry.

2012: Robert Lefkowitz and Brian Kobilka.

A few observations. There have been a total of 11 Nobel Prizes awarded since 1954 to x-ray crystallographers. That's not a lot and certainly nothing to complain about. There's of course more awarded to biochemists in general, but even there the count is 24 prizes since 1950. The crystallography prizes seem to become more frequent as we approach the 90s and the twenty-first century, and the reason is probably that the technology and methodology made it finally possibly to tackle the structures of fundamental entities like the ribosome and ion channels which couldn't be addressed before. It's also important to emphasize that each one of the protein structures provided insight into an important physiological process which involved a lot of actual, bond-breaking and bond-making, chemistry. It's natural for a chemist to lament his favorite field, reaction or molecule not winning a prize but the truth is that this reflect a provincialism that ignores chemistry's immense reach.

What's the future going to look like? Nobody can say for sure, but the increasing number of prizes awarded to biochemists and crystallographers since the 80s seem to indicate that this trend will continue, with prizes awarded even more frequently to protein crystallographers and molecular biologists. And this shouldn't be surprising. We are finally at a stage when we can use the full set of physical and chemical tools at our disposal to tackle the big biological and medical questions of our time. Chemistry through its use of structure determination techniques and small molecules will allow us to interrogate the function and find out the structure of increasingly complicated biological assemblies. 

But the take-home message is that any future chemistry Nobel Prizes awarded to "biologists" will only showcase the growing power of chemistry and spectroscopy to uncover life's deepest secrets. Synthetic and systems biologists for instance are just getting started in engineering cells and organisms and even that is chemistry. The location of the essence of biological existence in life's constituent molecules was one of the most revolutionary discoveries of all time. It seems fitting that this paradigm will shine in all its glory in the twenty-first century. Rather than resign themselves to what they see as an inevitable fate, chemists should celebrate this development as the ultimate manifestation of the power of chemistry in illuminating structure and function.

GPCRs win 2012 Nobel Prize in Chemistry

What a nice surprise! Ever since Brian Kobilka's group solved the first GPCR-G protein structure I have been convinced that he and others will win the Nobel Prize. But I didn't think it would happen so soon.

In any case, amble over to my Scientific American blog for a writeup. This has to be one of the fastest discovery-to-prize transitions in recent years. It's interesting that the prize was awarded to Lefkowitz and Kobilka. I think this was done partly to recognize Lefkowitz's early pioneering work, but also because a purely structural prize would have had to recognize Raymond Stevens and Krzysztof Palczewski in my opinion. It was a shrewd move on the part of the committee to hand out a broader GPCR prize and include Lefkowitz. As for Kobilka, I think it's fair to say that among the three groups his has probably done the most detailed crystallography work.

Personally I feel very satisfied since GPCRs have been an interest of mine for a while. I have blogged about them several times and once wrote a major research proposal on them. However, as significant as the discovery is, there's still a long road ahead. There's almost a thousand GPCRs from class A-F. The present structures constitute only a handful of members of class A GPCRs (although I hear class B is coming up soon). We are far from any complete picture of GPCRs signaling and we also don't understand functional selectivity yet. This discovery has every indication of being a grand beginning than an end. 

And I have to say that the whole "But is this chemistry?!" meme is getting quite boring. Binding of a small molecule to a GPCR is as much of a molecular interaction as anything in chemistry. Plus, think about the downstream chemistry that GPCRs do, including phosphorylation of the G proteins and salt-bridge breakage in the crucial helices that modulate the signal transduction. I thought chemists were supposed to rub their hands with glee at the reduction of biology to chemistry while biologists fret and fume. But I see the opposite, biologists being quite sanguine about proteins being awarded medicine Nobels while chemists continue to complain about proteins (chemicals!) being awarded chemistry Nobels. Something's not quite right here. In addition, this year's Nobel continues the proud tradition of honoring crystallographers, a tradition that goes back to 1962 when Kendrew and Perutz won it for hemoglobin and myoglobin. The point is that chemistry has traditionally been defined as structure and function. Chemists have studied the molecular constitution of matter since the birth of the science, and biological matter is no different in principle. Why would chemists complain when structure - of any kind - is recognized by a Nobel Prize?

However there is a bright side to the arguments. As I have said before, this very bickering shows the astonishing reach and diversity of the field. If you can't even agree on a definition for your field, well, that means your field is truly everywhere.

Congratulations to Kobilka and Lefkowitz, and a toast to more GPCR research!

Let’s all find out how meth works: Crowdfunding a novel scientific paradigm

Image: trident
In a previous post I described the benefits and enduring value of Small Science. I emphasized the fact that in the current economy and funding environment, Small Science is likely to be consistent while Big Science happens in fits and starts. And I talked about how crowdsourcing and crowdfunding could bring great value to both Big and Small Science. Now I want to describe a crowd funded Small Science project that could prove very valuable in understanding the root causes of one of the most pernicious scourges of our time - methamphetamine addiction. Ethan Perlstein at Princeton and David Sulzer at Columbia are interested in dissecting the different ways in which meth acts in and on the brain and they have taken the bold step of pitching this as a crowdfunding project. Their project and others like it could not only help us develop new treatments for meth addition but they could address a more general and key question; how do psychotropic drugs work?

It turns out that in spite of the legions of psychiatrists prescribing a record number of antidepressants and other medications every year, we still don't have a good idea how these compounds work. The same lack of understanding permeates our efforts in tackling the addiction epidemic. From a chemical standpoint the simplicity of psychotropic drugs like meth and PCP is breathtaking. The fact that a few carbon, hydrogen, oxygen and nitrogen atoms arranged in and around a simple ring can cause such profound behavioral changes in human beings continues to beguile and fascinate us. Sadly, our knowledge of the mechanism of action of these molecules as well as legal psychotropic drugs has reached a kind of roadblock. Of course we have made significant advances during the last half decade and we now know that these drugs work their magic by mimicking the action of neurotransmitters and binding to specific proteins called receptors, just like many other medicinal drugs do. However in case of psychotropic drugs the workings are much more complex since they usually have multiple effects, binding to different flavors of receptors to varying extents in different parts of the brain and provoking a cocktail of biochemical activity. The complexity of the process combined with the complexity of the brain itself has challenged CNS researchers for decades.

This whole paradigm of understanding how drugs work by looking at their direct interaction with specific proteins has productively driven drug discovery since its reductionist origins. But Perlstein, Sulzer and the project's chief experimentalist, Daniel Korostyshevsky, are taking a different tack in answering this question. In a very intriguing paper published earlier this year, Perlstein demonstrated that the antidepressant sertraline actually causes physical changes in the structure of cell membranes, affecting their curvature, fluidity and other properties and provoking autophagy, the degradation of a cell's own machinery. This study fits into a larger perspective. If you think of the cell as a building with girders, beams and floors and the drug as a small but very powerful iron ball hitting this building, you would in fact expect the ball to cause structural reorganization. Thus it shouldn't come as a surprise to find that small molecules like drugs affect physical changes in the structure of membranes and other organelles. But for some reason this morphological approach has been overlooked relative to the traditionally pursued protein-drug binding viewpoint. Now researchers like Perlstein and Sulzer are emphasizing the morphological paradigm and asking us to consider the physical, more global effects of drugs on the cell's structural machinery along with their interaction with specific proteins.

Meth is as good a candidate as any for this kind of thinking. We don't know the details of its mechanism of action, and any information gleaned from studying it could be potentially valuable in advancing treatments for meth addiction. It's clearly a problem that is both ripe for scientific study and of great public interest. So Perlstein has taken the novel approach of pithing it as a $25,000 crowdfunded project. $25,000 is a modest amount, far less than many of the grants that get routinely rejected these days from funding agencies like the NIH. But it's enough to start making inroads into the problem. Part of the money will support a master's level technician for 2-3 months and the rest will contribute to overhead costs. To study how meth works, Perlstein and Sulzer will use a classic technique called autoradiography which essentially tracks the movement and fate of drugs inside tissues using radioactive tracers. Once the localization of a drug is revealed, other techniques including those used to study protein-drug interactions can then be used to further find out what the drug is doing at that particular location in finer detail.

Perlstein has all the details on his site, along with a really nice video explaining the project. True to the spirit of crowdfunding and open source science, the progress of the project will be regularly documented on a public website. In addition, depending on the level of contribution, contributors will have access to regular project reports, brainstorming meetings and perhaps even a relaxing cocktail in NYC. The biggest contributors can even participate in lab meetings and discuss the resulting manuscript. All contributors will be acknowledged on the website. From a scientific sense, the biggest value of the project is in taking an alternative approach to understanding psychotropic drug action by looking at large-scale morphological effects on cell structure and function.

I think this project and the general idea look very promising and I hope that the project gets funded. Citizen science should play an increasingly important role in solving our problems. In one sense the scientific research and peer review process with its dependence on large grants, exclusive cliques and anonymous peer review is still stuck in the pre-Internet age. This project and others like it are making sincere attempts to punch through the wall so we can all contribute to both scientific understanding and the fruits of such inquiry. I hope we can do our part in taking out a few bricks.

Originally posted on the Scientific American blog.