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.

Why junk DNA makes perfect evolutionary sense

ENCODE (Image: Ed Yong)

The recent dustup over the ENCODE project and its confusing finding that "80% of DNA is functional" surprises me greatly. What surprises me especially is that people are surprised by junk DNA. Unfortunately this time the scientists are also culpable since, while the publicity surrounding ENCODE has been a media disaster, the 80% claim originated in the scientific papers themselves. There is no doubt that the project itself - which represents a triumph of teamwork, dogged pursuit, technological mastery and first-rate science - has produced enormously useful data, and there is no doubt it will continue to do so. What is in doubt is how long it will take for the public damage to be repaired.

There's a lot written about the various misleading statements about the project made by both scientists and journalists and I cannot add much to it. All I can do is to point to some excellent articles: Larry Moran has waged a longstanding effort to spread the true wisdom about junk DNA for years on his blog. Ed Yong exhaustively summarizes a long list of opinions, links and analysis. T. Ryan Gregory has some great posts dispelling the myth of the myth of junk DNA. And John Timmer has the best popular account of the matter. The biggest mistake on the part of the scientists was to define "functional" so loosely that it could mean pretty much all of DNA. The second big mistake was not in clarifying what functional means to the public.

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.

The standard evolutionary picture tells us that evolution is messy, incomplete and inefficient. DNA consists of many kinds of sequences. Some sequences have a bonafide biological function in that they are transcribed and then translated into proteins that have a clear physiological role. Then there are sequences which are only transcribed into RNA which doesn't do anything. There are also sequences which are only bound by DNA-binding proteins (which was one of the definitions of "functional" the ENCODE scientists subscribed to). Finally, there are sequences which don't do anything at all. Many of these sequences consist of pseudogenes and transposons and are defective and dysfunctional genes from viruses and other genetic flotsam, inserted into our genome through our long, imperfect and promiscuous genetic history. If we can appreciate that evolution is a flawed, piecemeal, inefficient and patchwork process, we should not be surprised to find this diversity of sequences with varying degrees of function or with no function in our genome.

The reason why most of these useless pieces have not been weeded out is simply because there was no need to. We should remember that evolution does not work toward a best possible outcome, it can only do the best with what it already has. It's too much of a risk and too much work to get rid of all these defective and non-functional sequences if they aren't a burden; the work of simply duplicating these sequences is much lesser than that of getting rid of them. Thus the sequences hung around in our long evolutionary history and got passed on. The fact that they may not serve any function at all would be perfectively consistent with a haphazard natural mechanism depending on chance and the tacking on of non-functionality to useful functions simply as extra baggage.

There are two other facts in my view which should make it very easy for us to accept the existence of junk DNA. Consider that the salamander genome is ten times the size of the human genome. Now this implies two possibilities; either salamanders have ten times functional DNA than we do, or that the main difference between us and salamanders is that they have much more junk DNA. Wouldn't the complexity of salamander anatomy of physiology be vastly different if they really had so much more functional DNA? On the contrary, wouldn't the relative simplicity of salamanders compared to humans be much more consistent with just varying degrees of junk DNA? Which explanation sounds more plausible?

The third reason for accepting the reality of junk DNA is to simply think about mutational load. Our genomes, as of other organisms, have undergone lots of mutations during evolution. What would be the consequences if 90% of our genome were really functional and had undergone mutations? How would we have survived and flourished with such a high mutation rate? On the other hand, it's much simpler to understand our survival if we assume that most mutations that happen in our genome happen in junk DNA.

As a summary then, we should be surprised to find someone who says they are surprised by junk DNA. Even someone like me who is not an expert can think of at least three simple reasons to like junk DNA:

1. The understanding that evolution is an inherently messy and inefficient process that often produces junk. This junk may be retained if it's not causing trouble.

2. The realization that the vast differences in genome sizes are much better explained by junk DNA than by assuming that most DNA is truly functional.

3. The understanding that mutational loads would be prohibitive had most of our DNA not been junk.

Finally as a chemist, let me say that I don't find the binding of DNA-binding proteins to random, non-functional stretches of DNA surprising at all. That hardly makes these stretches physiologically important. If evolution is messy, chemistry is equally messy. Molecules stick to many other molecules, and not every one of these interactions has to lead to a physiological event. DNA-binding proteins that are designed to bind to specific DNA sequences would be expected to have some affinity for non-specific sequences just by chance; a negatively charged group could interact with a positively charged one, an aromatic ring could insert between DNA base pairs and a greasy side chain might nestle into a pocket by displacing water molecules. It was a pity the authors of ENCODE decided to define biological functionality partly in terms of chemical interactions which may or may not be biologically relevant.

The dustup from the ENCODE findings suggests that scientists continue to find order and purpose in an orderless and purposeless universe which can nonetheless produce structures of great beauty. They would like to find a purpose for everything in nature and are constantly looking for the signal hidden in the noise. Such a quest is consistent with our ingrained sense of pattern recognition and has often led to great discoveries. But the stochastic, contingent, haphazard meanderings of nature mean that sometimes noise is just that, noise. It's a truth we must accept if we want to understand nature as she really is.

Originally posted on the Scientific American Blog Network

Fraud, not error, accounts for most scientific retractions

There's a new study in Proceedings of the National Academy of Sciences that should make the scientific community sit up and do a little pondering. Researchers from the University of Washington, the Albert Einstein College of Medicine and the firm MediCC! analyze retracted papers from 1977 onwards and investigate the reasons for their retractions. The authors focus on papers in the life sciences. And they find that about 67% of the 2047 retracted papers owed their retraction to plain old misconduct; only 21% or so can be traced back to error and honest mistakes. The misconduct can come in three forms - outright fraud, plagiarism and duplication. The other piece of bad news is that among these three, fraud contributes the most to the retraction with plagiarism and duplication tagging behind.

Number of retractions since 1977 and cause of retraction (Image source: Fang et al. PNAS 2012)

The study is disturbing, not just for the amount of misconduct it unearths but for the various trends it observes and for what it has trouble finding. The authors look at parameters such as the time to retraction, the impact factor of the journal in which the retracted papers were published and the geographic distribution of the papers. In each one of these categories it discovers something thought-provoking.

The first thing the study discovers is that fraud is not as easy to find as we think. There are several instances of papers where the retracted papers are still available and cited. Not only does this prevent the retraction from misleading other researchers  but it also depressingly means that, as the authors themselves confess, the study likely underestimates the number of retractions. Why this is so makes partial sense in at least a few of these cases where scientists seem to find something of value in the paper in spite of the retraction. Also opaque are the cases where the retraction is ambiguously communicated, giving the impression of error rather than misconduct. The problem is that the retraction notice is often published by the original authors and they are understandably reluctant to provide any hints of fraud. Thus, the notice for one particular study says that "results were derived from experiments that were found to have flaws in methodological execution and data analysis". What this note does not say - and what's confirmed later by an independent Office of Research Integrity inquiry - is that the "flaws" were actually a result of manipulation and willful fabrication. Retraction notices may thus clearly hide evidence of wrongdoing, and it seems that journals are not always correcting or modifying original notices wherever necessary.

An analysis of the geographic origins of retraction is also quite interesting since this seems to be split by the nature of the misconduct. The US, Germany, China and Japan accounted for 75% of cases of fraud or suspected fraud. Conversely, China and India accounted for a large percentage of plagiarism and duplication. Why this may be so takes us to the next step of the analysis; analyzing retraction by impact factor. The authors found that fraud contributed the most to retractions in high-impact journals like Science and Nature while plagiarism and duplication were responsible for retractions in lower-impact journals. This may be consistent with the geographic trends since the US, Germany and Japan publish in higher-impact journals compared to India or China.

Cause of retraction by geographic location (Image source: Fang et al. PNAS 2012)

Sadly and perhaps not surprisingly, this is also a case where a few bad apples give the whole field a bad name. Scientific controversies over the last few years are littered with the corpses of multiple papers published by the same author or the same lab. As the authors find out, a small number of authors were responsible for multiple retractions and nearly all the multiple retractions from the same author could be traced to outright fraud rather than plagiarism or duplication. A table in the paper has a rogues' gallery of infamous retractors, ranging from the infamous vaccination denialist Andrew Wakefield to Anil Potti, the Duke researcher who falsified data in multiple papers and then hired an "image consultant" to craft personal airbrushed websites with misleading information. Papers from these people have been cited a depressingly large number of times, and one factor which the study cannot gauge is the immense negative impact they must have had on other researchers' honest work before being retracted.

The authors also look at time-to-retraction and citation frequency of retracted articles and find both hope and disappointment. Over the years there's a general, gradual trend toward longer time-to-retraction that's independent of impact factor. As for citation frequency, while many retracted articles stop being cited right away, there are also several that continue to be cited for various reasons, ranging from a lack of transparency in the retraction notice to researchers still finding something of value in the papers.

What do we make of all this? The responsibility of journals and funding agencies to scrutinize papers and grants and detect fraud is obvious but the issue runs deeper. As with any large-scale endemic scientific problem, this one says more about scientific culture than about the technical details in the paper, although the technical details are important. It's worth noting that all these papers are from biological or medical fields. These fields routinely try to analyze and present complex, multifactorial data sporting error bars as tall as skyscrapers. Even honest, non-retracted work is having a hard time being duplicated in these fields. One only needs to look at the recent controversy about SIRT inhibitors, caloric restriction and lifespan extension to appreciate how messy biological research can get. In a field as messy as biology, it's easy to make stuff up and move a few gel lanes in Western blots here and there in what is typically a mountain of data involving multiple techniques and experiments. Biomedical research is likely going to continue to invite fraud because of its sheer and growing complexity. In addition the monetary benefits, fame and visibility associated with potentially important results in fields like caloric restriction are immense, leading to even more opportunities for fraud and wishful thinking.

However, the emphasis on biomedical research should not blind us to the greater problem the journal points to; the pervasive culture of publish-or-perish and grantsmanship that often views research as a zero-sum game. Science has very much turned into a high-stakes competitive business. More than ever, researchers are competing against each other for funding, resources, grants and publicity. Competition has now extended into the international arena with researchers in certain countries thinking it a matter of patriotic pride to score points against their transcontinental counterparts. There are cases where vast sums of money are allocated by developing countries to their prized scientific fighters to catapult themselves into the big league of top scientific nations. It should go without saying that these kinds of pressures are going to do nothing to dissuade researchers from tweaking a few experimental parameters here, adding a data point to the graph there; all for the sake of getting their papers into high-impact journals, ensuring tenure, awards and fame.

But sadly this culture is here to stay, at least for the foreseeable future. What can we do to curb its worst excesses? The paper points to encouraging solutions like the Office of Research Integrity and regular courses on ethics and data presentation. There are few counterparts to these measures in developing countries and this needs to be taken seriously by their governments. More importantly, researchers, journal editors and referees need to be taught both the value and the methodology of honest research from day one of their careers. They also need to be taught means of detecting fraud and plagiarism, a task which has been rendered somewhat easier by technology and software for detecting duplication and possible manipulation. The authors also suggest the creation of a centralized database of scientific misconduct. It's worth noting that in its own way Retraction Watch has admirably served this purpose. Finally, the study points to a great responsibility on the part of journals and unfortunately one which not all of them are fulfilling. As indicated above, many journals still communicate ambiguous retraction notices that give no hint as to the cause of retraction. Some journals still have retracted papers on their websites. Retractions will continue to be underestimated if journals don't tell us about them. One very valuable service that journals can provide in this regard is to make as many papers open-access as possible, or at least allow comments on most papers that might potentially point to suspicious data.

Ultimately though, the study asks what all of us - scientists, editors, educators, readers and the lay public- can do to stem this growing tide of scientific fraud. Retraction Watch is just one example of what we can collectively do to keep everyone honest. In the past few years, online sources like blogs have made it clear that they can be in the front ranks of detecting and reporting fraud. There have been at least some retractions in the past few years where the retracted paper was first discussed on a blog. It's quite clear that bloggers and journalists can often sniff out suspicious papers even before official sources. The official sources need to pay attention to these first responders and act on their analysis and recommendations. The quick and extensive dissemination of unworthy science will also hopefully provide a disincentive to scientists who are tempted by fraud and manipulation. Let's hope that the existence of a completely non-anonymous jury of thousands of eagle-eyed peers will nip any invitation to fraud in the bud. And in one sense the presence of scientific frauds keeps us all awake; paraphrasing Jefferson, perhaps it's best that "the tree of scientific honesty be refreshed from time to time by the words of wrongdoers and vigilantes of peer review".

Originally posted on the Scientific American Blog Network

Explaining Woodward to the layman

We scientists often, and rightly so, complain that even the best of our lot are hardly known to the man on the street. How many of my non-scientific friends and relatives, even otherwise highly informed and well-educated, have heard of Hans Bethe, Robert Woodward, Ernst Mayr or even Freeman Dyson (who has written great popular books)? 

The truth is that the number of scientists who are famous enough to count in the public imagination can be counted on your fingers. I feel saddened by this fact, but also realize that this situation is not going to change anytime soon; Bob Woodward the journalist would always be more widely known than Bob Woodward the chemist. And in any case, it's much better to do your part in publicizing the achievements of great scientists than to keep on lamenting their lack of recognition.

The fact is, there are ways in which the stature of scientists can be concisely communicated to those who may be unfamiliar with their achievements. Here's one way to do it:

“We arrived at the night club and Armstrong was already playing. I introduced Bob to my friend saying, “This is Bob Woodward.” My friend turned around impatiently, shook his hand, and returned his attention to the music. I said, “Look, Bill, Bob Woodward is to organic chemistry what Louis is to the trumpet!” At that my friend turned around slowly, looked Bob in the eye, and said, “Man, you must be one hell of a chemist!” Bob said he thought that was the most sincere compliment he ever got."

Well done. Although I will say that it was Louis Armstrong who was the Robert Burns Woodward of jazz.

Reference: Blout E. Robert Burns Woodward. Biographical Memoirs of the National Academy of Sciences, 2001; 80.

Image: Wikipedia Commons