On taking on big science's gatekeepers.

Is There a Scientific Establishment?

David Klinghoffer March 15, 2016 4:30 PM

The term "Establishment" is controversial. It invariably implies a critical stance, suggesting a system, a power structure, in need of a shakeup or worse. It's not a description anyone would welcome having applied to himself. Nobody wants to be seen as defending entrenched privilege. Depending on the context, some deny the existence of such an entity to begin with.

What about in the world of science, and specifically biology? Is it fair to speak of an Establishment there, primed to be updated by "rogue" outside forces? It seems so. Or perhaps "rigidly calcified mindset" is the better phrase. Today in the New York Times, Amy Harmon reports on hints of decalcification, a modest but significant move in science research publishing toward "preprints." That is, publishing directly online without first submitting your work to the official gatekeepers: peer-reviewed journals.

Don't worry -- it's not as if this research then goes unreviewed or uncriticized. Instead the review process happens immediately and organically. Those interested enough to read your work can tell anyone and everyone what they think. Minus the online aspect, it's the way Charles Darwin published his ideas:

On Feb. 29, Carol Greider of Johns Hopkins University became the third Nobel Prize laureate biologist in a month to do something long considered taboo among biomedical researchers: She posted a report of her recent discoveries to a publicly accessible website, bioRxiv, before submitting it to a scholarly journal to review for "official'' publication.

It was a small act of information age defiance, and perhaps also a bit of a throwback, somewhat analogous to Stephen King's 2000 self-publishing an e-book or Radiohead's 2007 release of a download-only record without a label. To commemorate it, she tweeted the website's confirmation under the hashtag #ASAPbio, a newly coined rallying cry of a cadre of biologists who say they want to speed science by making a key change in the way it is published.

Such postings are known as "preprints'' to signify their early-stage status, and the 2,048 deposited on three-year-old bioRxiv over the last year represent a barely detectable fraction of the million or so research papers published annually in traditional biomedical journals.

But after several dozen biologists vowed to rally around preprints at an "ASAPbio'' meeting last month, the site has had a small surge, and not just from scientists whose august stature protects them from risk. On Twitter, preprint insurgents are celebrating one another's postings and jockeying for revolutionary credibility.

One diagnostic of a genuine Establishment would be that its members maintain that the system, for everyone's good, couldn't be much different from how it is. In this case, there's nothing necessary about the traditional manner in which biologists publish their work. Physics, as Harmon notes, has had preprints for decades, and the field is healthier for it:

Unlike physicists, for whom preprints became a default method of communicating discoveries in the 1990s, biomedical researchers typically wait more than six monthsto disseminate their work while they submit it -- on an exclusive basis -- to the most prestigious journal they think might accept it for publication. If, as is often the case, it is rejected, they try another journal. As a result, it can sometimes take years to publish a paper, which is then typically available for a time only to colleagues at major academic institutions whose libraries pay for subscriptions. And because science is in many ways a relay, with one scientist building on the published work of another, the communication delays almost certainly slow scientific progress.

True, it's not that preprints are intended to replace traditional publishing. Those interviewed for the article are careful to say they aren't rejecting the big journals. You wouldn't want to offend the Establishment!

Many have taken pains to reiterate their wish not to disrupt the journal system, only to enhance it. With enough scientists pushing to legitimize preprints, they hope journals will allow the systems to coexist.

"It's not beer or tacos," as James Fraser, an assistant professor at the University of California, San Francisco put itat last month's conference, "it's beer AND tacos."

Still, this sounds exactly like a revolt, if mild, seeking to slip out from under some of the bonds of a burdensome hierarchy -- one that up till now has controlled the flow of ideas and artificially constrained debate through access and credentialing, with an eye to maintaining its own power and prestige. What will it mean for insurgent scientific ideas like intelligent design and the critique of Darwinism? Time will tell, but the development seems like a hopeful one.

Yet more on pre evolutionary design.

Collective Motion: A New Level of Design Found in Proteins

Evolution News & Views March 15, 2016 3:06 AM

A "previously unidentified mechanism for modulating protein affinity" has come to light. A team of scientists at the Max Planck Institute for Biochemical Chemistry, publishing in the Proceedings of the National Academy of Sciences, has identified new functional roles for collective motions within protein molecules. These motions, referred to as allostery, allow one end of the protein to affect a distant part through what is termed "allosteric communication."

Intermolecular interactions are one of the key mechanismsby which proteins mediate their biological functions. For many proteins, these interactions are enhanced or suppressed by allosteric networks that couple distant regions together. The mechanisms by which these networks function are just starting to be understood, and many of the important details have yet to be uncovered. In particular, the role of intrinsic protein motion and kinetics remains particularly poorly characterized. [Emphasis added.]

This is cutting-edge research. The team studied a common protein named ubiquitin which, as the name implies, is ubiquitous in the cell. It serves as a molecular "tag" on other molecules slated for degradation by the proteasome. As such, it needs to form connections with the proteasome and with a variety of other proteins. What they found is that distant parts of the molecule could affect binding affinity of other parts through motions transmitted throughout the entire molecule.

To determine how this collective motion influences bindingand other functions of ubiquitin (e.g., presence of different covalent linkages), we performed an extensive structural bioinformatics survey of known ubiquitin crystal structures. Because the peptide bond conformation was the most recognizable feature of the collective mode, we used its conformation as a "marker" for structural discrimination. Themost significant relationship we found was the universal association between the NH-in state and binding to the ubiquitin-specific protease (USP) family of deubiquitinases (Fig. S11). This association has been previously noted and issurprising because the peptide bond is at least 6.8 Å from any USP (Fig. 3A).

By comparing mutants with wild-type forms, the team found several kinds of motion that involve twisting, rocking and stretching. Mutations on a peptide bond between two specific amino acid residues, in particular, had a surprising effect, reducing binding affinity by a factor of 10 (or abolishing it altogether). This suggests low tolerance for mutation.

They found "strong allosteric coupling between opposite sides of the protein" in some cases. "Given the relative subtlety of the expansion and contraction" of allosteric interactions, they found it "surprising" again that two different states could produce large effects. It implies that ubiquitin and its ligand "appear to adapt their conformations mutually to establish a complementary binding interaction" for best fit at the appropriate times.

One mutant showed a two-fold weaker affinity for its particular USP. "Although this change may seem like a moderate effect," they note, "it isactually surprisingly large and highly significant when one considers that it is allosterically triggered by the simple rotation of a solvent-exposed peptide bond on a distal side of the protein."

These motions are so rapid -- on the order of microseconds -- they were not really considered significant until recently. Other motions they mention, like "pincer time" and "tumbling time," occur on different time scales, the former being quicker, the latter being much slower. This may suggest a kind of timing code for different functions.

Their conclusions reveal a significant new area of study: switch-controlled "allosteric communication" in protein molecules:

This study revealed an allosteric switch affecting protein-protein binding through collective protein motion at the microsecond time scale.... Whereas most known microsecond to millisecond time-scale motions involve excursions to excited, lowly populated states, this motion occurs between two ground state ensembles with nearly equal populations (NH-in and NHout). Strikingly, the peptide bond conformation is allosterically coupled through a diverse set of interactions that triggers contraction/ expansion of the entire domain. This type of global domain motion reveals apreviously unidentified mechanism for modulating protein affinity. The presence of this allosteric network suggeststhere may be heretofore undiscovered ways in which macromolecular assemblies and covalent linkages regulate ubiquitin binding. More broadly, this study demonstrates how relatively modest changes in hydrogen bond networks and the protein backbone can bring about distant changes in protein conformation and binding affinity.

We encounter, therefore, a whole new level of specificity in protein architecture. It's not the old picture of an active site surrounded by haphazard amino acid residues. Any change could affect the allosteric communication of the whole protein. Clearly, mutants were less able to take advantage of the benefits of collective motion.

How did an unguided process arrive at a molecular machine that not only grips its substrate and catalyzes a reaction efficiently, but moves with intrinsic twists and stretches to improve the grip? The design specs for proteins just shot up a notch, and along with them, the challenges to Darwinian evolution.

On Charles Darwin and Rube Goldberg

My Debate with Michael Ruse -- Evolution as a Rube Goldberg Machine

Cornelius Hunter March 17, 2016 3:32 AM 

Editor's note: Evolution News is delighted to welcome back Dr. Hunter as a contributor. He is a Fellow with the Center for Science & Culture, Adjunct Professor at Biola University, and author of the award-winning Darwin's God: Evolution and the Problem of Evil. He blogs at Darwin's God

It was great to see Professor Michael Ruse again last week in Northern California for our debate on the question, "Is Evolution Compelling?" He was in good spirits as usual, and his jokes were much better than mine. But I had one big advantage over my erudite opponent: I was not defending the age-old idea that the world of life arose by chance. The main problem, as I explained at the outset, is that the scientific evidence contradicts unguided evolution. That is a very simple point, but it opens new worlds of thought.

I used my time to discuss a range of scientific evidence from biology. On that evidence, unguided evolution simply makes no sense. But I almost hesitate to show you my list simply because there is nothing special about it. One of the difficulties in explaining the problems with evolution to an audience is the plethora of examples from which to choose. I had a long list of fascinating biological designs that refute evolutionary thought. I like every one of them, because they all add a different angle on why evolution fails. But there are far too many to fit into an evening's presentation. I was changing my mind right up to the last day, but as difficult as it is, one must pare back the list to fit the time constraint.

I began with one of my favorites, micro RNA. I then discussed the failure of evolution's nested hierarchy. Later I had fun with echolocation and the DNA code, and I finished with directed adaptation. The obvious and unavoidable truth is that evolution is believed to be a fact not because of the science, but despite the science.

I also punctuated my scientific examples with some philosophy of science concerns. One of them is the problem of parsimony. I explained Occam's Razor, and how a sure sign of a failing theory is if it becomes overly complicated. The appeal of heliocentrism over geocentrism was not that of an improvement in accuracy, but in simplicity. Like heliocentrism, Copernicus' geocentrism had epicycles. So why make the move? Because Copernicus was able to use fewer epicycles. That is how important simplicity is in science.

Theory complexity is the enemy in science, and it would require volumes to explain all the details in today's theory of evolution. The reason why evolution is so complicated is that with each scientific failure, the theory is adjusted yet again. Today it resembles one of Rube Goldberg's wonderful machines.

For this theory, there is no ray of hope. I think I left the audience convinced that evolution is an utterly failed attempt. That's not because of any rhetorical skills on my part, but simply because I took the side of science. This isn't at all complicated. What is complicated is the question of why people believe in evolution to begin with. But that's another story.