The theories behind black holes generally suggest that subatomic particles (electrons, protons, neutrons) are themselves black holes, in which time expands in the opposite direction of our proper (perceived) time. Huge amounts of information could be stored by the spin number of photons present in these particle black holes. Could it be possible that the organization of brain matter, in terms of the properties of subatomic particles (quantum mechanics), confers on brain matter the capacities of memory and cognition, and that these phenomena are not encountered in other types of matter structure in the human body?
Come again? I was not familiar with electrons, protons and neutrons being black holes. But even if they are, I fail to see their direct relevance to understanding memory and cognition. Sure, it's a trivial fact that it's a very specific organization of subatomic particles that leads to a brain rather than to a liver or a chair. But the real action all takes place at the level of aggregates of these particles which we call molecules. I get the feeing that Kraus is indulging in a classic reductionist fallacy here. While subatomic particles do constitute the brain, understanding the brain can only come at a higher level, that of rather old-fashioned physics and chemistry involving ionic currents and neurotransmitters.
But Kraus finds a valuable place for quantum physicists in the war on neurodegenerative disorders:
To me it has become mandatory to create an AD scientific community that includes not only medicinal chemists, pharmacologists, biologists, and medical doctors, but also quantum physicists, in order to understand how aging alters the intimate structure of brain matter, where memory and cognition are located, with the hope of finding new AD treatment research orientations.
To me this sounds suspiciously like Roger Penrose's argument in his rather startling book "Shadows of the Mind" in which he postulated a relationship between wavefunction superposition in quantum mechanics and the growth and shrinkage of microtubules as significantly contributing to consciousness. Even a cursory look at that argument raised serious doubts about the relevance of quantum behavior in microtubules and more formal analysis seemed to confirm these doubts. I am not saying that physicists won't be a valuable asset on a drug discovery team, it's just that they are probably not going to use the tools of quantum gravity to map out cognitive pathways anytime soon.
Somewhat ironically, Kraus ends his piece by extolling the role of a systems biology approach in addressing a problem as complex as Alzheimer's disease. With this I wholeheartedly agree, but systems biology is the opposite of reductionism, where new emergent phenomena provide causal explanations that cannot be reduced to the laws underlying their substrates. We do need a suite of analytical tools operating at various hierarchical levels to address the issue, but given enough time and smart people, we should be able to do the job using standard chemistry and biology, albeit at a more sophisticated level. No fancy biophoton entanglement may be necessary.
Kraus, J. (2011). Why as a Medicinal Chemist I Am Not Optimistic about the Possibility of Finding, in a Reasonable Timeframe, Small-Molecule Drugs Capable of Curing the Evolution of Alzheimer’s Disease ChemMedChem DOI: 10.1002/cmdc.201100431
But what really catapulted the story to public attention was the finding that resveratrol, a molecule found in red wine, might do this. The presence of a (relatively) cheap edible substance, universally consumed, savored and culturally revered that might slow down aging naturally led to unprecedented public attention. The French and Italians might say "I told you so", but suddenly the holy grail of medical science seemed to be within reach. As usual though, the initial euphoria gradually gave way to a more cautious and tempered belief in the benefits of red wine in mitigating the ill effects of age, and indeed in the whole field of caloric restriction itself. The complete story is fascinating and too convoluted to recount here, but the simple fact of the matter is that the biology of aging is much more complex than we imagined and the initial breakthroughs have not been as unambiguous as they seemed. Not surprisingly, ascribing something as complex as aging and its attendant physiological changes to the action of a single family of genes and proteins has turned out to be simplistic at best (as a comparison, even obesity is thought to be caused by dozens of genes with overlapping effects). In addition, anti-aging effects that got the attention of the New York Times turned out to be significant only in "lower" animals and not in mammals. As it stands today, while research on caloric restriction undoubtedly has great potential, many complications need to be ironed out before the initial optimism can be justified. Curiously, much of the high-profile work in the area can be traced in various forms to a single laboratory at MIT. A recent article in Science does a great job detailing the personalities, the findings and the controversies that sprang from this and other laboratories' work; the entire saga seems fit for a Sinclair Lewis novel.
But whatever the scientific status of the field, its high-profile nature and its potentially revolutionary implications promised ample funding for interested researchers, and over the years it has attracted both highly visible as well as lesser known scientists. One of the individuals who waded into resveratrol territory was Dipak Das of the University of Connecticut Medical School. Over the last few years Das published several papers detailing the beneficial effects of resveratrol in possibly preventing or mitigating oxidative damage caused in cardiovascular and neurological diseases. While most of his research has been published in low-impact journals, it seems that Das was on his way to a lucrative research career involving resveratrol and its role in health and disease.Until now. It seems that somewhere along the road, he started committing fraud on a massive scale, the likes of which haven't been seen in some time in biomedical research. It started when an anonymous tipster tipped off the university about fabrication in some of Das's papers. The university then launched its own probe and formed a review committee. For the past two years the committee has been working in the shadows with the Office of Research Integrity (ORI) and last week they released their findings in a 50-page document. The findings indicate wholesale fraud, manipulation of results and deliberate doctoring of critical data on a shockingly regular basis between at least 2002 to 2009.
There are two aspects of the report that bear closer scrutiny. One is the sheer number of Western blots found to have been doctored. The committee examined 26 papers and cited no less than 88 figures which appear to be manipulated (there were also several that appeared normal). This is a staggering amount of manipulation and rules out accidental oversight. Das would have to be involved in a conscious, deliberate and extended effort to tamper with so much data. It's quite clear that the magnitude of the manipulation alone points strongly to purposeful fraud.The second aspect of the report concerns the great difficulty of detecting the fraud. Western blots seem to be notoriously amenable to manipulation; for instance they prominently featured in another recent high-profile case of fraud in India involving a researcher at the National Center for Cell Science (NCCS). In the report on Das's work, single bands of proteins in Western blots have been enlarged and their borders further magnified to show the contrast between the background for that particular band and for others, indicating that the band in question was copied and pasted. Image manipulation software can sometimes produce such artifacts and some of the data appears like it could also have been the result of negligence or sloppy editing, but the number of such instances again rules out merely these possibilities.
The debacle is ending in ways that such unfortunate scenarios usually end. The university has already begun proceedings to fire Das from his position. It is very likely that he will never be able to do research again, and that's probably the way it should be given the extent of his fraud. Sadly, Das has not made things any easier by accusing university and department officials of racist prejudice. When you have to resort to such allegations in the face of massive evidence detailing your dishonesty, you only make your guilt seem more likely.Ultimately this episode speaks as much about the culture of scientific research as it does about the transgressions of a particular researcher. We may not know for some time why Das felt like committing fraud on such a massive scale, but I suspect that the high-profile nature of anti-aging research and the funding that such research commands may have had at least something to do with it. In the last few years, resveratrol, caloric restriction and sirtuins have made it into the public discourse about science like few other topics. The possibility of harnessing all this data to solve the ultimate mystery of aging has ensured both sensationalist news items and eager funding agencies wanting to enable the next breakthrough. When you work in such high-profile fields, it is more tempting to fabricate your results to snare more funding. In this particular case, Das's work was deemed to be low-impact and peripheral to the field and so the damage might be negligible, but in someone else's hands it could well be extensive. The case of Jan Schon immediately comes to mind.
The only remedy for avoiding such debacles may be more acute vigilance, self-policing and an honest willingness to accept failures. And some modesty before nature may be in order here.
The explanations run across the gamut of the sciences and the humanities including physics, biology, economics, neuroscience, politics and business. But conspicuously absent is chemistry, except for a few peripheral references like Charles Simonyi's listing of Besicovitch's theory of atomic forces. And this is in spite of our friend Derek Lowe of "In the Pipeline" being included in this august list. I was gratified to see a chemist being asked for his opinion, and was somewhat disappointed that Derek's favorite explanation was not chemical (his favorite is the rather deceptively simple notion of "freefall"). I of course don't blame Derek for his choice since there is no law dictating that a chemist's favorite explanation should be from chemistry just because he or she is a chemist. My own favorite beautiful explanation is probably Cantor's notion of multiple infinities.
But I did regret the striking omission of chemistry from the list. Sometime back I had a whole post on elegance in chemistry. And I certainly don't want people to think that deep and elegant explanations are limited to physics and biology, because they are not. Chemistry may not boast of profound philosophical explanatory frameworks like the Big Bang or evolution by natural selection. But it makes up for this fact by creating paradigms that directly touch the lives of millions of human beings in ways much more palpable than the Big Bang and evolution. So I thought I would add my own modest thoughts on my favorite deep idea in chemistry.
There's actually a few things at the top of my list; you certainly don't have to think hard to come up with several foundational chemical ideas. But if you really asked for my absolute favorite deep and elegant explanation, it is the shared-electron chemical bond. That's it. Right there is the simple concept that is at the heart of the material world, a concept that if you think about it has had a staggering impact on our quality of life, our relationships with other nations, our notion of prosperity itself. Chemical bonds as manifested in the foundations of modern civilization have certainly contributed as much to life, liberty and the pursuit of happiness as any scientific idea.
The idea itself as formulated by the great Gilbert Newton Lewis and comprehensible to any high-school student is simplicity incarnated; atoms combine into molecules and form a bond when electrons are shared. Everything that comes after the stating of this fact, important as it is, is details. All the quantum chemical wizardry, the thinking-in-orbitals, the great Gaussian simplification, it's after this basic groundwork has been laid. Heitler and London, Pauling, Slater, Mulliken, Pople, all of them made critical contributions to chemical bonding, but they all stood on Lewis's shoulders and built up from his landscape of the shared electron chemical bond.
Given the absolutely foundational role that the chemical bond plays in the thinking of chemists, it may be both ironic and a tad disturbing that chemists still cannot completely agree on the precise definition of every molecular bond out there. But that's not because the basic framework underlying bonding is uncertain. Part of the reason is simply because there is no such thing as "the" chemical bond. The bonding zoo sports a bewildering variety of animals, from the upstanding "normal" chemical bonds in, say the hydrogen or methane molecules, to the (literally) ready-to-snap pressure cooker entities in strained organic compounds, from the wily, shape-shifting bonds between metals and organic compounds to the ephemeral but biologically vital hydrogen bonds. Although the basic theory of the chemical bond is securely in place, it's going to take some time to craft a net wide and yet rigorous enough to snare the unruly and colorful creatures dotting the chemical landscape.
Now physicists may try to appropriate the chemical bond as their own, but they are out of luck. No explanation based purely on physics can truly impart a feel for the sheer diversity of bonds quoted above and their context-specific personalities. Just one bond serves to create a nightmare for purely reductionist approaches to defining chemical bonding- the hydrogen bond. Last year chemists convened at a meeting with the express purpose of tweaking their description of this all-important biological mediator, the glue that holds life together. Several questions were bandied about, but none more important than the very definition of a hydrogen bond. The problem was simple; hydrogen bonds can be weak or strong, sometimes so weak as to strain the definition of a bond, sometimes strong enough to suspiciously qualify as a covalent bond. How much of hydrogen bonding is electrostatic and how much is covalent? Is "bond" even the right term, or would "bridge" be more accurate? How do you define hydrogen bonds to metals? A consensus was finally reached on a new definition, but not even Linus Pauling could say that the definition would hold for all of eternity. Defining a hydrogen bond would give every physicist out there a run for his money. I find the concept of the chemical bond so enticing and elegant partly because even a single kind of bond like the hydrogen bond can hide a richly textured world of possibilities lurking behind its surface.
So there it is, why the concept of the chemical bond is my favorite idea, certainly in chemistry. It is deep because it underlies the making of the material universe, explaining the stuff that everything from crab shells to the Crab Nebula is made of. It is elegant because of the virtually unlimited amount of explanatory power that it hides in a simple statement of definition. And it is beautiful because of the sheer diversity of materials and structures that are created from a simple law of attraction. A lot of the thinkers in the Edge survey quoted evolution as their favorite deep idea. It certainly is beautiful. But Darwin could well have slightly paraphrased his words to apply to Lewis's shared-electron chemical bond:
"There is grandeur in this view of the material world, with its several powers, having been originally breathed into a single bond; and that, whilst this planet has gone cycling on according to the fixed law of gravity, from so simple a bond endless forms most beautiful and most wonderful have been, and are being, evolved."
He starts by asking what the real advances in the field have been in the past 25 years and by observing an apparently rather disconcerting fact about modeling and especially structure-based modeling - successes are still mainly anecdotal. He expresses his disappointment while noting that most of the successful results in modeling are still mainly of the "find protein pocket, fill pocket" type. The chief role of the crystallographer, it seems, is to supply pockets that the computational chemist can then fill. The problem according to Anthony is that chemists are not "abstracting principles of wide applicability; they are recognizing domains of expertise".
At this point let me interject and say that while Anthony's gloomy prognosis might be true, it's also true that "find pocket, fill pocket" (or "find pocket, kill pocket" if you are in a hunter-gatherer mood) campaigns are not as straightforward as we think. There can be unexpected effects on both protein conformation and ligand conformation, similar to the "activity cliffs" witnessed by medicinal chemists. Even if the binding orientation of the ligand stays constant upon small changes, the distribution of solution conformations of the modified ligand is likely quite different, leading to differing energetic penalties that the protein has to pay for binding. I am sure I am not alone in saying that small changes in ligand structure leading to changes in binding affinity enforced by ligand strain and conformation are uncomfortably frequent. But there's another dimension to the "find pocket, fill pocket" campaign; it can actually be quite satisfying to suggest changes to a medicinal chemist for filling the pocket that are borne out by further crystallography. Finding pockets may generate anecdotes, but chemistry is a more anecdotal science than say physics, and chemists often revel in these little successes and failures. Chemists are more frogs than eagles.
But the real sticking point for Anthony is not really the anecdotal success of structure-based modeling but the lack of general physics-based principles and laws for doing molecular modeling. Docking is an example. In the last several years there have been many attempts to use physics-based "scoring functions" - essentially ways to sum up different protein-ligand interactions to a number - for calculating the binding affinity of a ligand. Programs for docking have evolved to a stage where ligands can be docked in the correct orientation with a roughly 30% success rate, depending on how similar the docked ligands are to a reference co-crystallized ligand. But the truth of the matter is that we still fail miserably when trying to dock an arbitrary ligand to an arbitrary protein in an arbitrary conformation. And of course, we are light years away from predicting free energies of binding for the general case. There have been cases in which physics in the form of electrostatics and quantum mechanics (more on this later) has significantly accelerated the search for similar molecules, but the promised land still seems far.
Does this failure reflect an absence of general principles of physics for computing protein-ligand interactions? Paraphrasing Rutherford (not Niels Bohr), in the next few decades will we do more physics or simply collect more stamps? Is this concern even warranted? To some extent, yes. It would certainly be very satisfying to have a general explanatory framework, a pool of more or less universal laws that explained the wide variety of protein-ligand complexes as completely as Newton's laws explain the behavior of an astonishingly diverse set of particle interactions in the classical world. Curiously, such a general framework does exist in the form of statistical mechanics and quantum mechanics. In theory, both these disciplines encompass the binding of every single protein to every single drug. So does that mean we can look forward to a time when every modeler can "abstract these principles of wide applicability" and use them to solve the particular case of his or her protein and ligand?
Here is where I part ways with Anthony at least partly. The reason in my mind is not too hard to discern. Think about how far we have come in explaining protein-ligand binding using the rather extensive developments in either quantum or statistical mechanics over the past five decades. The answer is, not as far as we would have liked to. While we have indeed made great advances in understanding the basic thermodynamics of protein-ligand binding, we have not been very successful in incorporating these principles into predictive computational models. Why so? For the same reason that we have not been successful in using physics to explain "all of chemistry", in Paul Dirac's words. Quantum mechanics has been applied to chemistry for fifty years and exponentially increasing computational power has significantly furthered its application, but even now, for most practical systems chemists use a variety of empirical models to understand and predict. That's partly because most real systems are too complex for the direct use of quantum mechanics, and an imperfectly understood protein and ligand immersed in an imperfectly understood solvent certainly belong to this category. It's also because we are still far from calculating things like entropy and being able to model the differential behavior of water at interfaces and in the bulk.
But even more importantly, physics may not solve our problems because chemists need to abstract general principles at the level of chemistry to ply their trade. Thus, in expressing doubts about the utility of general physics-based principles, I am appealing to the strong sense of non-reductionism that permeates chemistry and separates it from physics. The same principle applies to biology and I have written about this often. Principles drawn from physics have always been very useful in gaining insights into molecular interactions and they will continue to be an essential part of the mix. But unlike Anthony, I see a far smaller role that pure physics can truly make in enabling a general, practical predictive approach to modeling that's "chemical" enough to be widely used by chemists.
So are there cases in which physics can make a contribution? Here I actually do agree with Anthony when he mentions two areas where physics really promises to have a substantial impact, both conceptually and practically. The first is crystal structure prediction for organic molecules which is a notoriously fickle problem (a measure of the difficulty can be gleaned by the fact that even the simple benzene can crystallize in more than 30 different geometries), essentially one of being able to predict fine energy differences between almost equienergetic arrangements. Yet I see this problem as one of the more reductionist problems in chemistry, and as Anthony notes, it is conceivable that it will yield to physics-based approaches in the near future.
The other problem is one of the holy grails of chemistry and biology - protein structure prediction. In various guises, the last few years have seen a startlingly impressive set of cases where protein structures of small and (some) medium-sized proteins were predicted with atomic level accuracy. Protein structure prediction has to overcome the twin challenges of sampling and energy estimation that are a mainstay of almost every other modeling method. In this case Anthony thinks that we will have to get the physics right to address this issue.
But we have to be careful to distinguish between two cases here. The first case is where we get the right structure even if we have no idea how we got there. This is the field of empirical (non-physics based) protein fold prediction and the biggest success in this area has been the ROSETTA suite of programs. ROSETTA has definitely turned heads within the community by its ability to generate accurate structures for hundreds of proteins, but the big drawback of the approach is that it only generates the end result. Curiously Anthony does not mention ROSETTA, but I am also surprised that he does not mention in detail another significant development that does fit into the physics-based paradigm. This is the molecular dynamics approach developed by David Shaw, Vijay Pande and others. Unlike ROSETTA, MD can actually shed light on the process leading to a correct structure, although the details of the process are subject to errors, most notably in the force fields that underlie the simulation. It's quite clear that with all their limitations, ROSETTA and MD have been the biggest contributors to successful protein folding simulations over the last decade.
And yet as Anthony rightly says, their success seems almost like a miracle. This becomes clear when we realize that even now we have trouble predicting something as simple as the solvation energy of a simple organic molecule or the interaction energy of two simple molecules using even sophisticated quantum mechanics calculations. If our ability to predict even such simple scenarios is dismal, how on earth are we getting the structures of all those complex proteins right? The answer deserves as much scrutiny as the solution to these problems, scrutiny that is severely lacking. Anthony's answer (and mine) is "cancellation of errors along with a need to calculate only relative, not absolute, energies" (it's well known that force fields are virtually worthless for the calculation of absolute energies). It still strains my mind to think that these two factors could contribute to so many successful predictions published in the likes of Nature and Science. Cancellation of errors was partly made famous by Enrico Fermi. If that's really what's happening in all these cases, then the entire field needs to start celebrating Fermi as their guardian angel.
Ultimately, there is no doubt that advances will continue to be made with increasing computational firepower, but the foundations of the field will stay brittle unless these fundamental issues are addressed. Anthony ends with something he has been doing for a long time now - appealing to experimentalists, industry and government to contribute a small part of their funds to the kind of basic experiments that can further the field of modeling. This especially involves experiments that can refute an idea, a philosophy that has been dominant in the practice of science since its modern conception but one which seems to be unusually neglected in drug discovery because of the emphasis on positive data gathering. Science has always progressed by the testing of ideas that have no immediate practical bearing, except that they perform the invaluable function of making future scientific research worthwhile. It would be fundamentally unscientific if such ideas are not supported. Anthony puts it well:
"The simple commitment to spend a small percentage of the science budget at the NIH or at pharmaceutical companies on nontranslational work, providing support for the small cabals of scientists actually interested in making fundamental progress would be enormous. Reestablishing the contact between theorists and experimentalists, the publishing of high quality data, conferences devoted to the actual testing of ideas—in 25 years we might hope molecular modeling could become a real scientific discipline."