College Chemistry Carbocation Cinch

Now here's a paper that reiterates one simple freshman organic chemistry principle; tertiary carbocations are more stable than secondary carbocations. Of course, that need not be the case with enzymes at all, but in this case Tantillo's theoretical results indicate that that may be the case (DFT studies using the popular mpW1PW91 functional). He finds that the biasobolyl cation which traditionally goes through a sec carbocation intermediate to the terpene trichodiene, actually follows a lower energy pathway if it involves all tert carbocations. But he ends up proposing a novel proton transfer and a "temporary methyl shift", that is a colour different from all those hydride transfers that we learn in terpene biosynthesis. It would be interesting to investigate experimentally what happens in the active site; enzymes can stabilize prim and sec cations through cation-pi interactions for example.

Org. Lett.; (Letter); 2006; ASAP Article; DOI: 10.1021/ol061884f



Incidentally, the muddle of terpene pathways in the paper brings back fond memories of a master's level course on the topic which a really great, senior professor had taught us. It was actually fun deciphering painfully, the various ways involving methyl, hydride, and proton shifts and cyclizations which could get you from an intermediate to the product in those terpene biosyntheses.

New Look

I am giving this blog a slightly new look, and hope to breathe a fresh breath of life in it. I hope to post more often on technical matters about chemistry and related topics, and indeed, because of emphasis on technical matters, this blog should complement my other general blog. But since I have always been interested in other aspects of science like it's practice, social standing and general philosophy, I will always also comment on those aspects when I find it interesting to do. Some posts will be cross posted on the general blog.

As far as the technical side goes, I hope to post on organic chemistry (including synthesis), computational chemistry/molecular modeling, drug discovery, and general topics at the chemistry-biology interface. But these are just general guidelines for myself based on my interests, not hard and fast rules, and posts will occasionally include anything scientific that I find interesting. So it should not be surprising if one suddenly discovers a post on astronomy and animal behaviour. I want to treat science on this blog as fun, and as a human endeavor. And I want to treat it as something which has an exciting and interesting technical side, but also seamless connections within itself, and with human beings and society. So here goes.

A word on copyrights: I will be posting images that I see on other websites, including professional publications like those from the ACS. Every image will be referenced, and you should not see any image that has not been linked to its source. If you see this, please tell me about it, because I don't want to run into any legal issues here and want to acknowledge the source of everything I post. Also, I will refrain from saying anything about my own research except in a very general way, again for propreitary reasons.

Killing the Hydra

As an addendum to the previous post, I want to note that the 'hockey stick' graph by Michael Mann and others which was so much in the spotlight recently has been endorsed in its general features by many bodies, including the National Academy of Sciences. (Link: Climateaudit)



Once somebody asked me a curious question; Mann's graph shows that the temperature anomaly has been the highest for the 20th century in the last 1000 years. What if we are looking at a cycle that repeats itself in, say, 2000 years? Won't the temperature anomaly that we see then be only part of a cycle?

I guess this is an objection that many people have about global warming. What if it is only a cycle? To my knowledge, the answer to this objection is now clear; computer models can reproduce the temperature that might have existed had mankind and greenhouse gases not been around. This natural variation in the temperature is far lower than what it is. Also, the simple fact that temperature rise can be concomitant with the rise of CO2 is a very telling one, and may appear deceptively simple. Also, it is a simple law of nature that CO2 absorbs certain wavelengths of light. Taken together, these three facts for me constitute as good a chain of reasoning as any. Also, the naysayer's objection is absurd for another reason. If the data had been collected for 10,000 years, he could still have claimed that it was not collected for 20,000 and renewed his objection. I am not sure it makes sense to play these childlish games till the world comes to an end. As I have noted before, do we really want to be one hundred percent certain about an event that could eminently mean the end of humanity? Maybe then we should also stop vaccinating ourselves.

Frankly, given our nature, I don't think any amount of moral reasoning, no matter how true, is going to sway public opinion soon. Indeed, people don't even stop smoking cigarettes when they know they can kill them, so it may appear naive to expect them to suddenly care about global warming, a phenomenon that probably won't directly affect them in their own life. No matter how lofty the moral pillars of reasoning seem, the one thing that can finally force people to pay attention is still the mundane allure of economic incentives. Consider this; this semester onwards, almost nobody from my lab is going to drive their car to work, and they are all going to take one of the three new shuttles that Emory University has begun. I don't believe for a moment that they are doing this for the environment. The simple reason why they are doing it is because Emory University is also going to double the annual parking fees to 700$ a year. If you can't show them the tree, just don't make it free. Do this more often; create new bus services, make wireless internet available on the shuttles, and make the parking fees prohibitive, and people will obediently avail of the service. It's surprising how the simplest of daily incentives can change people's minds about the most profound objectives. But evidently, things like public transportation are not that simple, because they are not being implemented.

The Kyoto protocol is being riddled with blame games, with the US saying they won't sign until India and China do, and India and China saying they won't sign until the US does. China is next only to the US in greenhouse emissions, and if anything, it's going to spew many times more in the atmosphere in the near future. (Link: BBC)



I for one think this is another childish game that can be played till eternity. Even though the arguments are valid, somebody has to get out of the loop. After all, deep down, does it really matter that the US has increased emissions over the last few decades? It's us who have to suffer the consequences to our environment if we don't cut them down. It is true that as of now, we cannot achieve a high standard of living without using conventional energy sources. But at some point in the future, we are going to run out of oil anyway. How does it harm us to start early and found our new standard of living on unconventional energy sources, an effort that actually can turn out to be profitable in case of a likely oil crisis? At least we have the nuclear deal with the US. Let's avail of it. On the part of the US, I think that if they want us to sign, they should also become ready to sell us some of their already developed research into uncoventional sources of energy, at a cheap cost, and save us the cost that we would have to expend in doing research using conventional energy in the first place. But finally, they also must be prepared to give their citizens incentives to cut down on their standard of living, a standard that neither they nor the world can realistically aspire to in the near future. I agree that governments are to blame, but ordinary Americans need to pitch in too, and they are going to do it only if they are provided incentives of the kind mentioned above regarding public transportation. As Al Gore says, we have the technology to stop global warming, but in a different sense, I think that statement can also refer to the technology needed to give people incentives to combat global warming.

The media has a very important role as always to play in this situation. As noted below, the media has many times embellished global warming research by spuriously connecting it with specific environmental events. However, much needed public awareness did come out of this misused connection. Now, the media needs to highlight the general effects of global warming that are becoming so certain. For example, not the number but the intensity of hurricanes is predicted to increase according to climate experts, and this has been so. A good connection has also been established between mean sea surface temperature and hurricane intensity. The media needs to highlight such facts that have been extensively investigated using sound science. In the US, the media has a considerable hold on the people's psyche. For once, they should exploit this hold for a good purpose.

Combating ignorance and galvanizing official policy and public opinion about global warming is like killing the Hydra; when one of its heads is cut off, another one appears from somewhere and grows in its place. But the truth remains that Hercules did kill the Hydra and win the battle, and so we also should know that we can, and fight it with all honesty and sincerity.

The Discovery of Global Warming

The Discovery of Global Warming- Spencer Weart

Any new scientific theory, when born, always comes into the world kicking and fighting back. That's because scientists inherently are skeptical, and in the opinion of one of my colleagues, also inherently mean. Whenever a new revolutionary fact is presented to them, their first reaction is of incredulity because skepticism is a reflex action for them, but also because another reflex action causes them to be galled that they weren't the one coming up with the new idea.
If 'pure' scientific ideas themselves have so much trouble coming up for air, what would the scenario be for a revolutionary new idea that also has a gory heap of political controversy written over it? Messy, to say the least. And so it is for the idea of global warming.

Spencer Weart has penned a lively, informative, and concise history of the discovery of global warming, that precisely demonstrates how difficult it is for such an idea to take root in the public mind and affect public policy. What is more fascinating is how research in climate change was spurred on by unseemly government and military interests, and misunderstood media coverage and inquiry. Weart starts with some old stalwarts from different fields, in the nineteenth and early twentieth century, and how they were intrigued by a fascinating phenomenon- the ice ages, which served as the driving force for suspecting the role of greenhouse gases in changing the temperature of the planet. If there's one singular fact that emerges out of the history of global warming, it is the public's extreme skepticism in underestimating humankind's role in changing the mighty earth's enormous environs, and scientists' reluctance to accept the role of small changes caused by humans and natural forces that could cause violent climate change ('The Day After Tomorrow' notwithstanding).

The discovery of global warming was a painful endeavor, often occupying many scientists' lifetimes. Almost everyone who wondered about it faced opposition in terms of opinion and funding. Almost no one could alone prove global warming without extensive collaboration; not suprising given the interdisciplinary nature of climate. Scientists had to grudgingly forge alliances with other scientists whose fields they would have hardly considered respectable. They had to beseech the government for funding and support. One of the most interesting facts is the government funding of climate studies in the 50s and 60s that was fuelled entirely by military purposes dealing with the Cold War. More than any one else, defense forces were interested in controlling the weather for military purposes, and they couldn't have cared less about global warming. But this was one of those fortuitous times in history, when a misguided venture proved to be beneficial for humanity. Just like building the atomic bomb produced a bonus of insights into the behaviour of matter as a side effect, so did the military's interest in the weather, absurd as it was in many ways, prove to be a godsend for scientists who were hungry for funding and facilities. Weart makes it quite clear how scientists found an unexpected asset in the military's interest in climate. Secretly, they must have laughed in the face of paranoid cold warriors. Publicly, they appeared most grateful, and in fact were, for the funding they got.

If the military unknowingly contributed to our knowledge of climate change by supporting dubious studies in the field, the media contributed to it by miscommunicating the facts on many occasions. During the first few years, the general public wasn't concerned and did not believe in climate change, again, because they could not believe that a puny entity such as mankind could disturb the grand equilibrium of nature. But then, as the general nature of events such as hurricanes, floods, and droughts began to be linked with climate change in the 70s, the media began to pay more attention to scientific studies, and began to exaggerate the connection of man's contribution to the environment and violent weather phenomena. Just like the military's venture, even thought this venture was completely misguided (even today, we cannot pinpoint specific events to global warming), the unexpected effect of the media's spin doctoring was that people began to believe that man could change climate. Of course, the media also was not afraid to point out and again exaggerate when the scientists' predictions and explanations failed, but for the better or worse, people for the first time in history began to take serious notice of global warming and mankind's contribution to it. In the 1960's, Rachel Carson's 'Silent Spring' provided yet another impetus for the public to consider the general relationship between technology and it's effects on the environment.

And yet, as Weart narrates, the road was tortuous. At every stage, speculative as the scientists' predictions were, they were opposed and overwhelmed by powerful government lobbyists who had influence in congress, and much more money to thwart their opponents' efforts. Whenever a new study linked greenhouse gases with warming, industrial lobbyists would launch massive campaigns to rebut the scientists and reinforce public faith in the propriety of what they were doing. As Joel Bakan says in The Corporation, one of the main methods of corporations in maximizing profits is to 'externalize' costs. Suddenly being responsible for environmental pollution which was previously externalized would put their profit making dreams in jeopardy. Until the 80s, scientists could not do much, as firstly there was not enough evidence for global warming and secondly, computer models were not powerful and reliable enough to help them make their case. Matters were made worse by the Reagan administration which has one of the worst track records in history when it comes to environmental legislation. So unfortunately for scientists, just when their efforts and computer models were gaining credence, they were faced with a looming pall of government and corporate opposition, against which their fight was feeble.

These scientists who researched climate change were and are an exemplary lot. They built computer models, wrote reams of codes, and ran simulations for weeks and months. They went to the coldest parts of Antarctica and the deepest parts of the ocean to gather data and samples, to collect climate 'proxies' such as pollen, ice cores and tree rings, for gathering data in past ages which thermometers had not. They spent lifetimes in their search for the contribution of mankind's action to climate change, even though they knew that their results could disprove their convictions. As far as dedication to science and policy is concerned, you could not wish for a more dedicated lot of investigators.

Slowly, in the face of opposition, predictions began to get more credible, and enough data began to get accumulated to make reasonable analyses and predictions. The discovery of global warming really came in the late 90s, but the culmination of efforts really came in the late 80s. During those few years, droughts and rain deficit around the US again brought media attention to climate change. Computer models became much more reliable. When a powerful volcano exploded in 1991, computer models accurately predicted the drop in temperature (one that was more than compensated by a rise in greenhouse gases) that was caused by the accumulation of sulfate particles in the atmosphere. Scientists began to appear before congress to testify. An Intergovernmental Panel on Climate Change (IPCC) was created that created authoritative reports on climate change and the 'anthropogenic' contribution to it. The evidence became too widespread to mock or downright reject. Global warming had to be given at least serious consideration. However, because of the uncertainties inherent in predicting something as complex as the climate, government officials always could do cherry picking and convince the public about the speculative nature of the whole framework. Here, they were making a fundamental mistake, of the kind that opponents of evolution make. Just because a theory has uncertainties does not mean it is completely wrong, as these officials would have the public believe. Of course nothing is certain. But in case of global warming, enough data had accumulated by the 90s to make one thing absolutely clear at the minimum; that we were altering the climate of the earth in unpredictable ways. Studies of past climates had also reinforced the conclusion (with some startling impetus from chaos theory) that very small perturbations in the earth's climate and ocean systems can result in huge effects on the climate (the so-called 'butterfly effect'). Man's contributions to the earth's environment are now eminently more than a 'small perturbation'.

However, when it comes to the fickle palette of politics, every colour can be shaded to suit one's interests. There was, and will always be, great hope from the fact that the opposition against CFCs worked and all nations successfully signed the Montreal Treaty. But In 1997, the US Senate rejected the Kyoto Protocol in spite of Clinton and Gore (naturally) ratifying it. After this, it was but a formality for George W. Bush to resurrect this policy by not agreeing to sign Kyoto in 2001, citing that it would bring about grave economic damage.

Today, there is no doubt that global warming is real. It has been endorsed by every major scientific body in the world. Its effects are many and each one of them is devastating. Enough data has now been accumulated to reinforce the relation between greenhouse gases and global warming. Individual details do remain ambiguous in certain respects. But they will soon be quantified. And as I noted in this post, does it matter that we don't know everything with one hundred percent certainty. The repurcussions of global warming are the biggest that mankind will ever face, and even a 30% certainty about them should be enough for us to make serious efforts to stop it. In my opinion, the unfortunate thing about global warming is that it is a relatively slow killer. And because individual events due to it cannot be predicted, people are not going to be flustered by even Hurricane Katrina and think it was caused by global warming. They will just consider it to be an unfortunate incident and move on. If they knew for sure that Katrina was caused by global warming, they would be lined up on the steps of Capitol Hill in Washington. But what they want is certainty. Strange that they don't seem to want it when it comes to terrorist attacks.

Weart's book is not an eloquent appeal to stop global warming. But that's what makes it striking, because the facts, as revealed by the dispassionate hand of science, make the phenomenon clear. However, that's probably the only problem I would find with the book. Weart is a good writer, but not a particularly poetic or eloquent one. I believe he could have made the book much more sobering and dramatic. He essentially weaves a history in the true sense of the word, even if he may fall short of making it read like a novel. The human drama is there, but kept to a minimum. He writes like a true scientist, making the facts matter. The science on global warming is now sound. What is not is human nature.

I cannot help putting in this cartoon again

Duplicate duplicate...And the sad case of hexacyclinol

Unrest is brewing in the world of chemistry, because a piece of research is raising eyebrows, and hackles, of those who think that it represents possibly dishonest science. The case also showcases the dilemmas in modern scientific progress, which have been illustrated before by some other famous cases. I think it would be worth it for me to elucidate the nature of the current entertaining fracas. But after a very short introduction to the art and science of organic synthesis.

* Magic in moleculeland and showdown in the house of hexacyclinol:

'Total synthesis', the multistep synthesis of complex organic molecules with practical and medicinal benefits, has been one of the cornerstones of the scientific foundation of the modern world. Look everywhere around you, and you see materials that have been manufactured tediously by organic chemists, one step and one bond at a time, since many decades. The greatest impact of this endeavor has been in the pharmaceutical industry, and most of today's important drugs would not exist if it were not for the patience and ingenuity of the organic chemist, nor could we hope to get future pharmaceutical products. Without synthesis of natural and artificial molecules, we would essentially be losers in our fight against disease.

So much for the practical aspect. The other reason why organic chemists synthesize molecules is for the sheer intellectual challenge. Building a complex molecule is like building the Eiffel tower or like painting the Sistine chapel, where not only does every bit and piece have to be put in its exact place, guided by known chemical principles, but the result, efficiency, and methods also have to be aesthetically pleasing. Many chemists are drawn to the synthesis of especially natural molecules, because they are dazzled by the beauty of nature's architectures, and want to make every effort to top nature in her magnificent constructions. Many have come close, if not surpassed, the rich and astonishing diversity of nature's creations.

So did James La Clair of the Xenobe Research Institute (?) want to synthesize a molecule called hexacyclinol, whose structural beauty and complexity only seasoned organic chemists can truly appreciate. It is a metabolite from a fungus isolated a few years ago, from a dead piece of wood in Siberia. Many of the top selling drugs of recent years have incidentally been based on molecules isolated from such obscure terrestrial and marine organisms in exotic locations, a resounding case for preserving biodiversity.

A couple of months ago, his synthesis appeared in one of the two top chemistry journals in the world. I am not a seasoned organic chemist, but when I saw the structure and synthesis, my first reaction was 'Wow'. But further reading of the paper made my jaw drop lower down. The synthesis was 30 steps, something not uncommon in today's synthetic protocols, although still a formidable feat. What was dazzling was the fact that authoring the paper was one man- La Clair. Today's syntheses are massive endeavors, usually involving at least four to five graduate students and post-docs who have toiled for months, if not years, on such a complex product. One man's crusade in synthesizing such a molecule would have been hard to believe even in the maverick days of the 30s, when rebels determined to overturn sacred cows could toil obsessively in their laboratories. Frankly though, I was not completely qualified to judge the synthesis, but I was astonished at the fact that one man had done all the work of procuring, synthesizing, and then characterising this gigantic succesion of molecules in the synthesis. Suddenly I remembered having seen La Clair in a session from the annual meeting of the American Chemical Society. I remembered his clever remarks in the session which he had chaired, which involved praising my friend's synthesis and saying that 'my friend is ahead of the bug that usually synthesizes the molecule by several steps'.

My astonishment and puzzlement at the solitary achievement of La Clair was justified when I came across Dylan's Tenderblog, where he pointed out the dubious nature of some of the steps and statements in the paper, followed by a world-class barrage of invective, hilarious comments, and astute observations. I was ROFL when I was reading these comments.

However, now, it seems that La Clair may have become A La Carte indeed. A chemist by the name of Scott Rychnovsky at the University of California Irvine, predicted that some structural data for the molecule actually matched the calculated data for a totally different molecule.
Note that the molecule which La Clair synthesized already existed. Its structural data was already known, and a structure had already been deduced from that data. What Rychnovsky did was use powerful computers and the methods of computational chemistry (my turf!) to conversely calculate the structural data from the molecule. What he got did not correspond to the observed data. Instead, he came up with a totally different structure which would correspond to the observed data. In a mammoth effort now, John Porco of Boston University has actually synthesized the alternative structure which according to Rychnovsky, should correspond to the observed data. Voila! It does.

Now what does this mean?? For one thing, it could mean that La Clair synthesized the wrong molecule. But remember, Rychnovsky's structural data calculated for La Clair's structure does not actually correspond to that structure. However, in his paper, La Clair has done the usual routine of presenting the experimental structural data for his molecule, comparing it to the original experimental data acquired when the molecule was isolated from its fungus, and then noting the exact correspondence between them, concluding that his structure is the same as the original one. This is standard and age-old scientific protocol; come up with something, then see if the data for that something matches the known data. If it does, you do have what you say you have. But again, according to Rychnovsky, La Clair's structure should NOT give the structural data which La Clair has presented. So there's a disconnect between La Clair's structure and its synthesis, and La Clair's structural data. Now, the structural data already exists (from the original isolation study) and so cannot be fabricated. Thus, by the rules of Aristotelian logic, that imperfectly perfect science, the fault lies with La Clair's synthesis. Ergo, the skeptics conclude, La Clair could not have synthesized the molecule which he claims he did. Ergo, La Clair's synthesis is not what he says it is.

Ergo, La Clair has committed scientific fraud, or that's what they are saying at least.

La Clair claims that most of his work was done in an institute named Bionic Bros' in Germany. This name sounds to me like something from an Asimov novel, a cross between a robotics company and a bagel bakery (I am thinking of Einstein Bros. of course) where an obscure genius toiling in an obscure institute with a funny name, comes up with a breakthrough to create artificial life or something similar.
Supporting the skeptics' conclusion is the dubious nature of some of La Clair's statements and experimental steps, which I would leave an experienced organic chemist to pontificate on.

To be frank, strictly speaking, the verdict is still out on the La Clair affair. La Clair himself says now that the structural data for both the molecules could be exactly the same. To my humble chemist's mind, this seems highly unlikely, given the very different structures of the two. But as it is the case, whether I or La Clair or the critics are wrong in this case, science will progress either way. No offense to La Clair. If he is right, we will be wiser anyway.
That's the good thing about doing science. Whatever happens, science always wins.

* I replicate, therefore I am:

But this case is illustrating some of the inherent problems of scientific peer review. Scientific results should crucially be testable. But who is going to go to the trouble of testing a 30 step synthesis, or any such mammoth endeavor? And mind you, dozens of such syntheses are published every month. All the reviewers can do is check for internal consistency and past conformity based on their own knowledge and experience. Nature has recently published a nice article, narrating the problems with the all-important replication of data that is paramount in the scientific method. How can you check each and everything in a paper? Even if you can, does failure to replicate mean shoddy work on your own part, or a fundamental problem in the original author's work? And more importantly as the article points out, scientific research has subtle details in the exact protocol, including elements introduced by the skill (or lack of) the experimenter. Such elements can hardly be evaluated, and are never mentioned in a paper. What if these subtleties are playing a large role in the results?

The Nature author recounts the efforts of several journals now going to be devoted to methods, as well as websites where readers can rank papers based on their own efforts in duplicating the data from those papers. As the author says though, this could have the adverse effect of having to include too many similar pieces of work, a fact that may make the journal less attractive for authors and readers alike.

Another quite different matter concerns the nagging question; Why do they do it? Is their behaviour an inevitable consequence of today's cut throat world of competition in science, the high-pressure world of publish-or-perish that is so emotionally taxing, that sometimes scientists just lose it a little and falsify their results with the hope that they won't be detected. In La Clair's case, hexacyclinol was one example among a dozen other interesting examples. But what about the celebrated case of Woo-Suk Hwang, the Korean celebrity, the scientist who became the lifeblood and then the pariah of his ilk with his work on stem cells and cloning. Surely he could not have assumed that crucial work such as his would not be subjected to the closest scrutiny possible. That scientists would not keep the midnight oil burning in their laboratories to validate his results. How can someone who does work of that calibre afford to be dishonest to any degree and think he would get away with it? What about another celebrated case, that of Jan Hendrik Schon, the trailblazing Bell Labs researcher who promised to revolutionise electronics, semiconductor and superconductor technology. Not in one but in sixteen papers did he duplicate the exact same graph. How could he think he would escape unscathed and in fact be lionized? The question defies explanation. However, if any kind of serious study found out that it is emotional strain and pressure that brings about such behaviour, then does our entire way of doing science deserve a second and serious look? Or do we just dismiss these few cases as bad apples?

I believe that psychologists should find this avenue of investigation a very fertile paradigm of study. In the 1930s, a publicised and comprehensive psychological study tried to document what kind of men and women become scientists. What is their personality, their origins, childhood influences that turned them toward science and inquiry? Maybe the time is ripe for a similar study asking a different question: What are the adverse effects of the framework of modern scientific research and peer review?

But in the end, I think that the Nature author says it best when he points out that the marvelous expositor of science Nobel laureate Peter Medawar once pointed out that all scientific papers are frauds, because they paint a false picture of science progressing in an orderly fashion from hypothesis, testing, confirmation, to theory or law! As the great philosopher Paul Feyerabend pointed out to the chagrin of others, science is an anarchic enterprise. As the Nature article enumerates, since the actual process of science is much more messier than is depicted, maybe the evaluation of the process should also be more messier. I agree. Let evaluation also be an anarchic enterprise.

The more the messier. The messier the merrier.

Once-a-day cocktail for HIV

One of the biggest problems with AIDS treatment always has been patient compliance. Viral levels can be reduced in a patient and maintained at that level only if you hit the virus early, hard, and repeatedly so. But because of the number of times that one has to take the drugs, many patients fail to keep up with this strict routine. There was a point when patients had to take drugs as many as 18 times a day, a grotesque regimen. If this fails to happen for even a couple of days, not only does the virus come back with a vengeance, but the diabolically chimeral creature develops resistance to that drug combination by clever mutations. After this, even the same previously highly effective treatment fails to have any efficacy.

The usual combination therapy of drugs consists of two drugs that inhibit the viral enzyme called reverse transcriptase which codes for viral DNA, and one which targets an enzyme called HIV-protease, which is reponsible for processing viral proteins into a form suitable for forming the viral coat. Both enzymes can rapidly develop resistance to these drugs through mutations, in an exquisite though unfortunate example of Darwinian evolution (People who think evolution is necessarily a slow process and therefore cannot be observed need only to look at HIV among other things)

In what I see as a major advance in HIV treatment, the FDA has finally approved a once-a-day capsule with a combination of three best selling drugs. The treatment still costs 1000$ a month, but this is assuredly affordable for well to do people in the developed world. The problem of making it available in India and Africa still persists, and I don't know if there's any easy way out, because given the income levels of many HIV patients especially in Africa (which are essentially none), there is no difference for them between paying 1000$ and paying a million dollars. Short of making the treatment free to at least some, I don't see any easy way out for pharmaceutical companies and governments.

In any case, this is an important new development, and I am proud that one of the three drugs (Emtricitabine®) is the one that was co-discovered by my advisor. Does this mean he will be away even longer than usual? Boo hoo.

Cyanide poisoning failed, student died

Rationale for smoking cigarettes while working in the lab- hydrogen cyanide can combine with tobacco to produce a foul smelling compound that can be an early warning for cyanide exposure.

Drawbacks- a dozen other things can combine with cigarettes and explode.

But who cares. We always plan for the worst and hope for the best, don't we? Must rush and remind my experimentalist friends of this fact. As for me, I can generate as much CN- as I want and be blissfully safe from it...

Update: My cigarette loving friend from Mexico has just admitted that he does not see much of an advantage in saving himself from cyanide poisoning, at the risk of dying from lung cancer or third degree burns. He would rather not smoke cigarettes near his apparatus. People are getting wiser. I am happy.

The reach of the penguins

This Ig Nobel Prize gem missed my attention before...

Polar Biology presents...*drum rolls*....the secrets of Penguinnnn Pooooooh!





God forbid them from becoming interested in elephants.
[Hat Tip: Everyday Scientist]

Fat fatter fattest

Reference: Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14

Note how Georgia and Washington are the only states to get catapulted from <10% to 20-24%. Another incentive for me to finish my PhD. and escape from the state with an abundance of the dark side of the meat as fast as I can.

The other day, someone asked me to truthfully say how frequently I eat fast food of the insidious type (namely burgers, fries, and their lofty fatkin).
The answer is, once every three or four months, and that too only to break the monotonous drudgery of Maggi Noodles and Curds-Rice with Bedekar Mango Pickle (those who are raising eyebrows...we can negotiate a non-disclosure deal later, but I am speaking the truth about the frequency). And from what I am reading in the engaging The Omnivore's Dilemma, I think that it's going to be a long long time, if at all, before I touch those Chicken Nuggets again.

The Ghosts of Molecules Past?

We are finally filing a patent for a compound on which we have been working since May 2005 or so...or rather, on which our collaborators at Imperial College in London have been working on. That is one of the downsides of computational chemistry (or upside actually). You design compounds on your computer that will target some protein implicated in a disease. That process takes perhaps a couple of weeks at the beginning. After which you fling your designer drug in the experimentalists' face. It's them who then have to keep the midnight oil burning for months; first to come up with a decent strategy to synthesize your molecule, and then give it to the biologists, who in turn take a few more months to test it in cell assays. By the time the compound shows activity, the next ice-age very well might have come and gone. Then you work on some more modifications during the interglacial, after which the experimentalists lock themselves up for one more extended round of geological time. Clinical trials and other events are way off into the next evolution of the Universe after the big crunch.
This is not intended as a put down to the experimentalists, but actually an appreciation of the lengths they have to go to in order to get some results. Also, the computational side of things is not always so easy or so quick, but on a relative basis, it can usually be less lengthier than the experimental side, and also less labour-intensive.

But that's why I decided to do computational chemistry; so that I would have to worry only about the thinking and leave the actual doing to everybody else who works at the bench. It would have been the perfect realisation of my indolence. Alas! I found out that even in computational chemistry, I am not spared the tribulations of learning programs, evaluating data, and actually typing on the keyboard, not to mention walking light years across campus to talk shop with the biologists. So much for the ennui for couch rumination.

I am tempted to say that we are filing a patent for a drug but how premature that statement would be is well summed up in this post by a Pfizer chemist:

"Another surprise is when people find out that I've been doing this since 1989 without getting any drug on the market. I think that some folks are just being polite when I tell that that this isn't unusual, thinking to themselves that I must be some kind of hack. But the general public has, as far as I've been able to see, a very exaggerated idea of how quick and easy it is to find a drug. When I say that if I found a wonderful new compound tomorrow that it might be on the market in about 2015, they think I'm delusional. I wish I were."

Another quote I found also applies to us lowly lab dwellers which the general populace could keep in mind:

"When I meet people with no particular scientific background and they find out what I do for a living, it seems that there are several things that they're usually surprised about. For one thing, many people seem to think that doctors discover new drugs. Some of them don't even think about the drug companies or their role - and if they do, they imagine a lot of doctors working there. Actually, as my readers in the industry can confirm, the only time that physicians really get involved is when the drug is headed into the clinic and dosing in humans. There's not an M.D. in sight while we're validating drug targets, screening compounds, and working to fix their selectivity and activity. (And there's that noisy subset that think that all drugs are discovered in NIH-funded academic labs, but we'll leave that one alone for now)."

In any case, the one thing that keeps cropping up an annoying number of times in such endeavors is luck. We were lucky that 4 out of 10 of our molecules showed activity; it could easily have been none. The whole process was exacerbated by the unfortunate death of one of our collaborators. It is revealing to what pernicious extent you must go to to get your hands on a new molecule that may or may not, probably may not, become a new drug.

The new compound is intended for women whose breast cancer is resistant to the standard treatment of Tamoxifen®, and it turns out there is a considerable number of these.
I hope this one does not end up as the ghost of a molecule past.

Obviously I cannot draw the structure of the molecule here, because then I would have to kill this blog to protect the secret.