Sunday, January 23, 2011

A government center for drug discovery?

The New York Times has an article about a new center for drug discovery that the government is going to set up in the face of the declining pace of new drug discovery in the pharmaceutical industry. We all know what's wrong with the industry, with the numero uno factor being the pursuit of short-term profit goals at the expense of basic science and long-term benefit. The question is, can the government make up for this shortfall?

Perhaps, if it's done right. But the vision for the new center does not inspire me with much confidence. The center seems to mainly be a result of NIH director Francis Collins's conviction that gene-based drug discovery is the wave of the future. Collins is disappointed with the fact that Big Pharma has been unsuccessful with "translational genomics" in spite of spending millions of man hours and dollars. He thinks that if done right, this kind of translational approach will result in new drugs. As he makes it clear in his book "The Language of Life", Collins is a longstanding proponent of genomics-based medicine.

But isn't this what everyone has been saying ever since genome sequencing became possible? We all remember the hype about genomics enabling a new generation of 'rational' drugs based on intimate knowledge of genes and their protein products. The fact that this vision has not panned out could partly be ascribed to the lackluster efforts and the constant waves of lay-offs in industry, but maybe there's also a deeper reason why the optimism has hit a wall. Maybe, and experts have been saying this
for a while now, it's simply because taking a genomics-based approach to drug discovery ignores all the other complexities of biological systems like signal-transduction and epigenetics. Discovering the gene and protein is one thing, understanding the intricate interactions of the protein as part of a multi-layered cellular communication network is quite another. We are still struggling to understand the very basics of how proteins and genes link up in cells to enable complex physiological and behavioral responses, let alone rationally design drugs to block specific parts of those responses. In the absence of such understanding, simply pinning your hopes on the promise of 'translational genomics' seems to me to be another big sink for money and personnel.

So what else can a government center for drug discovery do which could be more concrete and fruitful? Ironically, the article contains part of the answer when it highlights the complexity of biological systems stated above.

Consider this remarkable fact; in the last century, only two breakthrough treatments for mental illness have been developed, lithium for bipolar illness and chlorpromazine (Thorazine) for schizophrenia. Many other successful antipsychotic drugs were spinoffs of thorazine. Also consider that even today we have little clue about how these drugs work, let alone how to rationally design them. Thorazine likely affects multiple neurotransmitter pathways involving serotonin, norepinephrine, dopamine etc. While we have made great advances in the last fifty years, brain chemistry remains as complex as ever. At a molecular level, the main problem is in understanding the basic mechanisms and specificity through which a molecule as simple as dopamine binds to only certain subtypes of a neurotransmitter receptor, stimulates multiple second-messenger pathways to different extents and elicits a complex behavioral response. In this case we know most of the genes and we know most of the protein products, yet we are light years away from understanding how Thorazine works. Lithium is an even more mysterious substance whose workings are almost akin to black magic. Instead of chasing the genes, thoroughly understand the action of a few of these drugs on a biochemical level and we can make significant inroads into understanding brain chemistry.

So if there's one thing a new government center for drug discovery can do, it should be to focus on these specific problems in the most general way rather than pool together resources for "translational genomics". Doing translational genomics will simply mean advancing work which industry is already involved in; it will largely be more of the same and there's good reasons why it may not work.

Here's what I think instead. If the center truly wants to do something productive that pharmaceutical companies cannot, let it put together a mini Manhattan Project type team focused on understanding a few specific problems, like how lithium works in the brain. The problems should be picked based both on their medical importance and their potential impact in enabling general understanding of the field. Just like the Manhattan Project did, get together the best people in the country from several disciplines who are experts at multidisciplinary thinking and problem solving. If you want to attack the lithium problem for instance, get together chemists, biologists, neuroscientists, pharmacologists, doctors and perhaps even a few physicists, mathematicians and computer scientists. Put them in a couple of large rooms (and maybe even seclude them in the majestic mountains of New Mexico) and give them enough funds. And then most importantly, give them almost complete freedom to brainstorm about specific problems. Let them consider every possible approach, from running basic biophysical experiments to the most advanced neural imaging techniques. Don't limit yourself to any one philosophy like translational genomics or any other currently fashionable mantra. Genomics can certainly be part of the mix but it should not be put on a pedestal. Combine the oldest tools of classical pharmacology with the newest tools of molecular biology. If the industry has been missing one thing, it's been the presence of bright young people who are given complete freedom to focus on their diverse ideas without strings attached and constant fear of unemployment. The government can give these men and women what industry has taken away from them in recent years.

The government has always been good at this kind of free-for-all interaction among talented scientists who are unencumbered by research funds and job insecurity. A new government center for drug discovery could be a great idea, but only if it provides the kind of freedom to operate that brings out the best in creative minds. Focusing on translational genomics to me seems to be another way to repeat what has been done and to waste more funds, time and personnel. Instead, do what the government does best; let them think, and let their minds soar.

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Monday, January 17, 2011

How can we make the International Year of Chemistry successful?

2011 has been designated by the UN as the"International Year of Chemistry". For the community of chemists the question is simple: What can we do to make this year successful and enhance the public's appreciation of chemistry? Here are three core aspects of chemistry which I think should be constantly highlighted:

1. Explain to the public the essential nature and unique philosophy of chemistry: As a field, chemistry is inherently more challenging to pitch to the public compared to physics or biology. If you are a physicist and you say to a layman that you are investigating the Big Bang, you don't have to say anything more to get his or her attention. A biologist who works on human evolution will get similar nods. But what about chemists? One of the reasons for the relatively dim public appreciation of chemical science was mentioned before; it is because the field apparently lacks "big ideas" that people can instantly latch on to (but see below). But what chemistry may lack in terms of the grand picture, it more than compensates for in terms of its identity as a "central science" and the sheer number of explanations and applications that it lends to almost every other discipline, from physics and biology to art and engineering. No other field does this in such a palpable way. In this sense chemistry is akin to engineering, but much more fundamental.

The chemist more than any other kind of scientist is a discerning arbiter of patterns and a patterner of chaos. One of the manifestations of this quality is in the beautiful structures that chemists draw and encounter every single day. Chemists look at structures the way artists look at mosaics of colors and architects look at geometric patterns. What other kind of scientist spends his or her professional workday doodling and evaluating lines, rings and their myriad intersections? In its ability for visualization and pattern analysis, chemistry comes closer to art than any other science, and the public needs to appreciate this supremely important aspect of the discipline.

But it is in its ability to make new things which never existed before that chemistry is wholly unique. In the last few years synthesis and especially total synthesis have taken some flak as somewhat self-serving activities geared toward factory-style publication and the nurturing of slave labor, but it cannot be denied that synthesis is what makes chemistry different from all other disciplines. No other science can boast the creation of new substances that have improved every facet of human life, from the conquest of disease to the feeding of the poor. Of course chemistry also led to poison gas and nerve gas but this was true of other discipline too. The fact remains that chemistry has modeled and sculpted the material world familiar to the layman more than any other science. Other fields provided valuable input to the principles behind synthesis, but the end products were those of chemistry alone, shining examples of the very ability of human beings to create, manipulate and improve. In the future chemistry promises us improved materials for alternative energy and designer drugs and biomolecules for treating disease. Convince the layman of the enduring centrality of synthesis, and you would have convinced him or her of the essential value of chemistry.

2. Push the origin of life as chemistry's "big idea": We mentioned above that chemistry seems to suffer from a lack of big ideas as compared to physics and biology and that this is partly responsible for its lackluster public perception. But as I indicated in my last post, there is actually a problem as big as any other which is primarily within the domain of chemistry. This is the origin of life within its broader framework of self-assembly. God must have been a molecular self-assembler, because without self-assembly the first components of life could not bond to each other and the first cells could not form and segregate their cargo, sparking the interactions and reactions that led to replication and metabolism. Darwin solved the second problem of what happens when life gets started, but not the first one of how it all began. Again, other sciences will continue to contribute to the unraveling of this problem, but the first step was uniquely chemical. A narrating of the origin of life as a quintessentially chemical question would also lead to a general exposition on self-assembly (important in diseases caused by protein misfolding) as well as a spirited homily on the central importance of weak interactions and hydrogen bonding.

3. Emphasize the crucial connections of chemistry with medicine and materials science again, and again and again...: It's official. The biggest practical contributions of chemistry to the betterment of human life have undoubtedly been in the discovery of new drugs and new materials. It is remarkable that every one of us benefits from these tangibles at every moment of day and night and yet fails to recognize the essential role that chemistry played in their creation. Since almost all of us know someone who has been afflicted or taken by a terrible malady, one would think that the public would be singing chemistry's praises for saving lives. Yet most people seem to think that it's doctors who discover new medicines. Quiz people about great medical advances and they would enthusiastically tell you about Alexander Fleming and Jonas Salk, but not about Gerhard Domagk or Gertrude Elion. This perception has got to change. Chemists are as responsible as doctors, if not more, for most of the live-saving drugs developed in the past century and will be responsible for many more in the coming one. The era of rational drug discovery was essentially ushered in by chemistry, and it will likely bring us novel advances in the form of designer proteins and small molecules as selective drugs against new threats. The public needs to know this crucial function of chemistry, and it can only be accomplished by drilling the facts into the public's mind eloquently and ad nauseam.

The other field where chemistry promises world-changing discoveries is in materials science and nanotechnology, especially as applied to energy. With climate change looming on the horizon, the next generation of breakthrough solar cells or other technologies may change the lives of millions, dramatically reduce our carbon footprint and impact the international geopolitical landscape. A central player in this seismic shift will undoubtedly be chemistry. The public now thinks very highly of nanotechnology but very few people realize that chemists have been practicing nanotechnology since their discipline gradually emerged from the shadows of alchemy. Polymers have revolutionized our lives as much as anything else. In the future polymers will contribute in novel ways such as drug delivery vehicles and smart materials in electronics engineering and space science. Organic electronics is another lucrative area of polymer science which will pay huge dividends in improving communications technology, leading to improvements in everything from healthcare to education. As the world inches closer to potentially devastating climate change and its global and social repercussions, chemistry will undoubtedly play its important role in saving the planet.

By bridging all other disciplines, enabling human progress and knitting the tapestry of the material universe, chemistry encircles the world. This is our chance to let everyone know.

Image source

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Tuesday, January 11, 2011

An intimate portrait of India's people and their relationships

"India Calling: An Intimate Portrait of a Nation's Remaking", Anand Giridharadas takes a different tack from Thomas Friedman and others who have described the now familiar call centers and globalization that have turned India into an economic powerhouse. Instead Giridharadas decides to focus on the country's most important assets- its people and their changing attitudes towards the world, their families and themselves. Giridharadas has an unusual vantage point as an Indian who grew up in the US and who returned back to his country for a fresh look (although one wonders why he now lives in Cambridge, MA). The book is primarily about how India's new economic, political and social roles have changed Indians' relationships with themselves and their families. The most important consequence of the "New Order" is that Indians whose role in life was traditionally defined for centuries by their birth and their caste, class and gender are now seeking to make their own place in society rather than to "know" it. This is a great thing for a country where identity was defined for hundreds of years by where you came from rather than where you wished to go. As Giridharadas describes, in the new India someone from the lower caste can finally dare to dream beyond what was regarded as his indelible destiny.

To showcase these changing Indian identities, Giridharadas presents us with several "case studies" and describes the life stories of people drawn from a wide slice of Indian society. There's the poor boy in a small village who was born into a lower caste and decides to remake his identity by pioneering English language and "personality development" classes in his village and organizing a personality pageant. There'
s the "rat-catcher" whose job is to kill dozens of rats everyday in the slums of Mumbai. Then there's the Maoist, a member of the divisive Communist insurgency in India, who resents India's rise to wealth and fame but who has a complex relationship with the country he criticizes. The Maoist interestingly sees parallels between the old caste system and the new globalized order, with labor specialization replacing the role of labor-based caste. And in stark contrast, there's the Ambani family, India's richest business family whose clout extends over the entire Indian economic and political landscape. Giridharadas especially has an insightful portrait of Mukesh Ambani, one of the two Ambani brothers and one of the world's richest men whose empire stretches from petrochemicals to biotechnology. Giridharadas stresses how the Ambanis rose to prominence by cultivating relationships, a strategy that has helped them bribe slothful bureaucrats and journalists in creative ways that include paying for their children's education in Ivy League universities in the US. In an India where bribery is hardly an exception to the rule, the Ambanis' behavior is nothing novel. But one of the signs of a changing India is that while old-timers look with disgust upon the culture of bribery and corruption that the Ambanis have perpetuated, many young people see them as heroes who are cutting India's Gordian knot to an entrenched bureaucracy and socialist ethic and who are inspiring young Indians to dream big.

Further on, it is in describing the changing nature of the Indian family and relationships within it that Giridharadas really excels. Perhaps the two biggest changes in the Indian family during the last few decades have been the declining influence of parents on their children's lives and the empowerment of Indian women in middle-class families. This has led to new challenges and opportunities in the traditional Indian conception of marriage. Women are now regarded as men's equals in marriages and men are no longer supposed to be the sole bread-winners on whom their spouses precariously depend. Changing social mores have also awarded women an independence that was inconceivable for the older generation. Young men and women are now much more comfortable with casual sex and relationships. Indian women are now free to choose who they may or may not marry, or so it may seem. Yet as Giridharadas adeptly demonstrates, reality is more complex. Indian women and even men are still grappling with reconciling the modern with the orthodox. This has led to many of them living strange double lives where they have a wild time outside their homes but can instantly transform themselves into meek and dutiful sons and daughters in the presence of their parents. Ties to parents and family traditions are still too strong for many of India's young people to assert total independence. Thus an Indian woman who otherwise has a boyfriend and dictates the terms of her own life may still end up marrying a boy picked by her parents and sacrificing her freedom. The line between old and new is still not blurry enough for the young to casually transgress it, and it would be interesting to see how the changing dynamic between young people and traditions is played out in 21st century India.

Along with newfound independence come newfound problems. As young people are increasingly defying their parents and marrying for love, they are also increasingly become more intolerant of compromises and sacrifices. This has led to a spiraling divorce rate among young Indian families even as the taboos surrounding the word divorce have been as hard to abolish as that surrounding premarital sex. Giridharadas has a perceptive account of sitting in in an Indian court and watching divorce proceedings. Interestingly, contrary to popular belief, Indian divorces are no longer limited to the wealthy class and Giridharadas watches as a wide economic cross section of husbands and wives airs its woes in court. The reasons why these people are seeking divorce are varied and range from the unsurprising (marital infidelity, plain boredom) to the revealing (the husband becomes jealous when his wife starts making more money and living a more affluent lifestyle). Divorce in India promises to challenge traditional male-female hierarchies in marriage and social customs as acutely as any other modern liberating tendency.

As insightful as Giridharadas's book is, I have some minor complaints. Firstly, he says nothing about the negative repercussions of lowering standards in the educational system to accommodate the previously underprivileged. Liberation from the shackles of caste has been a wonderful thing for India, but on the flip side it has led politicians with vested interests to lower the standards of public education rather than to raise the standards of the lower castes through improvements in primary education. This is engendering divisive sentiments which the author does not discuss. Secondly, while Giridharadas eloquently describes changing perceptions of caste and class, he says almost nothing about how the changing dynamic has impacted religion and religious relationships which have always been a key part of the Indian identity. Thirdly, while he makes sincere attempts to be objective, Giridharadas cannot completely escape the biases of an Indian who did not grow up in India and who is coming back after a long time to inspect his former country much as an anthropologist would inspect a tribe. On one hand this has led him to offer us some fresh, out of the box perspectives, but on the other hand it has led him to quickly generalize from his own limited experiences. Indian is a complex and vast country, and even an observation that might apply to seventy percent of its citizens would still exclude a very significant portion of the population. Thus Giridharadas's observations should always be accepted as containing a significant element of truth but not the whole truth. Lastly, I found Giridharadas to be slightly verbose and rambling. Sometimes he seems to be too much in love with his words and phrases and belabors a point in too many different ways. This would have been fine for a work of fiction but it can tend to bore the reader and obscure clarity in a work of non-fiction.

Notwithstanding these minor gripes, I would strongly recommend the book. In a stream of books that have told us about India's economic and political rise, Giridharadas makes a valuable and rare contribution by focusing on the most important aspect of any country- its people and their changing relationships with themselves, their nation and the world.