Field of Science

Why drug discovery is hard, part 2: On the unpredictable and complicated origins of drug species

The Brazilian pit viper, a fascinating and unlikely source
of drugs leading to Captopril, one of the world's bestselling
blood pressure-lowering drugs (Source: venomstodrugs)
Drugs from the forest. Drugs from the sea. Drugs from every conceivable natural source ranging from fungi to frogs; that's much of the history of drug discovery. In the first part of this series we looked at the initial steps in drug discovery, from identifying key target proteins involved in a disease to trying to make sure that these proteins can be "drugged" with a small molecule. But let's say you have now identified a few promising proteins malfunctioning in Alzheimer's disease. How do you even begin to try to discover drugs that modulate this protein? Or more generally, where do new drugs come from?

In fact the ancients knew quite well where drugs came from. At a time when even the rudiments of science were barely known, our South American ancestors were cheerfully chewing on coca leaves to provide stimulation and energy and the Greek physician Hippocrates was prescribing a bitter powder made from willow bark that could ease fevers and aches. Similar narratives permeate the traditions of cultures around the world, with Chinese and Indian traditions playing an especially prominent role in the history of medicine. The Bolivians had no idea that coca leaves contained cocaine and Hippocrates had no idea that willow bark contains salicylic acid (from which aspirin is made), but they all knew that there was something in plant and animal extracts that could mitigate a variety of ills.

Fast forward two thousand years and the picture has not changed. Nature continues to be an enormously valuable source of new drugs, or at least of compounds that can be turned into new drugs. In fact about 50% of all medicines on the market are derived from what are called natural products. The term "natural product" means something quite different to a chemist than what it might to a layman. For laymen the phrase might conjure up images of bottles of herbal medicines lined up on the shelves of the nearest health food store, but for chemists it refers to molecules produced by living organisms for a variety of functions, from feeding to mating to defense against predators. These molecules are also called secondary metabolites to distinguish them from "primary" metabolites, namely nucleic acids, lipids, amino acids and sugars which are essential for life's functioning.

Quite fascinatingly, it turns out that these natural products can be astonishingly potent in serving a variety of functions sought by drug discoverers, most commonly killing other cells. This is perhaps not surprising, considering that defense against predators was a key housekeeping chore for most organisms throughout evolution. Fortunately for us, it also turns out that some of the most potent leads for new drugs are therefore found in the lowliest of organisms - bacteria, fungi and protists - since these organisms in particular are constantly engaged in chemical warfare with multiple other pathogens from their environment (including human beings). It's again no surprise to find that most successful antibiotics such as penicillin and streptomycin have come from bacteria and molds.

And thus it comes to pass that some of the most important drugs on the market have been derived from the humblest of creatures to whom we owe millions of lives. Three examples will suffice. Captopril is a bestselling blood pressure medicine that was originally derived from the venom of the Brazilian pit viper. Taxol, one of the world's bestselling anticancer drugs, comes from the bark of the Pacific yew tree. And rapamycin, a significant immunosuppresant that allows millions to survive organ transplants without violently rejecting them, came from a soil bacterium on the distant Easter Island of Rapa Nui. The potential for discovering new drugs from natural organisms is as good a siren song for preserving our biodiversity as any other; for instance marine sponges are an unusually fertile source of promising new drugs and their homes in coral reefs therefore need to be preserved.

Nature has thus forged an intimate link with human life and death through its production of novel drugs. And the fact that a fungus which evolved billions of years ago and had absolutely no contact with the human race produces a molecule that saves a young girl's life is as poignant and fascinating a fact in all of science as I have encountered.

However it's easy to point out these molecules and even easier to overlook how hard it is to discover them. In the post-war boom in pharmaceutical research, pharmaceutical, academic and government labs sent out legions of scientists to scoop up samples of soil and bring them back to their labs. Sometimes a glass vial would be thrust into the hands of a scientist who was leaving for a relaxing vacation in an exotic locale, just in case. The collected samples were then screened against different kinds of cells. Any kind of effect on the cells was carefully noted, and compounds which seemed to inhibit cell growth were selected (it's interesting to note that one can also discover drugs this way, simply by throwing molecules at cells without any knowledge of the protein target. More on this later). But the success rate from such screening was quite low, and only a fraction of extracts or molecules screened show promising activity. In fact one of the reasons we are facing such a big threat of antibiotic-resistant bacteria is because it's been extremely hard to find novel antibiotics using traditional methods that worked so well before. For every taxol or rapamycin or erythromycin, there were hundreds of thousands of extracts that did not deliver anything. Hundreds of millions of dollars were sunk into the collection, purification and testing of these natural sources. Most were either too weak or too powerful, completely killing any cells they encountered.

But nature, as inventive as its evolutionary processes are, cannot supply us with all the drugs we need. This is where the ingenuity of chemists comes in. The major triumph of chemistry, one which makes it unique among all sciences, is its ability to discover, design and synthesize molecules that don't exist in nature. Chemists can either tinker with existing molecules or create new ones from scratch by arranging atoms in specific configurations, a feature that makes chemistry an art akin to architecture. The employment of chemistry in the service of medicine has been one of the most successful scientific stories in history. Not only has it allowed us to discover molecules that never existed before, but it has also helped us preserve biodiversity; for instance, once chemists figured out how to cheaply make the anticancer drug taxol from abundant starting materials, they did not have to depend on the loss of thousands of Yew trees for delivering the drug. 

Over the years chemists have finely honed their capacity to rapidly make millions of compounds efficiently and in pure forms. They can test these millions of compounds and see whether any of them bind against protein targets, a feat helped to no small extent by automation and robotics. This process is called high-throughput screening (HTS), which as the name indicates can test millions of compounds against proteins or cells in short order. When it became fashionable in the 80s and 90s, HTS was regarded as something revolutionary; after all if you ended up testing tens of millions of molecules against any disease or protein, surely you would find at least dozens of promising leads. Sadly that dream has not come true, and while HTS is valuable it has turned up very few leads which were then optimized into drugs. As with natural screening, HTS success rates can also be quite low (about 0.5%).

Why is this the case? Well, one simple reason why HTS has not worked out is because the theoretical number of druglike molecules you can make is literally more than the number of atoms in the universe; even when you have a library of consisting of millions of compounds, you are barely scraping the surface of this unimaginably vast number. Another reason is a fact mentioned in the previous post, namely that nature had very little evolutionary incentives to create proteins that would bind to synthetic drug molecules that would appear on the scene billions of years later. Yet another reason is that you may be testing the wrong molecules and trying to put a square peg in a round hole; in that case quantity will never trump quality. Also based on the previous post, it's obvious that not all proteins are created equal and therefore it can be much harder to find hits for certain proteins compared to others. What is worse is that it's often very difficult to gauge this success rate beforehand. Thus as often turns out to be the case in science, nature is a very harsh taskmaster, yielding her secrets with great reluctance. If you want to find a small molecule that binds to an important protein, you are going to have to work for it.

A third strategy for finding drugs comes from studying the physiological life of whatever protein you are interested in. Most proteins already bind to a small molecule in the body which modulates their activity, for instance a hormone, neurotransmitter, peptide or some other signaling molecule. For example proteins in the brain work their magic by binding to small molecules like dopamine and serotonin. These molecules are very potent, but they lack the properties that would allow one to transform them into a neat white pill that can be taken once a day. But they at least provide a springboard; why start from scratch when nature has already given you clues? Thus, any of these small molecules can be a starting point for modification, a scaffold whose structure can be tweaked by imaginative chemists. Sadly this strategy also often fails, for the simple reason that changing the structure of a molecule even a tiny bit can completely change its properties. In mathematical terms, the optimization landscape of the structure-activity relationships (SAR) of the drug is rough. This is a general property of molecules that plagues every chemist and drug discoverers especially have a hard time circumventing it. It's one of the key reasons why drug discovery is unpredictable.

A great example of how difficult the process is concerns molecules called enkephalins. Enkephalins are naturally occurring peptide molecules which produce the same potent painkilling effects as morphine, and yet in spite of dozens of years of trying, nobody has been able to turn them into drugs. In addition not everything that comes from nature or HTS or physiological molecules is a perfectly formed drug that falls into your lap from heaven, and that leads us into a discussion of another important reason why drug discovery is hard. Almost every single time, irrespective of the starting source, a promising newly discovered molecule is what's called a hit. A hit is to a drug what a freshly minted West Point graduate is to a four-star general. It is weak and unpolished in its interactions with biological system and it can often be too toxic. It may be poorly absorbed or it may hang around in the body for much too long. It may be impossible to press it into a pill and it may be impossible to simply get it into cells in the first place. Namely, it may have a lot of potential but very few real credentials. With some effort a hit may be turned into a lead which is a better version of a hit but still inadequate. Turning a hit or lead into a drug occupies the mind of the best scientists in academia and industry and even after decades of efforts there is no general formula which will achieve this. But not for lack of trying.

In 1997 a scientist named Chris Lipinski came up with a set of four rules that would apparently allow us to predict whether any given molecule would be a drug or not. Each rule deals with a fundamental property of molecules and brackets them within numerical limits; for instance the number of atoms that form hydrogen bonds (which tether a drug to its protein target), the hydrophobicity or "greasiness" of the molecule (which allows it to get through lipid cells walls), and the molecular weight, which is a rough measure of size. After analyzing hundreds of drugs, Lipinski came up with ranges for these properties that he thought are featured in the world's bestselling medicines. Since then, "Lipinski's rules" have been used by many leading pharmaceutical companies to constrain the kind of features that their screening collections should have, presumably to bias the chances of success. And yet there is still no proof that adopting these rules has actually led to a higher drug discovery rate. The other strike against Lipinski's rules is that almost none of the natural products described above obey these rules. And yet these natural products like rapamycin are potent and widely prescribed drugs. The bottom line is that in spite of some guidelines, we still don't know what truly makes a molecule druglike and therefore we don't know how to fine-tune the properties of a hit and turn it into a drug. There are too many exceptions that fall through the sieve constructed by any general rules, and learning about these exceptions is a big goal of drug discovery scientists.

This concludes the second part of the series. Drug discovery is hard because it is very rare to discover a molecule - either natural or artificial - that is a hit against a protein target implicated in a disease. Hit rates from screening even millions of molecules can be very low. And even if you discover such a hit it can be very difficult to turn it into a drug, partly because our definitions of what a drug truly is are still hazy. In the next part we will consider something very simple that a drug has to do, namely get into a cell, and we will find that predicting even such a simple process is fraught with complications.

Summary: Why is drug discovery hard?

Reason 1: Drugs work by modulating the function of proteins. It’s difficult to find out exactly which proteins are involved in a disease. Even if these proteins are found, it is difficult then to know if their activity can be controlled by a small molecule drug.

Reason 2: Since nature has not really optimized its proteins for binding to drugs, it is very difficult to find a hit for a protein even after searching through millions of molecules, either natural or artificial. And even when a hit is discovered, we don't know for sure how to turn it into a drug with favorable properties.

Let's embrace this new era of private science funding

This week, Mark Zuckerberg and his wife Priscilla Chan announced an initiative to give $3 billion dollars to UCSF for funding biomedical research. The tagline accompanying the funding in which they promised to “cure, prevent or manage all diseases in our children’s lifetime” drew scorn from scientists, but the bigger message of their philanthropy should not be lost on us. In an era where public funding of science has been steadily flagging and more and more researchers are finding it depressingly hard not just to fund their own research but even to contemplate pursuing basic research in the first place, initiatives like the Chan-Zuckerberg gift to UCSF are not just helpful but essential. Even if the research arising from the funds does not cure a single disease, by recruiting influential researchers and giving them money to explore their favorite areas in basic science, there is little doubt that the funding will have an impact on biomedical research. The most important discoveries arising from this initiative will be ones that cannot be anticipated, and that's what makes it especially important.

Private funding of science ideally should not raise any eyebrows; it only does so because most of us are young enough to have lived in an era of mainly publicly funded research. In fact private funding of science has a glorious history. Just to quote some specific examples, William Keck was an oil magnate who made very significant contributions to astronomy by funding the Keck Telescopes. Gordon Moore was a computer magnate who made significant contributions to information technology and proposed Moore's Law; along with the Keck foundation, his organization has been funding the BICEP experiments. Fred Kavli who a few years ago started the Kavli Foundation; this foundation has backed everything from the Brain Initiative to astrophysics to nanoscience professorships at research universities.

A few years ago, science writer William Broad wrote an article in the New York Times describing the private funding of research. Broad talked about how a variety of billionaire entrepreneurs ranging from the Moores (Intel) to Larry Ellison and his wife (Oracle) to Paul Allen (Microsoft) have spent hundreds of millions of dollars in the last two decades to fund a variety of scientific endeavors ranging from groundbreaking astrophysics to nanoscience. For these billionaires a few millions of dollars is not too much, but for a single scientific project hinging on the vicissitudes of government funding it can be a true lifeline. The article talked about how science will come to rely on such private funding in the near future in the absence of government support, and personally I think this funding is going to do a very good job in stepping in where the government has failed.

The public does not often realize that for most of its history, science was in fact privately funded. During the early scientific revolution in Europe, important research often came from what we can call self-philanthropy, exemplified by rich men like Henry Cavendish and Antoine Lavoisier who essentially did science as a hobby and made discoveries that are now part of textbook science. Cavendish's fortune funded the famed Cavendish Laboratory in Cambridge where Ernest Rutherford discovered the atomic nucleus and Watson and Crick discovered the structure of DNA. This trend continued for much of the nineteenth and early twentieth centuries. The current era of reliance on government grants by the NIH, the NSF and other agencies is essentially a post-World War 2 phenomenon.

Before the war a lot of very important science as well as science education was funded by trust funds set up by rich businessmen. During the 1920s, when the center of physics research was in Europe, the Rockefeller and Guggenheim foundation gave postdoctoral fellowships to brilliant young scientists like Linus Pauling, Robert Oppenheimer and Isidor Rabi to travel to Europe and study with masters like Bohr, Born and Sommerfeld. It was these fellowships that crucially allowed young American physicists to quarry their knowledge of the new quantum mechanics to America. It was partly this largesse that allowed Oppenheimer to create a school of physics that equaled the great European centers.

Perhaps nobody exemplified the bond between philanthropy and research better than Ernest Lawrence who was as much an astute businessman as an accomplished experimental physicist. Lawrence came up with his breakthrough idea for a cyclotron in the early 30s but it was the support of rich California businessmen - several of whom he regularly took on tours of his Radiation Lab at Berkeley - that allowed him to secure support for cyclotrons of increasing size and power. It was Lawrence's cyclotrons that allowed physicists to probe the inner structure of the nucleus, construct theories explaining this structure and produce uranium for the atomic bombs used during the war. There were other notable examples of philanthropic science funding during the 30s, with the most prominent case being the Institute for Advanced Study at Princeton which was bankrolled by the Bamberger brother-sister duo.

As the New York Times article notes, during the last three decades private funding has expanded to include cutting-edge biological and earth sciences research. The Allen Institute for Brain Science in Seattle, for example, is making a lot of headway in understanding neuronal connectivity and how it gives rise to thoughts and feelings; just two months ago they released a treasure trove of data about visual processing in the mouse cortex, an announcement that gave some academic scientists heartache. The research funded by twenty-first century billionaires ranges across the spectrum and comes from a mixture of curiosity about the world and personal interest. The personal interest is especially reflected in funding for rare and neurodegenerative diseases; even the richest people in the world know that they are not immune from cancer and Alzheimer's disease so it's in their own best interests to fund research in such areas. For instance Larry Page of Google has a speaking problem while Sergey Brin carries a gene that predisposes him to Parkinson's; no wonder Page is interested in a new institute for aging research.

However the benefits that accrue from such research will aid everyone, not just the very rich. For instance the Cystic Fibrosis Foundation which was funded by well to do individuals whose children were stricken by the devastating disease gave about $70 million to Vertex Pharmaceuticals. The infusion partly allowed Vertex to create Kalydeco, the first truly breakthrough drug for treating a disease where there were essentially no options before. The drug is not cheap but there is no doubt that it has completely changed people's lives.

But the billionaires are not just funding disease. As Broad puts it in his article, they are funding almost every imaginable field, from astronomy to paleontology:

"They have mounted a private war on disease, with new protocols that break down walls between academia and industry to turn basic discoveries into effective treatments. They have rekindled traditions of scientific exploration by financing hunts for dinosaur bones and giant sea creatures. They are even beginning to challenge Washington in the costly game of big science, with innovative ships, undersea craft and giant telescopes — as well as the first private mission to deep space."

That part about challenging government funding really puts this development in perspective. It's hardly news that government support for basic science has steadily declined during the last decade, and a sclerotic Congress that seems perpetually unable to agree on anything means that the problem will endure for a long time. As Francis Collins notes in the article, 2013 saw an all time funding low in NIH grants, and it’s not gotten much better since then. In the face of such increasing withdrawal by the government from basic scientific research, it can only be good news that someone else is stepping up to the plate. Angels step in sometimes where fools fear to tread. And in an age when it is increasingly hard for this country to be proud of its public funding it can at least be proud of its private funding; no other country can claim to showcase this magnitude of science philanthropy.

There has been some negative reaction to news like this. The responses come mostly from those who think science is being "privatized" and that these large infusions of cash will fund only trendy research. Some negative reactions have also come from those who find it hard to keep their disapproval of what they see as certain billionaires' insidious political machinations - those of the Koch brothers for instance - separate from their support of science. There is also a legitimate concern that at least some of this funding will go to diseases affecting rich, white people rather than minorities.

I have three responses to this criticism. Firstly, funding trendy research is still better than funding no research at all. In addition many of the diseases that are being explored by this funding affect all of us and not just rich people; for instance, the Chan-Zuckerberg funding is geared toward infectious diseases. Secondly, we need to keep raw cash for political manipulation separate from raw cash for genuinely important research. Thirdly, believing that these billionaires somehow "control" the science they fund strikes me as a little paranoid. For instance, a stone's throw from where I live sits the Broad Institute, a $700 million dollar endeavor funded by Eli Broad. The Broad Institute is affiliated with both Harvard and MIT. During the last decade it has made important contributions to basic research including genomics and chemical biology. Its scientists have published in basic research journals and have shared their data. The place has largely functioned like an academic institution, with no billionaire around to micromanage the scientists' everyday work. The same goes for other institutes like the Allen Institute. Unlike some critics, I don't see the levers of these institutes being routinely pulled by their benefactors at all. The Bambergers never told Einstein what to do.

Ultimately I am a both a human being and a scientist, so I don't care as much about where the source of science funding comes from as whether it benefits our understanding of life and the universe and leads to advances improving the quality of life of our fellow human beings. From everything that I have read, private funding for science during the last two decades has eminently achieved both these goals. I hope it endures.

Note: Derek has some optimistic thoughts on the topic.

This is a revised and updated version of an older post.

Why drugs are expensive: Follow the science (and not just the money)

The RAS protein: A famously 'undruggable' drug target
Two years ago I started writing a series of posts on the scientific challenges inherent in drug discovery on another blog. Recently a handful of miscreants have again put a glaring spotlight on pharmaceutical research, for reasons that have nothing to do with pharmaceutical research per se. So I decided to resurrect, revise and add to that old series of posts.

Often you will hear people talking about why drugs are expensive: it's the greedy pharmaceutical companies, the patent system, the government, capitalism itself. All these factors can contribute to increasing the price of a drug, but one very important factor often gets entirely overlooked in all the public discussion: Drugs are expensive because the science of drug discovery is hard.

And it's just getting harder. In fact purely on a scientific level, taking a drug all the way from initial discovery to market is considered harder than putting a man on the moon, and there's more than a shred of truth to this contention. It can easily take up to ten years and about $5 billion to discover a new breakthrough drug, or even to discover a drug that’s marginally better than an existing one. In this series of posts I will try to highlight some of the purely scientific challenges inherent in the discovery of new medicines. I am hoping that this will make laymen appreciate a little better why the cost of drugs doesn't have everything to do with profit and power and a lot to do with scientific ignorance and difficulty; as one leading scientist I know quips, "Drugs are not expensive because we are evil, they are expensive because we are stupid."

I could actually end this post right here by stating one simple, predominant reason why the science of drug discovery is so tortuous: it's because biology is complex and ill understood. Biological systems are highly non-linear and emergent; large changes can result from small perturbations to them. The second reason is because we are dealing with a classic multiple variable optimization problem, except that the variables to be optimized again pertain to a very poorly understood, complex and unpredictable system.

The longer answer will be more interesting. The simple fact is that we still haven't figured out the workings of biological systems - the human body in this case - to an extent that allows us to rationally and predictably modify, mitigate or cure their ills using small organic molecules. That we have been able to do so to an unusually successful degree is a tribute to both human ingenuity and plain good luck. But there's still a very long way to go; there are very few diseases for which we truly have drugs that are almost always efficacious and have little to no side effects. Most important diseases like cancer and Alzheimer's disease are still problems looking for solutions, and even after a century of extraordinary progress in biology, chemistry and medicine the solutions seem a long way off.

That then, is the simple reason why discovering drugs is hard; because we are dealing with a biological system that still escapes our rational understanding and because we are trying to engineer a molecule that perturbs this incompletely understood system, and that too while being forced to satisfy multiple constraints. It's like being asked to throw a ball at a black cat in the dark; with the added constraint that one of your feet is bound to the top of your head. And you only get three tries.

The rest of this series will be devoted to a discussion of specific factors that contribute to this lack of understanding. The goal is not to list all possible complications in the discovery of new drugs but to give a flavor of the major challenges that drug scientists face at a very fundamental level, several of which have been known for decades and are still not circumvented. It is to drive home the fact that even on a basic level we are still groping in the dark. This forces us to often simply try out things, to navigate our way through the process by clumsy Edisonian trial and error, to try a hundred approaches before finding one that succeeds. If there can be one word that could be applied to the whole drug discovery and development process it is "attrition"; roughly 95% of candidates entering clinical trials fail, most commonly because of lack of efficacy, followed by unacceptable side-effects. Plain ignorance and attrition play a huge role in discovering new drugs (or rather, in not discovering them). Most of the stuff that drug researchers try fails, and the stuff that works then has to take into account all the sunk costs inherent in these failures. No wonder drug discovery is expensive.

To appreciate the scientific challenges confronting drug designers it is important to understand at a basic level how drugs work. Almost all drugs are what are called "small molecules", that is, small organic compounds like aspirin with a few dozen atoms, bonds and rings like benzene rings. Recently there has been a resurgence of "large molecules" like antibodies but for now we will focus on small molecules. For the purposes of this discussion the mechanism behind small molecule drugs can be boiled down to one statement: Drugs work by binding to proteins and modifying their function. As we all know, proteins are the workhorses of living systems, performing every single important function from growth and repair to response and attack. No matter what physiological process you are talking about, from launching an immune response to thinking creative thoughts, there will be a handful of key proteins involved in mediating that response. Not surprisingly, a fine balance between the activities of the hundreds of thousands of proteins in the body is necessary for good health and, equally unsurprisingly, any breakdown in this balance causes disease. While in theory the entire network of proteins in the human body gets perturbed in some way or another in a disease state (a problem that is of great interest to the discipline of systems biology), fortunately for drug designers it's usually a handful of key proteins that are the major rogue players in any disease.

Depending on the disease the protein may be malfunctioning in different ways. In cancer for instance there's typically an overproduction of proteins involved in cell growth. There may also be an underproduction of proteins involved in slowing down cell growth. This most commonly happens through mutations to the structure of the proteins, an unfortunate side effect of the wonders of evolution, which is a natural part of cell division. The overproduction of specific proteins is in fact a common determinant in most major diseases. The solution then sounds simple: discover a small molecule which binds to and blocks such proteins, which in the parlance of drug discovery would be regarded as drug "targets".

But this is where our troubles begin. Firstly, it takes a lot of sleuthing and arduous biochemical and genetic experimentation to find out if a particular protein is in fact a major contributor to a disease. One of the major reasons why drugs fail in clinical trials is because the protein that is targeted by the drug doesn't turn out to be that important for the disease, especially in large populations. There are several ways to probe the relevance of a protein to a particular disease state. Sometimes accidental clues come from natural genetic ‘experiments’ in human populations in which the effects of incidental mutations in that protein can be observed; for instance one of the hottest recent targets in heart disease is a protein called PCSK9, and its significance was realized in part through the discovery of a young aerobics instructor in Texas with mutations in the protein and incredibly low cholesterol levels. Sometimes insights emerge from so-called ‘inborn errors of metabolism’ in which specific proteins are mutated or silenced, leading to serious diseases. But such cases are rare; more often than not scientists have to artificially silence the function of a protein using genetic engineering or other approaches to find out whether it truly contributes to a specific disease state or a lack thereof.

But even if the protein's role in causing disease is established, not every protein can then actually bind to a synthetic small molecule and be modulated by it, for the simple reason that evolution had absolutely no reason to cause it to do so. For instance the heart drug lipitor (atorvastatin) binds to and blocks the action of a protein called hydroxymethyl-glutaryl-coenzyme-A (HMG-CoA) reductase, a key protein involved in the initial steps of cholesterol synthesis. Cholesterol is one of the most important structural and signaling molecules occurring in living systems, and the assembly line of proteins and genes for making it was put in place by evolution billions of years ago. There was no plausible reason why natural selection should have engineered HMG-CoA reductase to bind a bestselling drug which appeared on the scene a billion years later. And yet here we are, beneficiaries of the ingenuity of both chemists and nature in possessing a drug that is considered to be the most important heart disease medicine in history. HMG-CoA reductase does bind lipitor, but many other proteins don't.

The binding of HMG-CoA reductase to lipitor is what makes it "druggable". However many other proteins are considered "undruggable" and decades of attempts to "drug" them with small molecules have failed; an excellent example is a protein called Ras which is mutated and overproduced in one out of five cancers. PCSK9 which was noted above has also proved to be undruggable until now. In fact a widespread belief holds that drug discovery is much harder now because most of the druggable proteins were picked in the 80s and 90s; this is the so-called "low hanging fruit" theory of drug decline. There are several reasons why a protein might not be druggable but one of the most common reasons is this: Druggable proteins have deep, small, well-shaped pockets that can embrace a small molecule the way a lock holds a key. Undruggable proteins on the other hand have shallow grooves spread across an extended area; a small molecule which tries to bind this surface faces a challenge similar to that confronting a climber who is trying to grab a foothold on a giant rock face. However it must also be remembered that the designation for a protein as "undruggable" may be nothing more than a provisional admission of ignorance; future advances in technology may well make the protein druggable. A protein which is shown to be both a major causal component in a disease and druggable is called a "validated target" which is now ripe for drug discovery.

In any case, the first problem in drug discovery then is that even if a particular protein is implicated in a particular disease, it may not be druggable. In addition, even if we were to successfully drug that protein, other proteins may also be involved in that disease which may compensate for its loss of function by being overproduced. This routinely happens in cancer and that is why cancer patients often become resistant to one particular drug; when you block one protein with a drug, other proteins which are also mutated and over-expressed take over, like an alternative pathway for an electrical circuit. This also happens frequently in case of antibiotics where bacteria can compensate for a drug target by producing other disease-causing proteins, or sometimes even by producing proteins which can destroy the drug. It is almost impossible for now to predict such kinds of alternative rewiring, a factor that significantly adds to the lack of predictive power in drug discovery.

This concludes the first part of the series. Drug discovery is difficult for two initial reasons; it is difficult to find out which proteins are involved in a disease, and even if you find them they may not be druggable and able to bind to a small molecule drug. In the next post we will see how, if we do find such proteins, we then find the drugs targeting them. In other words, where do drugs come from?

Summary: Why is drug discovery hard?

Reason 1: Drugs work by modulating the function of proteins. It's difficult to find out exactly which proteins are involved in a disease. Even if these proteins are found, it is difficult then to know if their activity can be controlled by a small molecule drug.

Select references:

1. The Quest for the Cure - Brent Stockwell: An excellent account of many modern concepts in drug discovery including genomics and undruggable proteins.
2. The Billion-Dollar Molecule - Barry Werth: A swashbuckling ride through the exciting and high-pressure world of a pharmaceutical startup (Vertex) which has now grown into one of the world's most innovative pharmaceutical companies. The only book on drug discovery I know which reads like a combination of a fast-paced thriller and an epic romantic novel.
3. Real World Drug Discovery - Robert Rydzewski: A succinct and yet comprehensive guide to all aspects of the science, art and business of drug discovery).
4. Druglike Properties – Edward Kerns and Li Di: This is a professional reference for students and scientists, but it gives a great flavor of the number of variables that have to be optimized in a good drug, and strategies to do this.
5. Natural Obsessions – Natalie Angier: A fly-on-the-wall account of drug discovery at its most basic level. Angier spent a year as an observer in the lab of Robert Weinberg of MIT, a pioneer in discovering cancer-causing genes. This work is not drug discovery per se but is a splendid account of the basic science and human stories that leads to drug development.

Victor Weisskopf and the many joys of scientific insight

Victor Weisskopf (Viki to his friend) emigrated to the United States in the 1930s as part of the windfall of Jewish European emigre physicists which the country inherited thanks to Adolf Hitler. In many ways Weisskopf's story was typical of his generation's: born to well-to-do parents in Vienna at the turn of the century, educated in the best centers of theoretical physics - Gottingen, Zurich and Copenhagen - where he learnt quantum mechanics from masters like Pauli, Heisenberg and Bohr, and finally escaping the growing tentacles of fascism to make a home for himself in the United States where he flourished, first at Rochester and then at MIT. He worked at Los Alamos on the bomb, then campaigned against it as well as against the growing tide of red-baiting in the US. A beloved teacher and researcher, he was also the first director-general of CERN, a laboratory which continues to work at the forefront of particle physics and rack up honors.

But Weisskopf also had qualities that set him apart from many of his fellow physicists; among them were an acute sense of human tragedy and triumph and a keen and serious interest in music and the humanities that allowed him to appreciate human problems and connect ideas from various disciplines. He was also renowned for being a wonderfully warm teacher. Many of these qualities are on full display in his wonderful, underappreciated memoir titled "The Joy of Insight: Passions of a Physicist".

The memoir starts by describing Weisskopf's upbringing in early twentieth century Vienna, which was then a hotbed of revolutions in science, art, psychology and music. The scientifically inclined Weisskopf came of age at the right time, when quantum mechanics was being developed in Europe. He was fortunate to study first at Gottingen which was the epicenter of the new developments, and then in Zurich under the tutelage of the famously brilliant and acerbic Wolfgang Pauli.

Pauli who was known as the "conscience of physics" was known for his sharp tongue that spared no one, but also for his honesty and friendship. Weisskopf's first encounter with Pauli was typical:
"When I arrived at the Institute, I knocked at the door of Pauli's office until I heard a faint voice saying, "Come in". There at the far end of the room I saw Pauli sitting at his desk. "Wait, wait", he said, "I have to finish this calculation." So I waited for a few minutes. Finally, he lifted his head and said, "Who are you?" I answered, "I am Weisskopf. You asked me to be your assistant." He replied, "Oh, yes. I really wanted (Hans) Bethe, but he works on solid state theory, which I don't like, although I started it."... 
Pauli gave me some problem to study - I no longer remember what it was - and after a week he asked me what I had done about it. I showed him my solution, and he said, "I should have taken Bethe after all."...
In spite of this rather inauspicious start, Weisskopf became both a very good physicist and a close friend of both Pauli and Bethe; he credits Pauli for lovingly 'spanking him into shape'. After the war, when debates about the hydrogen bomb were raging throughout the scientific community, it was Weisskopf who channeled Bethe's moral dilemmas, and the two enjoyed a warm relationship until Weisskopf's death.

Weisskopf also spent a productive year at Niels Bohr's institute in Copenhagen, where he was the 'victim' of Bohr's extended walks and tortuous reformulations of scientific statements to render them as accurate as possible. He benefited immensely from Bohr's style, as did many other leading theoretical physicists of the time. Bohr was known for his Delphic utterances and his mesmerizing personality that left listeners both frustrated as well as filled with a sense of wonder; only Einstein was more famous in the world of science then. In Copenhagen Bohr had created his own kingdom, one to which almost every budding physicist was required to make a pilgrimage. Many memories of Weisskopf's time with Bohr are recounted, but one in particular attests to the man's fame, essential qualities and influence:
"One evening at six o'clock, my usual quitting time, Bohr and I were still deep in discussion. I had an appointment that night and had to leave promptly, so Bohr walked me to the streetcar stop, about five minutes from his house. We walked and he talked. When we got there, the streetcar was approaching. It stopped and I climbed on to the steps. But Bohr was not finished. Oblivious to the people sitting in the car, he went right on with what he had been saying while I stood on the steps. Everyone knew who Bohr was, even the motorman, who made no attempt to move to start the car. He was listening with what seemed like rapt attention while Bohr talked for several minutes about certain subtle properties of the electron. Finally Bohr was through and the streetcar started. I walked to my seat under the eyes of the passengers, who looked at me as if I were a messenger from a special world, a person chosen to work with the great Niels Bohr."
Weisskopf made important contribution to quantum electrodynamics, but he suffered from a self-admitted lack of confidence that sometimes kept him from pushing calculations through. In one episode that must have been rather jarring, he wrote a paper after the war on the famous Lamb Shift and compared the results with ones acquired by Richard Feynman and Julian Schwinger. When his results did not agree with theirs, he withheld publication; surely physicists as brilliant as Feynman and Schwinger couldn't be wrong? After a few weeks, he heard from Feynman who had realized that both he and Schwinger had made the same mistake in their calculation. Weisskopf was right, and if had published his paper, he himself admits that he might have won a Nobel Prize. None of this engendered a sense of bitterness in him, however, and he used the incident to illustrate the importance of self-confidence in science.

Weisskopf was also known for the occasional mathematical mistakes that sometimes slowed down his calculations. On the other hand, this kind of inspired sloppiness made him a truly wonderful teacher, one who could provide for a completely immersive experience for his students in a way that made them feel they were participating in, rather than being taught, the process of scientific discovery. The physicist and science writer Jeremy Bernstein captured this memorable aspect of Weisskopf's trade in a 1991 review of the book:
"My visits to Viki's class in quantum mechanics at MIT were, in every way, a culture shock. The class and the classroom were both huge—at least a hundred students. Weisskopf was also huge, at least he was tall compared to the diminutive Schwinger. I do not think he wore a jacket, or if he did, it must have been rumpled. Schwinger was what we used to call a spiffy dresser.  
Weisskopf's first remark on entering the classroom, was "Boys [there were no women in the class], I just had a wonderful night!" There were raucous catcalls of "Yeah Viki!" along with assorted outbursts of applause. When things had quieted down Weisskopf said, "No, no it's not what you think. Last night, for the first time, I really understood the Born approximation." This was a reference to an important approximation method in quantum mechanics that had been invented in the late 1920s by the German physicist Max Born, with whom Weisskopf studied in Göttingen. Weisskopf then proceeded to derive the principal formulas of the Born approximation, using notes that looked as if they had been written on the back of an envelope. 
Along the way, he got nearly every factor of two and pi wrong. At each of these mistakes there would be a general outcry from the class; at the end of the process, a correct formula emerged, along with the sense, perhaps illusory, that we were participating in a scientific discovery rather than an intellectual entertainment. Weisskopf also had wonderful insights into what each term in the formula meant for understanding physics. We were, in short, in the hands of a master teacher."
Throughout his memoir, Weisskopf's consistent emphasis is on what he calls the joy of insight; whether in science, in music (he was an accomplished classical pianist) or into human beings. His focus is on complementarity and totality, themes that were hallmarks of Niels Bohr's thinking. Complementarity means seeing the world from different viewpoints, each of which may not be strictly compatible with the others, but all of which are collectively important to make sense of reality. He realized that as powerful and satisfying as it is, science is one way of comprehending the world. It gives us the facts, but it doesn't always point us to the best way to use the facts. Religion, the humanities and the arts are all important, and it is important to use as many ways as possible to look at problems and try to solve them; this applies especially to human problems where science can only take us so far.

Nevertheless, in what would be a ringing endorsement of the joy of insight into the secrets of nature during these politically troubled times, here's Weisskopf speaking about the value of science as a candle in the dark:
"I can best describe the joy of insight as a feeling of aesthetic pleasure. It kept alive my belief in humankind at a time when the world was headed for catastrophe. The great creations of the human mind in both art and science helped soften the despair I was beginning to feel when I experienced the political changes that were taking place in Europe and recognized the growing threat of war." 
"During the 1960s I tried to recall my emotions of those days for the students who came to me during the protests against the Vietnam War. This, and other political issues, preoccupied them, and they told me that they found it impossible to concentrate on problems of theoretical physics when so much was at stake for the country and for humanity. I tried to convince them - not too successfully - that especially in difficult times it was important to remain aware of the great enduring achievements in science and in other fields in order to remain sane and preserve a belief in the future. Apart from these great contributions to civilization, humankind offers rather little to support that faith."
In today's times, when so much of the world seems to be chaotic, dangerous and unpredictable, Weisskopf's ode to the 'most precious thing that we have' is worth keeping in mind. Happy Birthday, Viki Weisskopf.

Image source: Alcheatron.