"Roman Candle" turns 20: Secrets of Elliott Smith's accidental masterpiece (slideshow)
Elliott and the friends with whom he recorded in middle school in Texas (photo courtesy of Dan Pickering)
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 contribute to increasing the price of a drug, but one very important factor often gets entirely overlooked: Drugs are expensive because the science of drug discovery is hard. And it’s just getting harder. In fact purely on ascientific 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. 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 much 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. 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 find 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. And as we will see, it is very hard to predict either of these parameters at the beginning. 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 consequence 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. But such cases are rare; more often than not scientists have to artificially silence the function of a protein using genetic engineering 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 (recently however there has been a very promising to attempt to drug Ras which I will describe in another post). 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 component of 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. It 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, do we then find the drugs targeting them. In other words, where do drugs come from?
Elliott and the friends with whom he recorded in middle school in Texas (photo courtesy of Dan Pickering)
Heatmiser publicity shot (L-R: Tony Lash, Brandt Peterson, Neil Gust, Elliott Smith) (photo courtesy of JJ Gonson photography)
Elliott and JJ Gonson (photo courtesy of JJ Gonson photography)
"Stray" 7-inch, Cavity Search Records (photo courtesy of JJ Gonson photography)
Elliott's Hampshire College ID photo, 1987
Elliott with "Le Domino," the guitar he used on "Roman Candle" (courtesy of JJ Gonson photography)
Full "Roman Candle" record cover (courtesy of JJ Gonson photography)
Elliott goofing off in Portland (courtesy of JJ Gonson photography)
Heatmiser (L-R: Elliott Smith, Neil Gust, Tony Lash, Brandt Peterson)(courtesy of JJ Gonson photography)
The Greenhouse Sleeve -- Cassette sleeve from Murder of Crows release, 1988, with first appearance of Condor Avenue (photo courtesy of Glynnis Fawkes)
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