 Hello and welcome to NewsClick. Today we have with us Dr. Satyajit Rath and we're going to discuss what could be a creeping crisis of medicine. Satyajit, this has been argued, I don't know how far it's true, you'd know better, that the era of small molecules is gone and we are not seeing new discoveries of drugs on the scale we saw 15-20 years back. We keep on hearing about new class of antibiotics which will be discovered soon because A, B or C has happened. Soil bacteria, this new era of that new era, none of it seems to have really happened. And what we see instead, what we didn't anticipate is appearance of now large molecules, small molecules, large molecules, much more complex and also the fact that large molecules seem to bring with it their own problems, cost and so on. Do you really, first before we get into the issue of large molecules, do you really see that small molecules as medicine which is what modern medicine is primarily based upon, this era is actually winding down? So that's an interesting question. My predicting the future is always a hazard. Crystal ball is very bad. Occupation. Can be a very damaging thing for our reputation later, your reputation. So clearly my reputation, but so let me hedge my bets but only just a little bit. Do I think that the era of the traditional small molecule is over? And my guess is that it is going to taper off a little. Do I think all small molecules are over? I don't think so. And I'll explain what I mean by traditional small molecule based medicine and a non-traditional one. Do I think that large molecule therapeutics is going to acquire greater and greater importance? Yes, I think that that is going to be the case. But I don't think it's going to be not this but that situation. Not in either or situation. I think we are going to see interesting reformulations of the landscape of medications in this sense. Let me explain that a little bit. How are small molecules made? Small molecules are made in two different ways. Small molecules are discovered in two different ways. Honestly, all molecules, all medical compounds are discovered in two different ways. One is you know some process that you want to interfere in and you've understood the structures of the enzymes that are involved in that process. You talk of the germ or bacteria. Even for diabetes, for blood pressure, for example, there are our own internal processes. So in those body processes, there are enzymes involved that are carrying out certain functions. Can you block some of those functions using a designed small molecule? This is been a dream. Once upon a time, what we used to do for even now, what we used to do was to look for small molecules. Do screens. Take a thousand small molecules, a million, a trillion small molecules of different kinds and just screen all of them for effects. Many of them had effects. Many of today's medicines have in fact been discovered by such activity screening. This should be called as brute force, large scale screening of molecules. You could either look at biochemical processes or you could look at whole physiologies. So how did we discover antibiotics? Even today, much of our antibiotic discovery is exactly the same kind that apocryphal stories of Alexander Fleming tell us. You are growing bacteria. You are putting some test compound on to the bacteria. Do the bacteria stop growing and die or do they not? You're not looking at biochemistry. You're just looking at, are you getting the effect that you want, which is killing of the bacteria? Trial and error, simple. But whichever it is, this is all trial and error with very large numbers of trial and errors. And therefore, you will always get some successes. Scatter gun effect, something. This has been the traditional discovery process. Now, this becomes, the more and more you discover paradoxically, discovering the next one becomes that much harder. Because you haven't understood the mechanisms. You're just doing this. So the next step that was done was to understand the mechanisms and to begin to say, can we design? Or look for those compounds which could then be, could actually effect these processes. The selection but in a limited sense. But let me point out a very practical problem. This is, we are talking at the level of the researchers. Okay, but the reality is that once you discovered a small compound, small compound, it means a few hundred atoms. Kind of small compound. So acetylsalicylic acid, that's a really small compound. The advantages of the small compounds are very many. One is because they are small, they are easily absorbed. Okay. So, make a tablet, make a capsule or take it. It will all get absorbed, very easily. Small molecules are very stable in their structure. Okay. So, when you make the small compound, it has that structure. You don't have to worry about structure. If that compound is there, then its structure has to be there. It's possible to tweak them chemically. Change their structure just a little bit here, just a little bit there by relatively inexpensive chemical methods. So, you can refine their activity. You can say, here is a small compound. It works with a certain potency. Can we tweak it and get a variant that is more potent? And this has been the bread and butter work of pharmaceutical R&D for decades. True. That's what we call the family and then new family members keep on emerge. Absolutely. Now, here is the difficulty with that. Once you enter this system of drug development, the chemists say, please don't work on that structure. It is very difficult to handle. It's very difficult to tweak. So, you generate something that the field calls, for example, the Lipinski rules, which are... Let's not get into what the detail is. Essentially, you develop rules of thumb which say certain kinds of compound structures we shouldn't bother with because they are very hard to work with. They are very hard to tweak or they are very hard to manufacture in large-scale processes and therefore drug prices will be much greater. So, let's not go there. So, we have excluded a large number of small compounds from consideration. Also, we have been using small compounds that vary very prominently. Not by all means all small compounds, but very prominently large numbers of small compounds that we develop. We develop as compounds which block enzyme activity. Now, enzyme activity blockade has an amplifying effect because one enzyme, one after another, will convert a large number of targets. So, if I block one enzyme molecule with one small molecule, it will block that entire chain of many, many, many targets. So, you have one to many relationship of effect. So, multiplier effect. So, there is a multiplier. But if one molecule pushes another molecule into doing something and I just block that, I have no multiplier effect. So, enzyme blockers have been... Enzyme blockers, small molecules of a certain chemical subset have been the mainstay of our drug development. Unsurprisingly, we are running out of things we can discover like this. So, the real question is, what are the different ways in which this scenario will change? One direction is, rather than depending on small molecules, we start making large molecules. And the simplest large molecules that serve currently as examples are antibodies. And antibodies bind to very specific targets. They bind to very specific shapes and our immune system functions in ways where we make antibodies that bind to some shapes and not to other shapes. Which means we can do the same kind of thing that a small molecule does. It binds to something and doesn't bind to something else and that is how you get a specific effect. Target. You can make an antibody and because the natural function of antibodies is to do this kind of targeting, we can now begin to redesign antibody binding to carry out the effect that small molecules would be carrying out. There are gains and losses. What are the negatives? The negatives are antibodies are very large molecules, hundreds of thousands of atoms. As a result, they are much harder to manufacture. Their quality control is much harder. They are far more expensive, therefore, to make as a manufacturing process. Number one. Number two, they are proteins. So, if you take them orally, you end up digesting them and they are not easily absorbed and functional. So, they have to be injected, which creates its own practical problems. So, there is a whole range of effort currently ongoing to see if we can figure out ways of getting them absorbed without having to poke and inject. There are ways that people are trying to stabilize molecules and to predict their structure so that manufacturing processes are easier. Antibodies are not heat stable particularly. So, you need a cold chain for their maintenance. So, all sorts of difficulties arise with large protein molecules as therapeutics. Vaccines are also antibodies. Smallpox vaccine particularly. Vaccines are, they are not antibodies but they are proteins. Proteins. And therefore, they have the same kind of difficulty. Cold chain requirements. The vaccines have an added difficulty. Many vaccines are live vaccines. The oral polio vaccine, for example, is actually live, very weak polio virus. So, it doesn't cause disease but it induces immunity. It causes immunity. But for that, you need again cold chain. So, similar kinds of difficulties arise. But there are odd gains. It has turned out over the past 30 years that large molecules have apparently a far lower likelihood of completely unexpected so-called off-target side effects than small molecules do. Okay. Now, this is again. It seems to be because antibodies tend to be designed evolutionarily to bind certain specific targets and not this, that and the other, everything. Whereas with the traditional small molecule, we are actually simply looking for accidents. Much for haphazard. We don't really know what to predict because it has not developed in that form. Unlike in the revolutionary pressure and like antibodies. Absolutely. So, under those circumstances, it's possible that a lot of large molecule therapeutics would have actually fewer off-target side effects. The completely unexpected side effects. This would be again. The jury is still out on whether this is true or not. Really, definitely, reliably true or not. But there are some indications that this is the case. But there is a whole other category of drugs that begin to be exploited. Remember, I said that certain chemical structures had been traditionally excluded. We are now beginning to look at them. They are small class of small molecules. They are still small molecules. Remember, I had said, we can now begin to ask the question with better and better more refined molecular level structural understanding. Can we actually build small molecules from scratch? Rather than looking for small molecules. So, look at what could work and synthesize such molecules. Make designer molecules. Can we make designer molecules? Has become a second pathway. Third is related to these two. Our understanding that in odd places, biological systems have created a great diversity of chemical structures that we hadn't even thought about. So, we have begun looking at odd ball bacteria growing in ocean vents. And what kind of chemistries that they have. And what kind of small molecules result. Plants growing in extreme conditions. What kind of small molecules? And does that expand our repertoire of small molecules? As a consequence, I think what we are beginning to see is what I am calling the emerging era of unorthodox small molecules. I think the era of orthodox small molecules will taper out. I think what will begin to grow are these what by those standards are unorthodox small molecules as well as the large molecules. And there is a whole range of very fascinating possibilities at the level of detail in each of these sectors that I suspect will begin to provide diversity for us. Just for our viewers again is Gleevec which is used against certain forms of leukemia. Is it a small molecule or a large molecule? So, Gleevec is a small molecule. And Gleevec is a small molecule that was discovered as a consequence of beginning to understand the structure of the enzyme that is critically involved in causing the leukemia. So, it is not true that cancer or such diseases can be only treated with large molecules. Gleevec is an example. No, by no means. In fact, let me point out that Gleevec is actually a trade name. The generic name is imatinib. So, if you read the word imatinib, the inib end is for small molecule inhibitors. Okay. But you also have a large number of drugs which end in Mab as in Rituximab which is used for treating another kind of leukemia. Mab stands for monoclonal antibody which is a large protein molecule. And at the moment, there are as many inhibs being made as new drugs as there are Mabs being made. So, what you are saying is we introduced a new class of rugs which are essentially large molecules. But we are also taking unorthodox roots to find small molecules which have properties which we didn't think about earlier, would not have gone to earlier. And also looking at designer molecules. That means look at what we really want, looking at the structure of what we want to prevent from growth disease, therefore. And therefore, trying to develop new designer molecules which otherwise may not exist. So, let me make a point here. Why have these unorthodox approaches not been in fashion? Because industry has been reluctant to let production costs rise. Okay. As a consequence, as these drugs begin to come up, there is going to be a major struggle in reshaping the landscape of the pharma industry. What we are going to see is the irresistible force meeting the movable object. The irresistible force is public need for new medicines. And new antibiotics at reasonable cost. The movable object is the profit making of the pharma industry. At some point, this is going to lead to creative disruption. We are going to see a fundamental restructuring of how manufacturing sectors look at these problems. And that is going to be both interesting, instructive and hopefully socially useful. And also look at how society values health of its citizens. So, that is the other part of the mix. Thank you very much Satyajit for being with us, looking at an area which is not publicly being debated as yet. Because it is still very much within the labs and one is we hear about it only in certain journals. And possibly it will become more popular when it enters the legal arena. How do you look at patents in light of these changes? Because that is not going to be the easy one either. Thank you very much. Hope that we continue these discussions at other locations. This is all the time we have for NewsClick today. Do keep watching NewsClick and visit our website.