What Goes into Making Therapeutic Medicines with Patrick Woster, PhD

You may have noticed a label on one or more of your prescriptions advising you not to take that medication with grapefruit. That label is the result of the discovery of a compound in grapefruit that alters the absorption of certain medications, impacting the effectiveness of the drug. This discovery was made in 1996 by David Edwards and today’s guest, Dr. Patrick Woster.

Dr. Woster is Professor and Chair of Drug Discovery and Biomedical Sciences at MUSC’s College of Pharmacy. Additionally, he is a South Carolina SmartState Endowed Chair in Drug Discovery, Director of MUSC’s Drug Discovery Core, a fellow of the Royal Society of Chemistry, and is an inductee in the American Chemical Society’s Medicinal Chemistry Hall of Fame.

Read The Transcript

[00:00:04] Loretta Lynch-Reichert: Hello, everyone, and welcome back to MUSC's Science Never Sleeps podcast. Many of our listeners may have seen a label on their prescription medications that says, "Do not take with grapefruit." That label is the result of the discovery of a compound in grapefruit that alters the absorption of certain medications. This discovery was made in 1996 by David Edwards and today's guest, Dr. Patrick Woster. Dr. Woster is Professor and Chair of Drug Discovery and Biomedical Sciences at MUSC's College of Pharmacy. Additionally, he is a South Carolina Smart State Endowed Chair in Drug Discovery, Director of MUSC's Drug Discovery Core, a fellow of the Royal Society of Chemistry, and is an inductee in the American Chemical Society's Medicinal Chemistry Hall of Fame. Welcome, Dr. Woster.

[00:00:56] Patrick Woster, PhD: Thanks, I'm really happy to be here.

[00:00:57] Lynch-Reichert: I'm happy to have you here. In the past year, we have seen new vaccines being fast-tracked to combat the COVID pandemic, and a push in academic and industry labs to find new therapeutics to treat people suffering from the COVID-19 virus. And just recently, the FDA has approved a new Alzheimer's drug, a decision surrounded by much controversy and debate, even among scientists and clinicians. Dr. Woster, there is a lot of confusion about the process of drug discovery. So let's begin with insight into the inner workings of drug discovery. How do pharmaceutical companies or academic laboratories identify a substance or chemical structure that is eventually developed into a drug?

[00:01:45] Woster: Well, drug discovery is a very long and involved process. Most companies start by identifying a disease state that they're interested in working on, and a specific biological target that goes along with that. The first thing they would do is validate the target to make sure that engaging it with a drug would actually have the effect that they want it to have.

[00:02:11] Lynch-Reichert: How do you validate a target?

[00:02:13] Woster: It's done biochemically. They usually will isolate-- say it's an enzyme, they'll isolate the enzyme, make sure that the drug -binds properly.

[00:02:22] Lynch-Reichert: Okay.

[00:02:23] Woster: Then, they look at it in cells to determine if it actually has an effect on the biological system that would be analogous to getting rid of -that particular protein.

[00:02:32] Lynch-Reichert: Okay.

[00:02:33] Woster: So, they're pretty thorough about that. Then they start the chemistry process, which is done a number of different ways. A lot of companies do high-throughput screening, where they'll robotically assay up to a million compounds.

[00:02:50] Lynch-Reichert: What's an assay?

[00:02:51] Woster: An assay is just-- it's a simulation of the process you're trying to interrupt. So, again, with an enzyme, it would be an enzyme reaction that you monitor the progress of, and if you'd put your drug in, then the product of that-should be reduced.

[00:03:04] Lynch-Reichert: Okay.

[00:03:05] Woster: So, they'll look at a million compounds, and they have the money and the people and the robots to do that kind of work. Eventually, they'll identify a number of different chemotypes, different chemical scaffolds or structures that they want to manipulate. A chemistry program will make on average probably about 10,000 compounds they want to look at. They have, again, a lot of people that can work on this. In fact, the ratio of drugs that are made, compounds that are made, to those that actually become a drug is about 10,000 to 1.

[00:03:50] Lynch-Reichert: Wow.

[00:03:51] Woster: So, there's a lot of failure involved with drug discovery, but the end product is well worth it. So, eventually, they'll find something that they want to test in cells. They'll look at the cellular effects of the compounds, and usually they'll start narrowing down to a manageable number of compounds. Ultimately, they'll look at the pharmacology, the effects of the drug in cells and also in animals. There's a number of different animal studies that have to be done. Toxicology, they look at how the drug is distributed in the body. They look at birth defects, things like that. Does it cause mutations for birth defects? They look at a number of different things.

These are all mandated by the FDA. So they end up doing animal studies in up to three different species, and that's just the first phase. Once they get to the end of that phase, they generally have maybe two or three compounds that they would call a clinical candidate. Then they have to file an Investigational New Drug Application and have that approved, and that gives them permission to what they call, "first in humans." They can do their very first human study. The first human study, they generally will get volunteers, a lot of times, they're students that are healthy, and they just give them the drug, and they find out what the maximum tolerated dose is. It's a short-term thing, and they're pretty sure it's not going to hurt anyone -when they get to that point.

[00:05:35] Lynch-Reichert: Right.

[00:05:35] Woster: Sometimes there are some little surprises, and some side effects that don't occur in animals. From there it can go into actual clinical trials in hospitals. They get larger and larger, and they spread out over the country. So, there are really three phases to that. The first phase is just to show efficacy. Does it actually work better than a placebo? Then, they get larger and larger, and in that phase, they're using patients that actually have the disease. So, ultimately, they put all this data together. It's a tremendous amount of data that they're required to have. They keep everything. All the lab notebooks, all the documents, everything they keep, and then they submit that to the FDA for approval. So, it's a very long process.

[00:06:24] Lynch-Reichert: Indeed it is. Let me ask you something, listening to what you've just offered us. I'm wondering, there was a time, I presume, that they didn't follow this process, because there were several drugs, I think long ago, maybe the '50s, where a tremendous number of birth defects for women who were suffering from, I don't know, -maybe it was... -Morning sickness. -...morning sickness.

[00:06:44] Woster: Mhm.

[00:06:45] Lynch-Reichert: So, tell me, have things changed that much, or was that just a sorry side effect they didn't know about? I'm curious.

[00:06:52] Woster: Well, the initial example of that was the Pure Food and Drug Act of 1906. Before that, there was no control, and you'd have these snake oil salesmen.

[00:07:03] Lynch-Reichert: Right.

[00:07:04] Woster: So, there was a product that was a weight loss product that actually contained tapeworms, so it worked.

[00:07:08] Lynch-Reichert: Oh, my gosh.

[00:07:10] Woster: It was effective, but it wasn't safe. So, the Pure Food and Drug Act said it has to be safe and effective, and from there, it's really been modified a number of times. The example you're thinking of was the thalidomide crisis, and there was actually-- They distributed this drug in England, and it caused these birth defects, where they had limbs that didn't develop. There was a woman at the FDA in this country who would not allow that, and this was before she knew anything about what had happened. She did not allow that to be tested in the United States. So, those defects were only in England.

[00:07:52] Lynch-Reichert: So we have a woman to thank for that.

[00:07:53] Woster: We do, yes. Then, there was a thing a few years ago with the Merck Pharmaceutical Company, where they had some anti-inflammatory agents that they made, and they caused some issues with an ion channel in your heart that's necessary for proper function of your heart, and they knew about this, but they marketed the drug anyway, so they were fined a tremendous amount of money for that. This channel is called the hERG channel, and they're all now required to test every drug against hERG. So, these things, over time, they will change the regulations. It's gotten more and more strict to the point where the public can be pretty sure that what they're getting is safe.

[00:08:45] Lynch-Reichert: Those things, I want to talk to you about in depth in a little bit, especially as it relates to the COVID vaccine that came on the market. It's not even on the market, it's actually for emergency use, -but we'll talk about that.

[00:08:57] Woster: Right.

[00:06:58] Lynch-Reichert: So, I guess my question to you is, because this process is so long, and because it takes so much manpower and high tech, is that the reason drugs cost so much?

[00:09:14] Woster: Well, there's multiple reasons for that. It is the time involved. I mean, think of all the people beyond science that are also involved in this. So, a drug development program on average now takes about 10 years. Now, remember that they only have a patent -that lasts 17 years.

[00:09:31] Lynch-Reichert: Right.

[00:09:32] Woster: So, if it takes 10 years, you've got 7 years left to make your money back. So, that's an important amount of time. Also, right now the current average expenditure is about $2.6 billion.

[00:09:45] Lynch-Reichert: To develop a drug?

[00:09:46] Woster: For one drug. The reason for that is they have lots of different programs going, and they sometimes have more than one candidate within one program, and they don't always make it. Sometimes they'll get into later human studies and they'll find something that can't be tolerated, or it's not as effective as they thought it was in earlier studies. So those fail, but they spend a lot of money on those. So, the pharmaceutical companies really need what they call a "blockbuster drug." So, a good example of that is Lipitor.

[00:10:21] Lynch-Reichert: Mhm.

[00:10:22] Woster: That paid for a lot of failed drug discovery campaigns that they had, I think the company was Parke-Davis at the time, now it's Pfizer. So, that's how they do it, and once they get something good and it goes on the market, they have to make their money back. So, the patients don't understand this, and drug prices have gone up dramatically. But the drug companies put a lot of their profits back into discovery. So, I mean, obviously they're in this to make money, but they also want to keep funding what they're doing.

[00:10:57] Lynch-Reichert: That brings a question to my mind, that they're looking for the blockbuster to recoup for all those other failed drug development opportunities. But also, is this fair to say, that they mostly focus on drugs for a large population, not the drug for the disease that is so horrific, but in very small parts of the population. -Is that a fair statement?

[00:11:30] Woster: Yeah, I think that's fair. I mean, you have to remember that the motivation of a company -is to make a profit.

[00:11:36] Lynch-Reichert: Absolutely.

[00:11:37] Woster: So, you're just working in an area where you should be somewhat altruistic. So, a good example, I saw a pharma executive one time who said that all of the drug discovery and development machinery in the world is in the Northern Hemisphere, and all the really nasty diseases are in the Southern Hemisphere, where people make no money. So they don't go after those diseases, because there's no market. It sounds callous, but I mean, it's a corporate philosophy. So some companies now have started programs almost like when a lawyer does pro bono work, where they will pick either a rare disease or, say, a tropical infection, parasitic infection, something like that, and they'll have a program in that.

[00:12:34] Lynch-Reichert: Well, is this possibly where partnerships between such as MUSC's Academic Medical Center and your drug discovery lab and your Core, is that where partnerships begin that will help those people who won't normally get any kind of help at all?

[00:12:49] Woster: Yeah, that's really a great question, because big pharma now, they keep saying that they're target rich and pipeline poor, which means they have lots of things they want to work on, and they don't have as many drugs coming through their pipeline as they would like. So, they have now begun, in the past five years, I'd say, it's really accelerated to make partnerships with academic institutions, and that's how they're getting their pipeline drugs. In academics, we talk about what we call "the chasm of death," which is, you can develop a drug up to a certain point, usually it's somewhere in the animal studies range where you can afford that, but universities can't pay $2.6 billion for something. So, we'd get to that point and we used to be stuck, because the drug company wanted it farther along -before they would...

[00:13:41] Lynch-Reichert: Oh! Invest.

[00:13:42] Woster: ...pick it up and develop it. So, now they've sort of covered that over. Companies are more willing to invest in things sort of earlier in the process. Also, a lot of academics have started their own companies. We've had some successful companies from MUSC. Generally the endpoint for those companies is that a large company will see what they're doing and buy it. So, that's a way that academics get over that chasm of death.

[00:14:10] Lynch-Reichert: Is there also-- Do you have any experience with venture capitalists, or angel investors in drug discovery? Or is that really-- would be a very small population?

[00:14:20] Woster: No, I think anyone who gets into the entrepreneurial part of science from an academic institution is going to be looking for angel investors and venture capitalists, and there are programs where you can go and meet these people. They have what they call speed dating, where very quickly you meet all of these people that have money to invest, and you have to give them an elevator pitch of what you're working on, and if they like it, they'll invest in it. Some companies and some venture capitalists will invest very early. Others want things that are more developed. But there's money out there if you have a good idea, and if you have made some progress, it's available.

[00:15:00] Lynch-Reichert: You are kind of a renaissance man in the world of medical chemistry. You don't limit yourself to one disease target. What types of drug discovery research do you do in your lab?

[00:15:10] Woster: Well, the beauty of chemistry is that no matter what biological system you're working on, chemistry is chemistry. So, we'll talk about the Drug Discovery Core in a minute, but we have a library of compounds that we can mine for a number of different projects. So, in my lab, our newest project is one that Catherine's actually working on now. We're looking for small molecules that can activate the immune system to attack and kill cancer cells. This is a new project that we've just started with, and we've gotten some leads from our library -that we have here on campus.

[00:15:52] Lynch-Reichert: Wow.

[00:15:53] Woster: I've done some work on sickle cell disease. We have some compounds that cause your body to start making fetal hemoglobin again, which you stop making when you're six months old. So, that alleviates the problem, because the fetal form doesn't have the mutation that causes sickle cell. We have a chemoprevention project where we're looking for compounds that inhibit an enzyme that makes reactive oxygen species that can cause cancer. We've made some progress there. One of our more recent projects, we've actually found some compounds that prevent inflammation and bone loss in periodontal disease. So we've actually started working with the College of Dentistry, and we've found some ways to prevent that problem. Half of the world's population has some form of gingivitis or periodontal. It's a huge market. Also, one of the first collaborations between our two colleges, so I think that...

[00:17:00] Lynch-Reichert: Wonderful.

[00:17:01] Woster: ...shows the interdisciplinary nature of how we do things around here.

[00:17:03] Lynch-Reichert: Exactly, which is why we are the premier academic health center in the state of South Carolina.

[00:17:09] Woster: No argument there.

[00:17:11] Lynch-Reichert: Yeah. It takes a while for a drug to actually get to a place where it can be marketed. Before the COVID pandemic, the vaccine holding the record for fastest development was the mumps vaccine, which took four years to develop. It is amazing that that record was beaten with the development of the vaccines to combat COVID. How were these vaccines rolled out so quickly while meeting safety and efficacy regulations?

[00:17:40] Woster: It's actually an interesting story, and I actually did a little bit of reading on this just to make sure I had my facts straight, but the first thing that happened was that government mobilized a tremendous amount of money. They redirected it from other programs so that they could attack this pandemic. Once it became a pandemic, it was clear that we had to work very quickly. The other thing that helped was the technology that they used to make the vaccine already existed. They were working on other viruses, and they just adapted it to work with COVID-19. They've been working, as I said, on other viruses, so a lot of that information transferred over. One of the big factors was, when you do human clinical studies, it takes a long time to enroll patients. We had so many patients that it went very quickly, and so they had a nice group of patients already. I guess the biggest factor was luck, because things worked out. They don't always work out perfectly, but in this case, we had a lot of things work out quickly.

[00:18:51] Lynch-Reichert: Can I ask a question?

[00:18:52] Woster: Mhm.

[00:18:54] Lynch-Reichert: This is of course out of ignorance, because I'm a business person, not a scientist. But you said that they had other viruses they were working on, and they were able, perhaps then, to use that material for the COVID, so how do you know you can use that material? -Tell me about that.

[00:19:15] Woster: Well, the way the vaccine works for COVID-19 is, it's just a piece of messenger RNA, so what messenger RNA does is it tells your cell, "Here's a protein I want you to make," and then it reads that and makes the protein. So, what they did was they made messenger RNA that corresponds to that little spike that's on the outside of the virus you see in the pictures. So, your body makes the spike protein, which is harmless, but it grows antibodies because it's identified as a foreign substance, so you make antibodies to this spike protein, and then when you get the virus, it binds to the spike protein that's on the virus and prevents it from replicating.

[00:19:57] Lynch-Reichert: Can you speak a little more to that? Because, as you know, there are many folks who are hesitant to get the vaccine, and one of the arguments that I hear is, "Well, it's going to change my chemistry, if you will, in my body." Can you talk to these folks about what this actually does, and what not to worry about?

[00:20:20] Woster: First of all, messenger RNA, it doesn't matter what the sequence is, when you have it in your body, it gets used or degraded. So the worst that could happen is you would make a protein that you don't normally have. It can't incorporate into your DNA, so it's not a danger there. There were even some rumors going around that the government was putting little tracking devices, and I'd love to see the technology where you can get a transistor through an 18-gauge needle, but we'll see if that's true or not. But, I mean, those things, it's just sensationalism, and there's no basis to any of that.

[00:20:57] Lynch-Reichert: Right.

[00:20:58] Woster: I think that, I mean, we've had, what, 160 million people have had this now. I think that's probably a big enough clinical study to show that it's safe and effective.

[00:21:09] Lynch-Reichert: Absolutely, I totally agree. Emory University in Atlanta revealed promising data from a phase 2 clinical trial for their antiviral use in COVID patients in March. Now we see a new virus called the monkey virus. With the unpredictability of diseases that cross boundaries from animal to human, do you think we will still see a push in development of antiviral drugs?

[00:21:34] Woster: Yeah, I think we'll see more of that, because the viruses that exist today seem to be able to mutate much faster than other viruses. Well, for polio, for example, we've used the same vaccine for polio for 70 years, or however long it's been. But the COVID virus is already mutated.

[00:21:57] Lynch-Reichert: Right.

[00:21:58] Woster: It's mutated that spike protein and luckily, the antibody still binds. But it could ultimately make a variant that doesn't. It's like the flu. We get a flu vaccine every year, it's always a little different because of which strain might be out there. So I think there's going to be a lot more research. The other reason I think that's true, if you're familiar with the product Harvoni that they talk about at night on the news a lot, that's actually a cure for a viral infection, -hepatitis C.

[00:22:27] Lynch-Reichert: Mm, yeah.

[00:22:28] Woster: And that's the first time anyone has ever been able to say, "We can wipe this virus out completely." You can't do that with HIV. And HIV is notorious for mutating, so patients take this cocktail of several drugs, and if they get below therapeutic levels, there's a danger of mutation. So, this Harvoni product is fabulous.

[00:22:54] Lynch-Reichert: And how long did it take to get that to market?

[00:22:55] Woster: That was probably in the seven -to ten-year range, because...

[00:22:58] Lynch-Reichert: Wow.

[00:23:00] Woster: ...that was not as urgent as COVID. It was something that needed to be done because there's a lot of people that have hepatitis C -and don't even know it.

[00:23:11] Lynch-Reichert: Right.

[00:23:12] Woster: So, it also drew attention to the disease, so. I think we're going to see a lot more things like this, and I think people are going to be looking now for agents that can actually cure a viral infection, rather than just prevent replication, and then the patient has to kind of tough it out -till it's over.

[00:23:29] Lynch-Reichert: Yeah. That's just fascinating. Tell me about the Drug Discovery Core -at MUSC.

[00:23:32] Woster: Okay. Well, I think the Drug Discovery Core is kind of a hidden gem at MUSC. We've been around, but we've really only formalized things in the past couple of years. I took over as director about two years ago. And we have a library of 130,000 compounds, and 100,000 of these were donated by a pharmaceutical company, Aeterna Zentaris. They have a presence here in Charleston. They wanted to get out of the early discovery phase and concentrate on some clinical things they had going on. So, they donated to us their library. And we have these compounds plated out in 96-well plates, which we use for assays. And so you can assay 96 different preparations in one plate.

So, this is available now to faculty at MUSC. It's available to people from the outside. There's a little cost involved, but it's much cheaper than doing it externally somewhere. And we're starting to get people coming in with their biological system and saying, "This is a target, can we find a drug?" So, we have about, I think, 11 or 12 ongoing projects right now in the drug discovery, and it's still pretty early. We do synthetic chemistry, so if you have a compound you're interested in, and you need a lot of it, we can scale it up and make it. We can make derivatives. We do what they call hit to lead optimization, where you change the structure and see how that affects the activity. Ultimately, that's how they get to their clinical candidate in industry. We also have some great imaging instruments. We have quality control instruments. It's actually a very well-equipped drug discovery center -for a university.

[00:25:26] Lynch-Reichert: Sounds like a state-of-the-art -facility.

[00:25:28] Woster: It is. Most of the equipment that we have is pretty new. We've also now had three companies that have spun off from-- just in the past two years-- from our library. So, it's really a gold mine because nobody else has access to these compounds, except this university and those people from the outside that we-- -we contract with.

[00:25:52] Lynch-Reichert: And so, we're the only academic institution in the state that actually has -something of this nature...

[00:25:55] Woster: That is correct.

[00:25:57] Lynch-Reichert: ...which is really a wonderful thing. As you've been, in your career, and with all your accolades, has there been any surprise for you in regard to medicinal chemistry? I recall hearing one scientist tell me that there's that ah-ha moment when you're working on something and you have one goal in mind, but lo and behold, it didn't work for that, -but it works for this.

[00:26:21] Woster: Mm-hm.

[00:26:22] Lynch-Reichert: How does that work in your world?

[00:26:24] Woster: Yeah, I think that's, that's--it's not really a surprise, but it is kind of unexpected when you find out that you can move into a different area, and, again, it's because of chemistry. We made some compounds for cancer, and those were the compounds that we found would work in sickle cell disease, and the reason is it was a similar target, but it had a different function. So, we've moved from one thing to another. If you'd have told me five years ago I was going to be working on periodontal disease, I would have laughed, but it's just how it goes. You follow the research. Actually, I remember the first time I made a compound that worked, I was pretty surprised. I didn't realize-- I didn't realize that that's actually what it did. But we've had a lot of surprises along the way, and we've turned in a lot of different directions. You have to be pretty nimble when you're a scientist -in drug discovery.

[00:27:23] Lynch-Reichert: Exactly. And you have to really be, I would also think, very creative, and pretty dang smart too.

[00:27:28] Woster: Well, you just have to keep your eyes open. Einstein said a genius is the master of the obvious.

[00:27:35] Lynch-Reichert: (laughing)

[00:27:37] Woster: I'm not a genius because not everything is obvious to me, but you just keep your eyes open and you notice. So, the sickle cell target being similar to the cancer target was the way that we got into that, and that then blossomed into a three-year grant from the Doris Duke Foundation. So, you just keep your eyes open. Sometimes things fall into your lap. Yeah, serendipity.

[00:28:00] Lynch-Reichert: Tell me something, how many-- what's the projected number of medicinal chemists coming out of our great institutions across the country that could fulfill the type of work that you do now? Because it sounds like there's going to be a big need going forth in the future.

[00:28:17] Woster: Well, it's interesting because the big companies, at one time-- a lot of the big companies are run by MBAs now. There's not a scientist sitting in that chair, which is fine, but a lot of their decisions tend to be based on finance. So, one of the things they decided to do-- this has been about 10 or 15 years ago-- was we can contract out our chemistry to India and China, and they did that. And they could, at that time, they could get three medicinal chemists in India -for the price of one here.

[00:28:55] Lynch-Reichert: Mm-hm.

[00:28:57] Woster: So it was a good move financially. But they found that what was missing was the creativity. That they were making compounds, but not necessarily looking at the results and figuring out what needed to be done next. So at that time, a lot of medicinal chemists-- they call it being downsized, but actually they just lost their jobs. They just said, "We're not doing med-chem anymore," and they let -all those people go.

[00:29:24] Lynch-Reichert: Wow.

[00:29:25] Woster: So, that happened to one of my former students, and he's now president of a drug company in China. So, what happened with the American chemists is they went into academia, and they're doing fantastic. And the benefit is that, as an academic, I was not trained to do things like industrial people do. And these people come out, they know what the process is. They know what needs to be done. They know all the pitfalls. And so, there are places that have fantastic drug discovery operations. Vanderbilt is one, Minnesota, Ohio State. There's a number of places, where they snapped up some of these chemists that came out of industry. Now industry is saying, "We better hire some people back."

[00:30:10] Lynch-Reichert: Let's partner, yeah.

[00:30:12] Woster: Right. So I don't know how many are out there. The American Chemical Society has an organization for young medicinal chemists, and it's pretty popular. The big companies tend to go to the big universities, and they'll hire an organic chemist and train them to do the biological part. There's institutions like ours-- I believe that the education of a scientist should be more broad-based, so my students do both things. And I think they're starting to realize that that's a good way to go as well.

[00:30:49] Lynch-Reichert: Yeah, because this is why folks, many folks, back in the day would start out with a liberal arts education because it helps you to think. And then you get into your specialty, where you already have been trained to think so broadly about big things, and that's how you become so creative in your particular field. I think that's really important. You're absolutely right. So, let me ask you this question: Why is chemistry so hard?(laughing)

[00:31:20] Woster: Chemistry is—

[00:31:21] Lynch-Reichert: You know they call it the fail course. In undergraduate school, you take chemistry and you fail. Then, bye!

[00:31:28] Woster: Yeah, we had a professor when I was in school, he was the make-or-break for getting in med school, so I know exactly what you're talking about. It has to do with aptitude and how you approach it. And my personal story is that I took first-semester organic, and I was completely lost. And, I don't know why, but I was sitting studying for the last exam and it just sort of all came together.

[00:31:54] Lynch-Reichert: No kidding!

[00:31:56] Woster: I got the highest grade in the class, and there were like 300 people, big university. It shocked me. I put it together, and I understand how all these things interact. So, I think it has to do with aptitude. It's not that I'm any smarter than anybody else. I just have the aptitude for it. Now, if you put me in a calculus class, it's a whole different thing. But I think that's what it is. The most successful medicinal chemists that I know are people who, it's almost like their hobby. They would rather be doing that. I know one person at Minnesota who is, he's like 86, 87, he still goes in every day 'cause it's really his hobby. I also, it's kind of like cooking, for me. I really enjoyed working in the lab. While I was in pharmacy school, I worked in a lab as an undergraduate, and I really got hooked on it. It's really amazing to-- You can't even see what's happening, and you've made these transformations. -That's how I got hooked on it.

[00:32:59] Lynch-Reichert: Glad to know about that. So, let me ask you this question. I go to Europe frequently, and it always surprises me that in Europe, there are drugs I can get over the counter that are only available here by prescription and vice versa. I remember, this was many years ago, but I would take for my sinuses an over-the-counter medicine, which now is not, but at that time it was over-the-counter. And I remember going to the doctor, in Holland at the time, and he said, "Where did you get this drug?" like it was something terribly illegal. And I said, "I got it at the grocery store." Why such a difference between our countries, as far as how they view these medicines?

[00:33:43] Woster: Well, every country has their version of the FDA. The European Union has one, and then all the member countries have their own. And they just have differing opinions on what things should be available and what aren't. I think in some cases in the US, they're somewhat restrictive. Antibiotics is a good example, but they're trying to prevent the overuse of antibiotics because it leads to resistant strains. So it makes sense to me. But I was in Russia and got an infection and needed penicillin, and I had to go in and figure out how to get it. And they just gave it to me.I mean, there was no doctor involved.

[00:34:19] Lynch-Reichert: Wow.

[00:34:20] Woster: So, in Russia, they have a different attitude towards that. It just has to do with the governing organizations -and how they view things.

[00:34:29] Lynch-Reichert: It's not some sort of-- What I thought at the time was that our FDA was, perhaps, much more stringent than other countries. Do they talk to each other, these governing bodies? Especially with the COVID-19, I'm very curious about that then.

[00:034:44] Woster: Yeah, they do. It depends on their situation. For example, this Emory drug that we were just talking about, they've already licensed that for emergency use in India because they have this huge problem with COVID there.

[00:34:59] Lynch-Reichert: Oh!

[00:35:01] Woster: So, yeah, they talk to each other. When we file patents for a new technology in drug discovery, new molecules, or whatever, generally we will file an international patent organization. There's an organization that oversees all the patents -in the world, basically.

[00:35:20[ Lynch-Reichert: Hm!

[00:35:21] Woster: It gets kind of complicated because at some point, you have to decide what countries you want to market in. So nobody is going to pick a country like the Congo, or some place like that because of the-- So, you pick Germany, Japan, European Union countries, Australia. And then you have a process in each one of those countries, so it gets to be very expensive and very complicated. There's milestone payments you have to meet, you have to renew every year. So they have people in the pharmaceutical industry, that's all they do is take care of those patent milestones and preparing things. But through that process, you can see what the regulations are in different countries.

[00:36:06] Lynch-Reichert: So you become very familiar with that. What you just stated, though, also goes back to what we talked about earlier. Those countries who have no infrastructure, or good, strong governmental compliance going on, they continue to suffer. And we're a global economy. So, at some point in time, for those who are not able to get the kind of drugs that we have available to us here, eventually, it's going to hurt us anyhow, right? I mean, that's what happened with COVID. People travel, people go exotic places, and then they come back with an illness. Luckily, we have great people that make some quick vaccines, but there's something kind of unsettling about this, that only the wealthy countries have access to-- -What are you thoughts?

[00:37:00] Woster: Yeah, I agree with you. In my lab, we've worked on a number of what you would call third-world diseases. We used to have a program for African trypanosomiasis. It's not anything we get in the Northern Hemisphere, but it kills about 500,000 people a year. Malaria kills about two million people a year, but we don't get malaria in the United States. We will, as global warming continues. So, yeah, we need to be more aware of what's going on there. But we have programs in malaria. If you go to these places and look at the people, it just breaks your heart because they have no means to-- The way they combat trypanosomiasis in African countries, in the rural areas is they, they soak cloth in DDT and hang it in their window, and that keeps the mosquitoes out, or whatever the bug is. In this case, it's a tsetse fly. But they keep the bugs away. So they're more doing vector control, killing the bug rather than trying to cure the disease.

[00:38:13] Lynch-Reichert: What do you see as the future of-- Actually, I'd love to bring your student in. Catherine, would you-- would you have a moment to talk with us? I'd like to know, from the standpoint of a student, A) why did you choose medicinal chemistry to study, and what do you see as the future? What are you hoping to be your career highlights from your study?

[00:38:39] Catherine (Student): What is the draw-to medicinal chemistry?

[00:38:42] Lynch-Reichert: Yeah!

[00:38:44] Catherine (Student): So, I had a choice to just pursue chemistry or to do more of a medicinal chemistry program with Dr. Woster. With the traditional just chemistry program, you're just synthesizing compounds. You don't get the cool side, where we actually get to test our compounds in a biological assay. That really-- it fuels the creativity. So, to me, it's design. It's almost like art, you're designing your compounds to a target. And then, eventually, you get to see the effect of that design that could potentially help someone. So, one of our projects, we're focusing on a rare disease, a pediatric disease, neuroblastoma, which doesn't get a lot of attention because it is rare, -but it's—

[00:39:36] Lynch-Reichert: It's fatal.

[00:39:37] Catherine (Student): Yeah, it's terrible. And we've come a long way in therapeutics for these children, but it's still-- the current treatment, these kids have to have a morphine infusion with the drug because it's just so painful. And so, that's one of the things that we're working on, is trying to maybe develop something that can help improve efficacy of therapeutics that are already on the market. So, for me, it's the creativity, but also the inspiration of the potential patients that you can help.

[00:40:19] Lynch-Reichert: Glad we have you here for sure, and I love the fact-- Catherine is-- Catherine is with us because she, too, is very much interested in trying to communicate to the public about the science and what a difference it makes in folks' lives. So she's got a lot of multitasking going on. Talking about neuroblastoma, and, again, I'm just sharing my ignorance, but I was reading something recently about the blood-brain barrier. When you guys are developing these drugs, do you also develop the way that they will get into the body? Or somebody else does that?

[00:40:56] Catherine (Student): So, that's something that we start early on in the process. So, there are five different parameters when you're developing a drug. So, solubility, blood-brain barrier penetration is one of those parameters that you can focus on. So it's basically kind of the pharmacology of how the drug is going to go through the body, and where it's going to be taken up in certain organ systems. So you think about that process early on.

[00:41:23] Lynch-Reichert: So you actually, you're not just designing drugs or biologics, you guys have to think about-- you go beyond just doing the chemistry. That's really fascinating. I didn't even think about that.

[00:41:30] Catherine (Student): Yeah, you have to think about the size of the compound, so that's important. How many carbons are in there? How many oxygens are in there? How many hydrogens? What are the hydrogen-bonding-- how many hydrogen bond donors or acceptors you have in the compound. That's really going to impact where your drug goes and how effective it's going to be. So you have to think about that early on, because you also-- To market and develop later, is it going to be an IV administration? Or is it going to be-- have oral bioavailability? So those are different things that we have to--

[00:42:07] Lynch-Reichert: How long is the program? Your program of study, how many years? Is that a four-year? Three, four-year?

[00:42:14] Catherine (Student): I'm going into my fourth year. But we love what we do, so... And we do--Dr. Woster, we do two full years of courses leading up to it. There's a lot of drug discovery, and Dr. Woster, he organizes all of the courses for us. And we do a lot of discussion weekly in lab meeting. So it's a constant process, but we love it, so...

[00:42:43] Lynch-Reichert: I'm so glad to hear that. You're right, it's not just having a certain ability to do this stuff, as you noted, Catherine, it's that creativity, it's the artistic part of it that probably brings forth the most success, I would guess. As you said, you could do chemistry, but this takes you to a higher level all together, and it does require a little something else to get to where you have a product that's going to help people.

[00:43:15] Catherine (Student): Well, we have a good PI. So, not many people can say that--every time I get data, I'll run down to his office, and kind of barge in and say, "Look what I got!" And I get really excited.-It keeps the ball rolling.

[00:43:28] Lynch-Reichert: Absolutely.

[00:43:29] Catherine (Student): Not many students can say that they're able to do that with their PI.

[00:43:31] Lynch-Reichert: Absolutely agreed. You're right, I've known Dr. Woster actually for a while, and he's a very generous soul, on top of really enjoying his work. Also has a great sense of humor...

[00:43:42] Catherine (Student): Yeah, we love that.

[00:43:43] Lynch-Reichert: ...as I recall.

[00:43:44] Catherine (Student): We have lots of jokes in lab meeting.

[00:43:45] Lynch-Reichert: So I want to thank you both so very much. Dr. Woster, our-- actually want to say it again, because it's just too much fun-- a fellow of the Royal Society of Chemistry, and an inductee into the American Chemistry Society's Medicinal Chemistry Hall of Fame. Those are big accolades. And, Catherine, you're quite lucky to be in this person's lab, working with such a prestigious person.

[00:44:11] Catherine (Student): I am!

[00:44:12] Lynch-Reichert: I want to thank you guys so much for a wonderful, entertaining, and informative conversation today. And, again, it speaks to the opportunities at MUSC, because we are an academic health center, and we get our students involved in really great work to go out into the world to make a difference. And that is so important. And can't thank you enough. There's so much more I'd love to speak with you about, but time's running out. So, thank you both so very much. Appreciate it.

[00:44:45] Woster: Thanks for the opportunity.

[00:44:46] Lynch-Reichert: You're very welcome. And to our listeners, join us again for another Science Never Sleeps podcast, and stay safe and healthy.