Aarati Asundi (00:12) Hi everyone and welcome back to the Smart Tea Podcast where we talk about the lives of scientists and innovators who shape the world. I'm Aarati. Jyoti Asundi (00:20) And I'm her mom Jyoti. Aarati Asundi (00:21) I am so excited, Mom, to tell you today's story because we are going to be talking a bit about drug development, which is right in your current wheelhouse. Jyoti Asundi (00:32) Absolutely that is exactly where I earn my bread and butter. And a bit of jam. Aarati Asundi (00:40) I was like, you know, drug development to me does not sound super exciting and fantastic, but this story has changed my mind. I am like, this is actually amazing. This is so cool. Jyoti Asundi (00:52) It's funny that you say that that drug development doesn't sound so exciting. That perception definitely exists that the creative genius has already been performed. Now it is just a matter of the donkey work, you know, plugging it in, making it go. But actually there are so many components to it and the translatability of an idea from concept to clinic requires a lot of thought, a lot of structure and adhering to the safety guidelines the toxicology guidelines, the pharmacokinetics, there are so many aspects to it. It's not an easy task. Aarati Asundi (01:32) Yes, this is going to be actually an incredible story. So if you had any misconceptions or preconceived notions about what drug development is, throw it all out the window. We are diving into the story of an incredible scientist named Gertrude Elion Jyoti Asundi (01:51) Okay. Aarati Asundi (01:52) So I'm taking it that you have not heard of her name before. Jyoti Asundi (01:56) No I have not. Aarati Asundi (01:57) Okay, well that's about to change. She's gonna be one of your new favorite people, I think. Jyoti Asundi (02:03) Awesome. Aarati Asundi (02:04) So Gertrude was born in New York City on January 23rd, 1918, to Robert and Bertha Elion. Robert had immigrated from Lithuania when he was a teenager, and Bertha had also immigrated from Poland when she was a teenager. Robert was a successful dentist, and so when Gertrude was born, the family lived in the small apartment next to his dental practice. When she was three, her grandfather came to live with them from Europe, and she really, really loved him. He would tell her stories, and then when her little brother was born, her mom inevitably started spending more time taking care of this new baby. Jyoti Asundi (02:46) Yes. Aarati Asundi (02:47) And so that just made Gertrude and her grandfather become even closer. Jyoti Asundi (02:52) Aw so cute. Yes. Aarati Asundi (02:53) Yeah, they spent a lot of time together. Jyoti Asundi (02:56) I had the same experience when my little sister was born I was kind of shepherded off to my grandparents' house and me and my grandpa had a really good time together. Aarati Asundi (03:06) Had a blast. Yeah. Jyoti Asundi (03:07) Yes, we had a good time together. Aarati Asundi (03:10) Yes. There's I think that's a such a special relationship, grandfather and granddaughter. It's so cute. Jyoti Asundi (03:15) Yes. Especially because I was the first grandchild to him. So yeah, it was really special. Aarati Asundi (03:22) So as she grew up, Gertrude was an excellent student and she really enjoyed school. She wanted to pursue higher education, but she wasn't sure what she wanted to do yet. Interestingly, she said, "I think perhaps it was my mother who influenced me the most. She was a housewife. She had no higher education, but had the most common sense of anyone I knew. And she wanted me to have a career." Jyoti Asundi (03:49) Excellent. That is really good thinking for that time. For those days women were highly encouraged to make themselves matrimonial prizes rather than think about how would you live your life and have a career. I like her mother already. Aarati Asundi (04:07) I knew you would because that's also something that I tell my friends when they ask you know, why did you go for your PhD? I was like, well, you know, because my mom. It's one of my first- the first things I remember her ever telling me seriously was, I don't care what you do, I don't care what you study as long as you get your PhD in whatever it is. So look at that. I really took that to heart. Jyoti Asundi (04:28) I don't know whether- I said I don't know whether- I don't know whether I said a PhD, but I definitely told you very strongly that you needed to get yourself a career. It was more about financial independence than a PhD. Aarati Asundi (04:42) Well that's what I took it at as a kid. Like, okay, PhD's the goal. Yep, got it. We're gonna do it. And I did it. Yeah. Anyway, back to Gertrude. So she graduated from high school when she was just fifteen. However, that same year her grandfather fell sick with stomach cancer and ultimately passed away. Jyoti Asundi (05:04) Oh no. Aarati Asundi (05:05) And it was very difficult for Gertrude because she basically watched him go. She was by his bedside in the hospital for months as he suffered and was there in his final moments as well. Jyoti Asundi (05:18) That would not have been easy. That is a very painful disease actually. Even today it is horrible. The quote unquote treatment plan is really extremely drastic where you basically chop away the cancerous parts of your digestive system, sew it back up, and there are people I know within our own circle who have had that. And so then if you don't have a stomach, you are only capable of ingesting and digesting and absorbing food of a different kind, more like protein shakes and things like that that have already been broken down to a certain extent. And everything else just kind of passes through. without allowing you to absorb the nutrients. So there is severe weight loss. So in those days I can imagine it would be even worse because the pain is still there, the stomach is not functioning. That is really a slow and painful way to go. Aarati Asundi (06:16) Yes. And she was watching this and it was her grandfather whom she really loved and she decided that no one should have to suffer that much. And so she decided to dedicate her life to finding a cure for cancer. Jyoti Asundi (06:31) Yes. Aarati Asundi (06:33) So that meant that she needed to pursue an education in science and either biology or chemistry. Jyoti Asundi (06:40) Yeah. Aarati Asundi (06:41) She said she decided on chemistry mainly because she did not like the idea of dissecting things, which I was like, fair enough. Jyoti Asundi (06:46) Hmm Yes, I was very squeamish as well. I do remember dissecting frogs, dissecting earthworms. Aarati Asundi (06:55) Yes, it's not for everyone. However, her family's finances unfortunately were in shambles. This is the time of the stock market crash and their savings had been completely wiped out Jyoti Asundi (07:08) Oh no. Aarati Asundi (07:09) And we're going right into the Great Depression now, so there's not much of a chance of having the tuition fees for college. Fortunately though, thanks to her excellent grades, Gertrude was accepted into Hunter College, which was a woman's college at the City College of New York, which offered her free tuition. Jyoti Asundi (07:28) She got a break. That's nice. Aarati Asundi (07:30) Yes, yes. And she said she owed almost like her entire career to getting that break. She would not have been able to progress if she had not gotten that. She graduated summa cum laud with a BS in chemistry, and here she also met her fiance, Leonard Canter, who was a statistics student at the City College of New York. Jyoti Asundi (07:51) Okay. Aarati Asundi (07:52) Afterwards, she wanted to go to graduate school, but again, we're still in the Great Depression. Her family's finances has not yet recovered. So she tried applying for financial aid, but all of her applications were rejected because she was a woman. Jyoti Asundi (08:07) Oh, in spite of the fact that she was at the top of her class. Aarati Asundi (08:10) Mm-hmm. Yeah. Jyoti Asundi (08:11) Oh no. Aarati Asundi (08:12) And again, it's that time period where it's like you're a woman, you are gonna get married and have a family, and we're not going to put this money towards someone like you. Jyoti Asundi (08:18) Yeah, they are not going to invest in a woman because they don't expect her to go for the long haul. Aarati Asundi (08:25) Exactly. So she decided instead to try to find a job as a chemist in a research lab. This also proved very difficult. Up to that point, she hadn't really thought about the fact or realized that the path that she had chosen was an unusual one for a woman in her time. She said, "I hadn't really been aware that any doors were closed to me until I started knocking on them." Jyoti Asundi (08:53) Oh my goodness. That's terrible. Yes, the discrimination is what is making her aware that as a woman she's being treated differently. Aarati Asundi (09:03) Yeah, she really thought like, "Hey, if I get good grades and, you know, do the work, then I should be able to move up. Like what's the problem?" Jyoti Asundi (09:11) That's the normal behavior of that would be expected. Aarati Asundi (09:14) That is how it should be. Jyoti Asundi (09:17) Exactly. Aarati Asundi (09:18) Yeah, and many labs outright refused to hire a woman because that age old sexist thing of they thought she would be a distraction to the other men in the lab. Jyoti Asundi (09:28) We ran into that one with the Kamala Sohonie actually. Where her mentor, Professor Raman, was saying that that she would be taken on only if she promised that she would not distract the men. And it's like, how about asking your men to behave themselves? Aarati Asundi (09:45) Yes, and not get distracted Jyoti Asundi (09:47) If they are so distractable, maybe they should be the ones who were left out of the program because they have such fickle minds. Aarati Asundi (09:53) Yeah. And that's what Gertrude was like, "I'm just here to work. Like, what do you mean be a distraction?" Jyoti Asundi (09:57) Yes that's right. Aarati Asundi (10:00) I want to do research. I want to do chemistry research. Like, I'm not going to be spending my time trying to... Jyoti Asundi (10:06) Distracting people. Yeah. Yeah. Aarati Asundi (10:08) Yeah, distract people. So now at this point she's desperate for money. So she started going to secretarial school. But six weeks in, she was offered a temporary position working as a biochemistry teacher at the New York Hospital School of Teaching. And she had realized pretty quickly that being a secretary was not for her. Jyoti Asundi (10:28) Absolutely. Aarati Asundi (10:29) So she dropped out and she took the job, even though that meant that just three months later she was out of a job again, because it had been a temporary position. Jyoti Asundi (10:37) Okay. Aarati Asundi (10:38) But as luck would have it, she was one day at a party where she met a chemist. And asked if he would take her on. And he said yes, but he couldn't pay her. And she was like, that's okay, you know what? I need the experience anyway, and I'm not getting any other jobs, so rather than sit around and, you know, twiddle my thumbs and not make money... Jyoti Asundi (10:59) Mope about it. Yes. Aarati Asundi (11:00) I might as well get experience and not make money. So sure, let's do it. Jyoti Asundi (11:04) Yes, yes. And in the line that she wants to be in, rather than making money as a secretary, let her at least do something that she's interested in doing. That makes sense. Aarati Asundi (11:13) Yes, exactly. So she stayed there for a year and a half, and somewhere along the road she did actually end up getting a small salary of twenty dollars a week. Jyoti Asundi (11:23) Okay. Aarati Asundi (11:24) And using this she was slowly able to save up enough money to enroll in night classes that would count towards getting a master's degree in organic chemistry at New York University. Jyoti Asundi (11:35) Yes. Aarati Asundi (11:36) And then during the day she taught high school to continue earning money. She graduated in 1941 with her master's, but tragically the same year her fiance, Leonard Canter, died from bacterial endocarditis, which was an infection in his heart valve. Even more tragically, just a few years later, penicillin became widely available and that would have cured him. Jyoti Asundi (12:03) Oh just a small... just a very short... Aarati Asundi (12:05) Just a few years, Jyoti Asundi (12:06) It is tragic though that she's losing so many people so close to her to medical illnesses and she's just standing by helplessly watching. History repeating itself for her. Aarati Asundi (12:19) Yeah. After his death, Gertrude never got married or had any children. She said that if she had, her life might have taken a very different path because back then, and I mean even today, it was very difficult for a woman to have both a career and a family. Jyoti Asundi (12:35) That is true. Aarati Asundi (12:36) And she says that if she had gotten married, she might have ended up going down the family route. Jyoti Asundi (12:41) Makes sense, yeah. That pressure definitely existed in... in fact you know, I remember when I came out of college and tried for my first job, that those were the types of questions that I was being asked. Are you planning to be married soon? Things like that. They would judge me on that. Aarati Asundi (12:59) Yeah. Yeah. Jyoti Asundi (13:01) And it is so totally illegal at this point, but... Aarati Asundi (13:04) Yeah, slowly culture is changing. Like now it's like none of your business. Why does it matter to you? Yeah, it doesn't matter. Jyoti Asundi (13:09) At least in America it's illegal to ask those questions. Aarati Asundi (13:15) Yeah, so like you were saying, it was very hard that she was losing these people. But this loss just reinforced her decision even more to pursue science and pharmacological research in order to treat diseases. Jyoti Asundi (13:30) Makes sense. Aarati Asundi (13:31) Again, though, she found it very difficult to pursue a PhD, despite her ambition and clearly strong academic record. So she again looked for a job and found a position as a chemist at A&P supermarkets as a food quality supervisor, testing the acidity of pickles and the color of mayonnaise. And, she was like, okay, that was kind of cool because it taught her some instrumentation use, but ultimately not very fulfilling 'cause she's not really working on... Jyoti Asundi (14:02) Yeah, because it's not really... it's- it's not a position that would allow her to fulfill her full potential. Aarati Asundi (14:09) Yeah. And so she was like, I need to get back into kind of chemistry and research. So she found another job at Johnson and Johnson, which sounded much more promising, but ultimately it ended up that she was just testing the strength of surgical sutures by hanging weights on the end of them and seeing how much weight it took until they broke. Jyoti Asundi (14:32) That sounds once again like quality control. Aarati Asundi (14:34) Yeah, not very exciting work at all. Jyoti Asundi (14:37) Yeah, it's more routine where everything else has already been put in place, the framework exists, she just has to implement the checks. It's like a checkbox, yes, this works, this works, reject this batch, accept this batch kind of thing. And for a person with so much more to offer, it is not enough. Aarati Asundi (14:57) Yeah. So then one day her father, the dentist, said, "Hey, I'm using this pain medication on my dental patients that was made at the Burroughs-Wellcome Pharmaceutical Company," (which eventually became Glaxo Klein Smith, FYI) "and they have a location in New York, not too far from home. So why don't you see if they have a job opening?" So she inquired and was told that in fact there was an opening for an assistant to Dr. George Hitchings, who ran a very small biochemistry department at Burroughs-Wellcome. Dr. Hitchings was a very rare person in that he honestly didn't care if you were a man or a woman, and in fact he did have another assistant who was a woman. Jyoti Asundi (15:43) Oh that's nice. Aarati Asundi (15:44) Yes. So she interviewed with him and a week later was offered the job. Jyoti Asundi (15:52) Her first break. Or second break, sorry. This was her second break. The first one was where she... Aarati Asundi (15:57) Was the education. Jyoti Asundi (15:58) She earned a scholarship actually. So- but the scholarship was offered to a woman, so that's itself is a break. And now this is her second one from Doctor Hitchings. Aarati Asundi (16:08) And honestly, you know, it may have also helped that World War II was starting and so a lot of young men who might have otherwise been her competition were leaving for the war. But it did seem that Dr. Hitchings was a very fair person. Jyoti Asundi (16:24) Awesome. Aarati Asundi (16:25) So Gertrude joins the lab and she even started getting her PhD in chemistry. So she started taking night classes at the Brooklyn Polytechnic Institute. But after two years, the dean told her that she had to quit her job at Burroughs-Wellcome if she was serious about getting her doctorate. Jyoti Asundi (16:44) Hmm. Aarati Asundi (16:45) She was very reluctant to do this because she had finally gotten a job that she had actually wanted and enjoyed. So she talked it over with Dr. Hitchings and he said, "Look, you don't really need a doctorate to do all the things that you want to do." Jyoti Asundi (17:01) Okay. Aarati Asundi (17:02) So she trusted in him and she gave up on getting her PhD. Jyoti Asundi (17:06) Okay. Aarati Asundi (17:07) So now Dr. George Hitchings and Gertrude are working together and they decided to try a new approach to drug development. So what scientists were doing at the time was they would find a chemical compound that seemed to have some beneficial effect. So for example, like take the classic penicillin. The scientist Fleming found that it killed bacteria in a petri dish. Does it also kill bacteria in animals? Yes, it does. So now we have a drug that can treat infections caused by bacteria. So that's what scientists essentially were doing. They were finding a chemical compound that did something in the lab. They would then test it in animals and humans. And if it worked, then great. And if it didn't, they would go and try and find another compound. Jyoti Asundi (17:53) Wow, two step drug development. This is incredible that we are so far away from that today. Because there is so many things you're missing with this. It's incredible. The safety, the side effects, what else is happening in long term, what is happening if a pregnant woman gets it, what happens to the fetus, and we saw stories. We have done stories where we have looked at that also. All right, but I don't want to I don't want to just take over. So please go on. Aarati Asundi (18:21) So Gertrude and George decided to try flipping this around and use what we now call rational drug design. Jyoti Asundi (18:31) Okay. Aarati Asundi (18:32) So instead of screening a bunch of chemical compounds, they decided to try and work backwards based on what they knew the disease did. So they reasoned that in diseases like cancer, for example, the tumor cells were growing rapidly out of control. Jyoti Asundi (18:50) Yes. Aarati Asundi (18:50) But for cells to be able to divide, they need some essential building blocks. You have to understand the time period that we're in here and how little we know about cellular pathways and which enzymes are important, or how cell proteins interact with each other to sustain life and reproduce. But one of the key things that they did know was that nucleic acids were important for cell division. They knew that nucleic acids made up DNA and RNA, although we still hadn't figured out the exact structure. Watson and Crick and Roslyn Franklin would figure that out in 1953, so we're not quite there yet. Jyoti Asundi (19:31) Okay, we are not quite there, but at least this much is known that the DNA and RNA, the building blocks, are these nucleotides. Yes. Aarati Asundi (19:39) Yeah, nucleic acids make up DNA and RNA, and those are essential for cell division So they reasoned: if that's the case, then it makes sense that tumor cells which are dividing out of control would need more nucleic acids than normal cells. So maybe if they were to make a chemical compound that looked like a nucleic acid the cancer cells would pick it up and try to divide with it. They would try to incorporate it into their DNA, but they wouldn't be able to, and so the cancer's biochemical pathway would be disrupted. Jyoti Asundi (20:15) Thei're basically creating a decoy nucleic acid. And the cancer cells will pick up the decoy and their whole pathway will stall... Aarati Asundi (20:25) Yes. Jyoti Asundi (20:26) ...because they are not now able to incorporate the decoy correctly. Smart thinking. Aarati Asundi (20:29) She and Dr. Hitchings started synthesizing hundreds of nucleic acid variants and testing them in different types of cells to see how they worked. Jyoti Asundi (20:40) Okay. Aarati Asundi (20:41) Some of them worked in bacteria, some of them worked in mice tumor cells, and some worked in human tumor cells. Jyoti Asundi (20:48) Okay. Aarati Asundi (20:48) And if they found a compound that worked well in tumor cells, they would try derivatives of it to see if they could get something better. So there's a bit of trial and error going on here. Jyoti Asundi (21:00) Yeah, with the chemistry they're making libraries of compounds that are similar to each other. I get it. Aarati Asundi (21:07) Based on what's working and what's not. So then in 1950 they synthesized a particularly promising molecule called 6-mercaptopurine or 6- MP. So this is gonna be a bit of a review for you, but just for our listeners so the nucleotides that make up our DNA are A, G, C, and T. Jyoti Asundi (21:27) That's adenosine, guanosine, cytosine, and thymidine. Yeah. Aarati Asundi (21:33) So these nucleotides come in two different ring structures. There's purines and there's pyrimidines. So purines are A and G. And so 6- mercaptopurine was a variation of the ring structure that these two bases use, that A and G use. Jyoti Asundi (21:53) They were decoys for purines, the A and the G. Aarati Asundi (21:56) Yep, so that's where purine comes from in 6-mercaptopurine. And mercapto means that it has a sulfur atom that replaces what would normally be an oxygen. And 6 means that it's in the sixth position of the purine ring. Jyoti Asundi (22:12) Yes. Aarati Asundi (22:13) So this one small change of an oxygen atom into a sulfur at the sixth position allowed 6-mercaptopurine to resemble naturally occurring purines, but they didn't behave normally. So theoretically, then it should interfere with tumor cells. Jyoti Asundi (22:32) Correct. Aarati Asundi (22:33) And sure enough, when they tried it in animal models, it seemed to be particularly promising for leukemia. Jyoti Asundi (22:39) Okay. Aarati Asundi (22:40) The compound was released under the name Purinethol and was quickly administered to patients, particularly children who had a very poor prognosis. And remarkably the patients who were given 6- mercaptopurine went into complete remission. Jyoti Asundi (22:55) Wow. Aarati Asundi (22:56) So at first they were thrilled. They were like, this is a great success. Jyoti Asundi (23:00) Okay. Aarati Asundi (23:00) But then six months to a year later the cancer came back and children started dying again. Jyoti Asundi (23:07) Yes. That is the story of cancer even today. You know, few cancer cells get left behind. You can't completely eradicate them without killing the normals because the cancer cells, you know, basically are your own cells who have gone rogue. So the rogue cells are well mixed with the good cells of your body and killing only the rogue cells specifically without creating... Aarati Asundi (23:31) I think this was slightly different though. It wasn't quite like that. Cause like now today if you have an actual cancer therapy that actually works, many people will stay in remission for a long time, like and it'll be like cancer is gone, it's cured, and it won't come back. But some people will relapse or some people will come, you know, back. Jyoti Asundi (23:50) Refractory. Because the cancer becomes refractory. It's not responding to the drug anymore. Aarati Asundi (23:56) But in this case, it was like the drug starts working, but then six months later it stops working for some reason. Jyoti Asundi (24:01) Okay, got it. Okay. Aarati Asundi (24:02) So it's a little bit different than just cancer, you know, coming back. It's like the drug has stopped working. Jyoti Asundi (24:09) Okay. Aarati Asundi (24:09) Gertrude was crushed, but she was like, we're on the right track though. The drug did help at first, but now something must be happening to the drug in the body. Jyoti Asundi (24:21) Yeah. Aarati Asundi (24:22) So she started to study it and she realized that the body actually metabolizes or breaks down 6-mercaptopurine. Jyoti Asundi (24:31) Uh-huh. Aarati Asundi (24:32) Because 6-mercaptopurine is not a targeted therapy, normal cells are actually being affected by it. Jyoti Asundi (24:41) Correct Aarati Asundi (24:41) And eventually the body does realize this and then starts to get rid of it. Jyoti Asundi (24:46) Yes, the body is washing it out, saying this is not what we want. Yeah, got it. Aarati Asundi (24:50) Yeah. And so Gertrude was like, okay, so in that case we need to make a compound that is more specific to tumor cells. So she and Dr. Hitchings went back to the drawing board and experimented with making derivatives of 6-mercaptopurine. And one of the compounds that they came up with was very interesting. It was called azathioprene. And essentially it was a protected form of 6-mercaptopurine Jyoti Asundi (25:22) Okay. Aarati Asundi (25:23) So azathioprene could be administered to the patients and then it was metabolized in the body into 6-mercaptopurine. Jyoti Asundi (25:33) So azathioprene is actually a prodrug. Aarati Asundi (25:37) Exactly. Exactly. So the body breaks it down into the effective drug. Jyoti Asundi (25:43) Okay. Aarati Asundi (25:43) And it actually turned out to be more effective against leukemia because instead of this 6-mercaptopurine that was metabolized very quickly, azathioprene converted more steadily into 6-mercaptopurine over time. Jyoti Asundi (26:00) Yes. Aarati Asundi (26:01) And so essentially what Gertrude was doing with this was that she was changing how and where the drug got distributed in the body. She was changing the timing and the distribution. Jyoti Asundi (26:13) Yes, the slow release is helping and the body is not quickly learning to identify this as something that is useless, wash it out kind of thing. Aarati Asundi (26:23) Yeah. The it's going into the body kind of protected. Jyoti Asundi (26:26) Yes. Aarati Asundi (26:28) But what was even more interesting was that at the time another scientist wrote to them and said that they had looked at 6-mercaptopurine's effect on the immune system in rabbits, and they had found that it actually acted as a mild inhibitor of immune response. Jyoti Asundi (26:46) Oh it brings down the immune response, I see. Aarati Asundi (26:49) Mm-hmm. So Gertrude was like, huh, that's interesting. I wonder if any of the other derivatives I have might also suppress the immune response. Jyoti Asundi (26:57) Yes. Aarati Asundi (26:58) And so she set up a screen in mice and she found that sure enough, azathioprene was also a stronger immune response inhibitor. Jyoti Asundi (27:07) Oh okay. Aarati Asundi (27:08) Yeah. So it's very important to note Gertrude and Dr. Hitchings definitely had not set out to make an immune response inhibitor. That was not a problem they were trying to solve. Jyoti Asundi (27:18) That was not- that this is just serendipity, they're just on the side they are finding it. that something else is happening. Their main aim is something else. This is like that they boarded a train to Saint Louis and found themselves in Florida, that Yes. Aarati Asundi (27:32) Yeah, but they went with it and they were like, huh interesting. Okay, let's Let's see what this about. Jyoti Asundi (27:38) True scientific curiosity. Aarati Asundi (27:40) Yeah. So then when a young surgeon came to them and said, Hey, I've been testing out using 6- mercaptopurine on kidney transplants in dogs, and when I give them this drug, the rate of organ rejection is much lower. Jyoti Asundi (27:56) Ooh yes, a completely different application now. Aarati Asundi (28:00) Exactly. So you're doing an organ transplant, and in order to avoid the body rejecting the new organ, you want to suppress the immune system. And so that's what this surgeon is trying to do with six mercaptopurine. But he he came to them and said, "Do you happen to have a better immune suppressant that I could test out?" And Gertrude was like, "Well, it just so happens...." Jyoti Asundi (28:23) Yes, please try this new drug that we have come up with. Aarati Asundi (28:28) Yeah. Try azathioprene and see how it goes. And sure enough, it worked even better to reduce organ rejection than... Jyoti Asundi (28:34) Wow, that's great. Aarati Asundi (28:36) ...6-mercaptopurine did. And soon azathioprene was being marketed as Imuran and made organ transplants in people possible for the first time ever without using total body irradiation or corticosteroids. Jyoti Asundi (28:52) Oh my god that is a huge breakthrough! Aarati Asundi (28:55) Huge. Yeah. Jyoti Asundi (28:56) That is a huge breakthrough! Aarati Asundi (28:58) Like I did not realize like until then if you had a organ transplant in order to like improve your outcomes, you had to basically go through full body irradiation in order to suppress your immune system. Jyoti Asundi (29:11) That's right, otherwise your body is just like "Intruder alert, intruder alert!" and shutting the new system down. It's like "This is not mine, not mine. Get it out of here!" and your own immune cells attack it and throw it away. So you do have to calm down the soldiers of your own body and say, "Let it be, please allow this intruder to stay so that we have a healthy kidney." Aarati Asundi (29:34) Basically just by keeping an open mind and exploring all the possibilities, Gertrude and Dr. Hitchings ended up making this really huge contribution in a field that they had not really meant to get into in the first place. Jyoti Asundi (29:49) Brilliant. _______________________________________________________________________________________ Aarati Asundi (29:56) Hi everyone, Aarati here. I hope you're enjoying the podcast. If so, and you wish someone would tell your science story, I founded a science communications company called Sykom, that's S-Y-K-O-M, that can help. Sykom blends creativity with scientific accuracy to create all types of science, communications, content, including explainer videos, slide presentations, science, writing, and more. We work with academic researchers, tech companies, nonprofits, or really any scientists. To help simplify your science, check us out at sykommer.com. That's S-Y-K-O-M-M-E-R.com. Back to the story. _______________________________________________________________________________________ Aarati Asundi (30:43) So then in 1953, Watson and Crick published their model of DNA, which of course relied heavily on Rosalind Franklin's X-ray diffraction data. Jyoti Asundi (30:52) Yes. Aarati Asundi (30:53) And this was huge for Gertrude and George Hitchings because now they could much better understand what was happening when they were replacing these nucleotide bases with their compounds. They could actually really start to understand why exactly the DNA couldn't divide or why the DNA tried to incorporate it, couldn't incorporate it, or did incorporate it, but then it had a weird shape that prevented enzymes from recognizing it. Like what's going on exactly? Jyoti Asundi (31:25) Yeah, they're not just shooting in the dark anymore, correct. Aarati Asundi (31:28) Yeah. So now because of this, all of a sudden everyone is sitting up and recognizing that, hey, these nucleic acids are really important and Gertrude and George are really on to something. They're not just playing around. And especially with the success of azathioprene, money started coming into the lab from the sales. And that was put right back into research. And so the lab now started to grow. Gertrude was put in charge of synthesizing purines and another person took over the pyramidines. And soon Gertrude had numerous assistants working under her. Jyoti Asundi (32:03) That's really nice to hear that even without her PhD they recognized true talent and rewarded true talent. Aarati Asundi (32:12) Yeah. Again it goes back to kind of also Dr. Hitchings just being kind of a one in a million boss. So he kind of took over the administrative part of the job. So I think technically Gertrude did report to him, but Gertrude at that point felt it was very much more of a partnership than he was the boss and told her like what to do. It was like that in the beginning, of course, when he first hired her, she was the assistant. But, you know, over time it kind of developed into a much more equal partnership where he encouraged her to follow whatever she was interested in, encouraged her to ask questions and spend time on the projects that she wanted to spend time on. Jyoti Asundi (32:53) Yes. Aarati Asundi (32:53) And so now with the larger team, Gertrude was able to start probing all sorts of different diseases. Jyoti Asundi (33:00) Yes. Aarati Asundi (33:00) And use this rational drug design approach on them. Jyoti Asundi (33:04) Okay. Aarati Asundi (33:05) And so now this is where we're getting into kind of what we do more modern day. She would spend time trying to understand the differences in the biochemical pathways between normal healthy cells and the diseased cells. So, what are these two cell populations doing differently? And then she would try to create drugs that specifically disrupted the diseased biochemical pathways. Jyoti Asundi (33:30) So basically it's like you're targeting the mechanism of action of the disease. MOA we call it in drug development. Like are you targeting the way the exact pathway that the disease is taking or is it just happening to kind of mitigate the disease by some random unspecified methods without actually addressing the underlying cause of the disease? That's something that we think about strongly in drug development. Aarati Asundi (33:56) Yeah, because in diseases a lot of these biochemical pathways are deregulated somehow. They're either producing too much of something or too little of something. Something is blocked, something is going out of control... Jyoti Asundi (34:07) Mainly because our body has a lot of redundancy built into it. Our chemical pathways have a lot of redundancies built into it. So that some alternative mechanism takes over. It's like, "Oh you didn't make this- what I needed- this way? Okay, then I'm going to go approach it another way and make it happen anyway." That kind of thing. Aarati Asundi (34:25) Mm-hmm. And so again, this is like kind of a new era or a new way of drug development and you know finding drugs in this time. So using this approach, Gertrude and her team were able to create drugs like allopurinol, which was a treatment for gout. I'm gonna struggle with some of these names... Pyramidamine Pyramidamine. Pyramidamine. Jyoti Asundi (34:52) Pyramidamine. Aarati Asundi (34:54) Yeah, Pyramidamine, which was for malaria, and Trimethoprim, which was for bacterial infections. In 1967, Gertrude was made head of the Department of Experimental Therapy for Burroughs-Wellcome. Jyoti Asundi (35:08) Oh wow, good for her and good for them! Aarati Asundi (35:10) Yeah. And that kind of gave her the power to steer the ship in another new direction. So around this time another interesting field was opening up. Gertrude had heard of a compound called adenine arabnoside, which was isolated from a sea sponge. And this compound was a version of a purine that had a sugar group that was attached to it. And it had antiviral properties. Jyoti Asundi (35:41) I see. Aarati Asundi (35:42) This was very interesting to Gertrude because at the time the prevailing theory with scientists was that since viruses basically are bundles of nucleic acid, there's no way to really go after them because any drug that you made would have to target nucleic acids, which would inevitably target normal cells and cause toxicity. Jyoti Asundi (36:05) Yes. Aarati Asundi (36:06) Yeah, so I didn't realize this at the time, but apparently people just kind of thought you couldn't combat a virus. But adenine arabnocide had a better therapeutic index than any antiviral compound so far. It was less toxic than anything that they had come by. And it wasn't great, but it's a purine, and Gertrude is an expert on manipulating purines. Jyoti Asundi (36:31) Yes. Aarati Asundi (36:33) So in 1970, a scientist named Dr. Howard Schaefer came to the Burroughs-Wellcome Lab and he teamed up with Gertrude to make a version of a guanine, so that G in DNA, that had a sugar side chain attached to it that had incredibly high activity against herpes virus and very low toxicity. Jyoti Asundi (36:55) Wow. Aarati Asundi (36:57) They were blown away by the data when they saw it, and they called the compound acyclovir. Jyoti Asundi (37:02) Oh okay. We are stepping into familiar territory in the modern day world. Okay. Aarati Asundi (37:09) Yes. But then came the harder bit of actually figuring out why. So they had made this compound, they found that it worked really well against herpes virus. It had very low toxicity, but they didn't know why. What was the mechanism of action, the MOA? Jyoti Asundi (37:24) Yes, yes. Aarati Asundi (37:27) So they dug into that and it turns out that acyclovir is actually activated by the herpes virus itself. Jyoti Asundi (37:36) Oh! Very unusual, very interesting. Aarati Asundi (37:36) Yeah. So the herpes virus has an enzyme called thymidine kinase that attaches phosphate groups to acyclovir. Once acyclovir gets those phosphate groups onto it, it looks a lot more like a normal guanine block that is used to build DNA, and so the virus then tries to use it to replicate. Jyoti Asundi (37:59) Yes. Aarati Asundi (38:00) But the trick is that acyclovir is missing one little chemical group on the end of it, which means that another nucleotide cannot be added to it, so the DNA chain stops. Jyoti Asundi (38:12) It truncates the DNA growth, Okay. Very smart. Aarati Asundi (38:14) Yep. On the other hand, the reason it doesn't affect healthy cells that are uninfected by the virus is because healthy cells have the human version of thymidine kinase, and the human version of thymidine kinase does not recognize acyclovir in the same way as the virus does. Jyoti Asundi (38:31) How clever how clever! Aarati Asundi (38:34) Yeah. And so it never adds those phosphate groups on, and so the cell never mistakes acyclovir for the guanine base that can be added into DNA. Jyoti Asundi (38:42) Fantastic. Aarati Asundi (38:43) Yeah, so it was a remarkable breakthrough. Acyclovir was approved in 1977 and used to treat herpes, Epstein Bar, Chicken Pox, and Shingles. It was the world's first antiviral medication. And again, this sparked a revolution of everyone jumping on the antiviral bandwagon. Jyoti Asundi (39:06) Yes. Aarati Asundi (39:06) But Gertrude made the point that creating acyclovir was really a much smaller part of the puzzle. Understanding why it worked and showing that the viral enzymes and the biochemical pathways are different in the virus versus the human and we can exploit that. That was what was truly important and what really made antivirals possible. Jyoti Asundi (39:32) Yeah, you're targeting that very selected difference between the virus and the human biochemistry pathways. And that small differential between the two pathways is where our drug is going in and doing its good work. Aarati Asundi (39:49) Yeah. And so again, she's not like, yeah, we came up with like a bunch of compounds, we screened them all, and then we came up we just like acyclovir just happened to be one of them. Jyoti Asundi (39:56) Yeah. It just so happened, whatever, yeah, yeah. Aarati Asundi (39:59) Yeah, and we don't care why or how. It's like, no. Jyoti Asundi (40:00) No. This is a very targeted... Aarati Asundi (40:01) We figured out why. Cause she could have stopped there. She could have stopped like they had made acyclovir and they found that it worked great and they could have stopped there, but she actually went back to discover how it worked, what was the mechanism of action. Jyoti Asundi (40:17) And because of that the whole thing becomes like a surgically precise attack and catching just the virus and not the other good cells that you don't want to target. Aarati Asundi (40:29) Yes. And then this way of thinking is what later led the group at Burroughs-Wellcome to invent the first antiviral to treat AIDS in 1985. Jyoti Asundi (40:41) Oh nice Aarati Asundi (40:43) Gertrude, however, did not take any credit for the AIDS antiviral because she retired in 1983. However, she continued to remain active as a consultant for Burroughs Wellcome. She was also an advisor to the National Cancer Institute and the World Health Organization, and she became president of the American Association for Cancer Research. Jyoti Asundi (41:05) Oh! AACR! She, oh wow! Aarati Asundi (41:06) Yes. Jyoti Asundi (41:08) Amazing! Aarati Asundi (41:09) And she was like on a bunch of committees. She has her name on forty-five drug patents. And, it's like just incredible, like with the amount that she did. Jyoti Asundi (41:19) Yeah, with the hard start that she had in her life where she was like literally struggling to cobble her education together through either poverty or locked doors because of the fact that she was a woman, in spite of that, that's absolutely fantastic. I love it. Aarati Asundi (41:38) Between all this, when she had time, she enjoyed going to the opera. Actually, when asked what she would like to be in another life, she said, "I'd love to be an opera singer. I have a terrible voice, essentially a monotone. As a kid I remember trying to sing and being asked if I really had to." Jyoti Asundi (42:00) That's very good self deprecating humor there. Aarati Asundi (42:04) She's funny, yeah, she's very funny. Then one morning, on October 17th, 1988, at 6:30 AM in the morning, Gertrude woke up and was in the middle of getting dressed when the telephone rang. She picked it up and there was a news reporter on the other end who said, "Congratulations, you've just won the Nobel Prize in Medicine." Jyoti Asundi (42:28) Ooh wow. Really? Aarati Asundi (42:30) Yes. Gertrude said, "Quit your kidding, I don't think it's funny. Whoever put you up to it, I think it's a sick joke." And he said, "No no, it's really true!" Jyoti Asundi (42:41) Oh my goodness! Aarati Asundi (42:42) And she said, "Well, I haven't heard anything about it, so how do you know about it?" And he said that she could check the news release from Stockholm, which had just come out at noon their time, so 6 o'clock in New York. Jyoti Asundi (42:56) Oh my god, these are the stories that legends are made of! Oh my goodness! Aarati Asundi (42:58) So she still didn't really believe it. but then he said she had won it together with Dr. George Hitchings and Sir James Black, who was a British pharmacologist who she knew of, but they hadn't actually like really collaborated on anything. And she was like, "Huh, I wonder where the reporter would have gotten those names if it wasn't true." But she still was like, "No, it can't be." Jyoti Asundi (43:25) Yes, yes. Aarati Asundi (43:26) So after she hung up on him, her phone kept ringing nonstop with people just like reporters and people congratulating her, and she's just like, you know, "What is this?" Jyoti Asundi (43:37) Yeah, completely fuddled. "What- what is going on? I don't have any official information." Aarati Asundi (43:43) Yeah. Later that night on the phone actually to yet another reporter, she said, I still haven't heard from the Nobel Committee. And it turns out that the Nobel Committee had been trying to reach her, but her phone had just been tied up all day and they couldn't get through to her. Jyoti Asundi (44:00) Because the news leaked before they could... Oh my goodness! This is so lovely. What a beautiful story. I love it. Aarati Asundi (44:09) She said, "I never finished dressing before there was a reporter at the door from a local newspaper, and I'm trying to answer the phone and trying to comb my hair and the photographer is taking pictures, and some of those pictures are really weird." Jyoti Asundi (44:24) Oh my god, that is so funny. I love it. Oh my god. Aarati Asundi (44:31) What made this win even more remarkable was at the time, Gertrude was only the tenth woman to have won a Nobel Prize for one of the science fields and only the fifth woman to have won in the field of physiology and medicine. Jyoti Asundi (44:45) Yes, and all without that PhD... Aarati Asundi (44:47) Correct, yes. Jyoti Asundi (44:48) ...which her mentor really advised her correctly after all. Aarati Asundi (44:52) Yes. So the fact that she didn't have a doctorate and won a Nobel Prize made her even more unique although by then she had been awarded many honorary doctorates and degrees, so you know, yeah. Jyoti Asundi (45:03) Of course, yes, of course, of course, yes. Aarati Asundi (45:07) In 1991, she was the first woman to be inducted into the National Inventors Hall of Fame and was awarded the National Medal of Science by President George H. W. Bush. Jyoti Asundi (45:17) Bush Senior. Okay. Mm. Aarati Asundi (45:19) But she also said that greater than any prize was the satisfaction of knowing that her work had helped save so many people's lives. Jyoti Asundi (45:27) Yes. Aarati Asundi (45:28) Patients would often write letters to her thanking her for her work and telling her about how the drug that she had invented had helped them recover from a kidney transplant or recover from shingles or that their child had been saved from leukemia. And she kept all of those letters that she received in a file. And she was like, "That's the best reward for all this work." Jyoti Asundi (45:52) That's the true reward. And that's really and it's some way might have mitigated her pain at her losses early in life. Aarati Asundi (45:59) Yeah, she set out to do something and she did it. She saved so many people. Jyoti Asundi (46:05) Yes. Aarati Asundi (46:06) Gertrude died on February 21, 1999, of a cerebral hemorrhage at the age of eighty one. So she lived a very long fulfilling life. Jyoti Asundi (46:17) And did so much good in the time that she was given on this world. This is beautiful story. Wow. I love the Nobel Prize story though. Aarati Asundi (46:26) Yes. I deliberately held back and didn't tell you that at the beginning. Yes. Jyoti Asundi (46:31) She couldn't even get dressed. She probably got photographed for the Nobel Prize photograph in her pajamas or something. Oh my goodness, with a comb still stuck in her hair. That is so cute. I'm exaggerating of course. Aarati Asundi (46:45) I got a lot of this information by watching like interviews that she gave and she's just- she's a really fun person. She's really funny. She has a good sense of humor, so very fun. Jyoti Asundi (46:55) Oh! Remarkable lady. I love hearing stories about such wonderful women. Truly inspirational. Aarati Asundi (47:02) And I wanted to end on this quote from her, which I hope will inspire anyone who's maybe thinking about becoming a scientist and wants to know what it takes. She said, "I think what you have to urge yourself to do is to say, okay, that one failed. It was a step which was in the wrong direction, so let's go back to the crossroads and go in a different direction, and not let the failure be the end of the line. Somewhere there is an answer. It may take five years, maybe ten. And I think you have to have infinite patience to be a scientist. I used to not realize that because I remember telling someone once that I didn't want to be a teacher because I didn't have the patience. And they laughed and they said, so you want to be a scientist? And she said yes. I didn't even think it was funny at the time, but now I think that was very funny." Jyoti Asundi (47:51) It's almost like a paraphrasing of what Edison has said also. That failure is not like a real failure. You just found another way that it does not work. You just have to now find the path the way it does work. Aarati Asundi (48:03) Yes, exactly. I thought that was a good quote, 'cause it's very, very true. And, you know, you have to be so incredibly patient to be a scientist. It's definitely one of the key qualities that you have to have. Jyoti Asundi (48:16) Yes, it is because things don't pan out as expected, the expected results don't come, and then you're left scratching your head. "Did I do something wrong?" That's the first thing. And then like, No, it's not you. Figure it out now. And figuring that out and finding out what really happens is a challenge sometimes. Aarati Asundi (48:35) Yeah. And I think that it was also interesting that she said she hadn't realized it because I think a lot of people don't realize how much patience it takes. Jyoti Asundi (48:44) That is very true. Aarati Asundi (48:45) Because we are so often just told, like, hey, these scientists have figured out this new, you know, amazing breakthrough thing. And we just hear the end news of it. We don't hear... Jyoti Asundi (48:49) Yeah. That's right. Aarati Asundi (48:54) ...like how the ten years that it took and the hundreds of people that it took to make that one breakthrough. We just hear it in like a little news article blurb. It's been distilled down to one sentence, whatever it is, like, you know, "We found this new antiviral therapy" or "We found this new treatment for this cancer." And it's all just like one little snapshot that you can put onto Instagram or whatever and grab headlines on the evening news. Jyoti Asundi (49:19) And the entire world of drug development actually is all about... The funnel is the ultimate paradigm of drug development where you pour in thousands of molecules and one finally makes through. So the amount of time, energy, resources, manpower basically that is expended on screening thousands of molecules so that one finally reaches the finish line. Aarati Asundi (49:45) Yeah. Jyoti Asundi (49:45) That- people don't see that part. They just see that shiny bright spotlight on that one drug that finally made it and say, "But why is that drug so expensive?" It's like because we tried a thousand other things. Aarati Asundi (49:57) Because it took us twenty years to make it and thousands of people to... Jyoti Asundi (50:02) Thousands of people and so much resources and we failed 9,999 others before this one finally came to the finish line. Aarati Asundi (50:12) Yeah. So I think it's it was a really good quote from her and very, very true. It does take so much patience and the willingness to not look at a failure as the end of the line. It's just like, nope, just go back to the drawing board and try something else new. So yeah. Jyoti Asundi (50:29) Yes. Beautiful story. I love it. she's Aarati Asundi (50:32) It was a good one, right? Jyoti Asundi (50:34) She's definitely hero material. Aarati Asundi (50:37) Yes, absolutely. And I was so upset I hadn't heard of her before. See drug development's exciting. Jyoti Asundi (50:43) Yes, and her perseverance right from the beginning she had to persevere through so much through lack of funding, through discrimination, closed doors just because she's a woman, and this whole thing where if you want the PhD you have to give up your job. It's like, yeah, but I need to eat, I'm sorry, Aarati Asundi (51:02) And then the knowledge that if you gave up that job and got your PhD, there's still no guarantee that you would get a job after your PhD that you really like because you're a woman. You know? So Yeah, so Jyoti Asundi (51:10) Because you're a woman and doors are closing for you and you may not be doing what you really want to do. Aarati Asundi (51:17) The PhD is not necessarily the door opener that you think it might be, you know? Or that it should be. Jyoti Asundi (51:22) Correct. Because you're a woman, it's not going to open the doors that you want it to open. Aarati Asundi (51:27) That you want it to, yeah. Yeah. Jyoti Asundi (51:29) Amazing. Aarati Asundi (51:29) So very interesting. Yes. Jyoti Asundi (51:29) Yes. This is lovely. Very nice. Very nice story. Aarati Asundi (51:32) I'm glad you liked it. Jyoti Asundi (51:34) I loved it. Aarati Asundi (51:36) Thanks for listening. If you have a suggestion for a story we should cover or thoughts you want to share about an episode, reach out to us at smarteapodcast.com. You can follow us on Instagram, TikTok, and Blue Sky @smartteapodcast, and listen to us on Spotify, Apple Podcasts, YouTube, or wherever you get your podcasts. And leave us a rating or comment. It helps us grow. New episodes are released every other Wednesday. See you next time!