#346 - Scaling biotech and improving global health: lessons from an extraordinary career in medicine | Susan Desmond-Hellmann, M.D., M.P.H.

27:28And you were doing at this point oncology unrelated to, not necessarily focusing on HIV and AIDS related cancer, breast cancer. I was doing good, old fashioned American oncology. I didn't take my oncology boards when we went to Uganda because I was in Uganda. So I still sort of laugh about taking the Divida and oncology book with a yellow sharp. I reread the big oncology book twice. Is this the Divida, Helm and Rosenberg book? Yes, yes, yes, yes, of course. Yeah, it's brown these days, I think. I reread it twice, took my boards and did fine. So I was ready. This is unbelievable. So you're sitting in Kentucky practicing garden variety oncology, talked to me about what that's like.

28:16I mean, that's completely orthogonal to what you've been doing for the past couple of years. It was so, so, so, so different. And Nick was in a practice where he was more like a hospitalist. Somebody'd get a fever in the ICU and they'd call that ID group. And my practice was a two -person practice. It was very classy. I saw a lot of lung cancer. It was Kentucky. So there's a lot of smoking, a lot of people from Appalachian. I actually like taking care of patients. So that part I like, but I really missed intellectual research, collegial stuff that I was used to at UCSF because we had been there nine years by that time because we were still UCSF faculty when we were in Uganda.

28:53Nick was called about Bristlemars quib search for an expert on HIV because they were trying to follow AZT with the next anti -retroviral. I think it was DDI and D4T, we're both in development then. And so they recruited Nick to come and work at Bristol Myers Quibb out of private practice. And Nick said, I won't come unless you have a job for my wife. And they said, no, we have a nepotism clause. We don't allow couples to work at Bristol Myers Quibb. So he said, fine, I won't come. He's a good husband. This is one of our favorite stories because it's a true story. So they called him back and they said, we really, really want you to come because we want this program to do well.

29:37And could your wife be a consultant? Would she agree to be a consultant and not a full -time employee? And he said, yeah, that'll work. So we moved to Connecticut. He had a job and I was the trailing spouse. And I can just see what this looked like. I'm making this up now. Oh, God, we've got an LMD. You know what an LMD is. We got this lady from Lexington, Kentucky. She's in private practice oncology. And we're stuck with her. Well, let's have her do drug safety on taxa. We have this new drug and it's really busy. It looks like it might work. And so we'll put her on drug safety. She can't hurt anything doing that.

30:15But did they not understand what you had spent the last couple of years doing prior to being in Kentucky? Did they not know what you had done in Uganda? I don't think that registered because there were so many people there who were very traditionally trained at NCI or at Yale or wherever they were and they were traditionally trained in oncology. My experience in Kampala and Uganda didn't make an impact but here's what was funny. Nick and I didn't have a statistician as I told you we just the two of us went so we brought this little compact computer and all the SAS manuals. We didn't have a TV, we didn't have newspapers, we didn't anything.

30:59So we taught ourselves how to do SaaS programming. When I got to Bristol, my squid, one of the really interesting things about tax all is it causes severe neutropenia, but it's short. It's like this short severe neutropenia. And so I wanted to study that because I thought it was really important and why people weren't really getting infections. I always have to remind myself, tell people what tax all is, how it works, just give them a quick, what is neutropenia, why would we care? When I talked before about how few new chemo drugs there were, Taxol was one of the first new chemotherapy drugs. So, Taxol is a product of the utri, and it's a microtubule poison.

31:38It is, if you think about it coming from the utri, and you think about sap, think about trying to dissolve sap in water and give that to a patient. That's plenty hard. The dissolving fluid that's given with Taxol... And the reason we would give somebody with cancer a microtubule inhibitor is because that prevents cells that are dividing. You can't divide. They need these microtubules when they create new cells and we want to block that. And we want to block that. So this was not just a good way to block cellular division, which is so important in cancer therapy. It's really important because it's very different than some of the old chemotherapy drugs.

32:15And if you're resistant to those old drugs, Here you have a brand new mechanism of action. So that's a terrific thing, but it's not easy to dissolve it. So the dissolving agents are like soap. They dissolve the tacks all. And when the National Cancer Institute tried to use it, some patients got severe allergic reactions from that and they got scared and put it on the shelf. So Bristol -Mars Quib went to the National Cancer Institute and said, you know, that drug might really be active. were willing to carefully go back in the clinic and test it and give people agents to counterbalance the allergic reactions and see if we can get away with it.

32:55So they did that and they got an approval in ovarian cancer, a brand new agent. Now, tax -all was really exciting because first ovarian and then breast cancer were these indications where we had not had new drugs or really any drugs that were active in the because I was the safety person. I was really trying to understand and put into context all these safety issues so it was possible to safely treat patients with these drugs. It had already been approved. It had been approved for ovarian cancer when I showed up. So you're now doing post -marketing surveillance on safety. We're doing post -mark surveillance on ovarian and putting together a US submission and a European submission for breast cancer.

33:37So I started talking to the statisticians there about how I wanted them to program. to get the data we needed for the safety level. And I'll never forget the guy looking at me and saying, do you know how to do this? And I said, well, I had to learn in Uganda because I didn't have somebody like you, you know? So it was sort of funny that I was very happy to prove myself. It didn't bug me. It made me more feisty. Like, I'll show you, I'm not under -dosed in the kinds of things you need to do in this place. And by the way, I loved every minute to being a bristlemire squib. They were pros at cancer drug development.

34:15They were pros at monitoring safety. And I thought it was so much fun because you got to make drugs. What was the formal landscape like in the early 90s? So you had bristlemire, you had Pfizer, you had Merck. You had Merck, you had Novartis. I think Novartis was a combo of a couple. It was smaller, much smaller, and cancer was bristlemire squib. I mean, they had made this platinum, carboplatinum. They had a lot of those drugs and people who had made those drugs were still there. And I was really happy to learn from them. I felt very lucky to get to be around these folks who knew about taxaul. So we got taxaul approved in the U .S.

34:56and in Europe for breast cancer, it became, uh, personal knowledge, quibs, number one drug. And I became the project team leader for taxaul. How long did it take them to thank your husband for forcing them to bring you along? It's too long. He really enjoys that story because he, like all good family stories, it gets embellished over the years and he tells the story like, you should actually want her. You don't know this, but he's a good husband. When you pause it where we are in this story to think of everything that would come from this moment forward and to realize there's a scenario under which nobody knows was everything that's about to happen and you're an oncologist in Kentucky right now.

35:37That's right, that's right. I'd be better at tennis. Yeah. I had more, I had more at free time. But yeah, no, I think that's the thing that I love to mentor. I think it's really underrated to listen to students and hear what's on their minds. And I remind students about the role of serendipity. And I think I'm a poster child for the role of serendipity. So you left Bristol, my rescuib in 95 and you went to Genentech. Tell me where Genentech was in its life cycle then. So Genentech had been around for a while. I mean, when did Genentech get founded in the mid -1976? Okay. Give folks a little bit of a history of Genentech.

36:19Genentech's a story company, but also a different company, and that it was founded on a new technology. Genentech's a really interesting company because it claims to be the first biotech company. there's some seedis back and forth about that, but it was based on genetic technology. That's where the genetic name came from. And what Herb and Bob, the co -founders of Genentech, wanted to do is kind of do a proof of concept that you could use genetic technology and make medicines. Make big medicines, proteins and antibodies, medicines that would almost certainly have to be injected rather than swallowed because they're large and they're protein.

36:58So you break them down if you swallow them, but their initial goals were focused on insulin, which they outlicensed to lily and phyzer and growth hormone, human growth hormone. So before genentech, when you were a parent and your child was short, you needed to give that child growth hormone that came from cadavers. And that had a risk of this slow virus disease, and that was not a good tradeoff for parents. So the concept of having recombinant, of having human -like growth hormone was a really wonderful thing. So genetics first drug was human growth hormone. And it was a tour de force. It was really amazing that in the late 70s they were able to do this fermentation and purification because they had to prove to FDA it was pure human growth hormone with no contaminants.

37:53and it became famous for that and people were excited and thought this was cool. Tell people briefly how this worked. What was recombinant DNA technology? What were they putting the gene into? How did they get the gene to make the protein? We take this all for granted today, because we have... It's tricky, yeah. Yeah, but it's so incredible. So what you see if you go to Genentech or a company like Genentech, it's you see these tanks. And the tanks are like a cell ICU. you, like an ICU for a cell. So the cell, what you're doing is you're teaching the cell to make it very high amounts growth hormone way higher than your cells or my cells would.

38:36And then you're teaching the cell through this genetic engineering to secrete it into a medium, into this soup that is really a lot of growth hormone. And then you're taking Making away the cells after they see created, you're purifying that growth hormone and you put in little vials. And that's the process about technology. And you can trick a cell into making almost anything you want, not completely, but almost anything you want, and make it very much like human, which is neat. So you don't have to go to a human to donate you growth hormone because it would be too small. Or in the case of insulin, I mean, they were using insulin from pigs and...

39:15porcine insulin that made allergies and expensive. So human insulin really changed how you thought about treating people who have diabetes. So genentech made growth hormone and genentech sold growth hormone and set up something I actually think is a really neat thing that genentech did, which people said, how do you know that by giving kids extra growth hormone, it won't cause leukemia or a fourth arm to sprout out you know, weird things to happen. In genetics, we'll follow every child. So they set up a patient registry, one of the first patient registries ever and followed every child until they reached their final adult height.

39:54And the physicians and their staff entered this into a computer. And so this is an amazing amount of information. So if the FDA ever asked us, do you have this with growth hormone? Did you have that with growth hormone? We had not an example, Well, you wouldn't even do statistics on it. Every child ever treated with genetics growth hormone. Do you have a sense of how many kids that was? Oh, hundreds of kids, thousands of kids by now. Yeah, yeah. So genetic got really good at that. And in fact, when I went to genetic in 1995, the chief medical officer of genetic was a pediatric endocrinologist, an expert on short stature and growth hormone.

40:32But it's a pretty small market. This is uncommon. By this point, it was being used rampantly in sports. But yeah, and that FDA was not happy about that and pushed really hard on genentech to control that use. Was it being used by this point also pretty heavily in HIV, right? People were using it in HIV, they were using it in sports, anything where you wanted to have more muscle mass. That's exactly right. Genentech had done some studies to look at whether that was a good idea and none of the studies came out successful. Meaning there was no benefit to an HIV patient being on growth hormone? The benefits did not outweigh risks of having increased blood sugar and some other things that would happen.

41:13So one of the aspects of Genetic that happened in the early years before I was there is they learned how to make enzymes. Same Genetic technology, telling the cell, make these enzymes. And some of the enzymes actually got outlicensed to make commercial enzymes like that you use when you wash clothes and things like that. So that wasn't core to genetic, but that an enzyme activates a TPA tissue pledge management activator that could break down blood clots. Did they go after that knowing what they were doing or was this a bit of a fishing expedition where they realized in the process of trying to do many things that, oh my god, we can actually make TPA, which you're going to explain in a minute why that changed the game of cardiovascular medicine.

41:57It was intentional that a really great, there's a clinician researcher, Dave Stump, who is a clotting expert. He's hemonc on the hem side. He was there and really pushed them to do this. And the concept was that if you could break down the blood clot, you could cure the heart attack. You could save lives. And the interesting thing, if you are interested in doing trials, is they started the concept of a large simple trial. This was early on and people in cardiovascular gene, brownwalled and his followers had started these large simple trials. So Genente had kind of bet the farm on this TPA. And the farm was that they could change the outcomes in 30 days that would be more people alive than dead if they were treated with activates.

42:46And two of the people involved in the studies, you probably know their names were Rob Califf and Eric Topel. Was Eric at scripts at that time or where was he? I think he was at the Cleveland Clinic. And they ran a group called the Timmy group, and they did all these studies named Timmy. And so they did this big trial, and it worked. If you treated with activates, you could break down the blood clots. So Genentech started this franchise in cardiovascular, and again, did this really interesting patient registry to look at 30 -day outcomes for post -marketing, but Stance came along. And so the franchise of Genentech and people who were treated with TPA really went down.

43:25And the stroke indication was tricky. You had to make sure it wasn't hemorrhagic or you could make things so much worse. And so the stroke indication on paper was really cool, but pragmatically it was really tough for hospitals to execute. Genentech also made another enzyme like molecule DNAs, pulmazine for cystic fibrosis. and that was approved very tiny. It decreases how thick your secretions are, but with vertexes, CF drugs, it's also been scooped. So when I came in 95, Janitek was really struggling. They had those three drugs. They had growth hormone, TPA, and Paul Mazzim. Why did they outlicense insulin?

44:08I think they needed the money. I don't think they have the scope to even make it. And why did you decide to leave? Bristol Myr squib is just crushing it. you finally earned the respect you deserve. You've got this struggling company, Genentech. Was it the opportunity? Oh, yeah. Yeah. For sure it was the opportunity. I will tell you, if you were me in 1995, sitting down with Art Levinson, and he was ahead of research then, and he was talking about the future and oncology, what the plans were, you'd have gone to. You'd got to. For sure it was an opportunity. we were doing well, I will say that further down on the list of pros and cons was West Coast's home.

44:49I mean, Connecticut was snowy and cold. I didn't come over on the Mayflower turns out. I mean, I loved people at Bristol, my or Squibb. I loved the job. But heading back to San Francisco. San Francisco. Yeah. That was a big deal. But I believed art when he said we're going to be a cancer company. So what was the first thing you worked on? Ah, thrombopotin. They hired me to to work on thrombopoetin. It was going to be the third leg of the stool. Epo, so make your red cells go up, Nupogen for your white cells and TPO for your platelets. And it was a big race. Amgen was in the race. We developed Epo.

45:27Amgen. Amgen, okay. Epo and Nupogen. Got it. Amgen and Genentech had always been kind of rivals. And when they cloned thrombopoetin at Genentech, I read the paper and then they called me, did I want to come work on it? It was that kind of thing. When you clone it, if you publish it, that doesn't give you the right, it's a race for everybody. It's a race. So let me ask a silly question, why do you publish the results of the cloning before you've gone and made the recombinant protein yourself? So you patent it, then you publish, then you make the recombinant. Okay. So once it's published after the patent, you get to make it.

46:04Genentech, one of their great assets started by her boy are they publish. They don't stop the scientists from publishing. They get the lawyers in their quick and they make sure that they protect the IP of the company, but they want people to publish very academic. So thrombo -poetons, EPO and Nupogen are as if you design them to make recombinant forms and give them for cancer patients or other patients who need them. Throbopoate, not so much to make it simple. If you said, okay, your platelets are going way down from your chemotherapy, and I'm going to give you Throbopoate to make them go up, they come back up really late and they go too high.

46:46So I'm making you at risk for a blood clot by giving you a million platelets, but later than you need to when you're recovering on your own already. Was that known only once you started developing and you understood the kinetics of it? Once we looked at how it worked in patients, we knew better than we had before. The kinetics are really recovering from not all chemotherapy, as you know, causes your platelets to go low. Yes, so you can't give it prophylactically because you don't know who's going to get thrombocytopenia. Right. Right. And this tricky thing about going too high if you're wrong, it's a problem.

47:19What do you do? You plasma for reach the patients if you've overshot or not plasma for reach platelet for reach? You could platelet for reach them. I mean, there are remedies, but you don't want to do that. Yeah, that's it. Anyway, so thrombopocean proved to be very, very difficult drug. And I learned a lot about the cancer equivalent or the product development equivalent of Tulip Mania. When everybody's so excited, you get excited too. And it's like, oh, I did learn a lot. I've often reflected on what might happen that I'm not thinking about now. But what also happened is the lab's etgenetic had been working on her septum on Tres Tuzumab for a while.

48:00Art became the CEO. Art Levinson became the CEO at 95 and he wanted to push on having Tres Tuzumab her septum get into the clinic. Tell folks how that drug worked. What it was for? Tres Tuzumab, or I'll call it her septum because it's less of a mouthful, is a antibody, like you and I have antibodies that fight disease in our bodies. And it's an antibody that targets this protein called HER2. And HER2 matters because about one in four women with breast cancer have too much of it. And when you have too much of it, if you've got too much HER2 from the time you're diagnosed, your median average survival is three years.

48:46If you don't have too much of it, it's seven years. So you know what matters. So the concept with this antibody is turn that off. Whatever bad thing that drives it down to three years, turn that off and go back to seven years. Pretty simple concept. Why do you mechanistically do you think that the overexpression of her too was impeding immune clearance? What was the thesis at the time for why overeexpression of her too was cutting life expectancy down? The thesis was that it was telling the cell to grow. That it was getting a growth signal to the nucleus to say grow more. And if you could shut that off, you'd grow less.

49:22Now later, we armed hercept and we put a payload on it. So then you could say, both changed the grow more signal and you've got a little bomb on there. Yeah, kill signal. So you'd get a two for in fact another company has one AstraZeneca that's so powerful with a bystander effect you don't even have to have overexpression. So that antibody I'm talking about it now because anybody in breast cancer knows about her too. Of course, yeah. You see it on TV and direct to consumer ads. Yeah, but I think what I really enjoy about this type of discussion those Sue is one it's the story of your career but it's also the story of oncology.

49:59It is. It's a sort of modern oncology. So you're one of the few people whose careers takes us through the walk of modern oncology. I mentioned that because it seems impossible. There was a lot of people at Genentech who were negative about her septum. Did not think we should invest. The dogma was that antibodies were all hype. They'd been overpromised as smart bombs, smart missiles, time magazine, all of this, but that they had flopped. What was the biggest failure at that point commercially? I don't think the things that even been commercialized. I don't think they had gotten out of the clinic that people just weren't seeing benefit.

50:41I have a very good friend who's an oncologist, and he said, you just can't treat a solid tumor, a solid tumor versus leukemia or lymphoma with an antibody. You need something more powerful. And remember what was happening at the same time is if you want to talk about the history of oncology, the amazing thing is being at Asco, the American Society of Clinical Oncology, and two different rooms. One room we hear that her septum is going to change forever how we think about antibodies in breast cancer. It way better than we thought, improved survival. The other room doing bone marrow transplant for breast cancer and having the South African group who published a paper saying it worked, retract the paper and go through and talk about how much of it was fraudulent, fraud, fraud, fraud.

51:32So at the same time, this nearly toxic, nearly lethal bone marrow transplant for breast cancer was debunked at the same time as we said what we call now, a naked antibody. No payload, no chemo, you give her septin, you're gonna help that patient with breast cancer. Just an antibody. Welcome to modern oncology. It could not have been more clear. I almost forgot the BMT stuff. It's so archaic. And it was a distraction because people felt like you just needed to hit the cancer hard. You just needed to hit the cancer smart. And hard wasn't the point. Yeah. I mean, we've got to be getting close to a vast and now too, right?

52:18Yes, but don't forget retoxic. So when I said people didn't believe in you could treat a solid tumor, they thought you could treat lymphoma because we did. Antibodies were so disliked. People did not believe in antibodies that in 95, 96, Idech was going to run out of money. So, I deck had made an antibody to CD20, a very important marker on all lymphomas. And they were going to run out of money. So some of our business development folks talked to them about genetic doing a deal with them on retoxin. It is impossible to overstate how important retoxin is in lymphoma. I often think when I'm in product development a patient I've cared for, I had this great 83 -year -old pharmacist when I was in practice.

53:12And he had an lymphoma that was low grade, a little tired, he was fine. And so we did watch and wait. My not favorite strategy of oncology. Let's watch and wait as you dwindle. He'd be a perfect candidate for retoxin. Four doses, you can repeat it. In fact, it works so well. Here's when I change my mind on antibodies. somebody runs in my office and said, oh, we have a case of tumor lysis syndrome. So tumor lysis syndrome being, somebody got retoxane, they had a lot of lymphoma, and the cells are breaking down so fast their kidneys can't keep up and they have to be dialized. Oh, that's only an antibody.

53:55No chemo, no payload, nothing. That's when you know you've got a good drug. How many cells in the body, how many types of cells in the body express CD20? It's mainly a B cell. But it's not as specific as CD -19, is it? I think 19 and 20 are both B cells. I'd have to look at it to see. Yeah, I know CD -19 is on the B cell, but I don't know the... Okay. Yeah. We were talking about this earlier. This is chimeric. It's chimeric, yeah. Yeah, so tell folks what that implies, because that's another wrinkle in the story. Well, that's the other thing that I think is... There's so many dogmas that we believe until data proves otherwise.

54:28So one of the warts of Vratuxen was thought that it was a chimeric. It had too many mouse parts to human parts, and that we would cause human anti -chamera antibody HACCA. And FDA was very concerned about this. So we measured and measured and measured. And it turned out probably because the patients had lymphoma that they didn't get HACCA. Very tiny numbers and they not clinically relevant. And you can treat them a lot. You can treat patients over and over again. Herceptance 93 % human, so not a chimera, but not fully humanized. And none of the patients treated with antibodies that I've seen, not with genetic or Idech antibodies, have really had problems.

55:07They've had other problems based on target related problems, not based on the antibody. And the CD -20 antibody was just also a straight naked antibody? Straight naked antibody. And targeted for an immune destruction? It's targeted to destroy the CD -20 positive cells. But it turns out that if you have lymphoma, you've got to reserve in your marrow of other CD -20 cells of more immature that grow up and replace. So it's not like you're really at a huge risk for untoward reactions from your CD -20. And why do those patients with marrow that's still producing CD -20 positive cells not go on in a constant state of lymphoma requiring?

55:46In other words, why is it that you can treat this and create a durable remission? I can guess. I don't know if anyone's done a formal study. I do think at some point in oncology treatment, if you have a tiny amount of disease, especially something like the phoma you may take care of it yourself. So it's just getting rid of enough of the diseased B cells until you get the load down, look at your load down. You can throw it low enough that the immune system can wipe out the clone. And honestly, if it comes back, that's the other thing that I find really interesting about antibodies. The dogma with chemotherapy, if you are on taxol and your tumor comes back, I wouldn't give you taxol again.

56:23If you're on her septin or retuxin and your tumor comes back, in a heartbeat I give it to you again. Yeah, it's a very different thing than chemotherapy. What was the price of these drugs at the time they came out? Were these the first chemotherapy agents, or you kind of wanted to distinguish them from traditional chemo, but were these the first oncology drugs that came with big price tags? Probably they were. I think taxal kind of went to that next level and then they went to the further level. Compared to today's prices low, But Rituxen, I think more than her septin because people started using it more like you do four times or eight times and recurring Rituxen sales went very high very fast and About this time we get the whole anti -vegette story, right?

57:09Yeah. Yeah, that was so juta folkman over at Boston children's Yeah, yeah, I never had the chance to meet him. Oh, you didn't mean I never met juta He wrote a fantastic book that I read in medical school poor it over the book. I'm blanking on the name of it. Do you remember the book? It was his story. Yeah, I don't remember. Again, a beautiful story. I'm smiling because I had a word for Judith Fuckman talks, which I heard many of. He was a phenomenologist. He would say, this patient had this, so it must mean that. He just connected dots all the time. I mean, some of it made no sense to me, but some of it was like, wow, I wish I thought of that.

57:46He was It's just a really fun person to listen to. I used to tell this story so many times. His thing was the cancer can't grow larger than a baby if it doesn't have new blood vessels. That was his thing. It stuck at a certain size. And so Vaget is the primary way, vascular endothelial growth factor, is the primary way that you grow new blood vessels if you're a tumor cell. People went crazy about this hypothesis. It was more than the TPO that I was describing because it was due to Folkman and he's very compelling and very charismatic. And just because the hypothesis really, it's logical. It's logical.

58:26It resonates. It sounds like a good thing. You know the saying that I love is it's the description of science as a beautiful compelling hypothesis slayed by an ugly fact. That's perfect. Napa Farara, also a great character, Italian, OBGYN, who came to Genentech and worked in one of the labs, made an antibody, actually same backbone as her septum, to VEGF. Mostly human. Mostly human again, I think about 93, 94 % human. And so we decided we should go after an antibody for VEGF as our next big oncology program. I still remember, by the way, one of the things that Gwen Fife, who's a great clinical oncology trials expert, was in charge of the program.

59:17And Gwen and I talked the day before the first patient was going to get treated with anti -vegas. And Gwen sent my nightmare. Is that all the blood vessels fall apart? We've just put that into someone's body. And I said, you know, we did all the talk studies. We're like, I don't think he's going to be that bad, but we have no idea what. I mean, it just felt... And I'm sorry, this was before the first phase one patient. This was the first phase one patient. This was the first phase one. So you're going very low dose. We're going to dose this late. Very low. This is the first time it's going into a human.

59:43It's the first human dosing of anti -vegethan. We knew how important Vegef was. So we were scared. And this is also mid -90s. Yeah. Yeah. This is all happening when you arrive. Yeah. And it just got in there. I mean, what a time to be a genetic. Yeah, it was wild. It was wild. Wow. So we're into the clinic and we make progress and it's really good news. and lots of studies and we're ambitious. We want to do a lot of different, we want to do lung cancer and we want to do breast cancer. How are you picking the cancer to study something like this? Herceptin's obvious because you're targeting a receptor.

1:00:17Receptin and retoxin were easy. Yeah, very easy. You know what you're doing. But here you could be targeting anything. There is one tumor where VEGF plays a seminal role and that is renal cell carcinoma. And yet, renal cells were really tough to study. It's just, it's not set up clinical trials wise. Why is that? You've got the IL -2 stuff going on where you've got 10 % of people will respond to it, but 90 % will. No, it should be easier. It may be the sites and where the clinicians are who care for it. It may just be that pragmatic. We kept struggling to figure out how to do a good renal cell study.

1:00:54But we thought we could do a breast cancer study because we had a lot of networks of breast cancer patients and particularly patients who weren't eligible for her septum because many of them weren't. So we wanted to do a late stage breast cancer study because if we could help these patients, we would find out right away. These were patients with metastatic breast cancer. Metastatic breast cancer who had already progressed to everything. Progress to everything. So really tough high bar. And the standard you're going to hold yourself to in the phase two is 50 % shrinkage? We wanted to have at least 50 % shrinkage.

1:01:31We wanted to change time progression. This is a great time to actually hit pause. I wanted to do this later, but I think this is the right drug to go through two things. One, even though I've done this probably half a dozen times on the podcast, you should never assume somebody remembers it. I want people to understand what the difference is between a phase one, a phase two, a phase three study. Also understand what's preclinical. It's not intuitive to people why it costs a billion dollars to get a drug to market and why it can take a decade. And then within that, if you could just embed enough of the details about decisions that you can make, that will make or break you.

1:02:07How many times has a drug failed? Because the experimental design, the wrong patient selection, the wrong disease selection. You have got to line up four pieces of Swiss cheese just right to get the pen through to hit it. Sorry to interrupt, but let's go back to... You got Judith Folkman talking about Vegev, Vegev, Vegev that then turns into, well, if we made an antibody to Vegev, okay, so there's your idea. Now, start the clock and start the dollars. So if you start with a target, often in oncology today, we'll start with a target. There's two things you have to start with. One is, what's the best way to turn down or turn off that target?

1:02:53Is it a small molecule? Is it an antibody? Tell folks the difference. How do you think of small molecules versus antibody? Where do we draw the line? So here's a really simple way I think of that helps me. Small molecules chemistry. Small molecule, it can be, not always, a pill. A small molecule you're impacting on often pathways or enzymes or things that happen in the cell. A large molecule, whether it's a protein or especially an antibody, an antibody's biology, an antibody you're trying to do something that may be immune in nature, or you use the antibody as a delivery device. You're getting something to the cell.

1:03:34A company like Genentech and many modern companies really like antibodies. I like antibodies because when something happens, it's on target. It doesn't tend to be off target. Small molecules at chemistry tends to have surprises in negative ways off target like liver toxicity or kidney toxicity. I do with this through cardiovascular medicine to explain to people the difference between a statin and a PCSK9 inhibitor. You have these two very common drugs that are used to lower cholesterol, but a statin is a small molecule. I don't say this in an insulting way, but we use the terminology it's dirty.

1:04:12It does block an enzyme, but it's got all these off target things. Your liver function gets whacked. You get insulin resistant. Some people get horrible muscle soreness. So five to 10 % of people taking this drug are going to have a side effect that prevents them from taking the drug. I've never seen a person yet who couldn't tolerate a PCS K9 inhibitor where you inject an antibody into them that binds to a protein and shuts it off. That's really a good example. And the choice of molecule is driven by that. When I was first in product development, there was this thing of, oh, you need a pill, especially for chronic indications, you need a pill for compliance.

1:04:51Right. Who would take an injection for cholesterol? Look at obesity drugs. turns out a lot of people would take an injection if they want to. But once you have your selection, you need to make sure you can make it. And one of the critical things for a biotech company, if it's a protein or an antibody, is the small scale production of it in small, they call it a mini -firm. The mini -firm has to resemble what is actually going to be used, because the next thing you start doing is a bunch of models. Judah Folkman, giving a great talk, doesn't mean you believe that blocking veg afw will help cancer.

1:05:27So we do models in mice, we may do larger animals. We do fewer animal models than we used to because they're really limited. I would rather have a great target with good biology than an animal model, but it's still helpful. It's still helpful. And then the critical thing is the preclinical work that you do, what FDA is going to want to ask you when they should. This is not them being bad. This is them being good. They're going to want to ask you about toxicology. What's your safety plan? Based on biology of edge off, what are you most worried about? I'm most worried about bleeding. It's an antibiotic.

1:06:01I'm most worried about an allergy to the antibody. Did any of the toxic studies show allergy to the antibody? What are you going to look for and how are you going to look? How often are you going to measure the patient? So the preclinical safety plan is really important and based on what you find in toxicology. The other thing that's essential is, and especially modern oncology, if you have a targeted therapy, you must have a diagnostic, and that is wicked hard, because you've got the therapeutic and the diagnostic at the same time. Now, things like CD20, things like VEGF are very ubiquitous, so it's not really targeted in the sense of her too, where we needed a diagnostic.

1:06:43But if you need to have that, We had what we call the clinical trials assay for her septin that wasn't to be marketed. Did you guys have to have somebody in parallel developing a clear certified assay that a pathologist was going to use or did you do that in -house? So we had an in -house clinical trials assay that we used all the way through phase three. And you could quality control the hell out of it? It was fine. It was nothing wrong with it except it wasn't approved. So not fine. So when we went to FDA, they said we're not approving hercept until you have an approved diagnostic. So whose responsibility is like how do you encourage the world to make that happen?

1:07:21So we went to Daco. We went to several diagnostic companies and Daco said we'll make you a immunohistachemistry test for her too. And her subtest is made by Daco. But we had to go back and correlate that with the clinical trials to make sure that it was the same as the clinical trials asking. Now why didn't you guys do that in parallel? Was the cost too great and did you want to de -risk the drug before you sunk the cost into that? We were too inexperienced to realize we should have. I see. Okay. So nowadays we're doing that in parallel. Oh for sure I'm sure. Yeah. Yeah for sure. It was a mistake.

1:07:52So how long just to again go back to helping people think through the arc of time From the moment you guys hit Go decision on we want to do this we want to pursue this path. How long until you file the IND? Oh gosh, it could be years. It could be two three years because you're doing animal models Maybe tell folks what the I and D is so they understand why that's an important milestone. So the Investigational new drug is asking the Food and Drug Administration permission to ship an unapproved drug across state lines. If you and I wanted to do something in Austin We could actually do it. Which is sort of weird to when you think about it, but most people don't do the Peter's shoe drug It's gonna be amazing.

1:08:32You're gonna set the lab up right over there But the moment we want to run a clinical trial and ship it and get it out of the state. You got to have the I &D So the investigational new drug is the request and what happens is that you take all this information I've been talking about that you know you have a molecule You trust the way you're producing the molecule you understand the biology enough you have a safety plan and you have a phase one protocol So phase one has one purpose. We're all greedy I've been there. It is only for safety. Phase one is, is it safe to give humans this molecule? Is it safe to give it once?

1:09:11Is it safe to give it multiple times? And there's an art to knowing where to start the dose, because it's an escalating dose trial. That's right. But you're extrapolating from what you learned about toxicity in a totally different organism that never translates one to one to the organism of choice. It's absolutely true, and it's not uncommon, and you see people all the time backing up on the dose. thinking, oh, that was more than we needed or more than we wanted. But phase one, with a good preclinical package, a good IND phase one should be uneventful. And because we are greedy in oncology, we always look to see if anybody responds just because that's what we do.

1:09:49But phase one, often to be fair, has some really tough patients who are trying something and have tried a lot of other things. So the patient population can be tough to find any efficacy in. So phase one, I always think of phase one as it might be a year that you're in phase one if you're doing really good job And typical cost given the relatively low numbers of patients. Oh gosh In the tens of millions. Yeah, yeah, tens of millions and then you get into the 20s and 30s and 40s of millions with the phase two depending on how big your phase two is and phase two I think that's where people can use their intellect I think in many ways phase two you start to look at What's the right dose and schedule?

1:10:31Very, very important to get the right dose and schedule. And... What's the right outcome? What's the right patient? Who do you want to treat? And really what phase two is supposed to do with one exception, phase two is supposed to get you ready for phase three. You've got a dose, you've got a schedule, you've got a patient selection criteria, and you've got a hypothesis of where this is going to be a drug. The exception in oncology is sometimes you want to get an approval off phase two. So when we tested anti -veg eff in breast cancer in phase two, we wanted to use that as an approvalable study because we would go in and say, look, it can be a contingent approval but these patients have nothing else to do.

1:11:10And so I think that can happen, especially targeted therapy where you've got the perfect target and FDA's feeling good about it too. That can be a phase two study. But most of the time you're getting ready for phase three. So, where were you guys with antivadgeph in phase two? You're at breast cancer, and did you do colon? We did colon, but not the kind of study that I just mentioned for approval. We did a traditional phase two in colon. So what happened is the breast cancer study failed. And so disappointed. I was so hoping that that would work. I still remember that day. For me, it was like, oh, we need more better drugs for breast cancer because I often heard from people when they're the three out of four patients, who her septum wasn't for them.

1:11:53If you looked at your stock that day, it also looked really bad, because all the hype about a vasin was there. But in colon cancer, we had a phase two got ready on the dose and schedule. And then we went to a phase three study in colon cancer much more traditional, just plus minus a vasin. So I've had you and the usual suspects. So I've had you and the usual suspects plus minus a vasin, and that's succeeded. That was a stage four. Only stage four. This is a median survival study. You're not doing overall survival career. That was a median survival study. I don't remember all the details of that one.

1:12:27I feel like it was eight more months of median survival. Does that sound about right? Probably right. It was the first new thing in colon cancer for a while too, so people were pretty excited. Now at this point, I'm in medical school. Just down the street, I'm at Stanford. And I remember we had a big discussion about this. I'm in my first year of medical school. and the discussion we had in class was, I think at the time, Aveston was $100 ,000 for the treatment. Extend's median survival by whatever, but I think it was eight months. The UK said, no, the NHS said, you're not paying for this, because at the time, the NHS had this $100 ,000 quality -adjusted life -year hurdle, which is understandable, right?

1:13:06That's how you throttle supply -side economics. They said, look, we can't pay for a drug. We can't pay more than $100 ,000 for an incremental year of quality -adjusted life -year. this is only giving you eight months. That's why I know it was less than 12. And so the NHS flatly said, we're not paying for this. And I do believe people in the UK could pay out a pocket for it. You can get it out of pocket, but not through the National Health Centers. That's right. People in Canada could not, because you couldn't have private insurance in Canada, you could come to the US for treatment. So of course, this just became a great topic of discussion for med school freshmen.

1:13:36What was your thought at the time of, have we moved the needle enough, how do we think about the economics of this? So I had a lot of different reactions. First of all, with a vast, and it was the first time I remember reading, and I think it was one of those curtain razor things in the Wall Street Journal for the breast cancer study. The headline was, a vast and might help breast cancer patients, but can they afford to take it? I was shocked that it was the first time I had read, and as long as I had been at Genentech, that somebody couldn't afford one of our drugs. That instead of saying, oh, isn't that cool?

1:14:12Protoxin, her septum, and a vastum, it was too much money. And that felt really important to me and really not good. We had as a company of philosophy that no patient should go without any of our drugs because of an inability to pay. So we had a bunch of patients, what do you call those patient support programs, whatever. So we had a bunch of different things in place. So I knew we had those programs, but that doesn't help the patients in the UK, and it doesn't help the overall cost because we're actually Supplementing but the cost is still really high and we started to have a lot more discussion at the executive committee about the price and how we would think about it and how we would price the drugs because that was, like I say, that was not good.

1:14:54Did you go straight from Genentech to being a chancellor at UCSF? Just because I want to stay with the story, I want to continue the arc of your career. We're at the halfway point, right? We're like, we're one -third of the way into it. Early days. We're in the 90s. How did you, given you are truly on the cusp of what is happening in oncology and biotechnology? And now the same institution that said, you can't come back here to have a clinical appointment after saving the people of Uganda is now offering you the highest post, essentially, outside of a provost, I'm guessing, right? I don't even know where the chance is.

1:15:31It is the highest post. Okay, so that's kind of remarkable. And does that just speak to what they saw as the vision of that institution, which was few people have learned what Sue has learned in the last 10 years, and we want that type of leadership here? So first of all, on the Genentech side of things, Roch Baudes. That's right. That was 99. That was 2009. Oh 2009. Oh my God. Okay. I'm off by a whole decade. I thought that was sooner. 2009, which was not what we wanted. It was a hostile takeover. A hostile takeover. Yeah. They call it in the business world a squeeze out. They squeezed us out.

1:16:08So I knew I was going to leave. I knew I was going to do something different. And UCSF, I had been really close with the chief of medicine, who was my chief of medicine when I was an intern. Holly Smith, you know Holly Smith. No, I don't. So Holly Smith was a South Carolinian, Harvard -trained, amazing person. And between him and Bill Rudder, who founded Kairan, who's a biochemist, they decided a long time ago that UCSF should not be a backwater medical school and should be a serious medical school. So Holly on the clinical front and bill on the scientific front just decided they would start recruiting people to have a great institution like a pretty amazing thing.

1:16:51Matt was starting in the 80s. It was probably 80s, 70s, 80s. I was still friends with Holly. I just think there's so many wonderful things about Holly that I admired that I was still friends with him. So Holly called me and said Mike Bishop is stepping down of Bishop Inverness. that we should be. Of course, no bell thing. And you should be chancellor. Of course I said to Holly, I'm not a professor. And I said, well, if they're interested in me, I'd be open to talking to them. They were. And I went through the interview process. I'm sure that when you're going through that sort of interrupt, because you're now interviewing with the Board of Trustees.

1:17:31They have a search committee. Yeah. And so they must be asking you to present a vision. They're not interviewing you to make sure you know how to use PowerPoint. Yeah. Do you remember what the vision is that you presented to them? What I do remember and I remember if you remember 2009 was just post -mapocalyptic horrible recession and California being particularly in a bad place. So I just talked to them about how I think about managing people, how I think about making sure that you use whatever assets you have Maximly, I admitted that I had never done fundraising, but I had done a lot of work with Wall Street and I could talk.

1:18:12You were the president. What was your title at Genentech before you left? Yeah, yeah. And I did a massive amount of investor relations because art didn't like traveling or talking. So... My kind of guy. Mine too. No, we were a good partnership, but I also said, look, if you think about running the faculty meeting, I'm probably not your guy, but that's what the provost does. I think they really thought they wanted somebody who could work on the business aspects of the campus. We needed to finish Michigan. You're really the CEO of the system. Yeah. Yeah. And you manage the hospital, CEO, and it's a big hospital system.

1:18:48There's no undergrad at UCSF. So that was what they were looking for, and I thought, well, why not? Were you nervous? I mean, when they called you and said you've got the job, Was there a moment where you thought, have I bit off more than I can chew? This is a huge responsibility. I was really concerned. I was really concerned about it. And I also realized that some of the faculty were pretty negative when I first started. Because you were an outsider, you were an alum, but you weren't coming up through the ranks as the CEO of the hospital or something. I actually think they were just as nervous as I was about money.

1:19:22They weren't convinced that I knew how to get them money. Because you know, if you were running a program, you need money. It's the mother's milk of doing science. So tell me about the budget of UCSF because it's a state school, presumably California provides what fraction of it? Almost nothing. So what's the benefit of being a UC? The brand, there's a curriculum thing, there's some things like that. So in that sense, you and Stanford aren't that far apart. Not that different. I mean, the most important things you've got clinical income, you've got NIH -driven income, right? You've got other grant income and you have philanthropy.

1:19:54P. Show me the P &L on those things there. So NIH is bringing in how much? Oh gosh. Percentage -wise, roughly. Of the money that you use every day, there's this discussion of over and out. The indirect now? It probably gets up to a third. A third of the revenue for general operations is coming out of the NIH overhead. Probably. And then clinical revenue. Clinical is a lot, but a lot of it goes back to the hospital. You know, it's a not -for -profit. They spend it on the hospital. Okay. And then philanthropy is some direct, some into the endowment where you're living off the interest. Yeah. And that's basically what your revenue streams are, those support.

1:20:31Yeah, that's the revolution. And then the tuition is tiny. Well, especially because you don't have undergrads, right? Right. Right. Because the number of students is really low. And the really good news at UCSF? I didn't even apply to UCSF, by the way, because I mean, I was not in California when I was applying to medical school. I was told, well, such a great medical school that I was like, there's no way I'm going to get in. as a non -Californian. So I didn't even apply. So the funny thing for me is - But you did and you got in. I did. Well, there's a story that we talked about me being at University of Nevada.

1:21:00What we didn't talk about is my first year at University of Nevada, my youngest sister was born. So I lived at home and had helped my mom in Reno. Because there's like seven of you, right? There's seven of us. Yeah, and number seven was born when I was a freshman. It was kind of crazy. But when I went to medical school, I used to have like this sign on the stairs be quiet. I'm studying down here. I was like probably a giant pain. But I wanted to go to San Francisco. My dad was born and raised in San Francisco. My grandma lived in San Francisco. So even though I was still pretty young in terms of ever living outside the home, I knew San Francisco I wanted to go.

1:21:41But UCSF had never taken a university and a father student because we were a pretty new medical school. I was only in the second for your class. Oh wow. Yeah. And I was excited like my head would blow off. Like I wanted to go to UCSF so big time. So I'm going back to UCSF and then really good news. What saved me as chancellor is philanthropy. It turns out that we needed people to care about the mission and the projects at UCSF right at the same time as the Mark Zuckerbergs of the world and the venture capitalists of the world. And a lot of people had come into a lot of money, even though the overall economy was bad, it was coming back.

1:22:26And we had some spectacular successes. And my successor, Sam Haagood, continues to have that kind of success. And people just really generous. Americans are hands down the most generous people in the world. I think that's demonstrable fact. Yeah, I'm big on New Year's resolutions. Among other things. One of my New Year's resolutions, I have a mini list. One thing that's always on the list is be more generous. I'm no Mark Zuckerberg, but I can be generous in other ways. I'm sure that you must deserve some of the credit for that. I don't think it's just that a bunch of people in the Bay Area came into money at that period of time.

1:23:03What was the approach you took towards philanthropy? And how did you reach donors that maybe previously hadn't been involved in UCSF? because again, one of the things that's working against you is you don't have an undergraduate. So Stanford has a big advantage over you in which you've got a lot of people that are coming through doing engineering degrees, doing CS degrees who are going on to create enormous enterprises. Anyone who's an alum of UCSF went to graduate school there. There's no business school. There's no law school. So you're missing out on a lot of this. Don't forget the hospital.

1:23:37It's a most important donor base is grateful patience. Yes. Or people who love science, technology. I hired John Ford, who had retired as the head of Stanford's fundraising. Moved up to the Northeast and he was my head of development. And I talked to John and I said, how do you do this? Teach me how to be a good fundraiser. And he talked about tell people your hopes and dreams. Tell people what you're excited about and ask them what they're excited about and see if there's a match. And I think that was really important. And then I also think that because I had been at Genentech and I was sort of gregarious and knew a lot of people and people knew that I had decent business savvy.

1:24:17I wasn't gonna waste their money. We were very committed to use the money wisely, especially in the hard times and do special things at UCSF. So I was surprised, I sort of worried that I would be sad if people said no. That it would be weird, especially if I knew them well. So I would get myself psyched up for the beginning of it and then by the end I would be like, oh that's fine Next time if you're in town, let's talk again, and maybe that it'll change or whatever But it was actually fun. I got to talk to and meet. Oh, how do great people? What percentage of your time was spent externally versus internally?

1:24:53Hmm probably 40 % externally a lot external and what was the internal focus then? Working with the team to who were your direct reports the pro -hosts? of the hospital, lawyer, all the deans, that was really important. And then part of it was monthly we met with all the chancellors with the president of the university. We was marked off at the time and then he stepped down after a while. But the chancellors means we're funny because they all had undergrads. I always felt like I was squirming, like we'd done yet. I thought it was just really important. my favorite thing every Friday lunch, mission bay, they had a science talk and they'd have some pizza, Chinese food, something and you'd look around the room and it'd be like Bruce Albergs, Liz Blackburn, there'd be four Nobel Prize winners in this little cramped room listening to science.

1:25:48This would be something you did as a scientist, not necessarily as a chance. Like the Chancellor's weren't doing this all the time. I'll just go over on the shuttle bus, eat a slice of pizza and enjoy. Yeah, amazing. It was really good. So then let's get to the next chapter. What all of a sudden in 2013, 2014 leads to the next transition to being the CEO of the Bill and Melinda Gates Foundation? Well, to my surprise, I think I got an email or, I think it was an email from Melinda. Did I have time to talk? And UCSF throws a big event every year. this kind of friend making fun raising everything and we give out awards, recognition to people whose work we respect a lot.

1:26:28So I had invited Mollanda the year before and thought she'll never come. You invite people, the throwaway invite. And she accepted and came, actually came with her mom and dad even better. I thought that was nice. So she sent me an email and she She said that she and Bill wanted me to look at being the next CEO of the Gates Foundation. And I was surprised. I had not expected that. And I started having discussions with them. It was actually funny. I went up to Seattle and they were having all this hush hush. You know, this was very cloak and dagger. So I went to their house because I had had a meeting with Mollanda and I needed me with Bill.

1:27:11And it was Halloween. I mean, the kids are coming and going. It was kind of crazy. As I had talked to him, and I talked to my husband, you know, my husband worked at the Gates Foundation. He led the HIV and TB programs about five years before. Was he still there? No, no, you had gone. He was commuting to Seattle, which was dreadful. But he knew the Gates Foundation. So he and I were talking about this, and I was like, God, you know, I've only been at UCSF five years, and I just found with a bathroom door, you know, that kind of thing. And it was going well. I was happy with that. They asked for a teleconference and they got on the phone and especially Bill made this big pitch that a lot of people could do the UCSF job with all due respect as Bill and put it.

1:27:56But I was the only person who they both wanted and who could do this job. I was perfect for the job and it's really important for the world and I needed to do it. I assume that the rationale for that was obviously their focus is on global health. Global health. And you have the background in the clinical side, the research side, the epidemiologic side, the management side. So there's kind of those are four legs of a chair. Were there other things that I'm missing that they felt were kind of essential pillars? I think it was less obvious then, but I think now they had started to kind of have disparate views of how the foundation should operate.

1:28:35Melinda's been really all over women's issues, all over. And Bill would do another run at polio. It's like the goal broadly that all lives have equal value, which by the way I think is a wonderful thing. They share, but they come at it from different ways. And so I think that the thing that resonated for me is that I could see both those points of view. But those points of view don't strike me as mutually exclusive for an organization with enormous resources. Yes and no. It's one thing to have enormous resources. It's another to know where one of the most important assets they have is the time and energy of Belomolinda.

1:29:15They actually show up. Things happen. So how did you weigh this decision? I thought that I could add value. I thought I would learn a lot. And I did think that UCS would be fine without me. I felt like we were back on our feet financially. I thought that Sam Haggood, who was the dean of the school of medicine, I had a ton of respect for him and thought he was the obvious person to take my place and that it would be okay. Were they surprised? Did they try to talk you out of this? I don't think they did. I actually think they had a lot of respect for the Gates Foundation and thought, oh, well, that's a cool job.

1:29:52At least the way they showed up with me, maybe when I wasn't there they did. Okay, so you head up to Seattle now. Yes. When you show up to the foundation, how many employees are there? What does it look like? It's a not -for -profit, but does it run like Microsoft? I mean, how does it operate? It's a couple thousand. It's a big foundation, big building, big foundation with people all over the world now. There was a lot I wasn't surprised by, like the global health stuff I knew what they were doing, and I thought it was interesting and great. And the challenge for me was bills, endless appetite for things like learning things, driving things, funding things.

1:30:30And me feeling like I could get my hands around a strategic plan. It was a little bit like, okay, this staff would be like, Bill's going to love this. Let's present that, you know, it was that kind of feeling and lots of money. So I kept trying to get my hands around like, okay, what should we do so it's just a little more orderly and we get a great return on our investment. That was the most important focus. I feel good about that. The funny thing was I sent the finance team to Genentech. And we had this really great portfolio management process that we put in place when I was there and they still use it apparently.

1:31:08And because I recommended to Bill, we just have a portfolio management process. Pretty simple. Everybody knows how you make decisions, what money's up, what we'll do, and we can use that here. doesn't need to be bureaucratic, but we don't need it to solve in my head. I remember that conversation, and I thought, if it wasn't you, I would think that was the smart -ass thing to say, but I actually think you're just being honest. So I encouraged him to understand that just because it was in his head didn't mean that the rest of us were there. We had a little more ability to make things orderly, I'd say.

1:31:44It was a wild ride. It was six years of a wild ride. What was the most difficult thing for you to impact that you wanted to change? Meaning, was there a global initiative that you wanted to get your hands around that you just couldn't do organizationally or technically or what were the challenges? I would say far the opposite. The things that I felt like I knew about, I felt like really good about the TV stuff. There's a HIV cure program now that I'm really psyched about. Technically, I felt really good. And probably the hardest thing for me was the people side of things. I have a very strong sense of how people should treat each other and the competencies that managers should have.

1:32:29And I'm not willing to move on that because you're a technical expert. And I found that if you do move on that, it just changes the culture. And I struggle with that. Say a little bit more on that. Is that because in the not -for -profit space, you have a different talent pool than you do at Genentech? No, I think it's because Bill really likes technical experts. And if he likes the technical expert, he doesn't want the CEO to come and say anything, but yes, they are very smart. What did the org chart look like? So I assume Bill and Melinda are co -chairs. They were, yeah. And then as the CEO, who are your direct reports?

1:33:08is it organized by a bunch of GMs in different programs? Yeah. So there's a TB person, an HIV person, a polio person, a malaria person. Oh, there's a global health person. There's a global development person. There's an ag person. So under global health, you then have sub... Then you have the subs. Yeah. Global health is a big job, obviously. It's the biggest job. That's the biggest. Yeah, it's the biggest PNL. And then US education is a pretty big job too. Oh, I don't even realize that. I'm not as familiar with the portfolio. Yeah, the one that has been ag is now ag financial services for the poor.

1:33:41So it's a pretty broad group. What's the annual budget? Eight billion. Wow. So much money. It's amazing. Yeah. So what are things that you could not have done there in that role? Had you not had the leadership roles at Genentech and UCSF? Oh gosh. I think more that people side of things. I remember there was a employee who was really struggling at Genentech and her boss, I was his boss. And he kept talking to me about how she was struggling. How she was struggling? Could we do this? Did we need to give her fewer reports, more reports, make her job harder, make her job easier? Like we couldn't figure it out.

1:34:21Couldn't figure it out. Performance was struggling. Performance was struggling. And just not acting like she had been. We just couldn't figure it out. And finally one day she said, oh, I'm getting a divorce. And after a little while, things got better. And I thought, you know, not everything's work. Not everything's work. So I think as a manager, I really care about people thriving at work. I really care about it. And when I went to Gates Foundation, I think I understood better, given Genentech and UCSF, that a very important principle, work never fills in for home. Ever. It never makes up for bad home.

1:34:59So if somebody needs a timeout, I always think, how can I improve work? And sometimes it's good to just understand that that's not always the case. Especially if you're working in global health or global development. You might be in South Africa, you might be in China, it's rough. So just thinking a little bit about how people can show up in ways, it's $8 billion. How do they maximize the benefit of that $8 billion? And what can I do to enable that? Are you basically only able to affect that through your interaction with your direct reports and just hope that that's the infusion of culture that then trickles down because it's hard to go to levels below your management and yet the people who probably need this compassion the most are people you're not even going to meet.

1:35:48Yes and no. One thing about traveling a lot, you have big events or things like that is you meet people on trips and that's different people throughout the organization. So I think there are opportunities. I also set up meetings when people would have a grant that needed to be signed. The business process was it would show up on my computer. So I changed the business process. So I got the group that could fit around the table in my office and we would talk about the grant. So I could interact with more people that weren't my reports, which I really liked. So I do think it is mostly through your reports, but I think there are ways that at a senior level you can interact with people culture wise.

1:36:28Yeah, the word culture, it's very misunderstood. When you think about the culture that you wanted to bring to the Gates Foundation, I'd like to understand what that was and how successful you think you were able to be. And I say that because you were in an organization where you also had very powerful other present people whose culture was also a part of the organization. So for me, I define culture in a really specific way that when you come to work, you feel like the atmosphere, the surround sound brings out the best in you, and that you have some ownership of tweaking it if it doesn't. So that's something that you feel like you can control, because if you're in thousands of people or hundreds, thousands, tens of thousands of people and you're the CEO, you're to do that, but that you set up that culture.

1:37:19One of my favorite stories from Genentech was being at a product development meeting that my successor as medical officer, Hal Baron, was running. And Art and I both attended just because we loved it and we wanted to be there, but we weren't decision -maker. We were just attendees. Which is kind of odd. The person who's the decision -maker is sitting in the presence of the two most senior people in the company leaving it to him. We're leaving it to him. Yeah. But in this case, there was someone who, the discussion was about her saptin and how well the test to find who was her too positive performed.

1:37:54And if you got more patients, you would get more commercial, but you would have patients who wouldn't benefit. And someone who I won't name said, but if we have a test that does like this, we can get more money. And as if in unison, Art and I both rose up from our chairs and said, we never do that. We don't do that here. Done. Everyone kind of sat down and we weren't the decision makers. But see that's culture. If you wondered, it's right where the decisions are being made and everything else. That for me is culture. The other one that because I'm in so many meetings and wasn't so many meetings at Gates Foundation, I had a practice.

1:38:33I would sit, Bill would be there or Melinda would be there, Bill often Bill and me there and you're presenting. And Bill's peppering you with questions, some of them very tough in a very tough way. I would look at you. You got this. I can't tell you how many people. I actually didn't even know I did it that I would nod. You were the coach. Smile, coach. I would also stall. Hey, hold on a minute, Bill, I think he's just getting ready to answer that question. You're talking over him right now. In a nice way, not confrontational, that for me is culture. I want you to succeed. I want you to know I want you to succeed.

1:39:09It's the guy who runs the foundation. It's the two people who are the chairs. So it's gonna be scary. That's why I think that bringing out the best in people and giving people agency To do that on their own means that if somebody sees art leavenson say that's not the way we do it here They'll go down the hall in a different meeting and say you know, I heard arts say I think that's really powerful. That's really powerful so this brings us up to of 2020 and were you at the foundation when COVID hit? I had announced that I was leaving and literally pack in the house as COVID hit. Actually a few miles from us, the first case in Washington State, nursing home.

1:39:52Yeah, interesting. Let's talk a little bit about COVID. So I've talked before about this idea of the difference between science and advocacy and I still haven't really wrapped my mind fully around it other than kind of a sense of lost opportunity with COVID? What do I mean by that? Well, on the one level, there was so many pretty incredible things that happened with respect to the speed with which a vaccine could be developed that really made a difference in terms of mortality for a subset of the population. But a lot of that's overshadowed today by the lingering doubts, the lingering suspicions, the mistakes that were frankly made.

1:40:31And my fear Here is, I'm not convinced we're better off today in terms of preparedness for a pandemic than we were in 2019, which seems like an unimaginable statement given what we've been through. Do you think I'm too pessimistic? How do you feel? I do not think you're too pessimistic. I am absolutely horrified. Horrified. It's shocking to me that the narrative is in the place it is today. And I'm honestly still processing how we got here from there. It is a really bad place. And I think you're right. I think if it happened again today, it would be the way it was with worst of COVID, but even worse.

1:41:17Because trust and the need to have sides and winning and losing, I don't remember health and medicine being winning and losing and sides as I've been in this business for 40 years. It's just weird. I don't get it. Yep, I concur with all of that, and I do wonder what it will take to restore confidence. Look, we could sit here and talk about mistakes. It might be that the medical community and the scientific community need to be more vocal about acknowledging mistakes. And I do think an enormous mistake, though it's understandable to me why it happened because so much was happening so fast, but I believe deep down it was an enormous mistake to be the head of science, to be the head of advocacy.

1:42:06I think having Dr. Fauci as being both of those hats was a cataclysmic error, and it's not about him. No human can do that. A scientist has to be an impartial observer of fact who is happy to change his or her mind in the presence of new information with no attachment to what has been said in the past. An advocate has to be driving policy and action, and sometimes they have to settle for the best you can do any port in a storm. When you put those two hats on the same people, I worry that you lose all trust. I do wish the medical community could have an open and honest discussion about that. I would say that not if, but when.

1:42:53We will have another pandemic. There's zero doubt in my mind. Bird flu is working hard on it right now. We will absolutely have another pandemic. I hope it is decades from now, but we will. I hope somebody will remember that lesson and say, we want our chief communicator of the state of the science to be completely uninvolved in telling the public what to do simply there to report what we know today. Today we think masks work. You know what? We just did a study and we realized they don't work worth a lick. Today we believe vaccines prevent transmission. We just did a follow -up survey. They don't prevent transmission.

1:43:32It's okay, it's okay. I think that's a very forgivable position. I think the public would welcome... Look, I just told you about bone marrow transplants for breast cancer. If you tell people, look, here's what we thought. We thought harder treatment was better for people. It's now proven that it's not. Science changes, people know that, but you're right. I think that being honest and open when it changes and how it changes matters a lot. It really does. I also think you didn't say, but I would add to your recommendation, which I think is a really smart one. The pace of communication, the social media and misinformation or just stuff gets out they're really fast.

1:44:16And having something slow doesn't keep up. I don't have a solution to that. I mean, the great example, which is a very good example, and I don't know the solution is in May of 2020, if you suggested that this came out of the Wuhan lab, I mean, you were kicked off social media, you were kicked off YouTube, you were in the doghouse. That was misinformation. Well, I think almost any observer today would agree that that was actually information, but where do you draw the line? I don't have an insight. This is so far above my pay grade. Yeah, I don't think it's a matter of kicking people off because actually I think you enhance that and you may be wrong, but being part of the dialogue.

1:44:58I'll give you an example that I've been reading the last couple weeks. I've remecting for cancer. Actually, I'm glad you brought that up. I wanted to have a discussion about this. Okay. Finish your point and then I want to make a broader point about oncology. So my point is a simple one, the nature of horrors of vacuum. So if you say I'm not going to kick off people, the lab is a good example, but I'm not going to remain silent. Here's what I know about that thing, about the lab. Here's the facts, here's the publication. You know, I think that the absence seeds that space to people. I feel like the anti -vax, specifically things like autism, Many people have seen it that space on social media because you are kicked in the butt if you don't.

1:45:43So I do think you can't leave a vacuum. Yeah, I think that's a great point. I'm glad you brought the Ivermectin and Cancer thing up. So a couple of my patients, which is a statement. I'm going to acknowledge that my patients are educated and affluent people for the most part. A couple of my patients have sent me clips of various people claiming that Ivermectin is curing people with stage four cancer. Now, because they're sending these to me in text and I'm really, really busy, I'm responding in a rather glib way, which is usually using phrases like this is effing bullshit. But I usually follow it up a few minutes later with a text that says happy to discuss, and usually they say no, Peter, I just needed to know that this was nonsense.

1:46:29But I also agree that I don't think people should just be taking thing on faith and I really want to be able to So I think I made a note that actually I wanted to discuss this exact example and hopefully we'll be able to clip this particular segment so people understand why this is such a idiotic statement. To believe that Ivermectin cures cancer and to listen to the stories of multiple people with all sorts of different metastatic cancers that are cured, you're almost explaining that cancer is a single disease. So explain why at face value the idea that anything could cure multiple forms of cancer is an impossibility.

1:47:06It is an impossibility. There's no doubt about it. Every cancer has very specific biologies that allow it to grow and spread and cause humans problems. and that's why you don't go to the cancer doctor. You go for prostate cancer, you go for gastric cancer, you go because the biology of each of the cancers is different. And when you go even one step further as you've alluded to, it's not just that colon cancer and breast cancer are as different as kidney disease and heart disease. It's that breast cancer with an estrogen receptor that lights up versus a HER2 new receptor that lights up versus no receptors that lights up.

1:47:50Those pretty much have nothing in common, other than the fact that they originated from the mammary cell of a woman's breast. Right. So we use anatomy to describe where the tumors are, but it is not irrational to use different doses of medicines in combination with other doses. The thing that we went over is the preclinical phase one, phase two, phase three, is meant to give whatever cancer patient, whether it's in this case, I think prostate cancer has been talked about a lot. All of the information they deserve on both safety and efficacy, does it work? Does it shrink the tumor? Does it help them live longer?

1:48:30I haven't read anything about Ivermectin doing that in patients and what the side effects are and how it could harm patients. So I think patients deserve that kind of information. The other issue I have with this type of rhetoric is the next line that follows is the pharma companies all know this works and the reason they're keeping it from you is so that they can make more money giving ineffective drugs. Now again, I'm going to offer my point of view on this, but you being the veteran of some of the biggest pharma companies in the world, feel free to correct me. I think pharma would be happy to have a drug like Ivermectin that cured all cancer because the first thing they would do is put a slightly different modification to it to make it more efficacious, basically less side effects and they would patent it and they would make all the money in the world.

1:49:25They'd be all over this. If they're able to make $100 ,000 on a drug that extends your life by eight months, I promise you they will be making millions per drug if it's curative. So again, such illogical arguments are put forth and it drives me sort of bananas. But if we want to go back and say, how did we get here? I think when my friend Joe Rogan took Ivermectin for COVID, which when Joe asked me what do I think? I said, Joe, I think it's a totally safe drug. I'm pretty sure it has nothing to do with why you're feeling better today. I think you're feeling better today because you have an amazing immune system.

1:50:00You're an insanely healthy human being. you did 10 other things to of which might have worked. I'm pretty sure the Ivermectin had nothing to do with it. That said, the medical community didn't say that to him. What they said is you're taking horse dewormer, you idiot. Well, that was a strategic error. That's an awful way to talk to somebody. And Ivermectin might be a horse dewormer. It also happens to be, and I look this up, so there is no drug on planet Earth that has been taken by more human beings than Ivermectin. And it might have the fewest side effects of any drug out there. And look, there may be human conditions for which Ivermectin helps.

1:50:36Works beyond, yeah, exactly. Beyond what we know. And I think that's an opportunity for somebody to study it, good for them. But again, it's something about the elitist nature in which that was handled that has now created this terminal effect of Ivermectin is a cause celebs for, I mean, pretty soon, someone's gonna say, it cures Alzheimer's disease, I'm sure. Well, I think it's a drug that's an anti -smarty pants drug. Yeah, that's a great way to put it. That's what it is. To me, that's heartbreaking. Because the answer should have been, I talked about this with Joe very openly on his podcast.

1:51:10I said, look, I've looked at all the RCTs of Ivermectin and COVID. There's no signal except my memory could be off on this, but there's a little signal in this Brazilian trial, but the methodology of that trial was horrible. So I have to believe this is not working. It's a good try all about trying. It was a great idea to take off the shelf drugs and see if they worked. Nothing wrong with that. We've done that for other things. When they don't, we have to move on by demonizing it and by demonizing the people that felt it might work. We find ourselves in a situation right now where it's very irrational.

1:51:44One of the things that I did over the last four years is participate in the President's Council of Advisors on Science and Technology and co -chair to report on the future of public health. And we ended up thinking that we're focusing on the workforce. One of the remedies for the issue you and I just talked about is having a broader set of people who we think of as the public health workforce. And I think people who are interested in Ivermectin, farmers, people who are up close and personal to some of the things with this bird flu, there are a number of different folks who would be really interesting to involve in public health efforts and we typically don't.

1:52:26And so I think that's one of the ways that we can go forward in public health is to think about how do we define public health and what does it look like? Yeah, I agree with that. Public health has really struggled in some ways. You've had these incredible success stories and then some awful failures. On the surface, it's such a great thing. I think that's why make America healthy again, resonates for people. People universally want... Yeah, how could you disagree with that? Want to be healthy. They want their families to be healthy. This is a universal thing. And how to capture that and make that real, not ivory tower, but real for people who just want their families to have a chance at being healthy.

1:53:07I think that's a real positive. Yeah. I want to talk a little bit about AI. A lot of people might not realize you're on the board of open AI. And you're the only person in medicine on that board. So talking a little bit about how that came about, I don't want to obviously talk about the implications of that, what you're excited about and what you're afraid of. So I joined the OpenAI board almost a year ago now when they had had in November of 2023 what they call the blip, which is CEO fire board changed over. And I have been so impressed by the intellect, the commitment, the sense of responsibility of folks at OpenAI.

1:53:54I hope this is maybe a little crazy, but here's what I hope. If I had a top two things for AI, one is in some of the things we've been talking about in product development. I mean, I love product development. I think it is the best job on Earth. You get to make new medicines for people who are sick. You go home and tell your mom and dad that they're happy. So what if we could take the tool of AI and make easy, the things we can make easy? So you don't use AI to change a clinical trial. I still want to know does your tumor shrink? Do you feel better? Do you have side effects? But there's a lot of study reports.

1:54:33There's toxicology reports. There are a lot of things that are labor and paperwork that are actually very important to establishing the safety, especially but also the efficacy of a drug. I think using AI more and more on pieces of the clinical trials process so that if something takes time, it's because it's benefiting a human, not because we just couldn't do it fast enough. So with the clinical trials, I think still has some opportunities for that. Give me a time and money sense in terms of savings. This is a very important question. If you said the entire clinical trials program for a drug is six years, let's just make that up.

1:55:14I indeed do approval. I indeed do approval. I would want to cut it down by two years. And you believe AI can do that right now or we're on the path to that? I think we could be on the path to that. Now, the challenge of it is going to be if you say this example I like to give because it makes sense for people. If I'm changing five -year survival, if this is sort of a mature, established thing, I got to wait five years. I can estimate things and I can work with FDA to make sure if people can benefit. And you could argue with a regulatory change in the FDA, if we said greater emphasis on safety to approval, greater emphasis on post -market surveillance for efficacy.

1:55:54We shift this thing a little bit. Now you could say at three years we're trending, you get a provisional approval, and now we're going to follow you. There's an example, like Paxle of it in my mind. You could argue maybe should have been pulled, maybe wasn't as effective as it looked in the trials, and that doesn't mean they were wrong to approve it, because it was any portant to storm. But after the fact, we could have been, oh, you know what? No harm, no foul. It was safe. You can always do that. And so maybe we do that for oncology. I think that the other thing is you and I both know if you have 500 patients in a trial and you look at safety, that's so limited.

1:56:29If you have a much more AI driven, why don't we follow safety in every patient on the Exactly, ongoing. So I think the opportunities in clinical trials are massive. The other thing I would love to see is a change in the things that cause burnout of nurses and physicians and others in the hospital. This is across the board, not just in clinical trials. Not in clinical trials. This is healthcare. Yeah. Healthcare should have tools where it's easier to decrease the load, the burden on both caregivers and families. I think that should be doable. It's not that hard. I think that that is absolutely correct.

1:57:07On the nursing front, there's a huge demand, obviously. How much of this do you think of absent robotics? So robots can really change the game. I'm not close enough to that, are you? I'm not close enough to the robotics piece of it. Yeah, so I don't know how long until a robot is doing what a nurse is doing. But when you think of medical and chart reconciliation and things like that, is that where you think the greatest opportunity is? I think it is when you're trying to connect all the dots. That's the thing. What AI does so brilliantly is it just takes a lot of data and it comes out with observations.

1:57:44And if there are ways that that can assist at the bedside, that's a massive improvement, especially when people are changing even me. University of Washington, do you see us F? It's so hard to change caregivers, to change health systems. Those kinds of things can decrease workloads, but I also think it's the kinds of things where clinical observations could be AI -driven. So the Nobel Prize last year was awarded for protein folding, AI -driven analysis. Explain to people why that is significant. How much do you think that particular achievement is going to advance biotechnology and what remains ahead of it as far as even greater molecule selection?

1:58:27These guys, what they did is they made possible. And we talked about preclinical. Well, this is pre -preclinical. This is how you even... This is figuring out what you're going to do. Just figuring out what you're going to do. If you can make figuring out what you're going to do much, much faster, which they did, you're going to have the opportunity, the way I think of it is you've got like a mountain of opportunity, but it's shown a light on just a limited number of things where you can see the opportunity and take advantage of the opportunity. I think it's a start, but I think it's great that they were recognized.

1:59:03Do you think this is the most important thing from a promise perspective that AI has brought to medicine since so far? Yeah, so far. And so what do you think would be the next mega unlock? Would it be on the data front? Would it be a predictive model? How could we shorten a clinical trial by 60 percent? Anything where AI can help us with outcome measures. I told him that my husband's an HIV doc. When we were both at Priscilla Myers' Squibb, I was doing two by two measurements of tumors on X -rays for tax -all, and he was looking at viral load. Viral load allowed us to have 20 HIV drugs in like five years.

1:59:46It was crazy how good it was. I want a viral load for everything. You need a good biomarker. We need a good biomarker for more things, and you were talking about all the different types of breast cancer. So think about what you just talked about with breast cancer that you have the air positive, your negative, her too positive, triple negative. There's all these. What if actually there's 15? Yeah, they're undoubtedly are. They're probably are. So then you're in 15 trials, but you only need 10 patients in each trial, because it's so obvious you have the perfect remedy for each of those patients.

2:00:20I always think of it as switches on, turn it off, and you see clinical benefit. Anything we do that sets up like that, especially if we can not just measure switch on, but switch off. That's why viral load is so powerful. So, what's your level of optimism or pessimism around liquid biopsies? And do you think that AI can help us with these? I have been pretty negative based on the data. I just have not seen the data that suggests to me that we're helping. And is this on the sensitivity front? Yeah. So can AI help us possibly? The problem is just really hard. Yeah, it was let us say. Do you think the problem is tumors don't shed enough DNA?

2:01:03I think that appears to be the problem because if they did, I think it would work. So that's the most important problem. The other problem is something that I think we all tend to underestimate. Because I love the concept of prevention and I think make America healthy again. And part is we'll go to preventive therapy and stop all these. And I understand that in oncology we've often celebrated tiny successes, but you can't have big successes before you have tiny successes. I don't think it's easy to do early detection. The only two things that are, what not three, the colonoscopy works. For cervical cancer, a pap smear works, even better, HPV vaccine is my ad, and now you can do a spiral CTE for lung cancer.

2:01:50I'm not even using one hand full of fingers, and we've been trying to do early detection as long as I've been an oncologist. I agree with you, by the way. I would add to that PSA in the hands of someone who understands what to do with it. So PSA by itself, pretty bad. PSA density, when you know prostate volume and PSA velocity, when you have serial measurements, begins, starts to become very predictive. So you take a man who has not had a prostate biopsy and you stratify his PSA according to PSA density. The ability to predict if he has a gleece in 3 plus 3 or 3 plus 4 or 4 plus 3 is really quite high.

2:02:25And at least you can then stratify those patients more quickly into a PHI or a 4K and ultimately decide do they need a multi -parametric MRI and you go down that path. So it's not turnkey and I completely understand why they've said, we're gonna make no recommendation. I do take comfort in knowing, it's sad to me, but I take comfort in knowing too many men are dying across the cancer. It should not be the third leading cause of cancer death. And yet I understand that it's a big ask to get every doctor fully up to speed on the algorithm. You know what? You just said that's something that if someone wanted to start a company, they could simplify that and make something more turnkey for patients and physicians.

2:03:06When you go through the four leading causes of cancer death, two of them don't need to be on the list. Colin Cancer and prostate cancer don't need to be on the list. They shouldn't be on the list. Now, long, I think we can reduce it a lot, but it's gonna be awfully tough. And breast is still really tough, because it's not half -steady. It doesn't have that straightforward progression from polyp to cancer. That's true. That's the neat thing is you can just take out the polyp. That's always been the beauty of Colin Oscar. What is your level of optimism that we could ever? So instead of just talking about a broad liquid biopsy, let's just talk about breast cancer.

2:03:38What do you think it would take? And do you think it would be a protein? Do you think it would be DNA? Do you think it would be RNA? If you had to guess what would be the earliest signature in the blood of different breast cancers, where would you put your money? I think it'd be interesting to look at protein. Think about how that would change breast cancer treatment. It would be tremendous. It's funny. I say the following deliberately not acknowledging your gender because I'm sure you hear all the time Sue you are the most remarkable example of a woman in medicine. Gender aside you are just a remarkable inspiration period as a physician, as a business leader, as a public health official.

2:04:16I have been a fan of yours for so long when I walked into that room, you know, last year and saw you sitting there. I was giddy. So thank you for humoring me and making the trip. It was fun. I'm delighted to talk with you. Really enjoyed it. Thank you for listening to this week's episode of The Drive. Head over to peteratia -md .com forward slash show notes if you want to dig deeper into this episode. You can also find me on YouTube, Instagram, and Twitter all with the handle peteratia -md. You can also leave us a review on Apple podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional health care services, including the giving of medical advice.

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