 Dr. Ladd, thank you so much for joining us today on This Is Purdue. I know so many of our listeners connect with cancer on a personal level, and you've actually helped create a drug that can find these malignant tumors. Tell us, but let's start at the beginning. How did you get into the chemistry field? Well, actually, my father was a chemist and he was a faculty member here at Purdue University and actually a very famous one. And as an obedient child, I took the courses in high school that I was asked to take. And he always signed me up for advanced science courses. So here at West Lafayette High School, I took advanced chemistry, advanced biology, advanced physics, and all of the math courses I could take. And I wasn't stellar as a student. I mean, I struggled through those courses. They were difficult for me, but in the end, I really enjoyed chemistry the most. And so when I went to BYU to undergraduate school, I instead what I should, he thought I should major in. And he said, well, why don't you major in chemistry? I suspect there may have been some selfish motivation in the absence. He was a famous chemist. But also he pointed out to me when you finish with your degree in chemistry, you could go if you waged in the business, go into sales, you could go into medical school or dental school, or you could continue on in science and sharpen your chemistry skills and get an advanced degree in chemistry. And at the time, I really didn't know what I wanted to do. But eventually, all the ducks lined up for me proceeding on and getting a PhD in chemistry. That's great. So you've founded numerous drugs, companies, you have patents under your name. Is that kind of along the same lines as you followed your dad in those footsteps? Or what made you so interested in innovation? I think what attracted me to innovation was the opportunity to do something that matters. A lot of chemists are motivated by the discovery of basic principles in science that can have a fundamental impact on lots of different studies. I was more motivated by doing something that would save lives or help people in some way or another. And I was always very intrigued by life sciences, how cells work, what caused them to be able to do so many wonderful and interesting things that cells do. And as I dug deeper, I learned I think a skill that a lot of people don't learn in their research careers. And that is whenever you discover something new or read about something new, sit down and ask yourself the question, how can I use this information to do something that really matters? And as I practice that fundamental principle, I found that simply asking that question opened up opportunities that I would have never envisioned had I not stopped to think about the potential value to humanity of the work that I was doing. And gradually, that just led me from initially working on cancer to more recently branching off into autoimmune diseases. Now we're working in CNS diseases like Alzheimer's and Parkinson's, and we're also working on fibrotic diseases and bone fracture repairs and things like this. So it's actually guided me in many areas I would have never envisioned and actually was never prepared to pursue, but had to learn on the fly because the ideas that I was coming up with brought me in that direction. And ultimately, I think we have over 500 patents in all of these different areas. And of course, as you know, we've founded six different companies all of which are successful. And speaking of doing good, your creation most recently gaining a lot of buzz is Cytolux, which is a fluorescent dye. And will you explain to our listeners how this dye works? Yeah, we have taken a dye that is that he emits light that is transparent to tissues, that is, it's light that will pass right through your hand, for example, it's not light that's visible to the naked eye, we have to have a special camera that detects it. But it is basically light, not radiation and damaging term of radiation. At any rate, we attach that near infrared fluorescent dye to a smart molecule that homes in very selectively on cancer cells. So when they're when the dye is piggybacked on to the this homing, this smart molecule, if you inject it in, for example, into the vein of a patient that is scheduled to undergo surgery, and perhaps an hour, the dye circulates through the body, but only attaches to cancer cells. And so when the surgeon opens up the patient and turns on the fluorescent light, the cancer cells glow brightly like bright stars against a black background. And so this allows the cancer surgeon to identify, locate and resect all of the malignant or cancer lesions in the patient and avoid removing too much healthy tissue because the healthy tissue doesn't fluoresce, but the cancer tissue does fluoresce. And this is a very important problem, because if you look historically, and even today, 40% of recurrent cancers recur in the tumor bed that was resected or removed by the surgeon. This means that the surgeon left a lot of diseased tissue behind, and that tissue grew back. And that means either another surgery or more often than not, it means because it's only caught much later that the patient is not going to do well, maybe not survive. And so enabling the surgeon to very clearly see they can just shave until all of the cancer tissue is removed, all the fluorescence is gone, when they see all the fluorescence is gone, they know they have removed all the cancer tissues. Kind of like painting by numbers, colors, you know, you see right exactly what you have to do. It's a very bright visual aid to the surgeon on how to remove the cancer. And you touched on it's important not to remove, you know, blindly some of these healthy cells. Why is that? Why is it so important to just get that cancerous cells out of there? Well, that's a good question. In some cases, it's not as critical to be really highly precise and not removing healthy tissue. But in brain cancer, people are fond of their brains and want to have as much of that left over as they can. And frankly, in other tissues, for example, in breast cancer again, if the cancer can be removed without removing extra healthy tissue, the patient would like would prefer that. In some cases, resection of healthy tissue actually does serious damage in prostate cancer. For example, if a healthy nerve is accidentally severed, the patient can be incontinent and impotent after the surgery and being able to see exactly where the cancer is and not cut anything that's non malignant will really benefit patients in all of these areas. Yeah, that makes perfect sense. So can you tell us about the difference between this targeted marker and others on the market that aren't specifically like tumor targeted? Yeah. Well, there are some other fluorescent dyes that passively concentrate to some extent in the tumor tissue. But the contrast between the malignant tissue and the healthy tissue is blurred. And the boundary between the two is generally not very and always not very exact. In our case, because the cell that our dyes bind to are malignant and the cells that it doesn't bind to are non malignant, the boundary between the cancer tissue and the healthy tissue is really quite sharp. So it allows the surgeon to really make a very exact cut and preserve healthy tissue while being quantitative in removal of the cancer tissue. And can you tell us everything that went into creating Cytolux and how many years in the making? What's this massive project? Yeah, I mean, I don't know where you want to start on that question. I could go way back and begin with the accidental discovery of a tumor homing molecule. Okay. We have all day. An interesting story. I was studying plant cells and asking the question how these plant cells detected pathogens like bacteria and viruses around because a lot of plants will wilt and die because of a pathogen infection like bacterial infection. And so we found that if you ground up some pathogenic bacteria and spread the dust on the leaves of a soybean plant that that would prevent that soybean plant from getting a bacterial infection later on somehow immunize the plant. And we wanted to find out what how that information was communicated from this ground up bacterial dust to the plant to create this immunity. And so I asked a graduate student to see if these any of these bacterial pieces were carried were captured by the plant cell and carried inside. I told him to radio label it and then see if any radioactivity went inside the plant cell. And he went away and then came back and said Dr. Lau I'm sorry I can't do the study. And I said well why not. He said because I didn't want to work with radioactivity. I thought gosh everybody you know our Elvis is doing it and we do it all the time. But anyway so I I deferred to his preferences and I asked him instead to put a biotin that's a biotin and attach that to some of these bacterial pieces and see if that went in. He did and it went in. We celebrated. Hey that shows how this signaling is taking place. But then I told him to conduct what we call a control study where you show that it really is recognizing the bacterial piece. So I said now put biotin on insulin plant stone have insulin. And I told him to put it on bovine serum albumin that's just a protein in the blood stream of cows and show that it doesn't go in because we know they didn't do anything to plants. And he put the biotin on those two proteins and they went into so this is how science works. And he came back he was terribly disappointed and said Dr. Lau we were wrong the experiment didn't work the biotin linked cow protein and the biotin linked insulin also went in. I said Mark you have just discovered a a vitamin uptake pathway in plants the plants are taking up the biotin because they can take up a biotin linked cow protein a biotin linked human protein and biotin linked bacteria. To make a long story short we decided to find out if animals had that capability to so we looked at animal cells and then we jumped to folate another vitamin and by the way animal cells did have that and when we jumped to folate we found out that only cancer cells had the ability to take up folate and that was a breakthrough by accident I must confess but that started my first company endocyte we used folate to deliver attached drugs very selectively to cancer cells avoiding uptake and the associated toxicity when you know a good drug goes into healthy cells and that made a huge difference and so the whole process got started by an accident but the outcome was that we noticed that something useful could be developed out of that accident and from folate we went to lots of other homing molecules and now we have a whole toolbox of homing molecules that we can use to target drugs to as I said not only cancer cells but cells involved in all the fibrotic diseases the autoimmune diseases the cns diseases bone fractures even inherited diseases and things of this sort so we're covering a whole realm of human diseases based on the principle that if you can concentrate a good drug specifically in the disease cell and not have it taken up in healthy cells you'll improve the potency of that drug and reduce its toxicity to healthy cells make making the drug far better than it was before and all six of my companies are are founded or built on that principle wow and so through all this trial and error and all this innovation and science that's exactly like you said that's how science works so that was a great story thank you for sharing um so this drug just went through the clinical trials process can you explain everything that goes into that yeah um well initially the whole discovery process uh is usually begun with a concept that you have for example a homing molecule and why not use that to color cancer cells or make them glow like light bulbs so that the surgeon can see it and so the first step is to do the chemistry in the laboratory which we did and the second step was to culture cancer cells in a little dish and what we did the initial study that we did was we cultured cancer cells in a dish in the presence of healthy cells in the same dish uh and they were human cancer cells and human healthy cells we added our tumor targeted fluorescent dye let it sit there and and bathe all the cells both the cancer and the healthy cells and then after a few minutes we washed off the the solution on the top and looked at them under the fluorescent microscope and only the cancer cells glowed the healthy cells did not so we thought by golly we've got something important there right then the next step was to take it into animals and the animals that we used we implanted into them um human cancer cells so we used special mice actually that would not reject the implanted human cancer cells and we looked to see when we injected into the tail vein of these mice would this fluorescent dye only go to the growing cancers and indeed we confirmed that they just went specifically to the growing cancers then we went to some naturally occurring cancers in dogs that came into the veterinary clinic and just looked to see if we could help there and helping the surgeons there find the malignant lesions in these pet animals and it worked there and then we had to prepare it for human clinical trials that's a long and whole process you have to demonstrate that you can reproducibly manufacture your drug exactly the same many times over so that they know that if you run these trials every patient's going to get the same molecules next you have to show that it's stable then you have to show in two different animal species that it's not toxic so we did it in mice and in dogs then you have to show that it can be very antiseptically bottled and stored and that it's stable during storage and and and filling and we had to do that and finally we had to submit what's called an IND in an investigational new drug application we submitted that to the FDA with all of these and obtained permission to begin trials in humans but then when you start in humans you have to start at a very very low dose and a dose that's far too low to even have any benefit so the first few patients received so little of this targeted fluorescent dye that you can't see anything but we just wanted to make sure that they didn't have a fever have accelerated heartbeat or had you know any adverse events and so we gradually escalated the dose and in the process we reached a concentration of drug that was very effective in revealing the tumors but not causing any associated collateral toxicity that that ended phase one then phase two clinical trials focus on finding really the precise dosing conditions more exactly and to give you the best contrast between the tumor and the healthy tissue then the phase three trials were just to test in a large population of patients that exact condition that we believe works best and then we test that in 150 to 100 patients and we show that we are able to find malignant lesions in these patients that would otherwise gone undetected and then that results in the ovarian cancer trial that has completed and was given expedited review by the FDA because it looked so impressive the results were very impressive in other words the surgeon never knew it was there turned on the fluorescent lamp and wow there's some extra cancer in there they cut it out they sent it off to the pathologist the pathologist says yes that's cancer and so that confirms that the dye enabled the surgeon to find cancer that was otherwise undetectable in the patient i have so many follow-up questions i'm not sure which one to ask um how did you feel when this was finally you know being tested on humans and like you said it's a matter of it's quite literally a matter of life and death especially in these aggressive cancers like ovarian cancer what what were you feeling like when this all kind of was coming to fruition well it was i must confess a eureka moment um bringing it to this stage was certainly a difficult journey i was not very familiar with the process and not not at all actually and so to be honest i and my colleagues at both endocyte my first company and on target labs the second company to some extent went through the school of hard knocks making mistakes that a more experienced drug discoverer wouldn't make but um i learned a lot in the process i'm not making those mistakes with my subsequent companies and i think that i've you know what i've learned will greatly benefit me in avoiding similar pitfalls in the future and moving drugs more rapidly from discovery through to a clinical application and so with my more recent drugs in these other areas where the sailing has been a lot smoother let's just say that sure sure i took the data and showed it to a lot of surgeons and it was interesting the surgeons told me oh we don't need this we can find the cancer very easily we're we've been doing this you know for all our lives and i heard that over and over again for about eight years i would present the data showing these very specific fluorescent images of animals and where only the tumor floresced and they in in no way disputed the fact that we could cause the tumors to floresce but they were not convinced that they would help them and then a surgeon over in the netherlands saw the data at one of my talks and said oh this is terrific let's do something with this and so they introduced it into human clinical trials and it was in ovarian cancer patients and we published the data in a very prominent scientific journal called nature and the results showed that they were able to find five times more malignant lesions with the aid of the florescent diamond without it and that a hundred percent of these fluorescent lesions were cancer and did you bring that back to the us and say see i told you that really that really created a stir i mean it really proved um unequivocally in a well care well run clinical trial that the surgeons really couldn't find all the cancer and that there was a lot that was being left behind that they didn't know about and so that changed actually the field that that paper was the first paper using a a tumor targeted fluorescent diamond humans and um so at that point we were able to raise a lot of money and that that was back in 2008 we created a subsequently a much better fluorescent dye and i think we patented that in about 2013 or 14 2014 and that's the fluorescent dye that just received expedited review by the FDA and should be approved within a couple of months so this has been a very long process almost 20 years do you foresee this drug being used in other cancers besides ovarian yeah we're um it will it is being used currently in phase three clinical trials for um resection of lung cancer and the data there are equally impressive but i'm not allowed to disclose them but i can say that with some confidence that it's going to also change the surgery for lung cancer um after that we have a different dye that we've designed that is very specifically useful for prostate cancer and that's gone through the phase one clinical trial stage uh and the data are looking very promising there we have others lined up in um in the uh refrigerator basically that we've designed and tested in animals that look very good for other cancers and i think very soon we'll have a toolbox of these fluorescent dyes maybe four or five that collectively will cover essentially all human cancers it was there a reason that you chose ovarian cancer in particular to start with um yeah there were a couple of reasons first of all ovarian cancer had this the receptor we call it that was recognized by this smart fluorescent dye um the second reason was that ovarian cancer is a very um insidious cancer it um emerges or is first detected usually only in stage three or stage four where it's already spread and i think the average survival is five years and um that's because it's been historically almost impossible to find the the metastatic lesions it spreads throughout the peritoneal cavity and little uh small malignant nodules and uh some of them are buried underneath the viscera and the intestines the walls of the peritoneal cavity on you know in different surfaces and it's just almost impossible to find but if you turn on this fluorescent lamp and we have videos of this you can see the surgeon moving the viscera around there's a fluorescent spot so they cut that out and they move it around there's another fluorescent spot these spots that are these nodules are often just um you know a tenth of an inch or less in size but if you let them go they'll grow huge and um so they would normally go undetected because they look exactly like healthy tissue you really can't distinguish them when they're that small they're not a bump they're just smooth and they don't feel hard or anything like that so anyway it seemed like a particularly um difficult cancer to successfully resect surgically and so it was a good place to demonstrate the benefit of having a tumor targeted for us. Sure so you mentioned before that now that you've gone through this process once with with your other companies now coming up you have um a greater knowledge of all of this where do you think that drug discovery will be in you know five or even ten years? I don't know you know I'm getting old and my days are long still and everybody keeps asking me when I am I going to retire I have a problem I'd like to retire but I have lots of ideas and most of these ideas are pretty good and so I'm not sure exactly um what the future holds for me to be honest with you um I've um you know we've been very successful uh both scientifically and financially and I don't have any problem getting started companies started anymore not only uh do I have a lot of ideas but it's a lot easier once you've been successful with one or two companies to go out and raise money for funding the um drug discovery projects and the additional companies um for example our third company is developing a tumor targeted immunotherapy that takes a patient's immune cells and puts in a new gene that enables them to very aggressively attack only cancer cells and we went out and within a few months raised uh over 250 million dollars for the company oh my and when we first uh just in comparison when I found at endocyte my first company it took me quite a while to raise one and a half million dollars so now you're just a prop so you know we're well it's uh it's easier once you've been successful uh the major investment banks and venture capitalists call you instead of you calling them it's going right back to your dad being a famous chemist it's another famous chemist so um what do you think the most gratifying part of all of this has been for you well I I think it's been very gratifying to be able to help people um I just uh watched a video of a lady from the Philadelphia area who was so thrilled that uh the surgeon there Janos Dr. Janos Tanya was able to find uh significant extra disease tissue in her that would have gone undetected otherwise and uh she listed off all of the different activities she was engaged in and how important her you know her ability to interact with these um charitable organizations and these volunteer activities and so forth and her grandchildren and so forth it was I was just uh I guess overwhelmingly uh rewarded by just seeing that you know what we likely did there was to give her an extra you know maybe 15 years or whatever to be able to carry out all of these wonderful activities that she was engaged in I think that's the most most rewarding aspect of it all you know and I've heard you have very strong ties to Purdue you talked about you went to West Lafayette high school your dad was a chemist here at Purdue why did you choose to come back here and work here um well it was the it was it was a good job I mean when I uh when I first started looking for faculty positions um I only had one other job offer and uh it was obvious my parents lived here I grew up in the town I liked uh West Lafayette very much so I decided to come back and uh yeah it was the obvious choice and I'm sure other people were trying to poach you as you got more and more successful yeah I've I've been obviously um given many offered many offers to move to other places and uh I um I grew up a very avid Purdue fan when I was a kid my dad used to usher at the basketball and football games and uh as a good father he bought me tickets so that I could go along with him even I and uh so I went to all the basketball and football games starting from the earliest days I remember and I grew up an avid Purdue fan it's interesting here's a here's a personal story that you might find interesting I played basketball at West Lafayette High School and uh was fairly good okay and um I got a basketball scholarship to BYU okay and I did play there okay and uh when um I got my job at Purdue um shortly afterwards BYU came out to play basketball here I had tickets for the game and uh so um um I wasn't sure who I was gonna root for and when the uh opening tip-off went up uh immediately I was a Purdue fan did you wear Purdue colors? I don't think I did it myself at the time okay but I do now you stayed neutral okay full wardrobe and as a matter of fact all of my kids have Purdue rooms and their homes where they have all the Purdue paraphernalia that we send them and so forth on the walls so are you still an avid sports fan here yeah I I I have tickets to both basketball and football games and what do you think um like when it comes to drug discovery work being done at Purdue versus other universities how does Purdue stay at the forefront of all of this? Well um I think Purdue made a decision and maybe it was just intrinsic in the nature of the university many many years ago to embrace the use of science for practical applications uh maybe this stems from the heavy focus on engineering which is really an application directed science um maybe it's was the decision of earlier administrators I don't know but in many uh schools finding a useful application for your discoveries is considered prostituting yourself for filthy lucre it's it's beneath the dignity of a good scientist to do something of that so in Purdue it's not crowned on as a matter of fact it's encouraged now in all fairness I will tell you that that attitude has changed 180 degrees at almost all the universities but when I first found at Endocyte at Purdue even Purdue was skeptical about the um compatibility of having a faculty member also engage in private enterprise and I had to go up through the department head first who discouraged me from doing it then to the dean who also discouraged me from doing it it went to the president and the president had just returned from a trip out to Stanford where they were already beginning to do it and he said well why not let him try and so I was given permission and we found at Endocyte I think it was the the first or not one of the not the first one of the very first companies it was 1995 and it was one of the first companies to be founded based on Purdue technology and since then as I say I've had over 500 patents all of almost all of them through Purdue University and Purdue is going to benefit financially a lot from these I think but also I there's been a lot of benefit to the university in terms of the training that students have obtained in my lab and in terms of the visibility that it brings to the university in terms of the money it brings into the university because it's my lab is extremely well supported now we occupy this entire top floor here and that money has come in because of the interest from industry and supporting all the work that we're doing and you know I think it's a win-win situation for the faculty member and the university to promote this within the you know appropriate limitations and restrictions I think those are important to just imagine that if you had stopped when those two levels of people said don't do it I mean look at all these things you've created so what would you say to a future student who might be thinking about coming to Purdue to pursue science oh I think Purdue is a great place for an education on science I think it's terrific they focus on the STEM curricula and the I think the atmosphere of encouragement for translating your discoveries into something useful is very prominent and helpful here my personal belief is it's the only way science is going to survive in the future the I think we have to demonstrate that public support of science is going to pay the public back it's in their benefit to do so and for many years it wasn't obvious we would discover new fundamental principles publish them in journals using language that only your colleagues would understand and no one who you know worked at the local factory and you know came home and watch ball games on TV had any idea of how that might benefit them and frankly in many cases it didn't but now with this emphasis on finding some practical use for your discoveries I think it will become very obvious that Purdue University and other comparable universities can become an economic engine for the state and local area and what does it mean to you we touched on this a little bit earlier but to to have all this success and you know like you said financially and you created all these different things but more importantly you've saved and you're going to save hundreds of thousands of lives what does that mean to you well I mean I I don't know how to answer it any differently than it is very gratifying it's very rewarding and it's nice to know that you have can leave a footprint on the planet when you leave and I think we'll be able to say that we've done that and feel comfortable that we've made a contribution to humanity and this is an easy one why are you proud to be a boiler maker I like Purdue yeah Dr. Lauer where does the name Cytolux come from well the prefix Cyt comes from the Latin for cell and lux comes from the Latin for light and so what you have is a lighted cell and that's where the name stems from one has to get these names approved through the FDA you can't actually claim any outcome or benefit with the name so usually go to companies that know what will be allowed and what won't be and you select four or five and send them to the FDA with your preference and the FDA that approves them or disapproves them and this was approved I like it I don't see it's easy to say some of the jugs that come out to me are like what so okay well thank you so much for your time I think it was wonderful um I am a true boiler maker that's a Purdue fight song on my cell phone I love it