Rice, Kenner C. (2023)

Shirko: Good afternoon. Today is July 21, 2023. My name is Matt Shirko, and I'm a contractor with the Office of NIH History and Stetten Museum. Today I have the pleasure of speaking with Dr. Kenner Rice. Dr. Rice is the Chief of the Drug Design and Synthesis Section, a joint lab between the National Institute on Drug Abuse [NIDA] and the National Institute on Alcohol Abuse and Alcoholism [NIAAA]. Today he is going to be speaking about his background, career, and accomplishments. Thank you very much for being here and agreeing to do this.

Rice: My pleasure.

Shirko: To begin, just a little bit of personal background. Could you discuss your childhood, your family, and any formative experiences or interests in your earlier years, including what might have sparked an interest in science?

Rice: I was born in 1940. My father was in the Service during World War II. My mother and I moved around a bit with him and between my grandparents on both sides of my family to live during the war. My father was actually a graduate of the VMI [Virginia Military Institute] class of 1931 in civil engineering. His job after the war was with the Department of Agriculture in Courtland, Virginia, which back then was a small town of only about 1,000 people. We moved there when I was six. We moved onto a street that was basically for the veterans returning from the war. That’s where I started the first grade. I grew up there until the time I left home to go to VMI for undergraduate school.

My mother was from the Shenandoah Valley. Her family was the Earleighs of Southwest Virginia. We lived with Grandfather and Grandmother Earleigh during the war. Mother was a graduate of Blackstone College. She was a high school teacher when I was growing up, and my father was a civil engineer. It was basically a small farming town where I grew up. It was just the usual growing up experiences with the rest of the guys and gals. I got my first car there—a 1949 Ford, which was wonderful. I could ride around in the country and visit my friends and so on. I went away to college in 1957 to go to VMI. That was an experience—a small town boy going into VMI, which is a lot different than it is now. It was a tough time the first year.

The professor who taught me organic chemistry at VMI really cemented my interest in organic chemistry. My first experience in chemistry is when I was a little boy, and mother showed me what happens when you mix vinegar and baking soda. You get froth of carbon dioxide coming out, and it’s foamy. Boy, did I like that! Mother’s sister, Aunt Hope, bought me my first chemistry set when I was about eight years old. Of course, my mother was terrified I would hurt myself. But I was doing simple experiments. Then I got a larger chemistry set. I had really established my interest. I was really interested in chemistry in general. Then when I got to VMI and took organic chemistry in my third year, that was it! The guy that taught me organic chemistry was a guy named Herbert Richie. It turns out he’s the uncle of Kenneth Kirk, who was a chemist in the same building [at NIH]. We started in Building 4 and much later moved to a different building, but that’s kind of a coincidence. He called him Uncle Herb; I called him Colonel Richie. He was a tough guy in terms of keeping you focused on organic chemistry, but boy, oh, boy, did he motivate me. He helped me pick a graduate school—Georgia Tech. I went there and studied organic chemistry related to streptomycin. Streptomycin was one of the main antibiotics in those days, back in the early 1960s. I started in that type of work around 1963 or 1964. At that time, it was a major problem to determine the structure of those compounds. The chemists could isolate these crystalline substances, but in those days, they didn’t have what we have today. They had to take it apart, try to identify the pieces, and then figure out how they go back together. For example, morphine alkaloid was first isolated in 1806, but the structure wasn't known completely until 1955. It took all those years to figure out the structure of it. Whereas now, if we had a molecule of about that complexity, we could figure out the structure in less than two days, crystallize it, send it out for X-ray, get the X-ray crystal structure back, and be done. But it wasn't like that. They didn't have that when I was in graduate school. It was just starting, along with NMR [nuclear magnetic resonance] and other techniques. That’s how my interest in chemistry developed.

Being commissioned out of VMI, I had an obligation of two years of active duty. I was assigned to the biochemistry department of Walter Reed Army Institute of Research [WRAIR]. The Vietnam War was going on during that time, and there was a lot of malaria that was resistant to the drugs developed during World War II. The Army had a very large effort focused on finding compounds that could treat the resistant malaria. This was falciparum malaria—cerebral malaria. It was killing a lot of people that had it because it wasn't that treatable with anything. I was given several choices on what structural class to work on by Tom Sweeney, who was then in charge of the in-house medicinal chemistry of anti-malarial drugs. But they didn't have a chemistry section that worked on that, so I was basically the chemistry section with an assistant. The World War II drugs were good on World War II malaria, but not so good on the malaria parasites of the Vietnam War. One problem with the anti-malarial drugs of World War II was that the best ones produced phototoxic reactions in people. If you get treated with the drug and you go out in the sun for an hour or two, most people will end up with very severe exaggerated sunburn that would put them in the hospital for a period of time. The main problem was how to get rid of the phototoxicity of these World War II drugs. This may be too technical, but I had an idea on how to suppress this toxicity. The quinine-like drugs that were developed during World War II had a phenyl group attached adjacent to the quinoline nitrogen in that part of the molecule. That ring could rotate and become coplanar with the rest of it, and that would extend the conjugation. Then that would put it right into the part of the spectrum that produces sunburn. My idea was to make some changes in the molecule where the phenol ring wasn't necessarily coplanar, so that would break up that conjugation—so that's what we did. We made quite a few compounds, some of which were very interesting, and we got a nice paper in the Journal of Medicinal Chemistry for the work we did on the antimalarials.

Shirko: You briefly worked outside of government. Would you discuss the type of work that you performed and any notable accomplishments during this period?

Rice: Up until that time, I'd never done process chemistry. I was always on the side of the discovery chemistry, determining the structure of streptomycin compounds. Process chemistry is about how to make a compound that's already proven to be a potential new medicine, how to make it on a large scale, and how to make it safely and cost effectively. First, I joined Geigy in McIntosh, Alabama and then pretty soon transferred to Summit, New Jersey to the pharmaceutical part. They made a compound at McIntosh—it’s near Mobile—that a lot of people have become allergic to, and I became allergic to it. It predisposes most people to repetitive chest and lung infections. It irritates the lungs, and then you start getting an immune type of response to the drug. The compound is cyanuric chloride. I had to leave Mobile. I went to Summit, New Jersey, to the Ciba part of it. There, I was assigned to work on developing a process for a compound that they hoped to market. I worked with some older fellows—one in particular that I learned a whole lot from. I've never worked in process before, but I learned quite a bit in that year and a half that I spent there—things that you couldn't learn in academia. It's a different ballgame when you're trying to figure out how to make a compound safely, cheaply, and as efficiently as you can. I was working on SU-23397—that’s the name of the compound. That was fun, I learned a lot, but I really wanted to go back into academic type of research. A fellow whose name was Dan Clayman worked at Walter Reed, and I had met him when I was in the Service. I would go to Washington from time to time from Summit, New Jersey. He told me about a position as a postdoctoral fellow at NIH. I interviewed for that and got that position. Some people thought I was making a big mistake, because I had a very nice job making a very nice salary. I was slated to go to Basel, Switzerland, to learn more about the company. At that time, I did a very nice job for them—Dan said I was different from the rest of them. I guess it's my interest in chemistry. They had a nice plan all set for me, and I said, “Sorry, boys, I want to go back and do academic research.” I went down and took a temporary position in NIDDK, then left that position and went to work for Everette May [at the National Institute of Arthritic and Metabolic Diseases]. In two years, I had gotten a tenured position there—once I showed him what I could do, basically.

Shirko: Can you talk a little bit about working with Dr. May and what that was like?

Rice: It was just another level of working with Colonel Richie. He was a Virginia boy. He was just a very sensible, very smart, highly accomplished scientist. I only got to work for him for three years, but I would have liked to have worked for him for 20 years or more. He retired, went down to MCV [Medical College of Virginia] to be an adjunct professor down there. He originated the class of analgesics known as a benzomorphans. Phenazocine is one. It was a simplified morphine. Morphine is a big molecule; he simplified the structure and originated these benzomorphans. He also originated phenylmorphans, which we’re still working on—and getting some very, very interesting compounds right now, going back to what he originated in the 1950s. It was wonderful working for Everette May. I helped him complete the last set of compounds in the benzomorphans he had discovered. Talwin [pentazocine] is a benzomorphan and it’s a drug on the market. When you get into something like that, people generally save the most difficult one for last. They make the easy ones first. Well, this was a difficult one. The starting materials for these are substituted pyridines. The particular pyridine that was needed for this wasn't available commercially. I don't even think it was a known compound. Using my process experience, I said “This is not that tough of a problem.” I figured out how to make about 250 grams of the stuff over four or five steps—so we had plenty of pyridine. I completed that series, and we published three or four papers on that.

After Dr. May left, I worked on some other stuff, isoquinolones and stuff like that. While this was in progress, the opium shortage of 1972 began to take effect. It was a worldwide shortage of opium and opium products. It got to the point where you couldn't get a prescription filled for codeine if you had a root canal in some parts of the country. Our group, or at least me, and others in different places around the world, started working on how to make opium products by total synthesis—in other words, how to make opium products starting with compounds that are already on the shelf as the starting material. The way chemical synthesis works is you start with an available compound, and then you do reactions on it, called “synthesis,” until you get to the point where you want to be. There was a group in the Netherlands. It was run by a Professor Bayerman and then he retired. It was taken over by Lynn Mott. There was also a group in California led by Henry Rapoport, our group, and another group in New York that Sid Archer was running. I figured the shortest route would be the best. Since then, there’s been many different chemical syntheses of morphine and those compounds, but there are always many, many different steps. If you put a protecting group on to protect the molecule from this reaction, you’ve got to take it off in so many steps—and every step lowers the yield.

Again, I pulled my process chemistry out and said, “None of this is feasible; we’ve got to come up with something else.” This type of reaction forms a carbon nitrogen skeleton and had been done with simple compounds. But it wouldn’t work to get the intermediate that was needed to make codeine, morphine, and so on. I was able to get it to work by using superacids. Triflic acid is the one that works best. Without going into a detailed chemical explanation, it was a reaction that others some others had tried, but were unable to get it to work, and I was able to get it to work. That's what basically enabled what we now call the NIH Opiate Synthesis. It was developed by several companies—Mallinckrodt [Pharmaceuticals] was among them. They never could get it. Then later, the problem became, we don't have enough thebaine, which is one of the three main opium alkaloids to make naloxone and naltrexone, the antagonists. At that time, it looked like these antagonists were going to be widely used for different things. The problem with codeine and morphine is that they’re at the end of the synthesis, so it's the most steps. Then the problem became how you make thebaine to make the antagonists in a large enough quantity. This was taken up later in the 1990s by Mallinckrodt, who worked on how to use the Opiate Synthesis to make naltrexone economically. They did a lot of work on that with real hardcore process chemists. I'm not a hardcore process chemist; I just happened to learn a little bit about it when I was in industry, but these guys, they could never quite get it down cheap enough. They could make it; it's just that it wasn't cheap enough. Then the supply of thebaine and all the poppy products came back with the Johnson and Johnson work on it. They have a big farm on Tasmania to grow poppies that make mostly morphine, or mostly codeine, or mostly thebaine. They did mutations on poppies using a mutagenic agent, so eventually they got one that makes mostly codeine, another one that makes mostly morphine, and another one that makes mostly thebaine. Now they could grow these poppies and get whatever ratio of alkaloids they want, rather than regular opium poppies where you have about 12% morphine in the opium and then you've got 2% or 3% of codeine and thebaine. The NIH Total Opiate Synthesis never became commercialized—it almost did, but not quite.

Shirko: The “NIH Total Opiate Synthesis” seems like a fairly significant point in your career. You've now spent pretty much your entire career researching drugs and drug addiction. Is this a topic that you were drawn to?

Rice: Originally, it was my association with Everette May. They were trying to find the ideal substitute for morphine when they were working on the benzomorphans that Everette May originated. It’s an interesting field. It’s got interesting chemistry. I guess that’s why I’m still doing it! [laughs] We got really interesting results with Everette May’s phenylmorphans. We published quite a number of papers recently on compounds—they’re not very related structurally to the morphine alkaloids, the phenylmorphans, but we’ve got very potent antagonists out of that. We've got very potent full agonist, partial agonist, and stuff like that. It’s continuing to yield important compounds.

Shirko: In 1984, your group at the Laboratory of Medicinal Chemistry, using an opium-derived antagonist narcotic, reported the first image of opiate receptors in a live primate brain using PET [positive emission tomography]. Please talk about this accomplishment and the impact it had.

Rice: Yeah. In 1983, PET scanning was just starting. It was being developed at NIH, and it was being developed at Hopkins. The opiate receptors were a good first target. They had a PET group at NIH, and they had the PET scanners and [inaudible] scanner and so on. They just needed the right compound for the job of imaging receptors. There’s a reason for the name cyclofoxy. It's related to naltrexone, the narcotic antagonist. We figured out how to put a fluorine-18 atom in that molecule. Fluorine-18 is one of the few isotopes that can be used in PET scanning. It has a half-life of about 110 minutes. That's not that long, but it's the longest half-life of anything practical. We had to figure out how to put fluorine-18 in the molecule. Of course, we did that.

In 1984, we published the first paper on a positive study on PET scanning of opiate receptors using the imaging agent cyclofoxy. We were competing with Bob Dannals and Henry Wagner at Hopkins. They had a different compound; they had carfentanyl, a very potent, strong bonding compound. We had the best compound, in my view, because cyclofoxy has mirror images, and they’re different compounds. The opiate receptors even then were known to only bind one stereochemistry. You could call it the left-handed form, and it doesn’t bind to the right-handed form of the molecule. The same is true for the antagonist. Narcan is the left-handed form, if you will, and the right-handed form is the mirror image form that doesn't bind to opiate receptors at all. We had the natural form of cyclofoxy, which binds to the receptors; and we had the unnatural form of naloxone that doesn't bind to the receptors; and naloxone itself. We were able to show that once the drug was localized on the receptor in the living baboon brain, that we could knock it off the receptor with the monocytes. The [inaudible] bound to the receptors, but not with the (+)isomers. We also showed that Narcan, the (-)isomer, knocks it off, but the mirror image of Narcan doesn’t. That was very, very powerful evidence that we were really imaging opiate receptors and not some other receptor or some nonspecific site or whatever. We published that in FEBS [Federation of European Biochemical Societies] Letters in August of 1984, and Hopkins published their study in 1985 with carfentanyl. Candace Kerr was a very famous biologist at NIH, and she named she came up with the name of cyclofoxy. One of the closely related compounds is oxymorphone—a compound that's used in the practice of medicine now—so oxy. In cyclofoxy we had a fluorine-18, so that's the “foxy” part of it. “Cyclo” is the cyclopropyl methyl that we have on nitrogen to convert it to an antagonist. That’s where Candace came up with that.

This was a big deal. It was the first time that opiate receptors have ever been imaged with PET, and we had proof that we had done that with the stereochemistry and all. Now PET scanning is [more common]. We didn't have a huge selection of compounds in 1984, but now there's many different ligands to do PET scanning with—a lot of different receptors. But we were able to design cyclofoxy, synthesize it, and make the fluorine label analog isotope, and Bill Eckelman was the main guy in the cyclotron unit in this study.

Shirko: You moved to NIDA in 2006. Would you describe your roles as chief of the joint Drug Design and Synthesis branches at NIDA and NIAAA? Also, could you please explain the structure of this dual-institute joint lab and how the collaboration between the two institutes came to exist?

Rice: We were originally in NIDDK for historical reasons. We decided that we should move to NIDA. The people in NIDA had been asking us for years to move to NIDA because of the work we do. It didn't belong in NIDDK, it belonged in NIDA. We did that in 2006. It was a joint appointment. We had a fairly big section, so the amount of money it took to run this was substantial. Barry Hopper was the Scientific Director of NIDA in those days, and so he and George Kunos, who was Scientific Director of NIAAA, decided to make it a joint appointment to share the expenses of the group. We had horrible labs in NIDDK down in the basement. Everything was cheap when they remodeled the building; there were no windows and a lot of other stuff [wasn’t ideal]. We had wondrous new laboratories when we moved to 9800 Medical Center Drive. Also, it's virtually impossible to park on the NIH main campus, but we just drive in and park in our parking space up there. That’s one headache that is also removed. We did a good a thing on that. It’s just an exercise of being a part of two different institutes. We structure our projects and collaborations with what’s appropriate. This is just a nametag basically.

Shirko: Are there any kind of administrative complications having to deal with two institutes?

Rice: No. We’re mainly in NIDA. NIAAA picks up the expenses for our space, and NIDA picks up everything else. NIDA is the lead institute on this.

Shirko: Some of your research on drugs and the role of addiction also veers off into behavioral issues, stress-related diseases, neuropathic pain, and psychiatric disorders. Could you explain on a big picture level some of the connections that exist between the work looking at addiction and the impacts of the drugs themselves and some of these more psychiatric or neurological issues? How does the research interrelate between addiction and some of these other issues?

Rice: Our group’s main role is to design and synthesize compounds to study a particular question. I tell these biologists, “Tell me what you want the compound to do, and we’ll make one that probably will do that.” I’m not into the biology of this very deeply. Neuropathic pain is a problem. It doesn’t respond to opiates very well, if at all. Linda Watkins at University of Colorado Boulder, one of the main people in neuropathic pain, was using the unnatural Narcan—the mirror image form of Narcan. People use unnatural Narcan to prove that they’re actually looking at an opiate receptor site with the monocytes. She had an affect [occur]; she wasn’t sure it was an opioid receptor mediated affect in the neuropathic pain receptors—the toll 4 receptors, a major player in the mediation of neuropathic pain. She was working in that and was trying to see whether this effect she was looking at was an opiate receptor mediated effect in the animals. She did the experiment with Narcan, and then she put in the mirror image effect of Narcan, and it wasn't supposed to do anything because the mirror image form doesn't bind to the opiate receptors. To her surprise, she found another effect—a very strong effect on neuropathic pain. It's now known it's mediated through the toll receptors, toll receptor 4 mainly. Then she started to really go into this and needed the unnatural form of naloxone, which is not such an easy compound to make if you make it. We can make 12 steps from an alkaloid known as sinomenine that we can buy. It's cheap and used in Chinese medicine. We can buy sinomenine, but it's still 12 chemical steps to get to (+)-naloxone. The “+” is the unnatural form; “-“ naloxone is Narcan. For probably over ten years now, she’s used (+)-naloxone to study neuropathic pain, and it actually has a positive effect on neuropathic pain in the rat, and it’s acting through toll receptors. For several decades, we thought that (+)-naloxone was just an inert research tool. Now we know it's a drug that can treat neuropathic pain.

Shirko: Turning to some of your work on drug addiction, you’ve also worked on the development of medications that prevent cocaine self-administration in rhesus monkeys, which may be useful in treating cocaine and methamphetamine abuse in humans as well. Could you describe some of this work?

Rice: You have the postsynaptic and the presynaptic nerve terminal. The presynaptic nerve terminal during normal neurotransmission releases dopamine, and then that goes to dopamine receptors on the postsynaptic terminal. This process is regulated by what's known as a transporter protein, a protein transfer that basically moves the dopamine from one side to the other side of the transporter. It was found by others that this compound GBR 12909 binds to the same site as cocaine does on this transporter protein, but it's a low intrinsic activity agonist, so it basically crowds out or outcompetes cocaine. If this transporter protein is loaded up with GPR, then cocaine can’t get in there and do its thing. That's the rationale for preventing cocaine self-administration. It really works in monkeys very well. You have monkeys working for food. They press the bar a certain number of times, and then they get a food pellet as a reward. On the other side, they press the bar a number of times, and they get cocaine as a reward. If you treat with GBR, they don't press the cocaine bar very much anymore, but they still press the food bar. That's what's called “self-administration” of food and cocaine. GBR blunts the effect of cocaine on the transport protein. That was actually developed for humans for something else, but it never made it through as a drug because it extended the QT interval [electrocardiogram measurement] with the heart. There is potential cardiotoxicity with it, but it’s a great research tool. That was a lot of the work of Richard Rothman when he was at NIH, and we were collaborating.

Shirko: Could you discuss your work on potential heroin and fentanyl vaccines?

Rice: We've been working on these vaccines for quite a while. The vaccine work is going very well. We have an anti-heroin vaccine, we have an anti-fentanyl vaccine, and we have a combination anti-heroin and anti-fentanyl vaccine. The way a vaccine to a small molecule is made is you've got a small molecule, you attach a derivative of the small molecule to a large immunogenic protein like tetanus toxoid, and the body will make antibodies to the small molecule. After immunization is complete, in a few weeks, the animals have antibodies to whatever drug you're making it against, like fentanyl or heroin. Then when they sense the heroin or fentanyl that comes into the blood, the antibody grabs the drug, it sequesters it in the blood so it can't get into the brain and act on its sites. This is working well. It's not the be all and end all, but it's another tool in the toolbox. If you do a dose response curve in naive animals to heroin versus immunized animals, it can shift as far as nine-fold to the right. It might be useful in helping people that want to quit drugs avoid relapse because they wouldn't get very much, if anything, out of the drug—so maybe they would decide it's not worth the effort they’re extending to get virtually nothing. It might prevent relapse in people that are already detoxified. In people that aren't detoxified, it might change a potentially fatal dose into a non-fatal dose. We've got very good vaccines for both of these compounds and for the mixture. That's one topic. Another topic is going back to the phenylmorphans that Everette May discovered and first published in 1955. We have the very potent antagonists that bind only to the mu receptors—it mediates the effects of morphine. It doesn’t affect the other receptors, like delta receptors or kappa receptors. It’s a very clean, very potent antagonist. Then we have the mixed agonist-antagonist. That's a very nice series of compounds; we’re still working on those.

Shirko: Broadly speaking, what are your thoughts on the current opioid epidemic, the impact of synthetic opioids on the addiction crises they were originally intended to minimize, and NIH’s role in addressing the epidemic? Yours is a different perspective considering you’re actively working on these things.

Rice: The fentanyl epidemic is a horror story as far as I'm concerned. If you’re a bad boy or bad girl and want to produce heroin, you’ve got to grow opium poppies—an agriculture product—and a lot of them. Then you have to process them, which is a huge undertaking. Then you've got to convert the opium, which is around 12% morphine, into pure morphine, and then convert to heroin—in the middle of Afghanistan—and then you've got to run the gauntlet to New York or Chicago. It's a huge, complicated story to make heroin, but to make fentanyl all you need are some chemicals and people that know how to make it. They do it in the backyard, which is what they're doing in Mexico. Fentanyl is a lot more potent than heroin—and it's a much bigger headache. Then there's another compound that's kind of like fentanyl only it’s a lot more potent. It’s called etonitazine. That's another different class of fentanyl-type compounds that are made pretty easily—a little easier than fentanyl—that are coming into the illegal drug market now. They can do the best they can at suppressing the raw materials and intercepting raw materials and stuff. I don't think it's possible to eliminate it. But what do I know, I'm not a law man or anything. It's just too many marbles out of the box for me, you know? It’s just a personal opinion. I hope that somebody will figure out how to eliminate it or even greatly suppress it, but right now, in my view, it’s not looking very good.

Shirko: Over the course of your career, from a general history perspective, how has NIH changed physically and administratively? What kinds of technological changes have made your work easier—or maybe even more complicated?

Rice: NIH has changed. When I first came up to NIH and became an independent investigator or a senior scientist in the 1970s and 1980s, it was an amazing place. It was like academia; everybody wanted to help everybody do as much as possible. It was just amazing. There were very few rules except to be honest, do the sensible thing, etc.—that level. Now you’ve got a rule for just about everything. In those days, if you wanted to communicate or send a paper to somebody, you’d put it in one of these holey envelopes and put it in campus mail, and then they would get it and read it and do whatever with it. Nowadays, you can get a barrage of emails in your email box. It's so much easier for people to invade your space now with the emails. You gotta just drop what you're doing and do this or do that and so on. That’s probably good, in a way, because it speeds things up a lot in terms of submitting manuscripts and getting them published. Now you send your manuscript by email, the editors send it by email to reviewers, and the reviewers come back with their review. If it’s satisfactory, the editor will send it back and say to consider the suggestions by the reviewers. You amend the manuscript as appropriate and send it back. We had one the other day. We sent it back on one day, and the next day, we got an email from the editor saying the paper is published. Really?! There wasn’t very much to do on it, and the editor took a look to make sure we did what we were supposed to. Then he pushed a button, and it’s published!

Shirko: That’s quick!

Rice: Yeah, it is! Every one of them doesn’t go that smoothly, but that’s how smoothly they can go.

Shirko: Still, faster than it was a couple of decades ago. 

Rice: Yeah, a whole lot faster! [laughs]

Shirko: You’ve been involved with over 55 (56) patents or pending patent applications. Would you discuss some of the patents and explain a bit about the drug patent process, specifically relative to the broader drug development work you do?

Rice: When we find something that might be patented, we fill out an invention report. That’s the first step. It lists the authors and a short explanation of what we’re talking about and why it might be useful. Then we send it to the NIH patent group people, and they decide what to do with it. They may have questions for us. They may decide that it looks like it may be useful, so they send it to the patent attorneys. Then the patent attorneys look at it and do a literature search to make sure it might be patented. That’s aided by computer assisted literature searches. This is a huge change from what it was in the 1970s and 1980s. If you wanted to do a literature search in the 1980s, you went over to the library, brought your lunch, and sat there. You’d want to look up compounds in the books—chemical abstracts. First, you’ve got to figure out what the chemical name is for the compound before you can look it up. Once you look it up by chemical name, it'll give you a reference to an abstract number. You go pull another book and you read the abstract if it looks interesting. That'll give you a reference to a journal. Then you go pull the journal where the compounds are mentioned in a paper—and then decide where you want to go from there. Nowadays, we have organic chemical structure searching on the computer as well as topic searching. It's now just 15 minutes, and you can figure it all out right away. That helps a lot. Rather than spending a day or two in the library, lugging these big green books around, you can just sit there for 15 minutes on your computer and draw the structure into the chemical abstracts database and find what you want—and they've got all the structures of all the compounds that are known. That's a huge change.

Shirko: Are there any specific patents that you’re most proud of or that have the most significance?

Rice:  In the old days, you basically had to help the patent attorney write the patent yourself, because these guys are not chemists. They may be knowledgeable in chemistry. One was set to time out because they had forgotten about filing it on time. We spent July 3 over at [patent lawyer] John Roberts’ house rewriting it so it could be submitted the day before it expired. That was on the Opiate Total Synthesis. We would have lost all of that if we let that go, but we got patents on that and on the chemistry that was involved in backing up the synthesis and stuff like that. That was one of them that was an important patent at the time. As time goes by, some things are important and then they fade away or go into the background, and something else comes up. Right now, we have a number of patents in progress and issued on these phenylmorphans. They look really promising—very potent, very clean antagonists and partial agonists—just the profiles you might think about for getting an ideal morphine.

Shirko: You’ve been recognized for your mentorship and have mentored over 100—102 to be exact—postdoctoral fellows from over 24 countries. Could you discuss your thoughts on the importance of mentoring and structured mentorship programs, as well as your approach to providing guidance and career development?

Rice: Mentoring is very important. You’re training the next generation of scientists. Each person is different, so I try to adapt to the particular postdoc and try to help them. Some people are better trained in organic chemistry and chemical synthesis than others are. I try to help bring them up to speed in whatever they're less trained in. And I encourage them. I'm not one of those guys that goes into the laboratory every day and says, “What's new?” We have our group meetings every two weeks. I say, “My door's always open, so come in and 98% of the time, I'll be able to talk to you right there.” When they have questions, it's better for them to feel free to just come in and ask the question. If they do that, I'm more than happy to help them—show them how to crystallize compounds or show them this technique or that technique. They all come from different backgrounds. One guy we have now was trained in amino acids and peptides, so he didn’t know much about alkaloid type of chemistry. He’s doing very well. I just try to adapt my mentorship to what they need. I’m a practical guy at heart, you know? Let’s get the job done.

Shirko: That sounds like something you enjoy, which is nice.

Rice: I do, but I don't want to be a person that's overbearing and pushy. I've seen these in action, and I think it's counterproductive. I think you can encourage them a lot further than you can push them, in general.

Shirko: Was there anything additional you wanted to comment on for the record?

Rice: Now that we have the patent situation as it is now, where it's very efficient with the NIH people in the patent offices and the patent attorneys filing these things, that's a big help. These patent attorneys we're dealing with right now know a good bit of organic chemistry. They can write a patent. Whereas I may know the organic chemistry, but I don't know the ins and outs of writing patents. They can write a patent, I'm sure, in a tenth of the time that I would take to write one. It’s basically a different message on the same mold for the type of work we do, but we're lucky that NIH has that. It lets us keep working to come with more stuff to patent. [laughs]

Shirko: You’ve done work on behavioral and physiological responses to stress in the hopes of understanding more about stress-related diseases. Can you discuss some of the findings, and the connection between stress-related diseases and addiction?

Rice: The corticotrophin releasing hormone [CRH] antagonists was a project we were working on around 15 years ago now. This is when George Chrousos was still at NIH; he’s in Greece now at a university over there. There’s a lot more to this corticotrophin releasing hormone system than you really think about. Stress-induced immunosuppression is one thing. Stress can suppress immune function. We were using a compound that had been published in a patent. Once the patent is published, anybody can use the compound as long as you don’t sell it—you can use it for research purposes. We synthesized this compound, which is a CRH antagonist, and studied it. Phil Gold, who’s still at NIH, George Chrousos, and other groups studied the compound. It basically reduces stress in stressful situations. We got a lot out of that. One of the paradigms they use is what's called the intruder paradigm, where you have two male monkeys that don't know each other. They put the cages together with a piece of plexiglass in between so they can't hurt one another. They are not happy campers—they try to fight. The behavioral pharmacologist has 15 or 20 different things they look for where they come up with a composite score for stress—how much they try to fight, how much they try to bite, how much they do this, how much they do that. These monkeys are not happy. That was the baseline, and then they dose them with this antalarmin compound out of the patent. It’s a pretty good name—George Chrousos gave it to us. It reduces alarm. “Anta. Larmin.” And boy, the monkeys greatly reduce their aggressive behavior. We did a lot of studies on mice and stuff. That was another big piece of our work back around 2000.

Shirko: You regularly work with pharmacologists. Could you briefly explain the difference between a chemist and a pharmacologist, and why your work requires collaboration with pharmacologists?

Rice: Pharmacologists sometimes know what compound they want to study. Other times, they don't know what the compound is, they just know what they want it to do. The chemist—if you decide to collaborate—is dealing with finding an existing compound that does what they want to do. For example, let’s see if we can come up with a corticotrophin releasing hormone antagonist. Well, we happen to know that this one compound is a good CRH antagonist. They were using a lot of it, so I worked out a process in the lab to make kilograms of this material. I made about three kilograms of big containers of this six or seven step synthesis, drawing on my chemical process knowledge. This compound had never been crystallized before, so I was able to crystallize it. That simplified purification a lot. If you can crystallize a compound, you can wash the crystals, and the impurities mostly go away. The pharmacologist may not know what compound, but they do know what they want a compound to do. It’s up to the chemist to make a compound they already know of or figure out how to come up with a compound that would do what they want it to do. If it’s not quite the right compound, then you can go into a structure activity study around the lead compound. In other words, does the lead compound do some of what they want it to? You can change the structure a little bit and it might be better at what the pharmacologist wants it to do.

Shirko: Are there any other career highlights you can think of?

Rice: No, not right now. One thing for sure, in my view, is that you need both chemists and pharmacologists because pharmacologists can’t make the compounds. Most of them don't know much organic chemistry. Few of them do. You need a chemist also. Amy Newman is one of my former postdocs; now she is my boss. She's the Scientific Director of NIDA.

Shirko: That brings some credibility to your mentorship, doesn’t it?

Rice: Yeah, it does!

Shirko: On behalf of the Office of NIH History and Stetten Museum, thank you for being here and for agreeing to do this, and for sharing your story and many, many accomplishments with us.