A possible vaccine to protect newborns; creating cancer drugs; helping aging skin: Upstate Medical University's HealthLink on Air for Sunday, July 16, 2023

Host Amber Smith: Coming up next on Upstate's "HealthLink on Air," a pediatric infectious disease doctor tells about a virus that newborns will be screened for in New York, and related research he has underway.

Joe Domachowske, MD: ... Because all of them are at risk for hearing loss, both hearing loss detected at birth if we test for it, and having progressive hearing loss over that first year of life, we need to know which babies are infected because we can treat them. ...

Host Amber Smith: And a cell and developmental biologist discusses cancer drug development.

Jason Horton, PhD: ... It can take anywhere from five to 30 years for a drug to go from the the bench at the basic level to the bedside. ...

Host Amber Smith: All that, some advice about reducing visible signs of aging, and a visit from The Healing Muse, right after the news.

This is Upstate Medical University's "HealthLink on Air," your chance to explore health, science and medicine with the experts from Central New York's only academic medical center. I'm your host, Amber Smith.

On this week's show, we'll learn about cancer drug development from a cell and developmental biologist. But first, newborns in New York will be screened for cytomegalovirus -- which can affect their hearing -- and an Upstate researcher is studying a potential vaccine.

From Upstate Medical University in Syracuse, New York, I'm Amber Smith. This is "HealthLink on Air."

Starting this summer, all babies born in New York state will be screened for congenital cytomegalovirus. And this is happening coincidentally at a time when Upstate researchers are recruiting women of childbearing age into a study of a vaccine that could prevent congenital CMV.

I'll cover all of this with my guest, Dr. Joe Domachowske. He's a professor of pediatrics and also of microbiology and immunology, and he specializes in pediatric infectious disease.

Welcome back to "HealthLink on Air," Dr. Domachowske.

Joe Domachowske, MD: Thanks, Amber.

Host Amber Smith: Now let's start with some background on CMV. What can you tell us about cytomegalovirus?

Joe Domachowske, MD: It's another one of those viruses that's so common, but not everyone's heard about it. It's in the community because young children shed a lot of this virus in their saliva and their urine based on a previous infection that they've had.

Host Amber Smith: Is it dangerous for people to contract?

Joe Domachowske, MD: In otherwise healthy, younger people it's not dangerous, but the problems that can occur mostly happen in pregnant women, when they become infected -- and the risk is to their growing baby -- and in immunocompromised individuals,people who have needed treatment for cancer, for example, or have had a transplant.

Host Amber Smith: Once someone is infected with CMV, does a healthy person's body get rid of it, or does the virus stay with us?

Joe Domachowske, MD: No, this is one of those herpes-like viruses. It's in the big herpes family. And just like the cold sore viruses, CMV can come back and reactivate. It's just usually very asymptomatic, so we don't even know when we're shedding CMV, unlike a cold sore, where you can see it and feel it.

Host Amber Smith: If CMV is so prevalent in society, is there any way to avoid being infected, or are we all going to be exposed?

Joe Domachowske, MD: The vast majority of individuals, more than 70%, are exposed and infected by the time they're in their 50s to 60s. About 40% are infected during young childhood, so the best way to prevent infection altogether is good hand washing. And we know that, especially when you're taking care of young kids who may be shedding the virus, that's where most of the contagious virus is.

Host Amber Smith: Are there effective treatments for people that are infected and that this is causing problems for?

Joe Domachowske, MD: Yeah, there are nice antiviral medications for very serious infections and compromised individuals that we can fall back to. The vast majority of people don't need treatment for this because it's not going to cause them much harm.

Host Amber Smith: Now, New York state is adding congenital cytomegalovirus to its screening panel for all newborns. Is that a simple blood test that will be added to the other blood tests that are done routinely at birth?

Joe Domachowske, MD: Right. So every state has a newborn screening program. And in New York state that involves taking some blood from the heel stick of each of the babies to put it onto filter paper. The filter paper is allowed to dry, and then it's sent to Albany to the New York State Department of Health laboratory at Wadsworth. Those pieces of paper are then tested for a number of different metabolic problems, for HIV and now coming forward for CMV, because we can do something with those results that may be beneficial for the babies.

Host Amber Smith: Now, without a blood test, how would a parent know that their baby was infected with CMV? Are there symptoms for newborns?

Joe Domachowske, MD: Only 10% of babies will actually have symptoms suggesting that they had a congenital infection. Ninety percent are completely asymptomatic. But because all of them are at risk for hearing loss, both hearing loss detected at birth if we test for it, and having progressive hearing loss over that first year of life, we need to know which babies are infected because we can treat them and prevent the hearing loss from happening altogether.

Host Amber Smith: So the hearing loss is tied to the virus, in babies?

Joe Domachowske, MD: Yes. And if it's not treated and controlled early on, that hearing loss can worsen over time. About 50% of those that have no hearing loss at all at birth, where we do newborn testing for hearing -- we actually do that now as a law in New York state -- those that fail the newborn hearing test, if it's because of CMV, half of them will go on to have more progressive hearing loss, so it gets worse over time.

Host Amber Smith: I was going to ask you about the potential longer-term health consequences, but it sounds like hearing loss is one of them.

Joe Domachowske, MD: That is the major one. More serious things can happen to the fetus, and we know about those when they're born because they have clinical signs and symptoms of congenital infection. And those babies we can often treat with the antiviral medications and improve their long-term outcome. But the damage that's already been done, we can't reverse.

Host Amber Smith: Now, I don't know if you'll know this, but if an older person is infected with CMV, will that impact their hearing ability?

Joe Domachowske, MD: It's unlikely, because it's thought to happen during developmental stages of hearing, growth and development, which is mostly before birth, but some of those steps happen after the baby is born.

So, hearing loss is not a major consequence for compromised individuals who develop CMV infection, but they have a whole long list of other things that they can get into trouble with.

Host Amber Smith: Well, what will happen if the blood test reveals a CMV infection in a newborn?

Joe Domachowske, MD: So the New York state newborn screening test, if that comes back positive for CMV infection, all the babies in the region will be referred to our center, and one of the five infectious disease specialists in our group will see and evaluate the baby and talk with the family about the risks associated with hearing loss, check for other signs or symptoms that may not be obvious. We'll do some imaging studies to make sure the brain development was OK. We'll do some blood tests to make sure that the blood counts look OK, and then have a discussion about whether or not they would consider antiviral therapy for a period of time, either six weeks or six months depending on the findings of all the screening work we do.

Host Amber Smith: What percent of babies do you suspect will test positive for CMV?

Joe Domachowske, MD: So, in New York state, it's about 1% total. We have a birth cohort of roughly a quarter million babies per year. We know that certain ethnicities are more likely to be affected by congenital CMV infection. Black babies and other babies of color are more likely, it's about 1% of all of those infants will be infected. But for Hispanic ethnicity and for Caucasians, it's about half of that, maybe a little bit less.

Host Amber Smith: Is there anything that the routine pediatrician will need to do differently for a CMV-positive baby going forward with their primary care?

Joe Domachowske, MD: The law is built to try to simplify the referrals as much as possible. So the New York State Department of Health, anytime they have a positive newborn screen result, they contact the referral centers, if it's a metabolic disease, for example. Our group will see all the babies with possible HIV, CMV and severe combined immune deficiency. So that should happen automatically.

But as a built-in safety step, the pediatricians or primary care doctors are also made aware. They receive the report themselves, and there's information on the report: This baby should be referred to one of the following groups for this particular problem.

Host Amber Smith: This is Upstate's "HealthLink on Air" with your host, Amber Smith. I'm talking with Dr. Joe Domachowske about cytomegalovirus.

Now, you and your team are working toward developing a vaccine that would offer protection against CMV, is that right?

Joe Domachowske, MD: That's right.

Host Amber Smith: So what can you tell us about where things stand with that?

Joe Domachowske, MD: Things are progressing quickly. We have finished Phase 2 trials and Phase 3 trials, which are the large trials, looking at always safety, but the possibility of efficacy to prevent congenital CMV in babies born to infected moms when they're infected during pregnancy.

Phase 3 is an RNA vaccine, just very similar to the RNA vaccines that were developed for prevention of Covid-19. And it appears that this is the strategy that's most likely to work. It's progressing quick. We are in enrolling individual females between the ages of 16 years and 40 years who are otherwise healthy and who are negative when screened for prior infection with CMV.

So the first step is to draw the blood and see if they've already been infected with CMV. At this point for this trial, they would be excluded from the current study. But if they're seronegative, meaning negative antibody testing, then we can go forward, enroll them. They get either a placebo for three doses of the vaccine, or they get three doses of the vaccine itself, and we follow them for two full years. If they get pregnant, we follow their babies even longer than that.

Host Amber Smith: So the way this vaccine would work, then, the moms would be vaccinated, ideally before they become pregnant, so that they wouldn't infect their unborn babies?

Joe Domachowske, MD: To reduce the possibility of infecting the babies when they do become pregnant. Because even prior CMV infection, there's a very low risk, but prior CMV infection, if it reactivates during pregnancy, the virus can get into the blood and cross the placenta and infect the baby. That happens much less commonly than if the mother's infected for the first time. So we're trying to prevent that first-time infection altogether.

Host Amber Smith: So this vaccine wouldn't help the baby, per se, later, like after the baby's born, this doesn't offer that baby protection against CMV, or does it?

Joe Domachowske, MD: No. If this vaccine works as designed and as expected, then the end goal here is to prevent congenital infection and the hearing loss and other consequences that can be associated with congenital CMV infection.

But it will also sort of pave the way for an active vaccination to give to individuals who are either known to be at high risk for acquired CMV after birth, because they're prepping for cancer therapy or they need a transplant, something like that. Right now we do not have any way to prevent CMV from a vaccine side in those higher-risk groups, even if we know that they're at very high risk.

For example, a transplant patient who we know is negative antibody for CMV, they've never been infected before. But we're going to give them an organ, a kidney or a liver or something else, from a donor who we know is CMV positive. CMV is going to be present in that organ. And so we know those individuals are extremely high risk for a CMV type disease, and we have to control it with medication.

It would be great if we could vaccinate them ahead of time knowing that we're going to place them at increased risk.

Host Amber Smith: What can you tell us about previous potential CMV vaccines?

Joe Domachowske, MD: Very simple, and one line: They didn't work.

Host Amber Smith: So these are the mRNA. It's a different approach, it sounds like.

Joe Domachowske, MD: Yes. And one of the benefits of the mRNA vaccine, probably the reason why it works, is that the RNAs that enter the cells, they create the protein itself, the CMV protein that acts as the immunizing agent. And one of the immunizing agents that's so important is a very large molecule. It's actually five different molecules of the same thing that come together and form a macro, a very big, molecule.

And when that happens and the protein is made inside the cell, those five pieces self-assemble, almost like they're trying to make the virus itself, but they can't because they don't have the rest of the machinery. But those five proteins come together and make the molecule that's needed and then they get kicked out of the cell and function as an immunizing agent.

We don't have a good way to do that otherwise because it's not a stable enough protein confirmation to make in a laboratory. So we use our own cells to do it.

Host Amber Smith: So for the trial that you're doing now, how many people are you looking for?

Joe Domachowske, MD: We have screened about 40 women between the ages of 16 and 40 years of age. About half of them were antibody negative, so we've started vaccinating 20 individuals. We will continue to enroll patients, research subjects, until the end of October of this year, unless the study fills before then.

The sponsor, Moderna, they're particularly interested in having more 16- to 18-year olds enrolled in the trial because there's not very many of them so far. So we're looking at adolescents and the younger adults that have maybe been in other trials we've done to see if they might be interested. And we've had really good success. We're screening four or five individuals each week.

Host Amber Smith: Are other sites participating, or is it just in Syracuse?

Joe Domachowske, MD: This is both multi-centered in the U.S. and international, so there's both U.S. and global sites. The total enrollment that's needed to try to address the question is about 15,000 individuals, knowing that only about half of them will actually be eligible for receiving the vaccine.

Host Amber Smith: So if a listener is interested, is there a phone number or a website where they could learn more or sign up?

Joe Domachowske, MD: Yes. We have a single phone number that we can use to one call, one person. If the person doesn't answer the phone, just try again. Leave a message. We'll get back to them right away. It's 315-802-1105.

Host Amber Smith: Now are participants compensated for participating?

Joe Domachowske, MD: Yes. We compensate everyone who is screened and enrolled for onsite visits. In addition, there is compensation provided for an e-diary, an electronic diary where they fill out information about any signs or symptoms that they have experienced about a week or so after each of the three doses.

Host Amber Smith: So there'll be generally three site visits over the course of, did you say, two years?

Joe Domachowske, MD: Oh, many more than that.

Host Amber Smith: Oh, OK.

Joe Domachowske, MD: Three site visits involve vaccine or placebo injections, but we see them regularly. It's about every month for the first six months of the study, and then they're spaced out. I think it's a total of about 14 visits overall.

Host Amber Smith: Now, at this stage in the trial, though, this substance has been found to be safe to use in humans, is that right? Or are there any risks that people should be aware of?

Joe Domachowske, MD: This particular vaccine formulation has been determined safe in Phase 1 and Phase 2 trials, which represent a couple of thousand young adult women. But we know much more about the mRNA platform safety profile from the COVID vaccines. And it's exactly the same platform that Moderna used for their COVID vaccine. So, we have a lot of information. Much of the side effect profile relates to the lipids, these nanoparticles that are used to protect the RNA that are the immunizing portion of the vaccine. So we know that's the case, and the mRNAs themselves don't really contribute to the safety one way or another.

Host Amber Smith: Well, Dr. Domachowske, thank you for making time to tell us about this. I appreciate it.

Joe Domachowske, MD: Yes. Thanks for giving me the chance to tell you about all these things. It's an exciting time for CMV.

Host Amber Smith: My guest has been Dr. Joe Domachowske. He's a professor of pediatrics and also microbiology and immunology, and he specializes in pediatric infectious disease. And if you're interested in learning more about the CMV trial, the phone number to call is (315) 802-1105. I'm Amber Smith for Upstate's "HealthLink on Air."

Can cancer drug development go faster? Next on Upstate's "HealthLink on Air."

From Upstate Medical University in Syracuse, New York, I'm Amber Smith. This is "HealthLink on Air."

The majority of the promising new cancer drug candidates never make it to market. Only a small fraction of the drugs that make it through clinical trials will end up with FDA (Food and Drug Administration) approval.

For help understanding some of the reasons for this, I'm talking with Dr. Jason Horton. He's an assistant professor of cell and developmental biology, orthopedic surgery and radiation oncology at Upstate.

Welcome to "HealthLink on Air," Dr. Horton.

Jason Horton, PhD: Hi, Amber. Thank you for inviting me.

Host Amber Smith: There are different types of research, and I think it's important to explain that and where the idea of translational research fits in. Can you please explain the difference between basic, clinical and epidemiological research?

Jason Horton, PhD: Sure. So, basic research, which is where I spend a lot of my time, really deals with the fundamental aspects of, in the case of medicine, biology, how different types of cells talk to each other, how different molecules interact, things at a very fundamental level where we're just really trying to understand how nature drives some of these processes.

Now, clinical research is at the other end of the spectrum, and that's really devoted to understanding how patients might react to drugs, how different drugs are used to treat different diseases, and ultimately whether these drugs work and have the desired benefit, as well as demonstrating that they're safe for use.

So in between we have these other concepts of applied research, which is where we take that basic research that I talked about initially, and how we use that information to begin to move things toward a very practical application.

And then in between applied research and clinical research is what we call translational research. And this is where we move different drugs or different devices, things of that nature, between the applied phase and into the clinic. And so this is where we start doing preclinical models, some animal research, some more complicated cellular research, things like that where we can screen out a lot of things that may be toxic to humans or, also, ineffective.

Unfortunately, and kind of, I think, what brings us to the topic today is that's the spot where a lot of things don't ultimately carry over into clinical research and making real impact.

Host Amber Smith: From day to day, do basic scientists collaborate much with clinical research? Because that would make it translational, right?

Jason Horton, PhD: In a certain sense, yes. I think at the basic science level, people are really trying to focus on discovery and understanding the real fundamentals, but it is really important for clinicians in medical research and the basic scientist to sort of work hand in hand and bridge that gap between the two through the applied and translational disciplines.

Host Amber Smith: Well, let me, before we get into drug development, epidemiological research, that would be more like population studies?

Jason Horton, PhD: That's correct. And that's an important part of this too, because you have to be able to study these things in the right populations of people, the right populations of animals. Certainly there's a lot of drugs and diseases which have genetic basis to them. And if you're not studying the right population of people that has, say, a particular trait or particular gene, that carries a disease, or that codes for a disease, you may not be testing the right people and ultimately kind of doing some fruitless research.

Host Amber Smith: Well, let's talk about how long it takes for a drug or a device to be developed.

Jason Horton, PhD: So that's a good question, and it varies quite a bit. I think the average sort of description is that it can take anywhere from five to 30 years for a drug to go from the the bench at the basic level to the bedside.

And it varies a lot, both in terms of how long it takes to progress through those different phases, but also how the partners that are involved in whether you're able to, in an early stage, get sponsorship and interest from industry who ultimately see some potential for investment in a particular technology and wants to try to capitalize on that potential in the future.

Host Amber Smith: So how does it go? You have to start with an idea first, right?

Jason Horton, PhD: Absolutely. It all starts with the idea and again, a lot of that starts at the basic science level where we can find things like different targets, say, a certain molecule that we know is associated with a particular disease, and then find different molecules or chemicals or even other proteins or different biomolecules interact with our target and try to understand how those things work together and if we can interrupt the function of the protein or of the cells that are diseased and kind of go from there.

Host Amber Smith: Now, I know publishing or sharing your results at conferences and things, you have to let other scientists know what you're doing, right?

Jason Horton, PhD: Well, that's absolutely a critical part of it is, is getting the information out there, and a big part of it, you want to be careful when you're making these discoveries, that you're sharing it with the world and the scientific process. But then also you want to be able to protect intellectual property, which is how through the patent process where we can develop something that has potential, potential to make money, obviously, but also the potential to deliver cures or interventions that are useful.

And you want to be able to protect your investment in that process. And so, really very early on, we get involved when we're doing a drug development type thing, we get involved with, at Upstate, SUNY has an intellectual property office.

Host Amber Smith: Do you have any examples of a drug that moved through this system or the process quickly?

Jason Horton, PhD: I can give you an example of one. I don't know how quickly it went through the process. But there is a particular leukemia, chronic myelogenous leukemia, that has a very consistent chromosomal translocations. That's where two parts of the genome in our cells, which are supposed to stay in a particular order, in a particular place, become lost, and then they join up to each other.

And when that gene is expressed as a protein, we have a protein that has parts of two different genes stuck together. And so in this case, for chronic myelogenous leukemia, it is termed, or it's what was called the Philadelphia chromosome because it was discovered in Philadelphia. And what people found is that there is a small molecule that fits into the protein that's produced from this gene. Initially it was called imatinib, but then sold as the trade name Gleevec. And that was really an important development in medicine overall, as an example of a precision targeted medicine.

So they were able to take the structure of the protein that was formed by the fusion of these two genes, look at the structure of that protein and find a little pocket where they could stick an another molecule into it. And that molecule disrupted the function of the whole protein and essentially wiped out the cancer in those patients.

Host Amber Smith: Wow.

Well, let's talk about some of the reasons that a drug might drop out of development along the way.

Jason Horton, PhD: That's really the what's sort of called the "valley of death." So we can test and develop a lot of these small drug compounds or small molecules in the lab. And they do great things in a dish. But we start to lose them to attrition when we test them in the sort of translational phase, say in small animal models, mice, etcetera. And we find that they may provoke some sort of toxicity or that they're metabolized in a strange way that makes them no longer active or makes them overactive and again, leads to toxicity, or they just don't ever get absorbed. So those are kind of the main things that would come out in the translational phase. But then ultimately, there's quite a bit of difference between mouse and man when we go to test some of these molecules.

And ultimately, certainly the different drugs have different effects in different species. And so a lot of drugs fail at each of these phases along the way. And so we start with these sort of lead compounds, and by the end of the drug development process, we're kind of left with one.

I can speak to a particular case in a drug that I'm working on developing now, where it was picked out of a screen of approximately 50,000 small molecules, and was found to have very specific activity against one particular pediatric cancer that we're studying. And over the course of several years, the team that discovered that, went through ... so they discovered this and published it. In about 2011, they finished their first clinical trial with the drug, and this was done at the NIH (National Institutes of Health). They published their first clinical trial on the drug in approximately 2017. And while they found that it had fantastic outcomes for some patients, about 25% of these patients experienced dose-limiting toxicity. And so they decided that it wasn't worth pursuing that drug anymore. So that's an accelerated process where the drug had been around for years. It was sort of an orphan drug. They went and revisited it as part of this screening library. And then ultimately after testing it both in cells, then in animals, and then in humans, in some cancer patients, that they found that while it was reasonably effective at each of those stages, once they got it to humans, they found that it was really toxic in some of them. And so they decided to stop the trial there.

Host Amber Smith: What are some of the existing barriers for a health provider who thinks of a drug or a device that they believe might help patients? How do they typically proceed with that idea, or can they?

Jason Horton, PhD: Well, that's a very important question, and I think that's one of the particular challenges out there is being able to find and take those ideas and pass them along to the right people in a collaborative nature, or in a collaborative endeavor, to really see where it can go.

Certainly it's a challenge for physicians just to find time to do basic and translational and ultimately clinical research. And that's one of the great things of being at an academic medical center like SUNY Upstate, is that it definitely facilitates the interaction of those clinicians with the basic scientists and really is able to make those connections at those very early stages and then be able to sort of build on that initial idea and keep chugging it forward, and hopefully leading to a point where you can get to a trial.

Host Amber Smith: Do you think it's better to have doctors who care for patients and doctors who do research, separately? Or can there be physician scientists who excel at both?

Jason Horton, PhD: Oh, there are absolutely physician scientists that excel at both. Certainly physician scientists are indispensable in this, but really it's a team effort. And so you need specialists in a lot of different areas that can look at some of these questions and some of these ideas from a lot of different angles.

There's sort of a saying that the more training you get, the less you know, and that's because we become also specialized. And so, really, interdisciplinary research, at least in my opinion, is really the way that we can make these important developments in science become clinical realities.

Host Amber Smith: Upstate's "HealthLink on Air" has to take a short break. Please stay tuned for more of our discussion about drug development with Dr. Jason Horton.

Welcome back to Upstate's "HealthLink on Air." This is your host, Amber Smith.

We'll continue our conversation with Upstate assistant professor Jason Horton about the process of drug development in America.

What is the "bench to bedside and back" development pipeline?

Jason Horton, PhD: Yes. That's really a philosophy of where something might be, and I would even say take it one step further back, and say it starts at the bedside, goes to the bench, and then back to the bedside again, sort of flipping that arrangement around.

And so a lot of this stuff, in my experience, a clinician will come to me with a problem that they've had or that they experience in their practice, and maybe they don't have a great way to address it. I'll sort of think about it in a lot of different ways.

I may talk to a few colleagues and sort of collect a bunch of different ideas of how we might be able to help. What can we do in the lab? How can we test this idea? What do we know about it? And certainly for all the things we know about medical science, we're really just on the early edge of understanding how a lot of these systems and cellular biology and physiology work together. You know, in the basic science end, we become so focused on one discrete aspect that we kind of have our blinders on to some of these parallel things. And then, as we make our way through the translational process toward clinical trials, we begin to narrow some of those things down.

And so that also kind of runs in parallel to a process where we fail drugs. We want to fail drugs faster. And what I mean by that is we want to get those drugs, which are probably never going to make it to a clinical trial for various reasons, like I said earlier -- toxicity, ineffectiveness, metabolic complications. We just want to get those out of the way faster so we can really get from a very broad range of possibilities down to a few discrete, promising ones as quickly as possible, both as a time, but also as a resource-saving endeavor.

Host Amber Smith: Like the example you gave before, though, that the drug that went all the way through rodent trials, but then it was toxic in humans. If rodents aren't the best model for testing things that are going to be used in humans, what is the alternative to that?

Jason Horton, PhD: And that's one of the really hot topics in translational and biomedical research at large, and certainly something I'm beginning to be involved in, again, in the context of the drug that I talked about earlier. There's been a recent emphasis on things like microfluidic or microphysiologic systems, where we're able to use human cells and tissues, grow them outside the body, from a variety of different donors. We can sort of sample a reasonably sized population in a relatively small footprint using some complicated tissue engineering approaches with these patient-derived or human-derived cells and really get testing in human tissues, in human cells, as early as possible.

Host Amber Smith: Can you test a drug on, say, for example, you've got cancer cells that you saved from a tumor, or you've got normal cells that you scraped off someone's arm. Can you test a drug and know what it's going to do with simple cells that have not yet turned into an organ, let alone an organ system? I mean, they might react with the cell one way, but once the cell is attached to a body and the body is functioning, will they react the same way?

Jason Horton, PhD: Well, that's a complicated question because they may and they may not. So, you know, one of the big things that's going on in my lab right now is understanding how this drug that we're testing in the lab, we want to kind of know how ... it's primary toxicity is to the liver, and this didn't really come up when we were testing just tumor cells. I mean, we knew about it in the background because that other group, like I said in the clinical trial, had found this liver toxicity. And we had tested it in animals, on sort of recovering a lot of their experiments, or redoing a lot of their experiments in our hands, to try to understand toxicity.

We made a slightly different formulation of that drug that we hope, and at least our preclinical data seems to suggest that, we can prevent the toxicity by causing the drug to accumulate specifically in the tumor rather than in the liver where it's doing damage. We developed a nanoparticle encapsulation technology with some scientists in the department of pharmacology here.

Host Amber Smith: So you don't need the full liver?

Jason Horton, PhD: You don't necessarily need the full liver. I guess I was focusing on that end on, on how we can show efficacy. But then on the toxicity side, you don't necessarily need the whole liver. The early indications seem to be that it is a specific type of cell in the liver that we can model. And so we're developing a microphysiologic system now, essentially a liver on a chip model, in my lab. And so that was with the grant that I just got from the cancer center is going to develop this liver on a chip system where we can integrate cells from a number of different donors and kind of get a broad representation of different genetic variability.

We have some notion that this drug in particular affects the process of bile transport. And in that initial population that was published by the people at NIH, where they said about 25% of their patients showed toxicity. In a follow-up paper, they were able to attribute that to single nucleotides, so single ATCs or Gs, variants between different individuals, and show that those single nucleotide polymorphisms are single letter changes in how a gene is spelled, predicts whether a person is going to have this toxicity syndrome or not. But ultimately the process that all of these different genes play a part in is how bile exits a hepatocyte and then enters the digestive system.

If they can't put the bile outside of the cell. The hepatocyte makes bile. If it can't export that bile and put it into the bile ducts, the hepatocyte dies. That's the sort of mechanism of toxicity for this particular drug. And so we're trying to now curate liver cell samples from a variety of different donors and understand what that level of toxicity is, and if there are different ways that we can augment that, either by changing the molecule that we're using, or as I said earlier, in this nanoparticle encapsulation direction, enhance its ability to go to the tumor and stay in the tumor so that it doesn't cause the injury to the liver.

Host Amber Smith: So what you're doing, then, essentially means we won't need cages full of lab rats anymore.

Jason Horton, PhD: I mean, I think that's one of the, definitely one of the things that we're trying to alleviate.

There's certainly ethical concerns with doing animal experiments. There's costs associated with doing those animal experiments. And then ultimately, a lot of in the case of this drug in particular that I was talking about a moment ago, the mice don't seem to have very much trouble until you get at very, very, very high sort of not really physiologically achievable, doses in humans before they start to show a lot of toxicity.

And so that's one where, probably the toxicity didn't show up in the animal model, and so it went to that clinical trial and then they found the toxicity there -- in some patients.

Host Amber Smith: This is like revolutionary stuff.

Jason Horton, PhD: I'd like to think so. It's certainly interesting to do and gratifying and it's certainly not anything I thought it would have been doing when I started here, going on eight years ago now. So it's been a really exciting time to be here and to be doing this sort of research.

Host Amber Smith: Well, before we wrap up, I wanted to talk about what the ideal translational research team would be like. Who would be the members of that team, and what would their roles be?

Jason Horton, PhD: Well, sure. At the one end of the spectrum, you have somebody like me who's a bench scientist, and those folks also include graduate students, postdoctoral fellows, and other people that work in the lab, technicians, et cetera, that really do a lot of the very early stage hands-on research and really try to weed out some of the either ineffective things or really just screening things at the very earliest stages to get rid of drugs that just don't have any particular viability.

Moving through there you have people who are engaged in the translational phase with that level. Again, it's a mix of basic scientists, some clinicians, oftentimes veterinary researchers will also participate. And then at the clinical end you also have the physicians who are managing the patients, who are overseeing the trials. Running parallel to the basic scientists and the clinical scientists we also have epidemiologists and statisticians who are really the gatekeepers to say whether something is good, is effective, is safe based on the numbers and the data that come out of it.

And so we have what are called different levels of trial blinding. So in a double-blind trial, which is considered the gold standard, where neither the patient nor the physician who's overseeing the trial knows exactly which patient is getting the intervention or the experimental intervention or the standard of care or control intervention, to study that efficacy.

And so really it's those statisticians that sort of are able to say definitively whether a drug works or not based on the unbiased data that we hope will come out of the studies. And then finally we have our partners both in administration at a place like Upstate, the office of tech transfer, who helps us manage intellectual property and patents, but then also facilitates interactions with industry, where these things are able to be scaled up and large investments are able to be made for a device that's very promising.

Host Amber Smith: How would you go about improving quality control in research? How would you weed out ... you talk about failing drugs faster, but what would you do to avoid just bad ideas from the outset?

Jason Horton, PhD: Well, I think a big part of ruling out bad ideas is getting a lot of divergent opinions, and I think at a certain level you have to weigh them each with their own merit. But at the end of the day, the more people you get involved and the more perspective that you bring to a particular question, probably the better insight you're going to have in whether there's viability, say, in testing a drug, if there's a reason to keep going with it. If this is a reasonable target, what are some of the sort of known unknowns, at least to the person who's asking the questions and try to identify as many different facets of these questions as possible.

Host Amber Smith: Does AI (artificial intelligence) have a role in any of this, do you think, now or in the future?

Jason Horton, PhD: Well, that's a fantastic question and very timely.

So that is something that is definitely actively being used. But there are also certain barriers that we have to think about there. So artificial intelligence just for the audience, is essentially a computational algorithm that is used to automate a lot of decision-making processes. And so in this context it may be understanding how different molecules physically fit together, or how a drug interacts with a particular protein. It's something that we make the use of the computers to iterate through these different interactions that might be present. And I'm just using this as a particular example. And I think in that context, artificial intelligence and machine learning is extremely powerful.

But on the flip side of that, we also have to be careful to protect patient privacy and protected health information, because right now at the pace that the artificial intelligence technology is growing and accelerating and really kind of becoming a part of everyday life, we have to be careful that there are the appropriate protections there because these things are so new that it's a little bit of a cat and mouse game on the safe artificial intelligence, or the benevolent use of artificial intelligence, in different levels, both of biological research, but I think where it really becomes concerning is when we get into clinical research.

Host Amber Smith: Well, Dr. Horton, thank you so much for taking time to explain this to us. I appreciate it.

Jason Horton, PhD: Thank you very much. It was a pleasure being with you.

Host Amber Smith: My guest has been Dr. Jason Horton. He's an assistant professor of cell and developmental biology, orthopedic surgery and radiation oncology at Upstate. I'm Amber Smith for Upstate's "HealthLink on Air."

Here's some expert advice from dermatologist Ramsay Farah from Upstate Medical University. What can we do to reduce visible signs of aging?

Ramsay Farah, MD: You know, the No. 1 thing we can do is protect ourselves from the sun, right? So that means wearing sunscreens, and starting at an early age in childhood. And, it's interesting because a lot of the studies show that quite a bit of the sun damage we see in ourselves as an adult, we've acquired in our childhood. But there's a long latency period of it, so you don't notice it immediately when you're a child playing outside, but decades after is when we start to see it on our skin. So sun protection is the No. 1 thing that we can do starting from early childhood and continuing on into adulthood.

Now the other thing, that we can do is, we can have a healthy lifestyle. And that really, in a roundabout way, not in a very direct way, but in a very real way and meaningful way, has an effect on how we age. And so, what do I mean by lifestyle changes?

Well, good sleep habits so that your hormone levels are always more uniform and not going up and down; a good diet that is high in antioxidants, which can help absorb some of what are called free radicals from developing. And free radicals are the byproduct of sun exposure and other physiologic stresses. So when the system is stressed, it produces these chemicals called free radicals, and they damage the cells, and they age the cells. And antioxidants, whether they're in your food or whether they're through topical creams, can absorb those free radicals and help decrease the physiologic stress that adds to aging.

And you know, when organisms are stressed, they also age. So if you can take those chemicals out, I think you age less. And that's what an antioxidant does. And one of the more common ones, and one of the older ones that was discovered to do this, is vitamin C. Without endorsing specific products, you want to look for things that have vitamin C in them. Other antioxidants are things like zinc or copper or selenium, even vitamin E. So all of those have antioxidants. I'm partial to vitamin C because vitamin C also helps promote collagen production.

There's another broad category of plant-derived antioxidants. For example, curcumin and things like that. But in terms of the products, most of them to date contain things like vitamin C, zinc, copper, selenium, vitamin E. Those are all good antioxidants to look for.

Another category that one can find over the counter are products that contain what are called retinols. Retinols are another large category of products that I think are quite helpful. Retinols are derivatives of vitamin A, and of course vitamin A is a naturally occurring compound in nature, and we get it through our diet. But vitamin A is extremely, extremely important in our physiology. Every cell in our body has vitamin A receptors, and it does thousands of things, but it's been proven beyond any doubt that applying retinols or retinoids -- and you can think of them as being fairly equivalent. They all go to the vitamin A receptors. So retinols and retinoids have been shown to even skin pigment. They've been shown to help increase skin turnover. They've been shown to help plump up the collagen. And they've been shown to be anti-cancerous. So if you have a product that's over the counter that has a retinol or a retinoid in it, that's another category of product that you can get for anti-aging purposes.

So, I think in short: sunscreen; as healthy a lifestyle as possible with things like a healthy diet that includes antioxidants; and other general measures, like good sleep habits, stress reduction techniques. All of those, I think over the years do make a difference for sure. And the other thing I want to mention is those healthy lifestyle habits and the antioxidants in our diet, those also promote skin health by improving our immune system. And the immune system is extremely important in skin physiology and also has a function in the aging process as well.

Host Amber Smith: You've been listening to Dr. Ramsay Farah from Upstate Medical University.

And now, Deirdre Neilen, editor of Upstate Medical University's literary and visual arts journal, The Healing Muse, with this week's selection.

Deirdre Neilen, PhD: E.D. Watson is a poet in training at the Institute for Poetic Medicine. She sent us an exuberant celebration of the body and urges us to do so, even as it ages and seems to turn against us. Here is "In Praise of the Body":

So much is made of the soul,

a thing we cannot prove or hold

and yet for this we pray, we sigh

we kill we moan

and damn ourselves, imagining

some place else is home --

but the body

the body is a fact

and I say bless it, bless its appetites

bless it limp and bleeding

each labored breath, the skin gone slack

bless its cavities and hollows

bless the curve at the base of the back

and bless each toe.

Call it friend instead of traitor

for no greater intimacy exists

than to be within its wetness

slickness pulsing, breathing

aching and excreting. Sleeping.

And when we say we love, remember

what we love is this: a mother's veined

and freckled hand, a child's nub of chin

the inside of a lover's thigh

where hairs grow soft and thin --

oh bless it

bless it all

and kiss your friends upon their mouths

that they may feel your lips

press your nose into their scalps

bear witness to what unravels them

the nodules, failing kidneys

gout, each one of us an envelope

of pain and iridescence, each ecstasy

so fleeting. Place your hand

upon your chest and feel your heart there,

beating

beating.

Host Amber Smith: This has been Upstate's "HealthLink on Air," brought to you each week by Upstate Medical University in Syracuse, New York.

Next week on "HealthLink on Air," living with mild cognitive impairment.

If you missed any of today's show, or for more information on a variety of health, science and medical topics, visit our website, at healthlinkonair.org.

Upstate's "HealthLink on Air" is produced by Jim Howe, with sound engineering by Bill Broeckel.

This is your host, Amber Smith, thanking you for listening.