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Discussion Guide and Transcript
Season Three - Episode Eight
Research Ethics Reimagined Podcast Season Eight: Episode Seven “'It's the And': Bridging NAMs and Nonhuman Primate Research" Guests: R. Paul Johnson, MD and Joyce Cohen, VMD, DACLAM
- In this episode of PRIM&R's podcast, "Research Ethics Reimagined," we learn more about the advances taking place the Emory National Primate Research Center, recently renamed the Emory National Biomedical Research Center, with Dr. R. Paul Johnson, the center's director and an infectious disease physician-scientist, and Dr. Joyce Cohen, VMD, DACLAM, the veterinarian who oversees the health and welfare of the center's animals. Dr. Johnson traces the center's scientific contributions to HIV/AIDS research and organ transplantation, and Dr. Cohen elaborates on what it takes to build and run a complex animal welfare program. Together, they discuss the growing role of New Approach Methodologies (NAMs) alongside nonhuman primate models. Listen on Spotify | Listen on Apple| Listen on Amazon
Discussion Questions
The Case for Nonhuman Primate Models in Discovery Science
- Johnson traces the "arc of research" behind belatacept, an immunosuppressant now given to every kidney transplant patient at Emory, describing how a promising drug candidate failed in monkeys before a refined version succeeded — sparing patients from a potentially failed human trial. What does this example show about the value of allowing research to be "recursive," and how should institutions communicate with the public about setbacks that occur along that path?
- Johnson explains that nonhuman primate models provided the first "rigorous evidence" that lentiviruses cause immunodeficiency and revealed how HIV and SIV rapidly deplete immune cells in the gut — discoveries he says could not have been made in humans. How should IRBs and IACUCs evaluate proposals for foundational research where, unlike in the belatacept example, the ultimate clinical payoff is not yet known?
Building and Running an Animal Welfare Program
- Cohen describes her role as extending beyond clinical oversight to physically redesigning how animals live. How should institutions structure the veterinary role so that advocating for welfare and enabling research design to work together rather than compete?
- Cohen notes that Emory's combined primate center and school of medicine IACUC has grown, and that many of the field's welfare improvements have been driven internally rather than imposed by regulators. What does it take to run an IACUC at that scale effectively, and how can institutions channel that kind of practitioner-driven momentum into a consistent, lasting policy?
New Approach Methodologies and Public Trust
- Johnson notes that primate centers have used New Approach Methodologies for decades without calling them that — three decades ago, he built a "thymic organoid," a lab-grown model of the environment where immature immune cells mature into T cells, to study those cells outside of a monkey. He pushes back on framing NAMs and nonhuman primate research as a "false dichotomy," and cautions against arbitrary timelines for phasing out nonhuman primate models. How can institutions evaluate, in a scientifically grounded way, when a NAM is mature enough to reduce or replace nonhuman primate use in a given line of research?
- Cohen says "risk avoidance" in the past kept institutions from sharing enough information with the public, allowing a different narrative to take hold; Johnson notes points to regularly held open houses at the center's field station as one way to help build transparency. What other steps can research institutions take to proactively build public trust, and how should they balance openness about their work with the animals' welfare and researchers' safety?
Key Terms
- Thymus/Thymic: The thymus is the organ where immature immune cells from bone marrow mature into T cells, the specialized white blood cells that fight infection. "Thymic" describes anything related to this organ or the environment it provides, such as the lab-grown "thymic organoid" Johnson references.
- New Approach Methodologies (NAMs): NIH's broad term for alternative research approaches — such as organoids (miniature, lab-grown clusters of cells that mimic an organ's structure and function), in vitro systems (studies conducted outside a living organism, such as in a test tube or petri dish), and computer (in silico) modeling — that can complement, and in some cases reduce reliance on, animal models.
- IACUC (Institutional Animal Care and Use Committee): A federally mandated committee, required under the Animal Welfare Act and Public Health Service Policy, made up of researchers, veterinarians, and public members that reviews and approves every animal research protocol at an institution.
- SIV (Simian Immunodeficiency Virus): The nonhuman primate counterpart to HIV, studied in rhesus macaques (a species of monkey widely used in biomedical research). The animal model built around SIV provided early evidence that lentiviruses cause immunodeficiency and remains central to HIV/AIDS research.
- Lentivirus: A family of slow-acting viruses, including HIV and SIV, that cause chronic, progressive disease by steadily damaging the immune system over time rather than producing immediate illness.
- Belatacept: A targeted immunosuppressive drug (a drug that dampens the immune system's activity) developed and refined through nonhuman primate testing before FDA approval. It is now used to help prevent organ rejection in kidney transplant patients while limiting the side effects associated with older immunosuppressants.
- VMD, DACLAM: Cohen's credentials. VMD (Veterinariae Medicinae Doctoris) is the veterinary degree awarded by the University of Pennsylvania, equivalent to the more common DVM. DACLAM means she is a Diplomate of the American College of Laboratory Animal Medicine, the board certification for veterinarians who specialize in the care of animals used in research.
Resources
- Emory National Biomedical Research Center - The center Johnson leads and where Cohen oversees animal welfare, discussed throughout the episode under its new name (formerly the Emory National Primate Research Center).
- National Primate Research Centers Consortium - NIH overview of the seven NIH-supported centers, including Emory's, that Johnson describes as a national network advancing human health through nonhuman primate research.
- PHS Policy on Humane Care and Use of Laboratory Animals - The federal policy, alongside the Animal Welfare Act, that Cohen cites as the legal basis for IACUC composition and oversight.
Transcript
Please note, a transcript generator was used to help create written show transcript.
The transcript of this podcast is approximate, condensed, and not meant for attribution. Listen to the full conversatio on PRIM&R’s Research Ethics Reimagined podcast.
The transcript of this podcast is approximate, condensed, and not meant for attribution. Listen to the full conversatio on PRIM&R’s Research Ethics Reimagined podcast.
Ivy Tillman: I am happy to welcome our special guests to the podcast today. Earlier this year, the PRIM&R Board meeting was held in Atlanta at Emory University. During our time there, we toured the Emory National Primate Research Center, where the leaders and staff graciously gave us a tour.
Joining me today are two of the people who make that work possible: Dr. R. Paul Johnson, who leads the center, and Dr. Joyce Cohen, who oversees the health and welfare of the animals at the heart of this research.
Together, they represent an intersection of scientific discovery, veterinary medicine and ethical leadership that is central to advancing research responsibly. I want to take a moment to welcome Paul and Joyce to the podcast. Thank you for joining us.
R. Paul Johnson: Ivy, thank you for having us. We’re looking forward to the conversation.
Ivy Tillman: First, can you each take a moment to share a little bit about your career path? We appreciate having the chance to learn from our guests about how they developed the expertise they have.
R. Paul Johnson: I can go first. I am an infectious disease physician-scientist. My area of interest has been HIV/AIDS research. I did not go to medical school intending to be a monkey doctor.
That was not my planned career path. I graduated from medical school in 1984 and then completed my internship and residency in the mid-1980s and my infectious disease fellowship in the late 1980s. That was when the HIV/AIDS epidemic was first taking off in the U.S., and it was a time before we had effective antiretroviral treatment.
We were still figuring out a lot about the virus: what type of immune cells it infected and how it damaged the immune system. We were working to develop effective antivirals and determine whether a vaccine was possible.
My initial work started with people with HIV in Bruce Walker’s laboratory at Massachusetts General Hospital. We were looking at a particular type of cell called a killer T cell, or cytotoxic T cell. We learned a lot about those cells, but there were fundamental questions we couldn’t address in people, including what happens early in infection.
That is a really critical period of infection that was very difficult to study in humans. What would happen if you had a candidate vaccine? We weren’t ready to test anything in humans yet, so we needed an animal model.
Fortunately, there was work underway at the New England Primate Research Center at that time that established an incredibly valuable nonhuman primate model of AIDS. It has spread throughout the world and models what happens in people very well, from the cells the virus infects to the course of disease—which is a little more rapid in monkeys than in people—and its susceptibility to vaccines and antivirals.
I started working part time at the primate center, trying to extend some of the skills we had developed looking at immune responses in people with HIV and translating those to nonhuman primates.
It took off from there. I was trying to split my time between Massachusetts General Hospital and the New England Primate Research Center while also being a clinician. That was hard.
Ivy Tillman: I bet.
R. Paul Johnson: As time went on through the 1990s, I spent more and more time at the primate center and eventually focused my career there.
Fast-forward to 2014. The longtime director of the Emory primate center, Stuart Zola, decided to retire, and I was lucky enough to be selected as director. I came here in 2014 and have been having a wonderful time since then.
Ivy Tillman: Absolutely. Joyce, tell us about your career path.
Joyce Cohen: Sure. First, I have to say that I’ve worked with you for 12 years, Paul, and I’ve never actually heard that story. It was really interesting to learn that.
My career path was also not set. It took a somewhat convoluted path. I definitely was not one of those people who grew up knowing I wanted to be a veterinarian.
I was premed all the way. That was definitely my plan when I started college. It was actually a combination of two things that changed my path.
I was taking Psychology 101, and the professor was a renowned primatologist, Robert Seyfarth. He talked a lot about animal behavior and behavioral primatology. I became fascinated with it and really interested and excited.
I added anthropology as a second major because I was so interested in it, but I was still continuing on my premed path. Then, one summer in college, I was putting together my résumé while looking for a summer job. When I finished it, I looked at it and thought, “Everything I’ve ever done has been with animals. I haven’t done anything in human medicine.”
I had shadowed a veterinarian at Ocean World. I worked at the Wild Bird Center. I followed a veterinary clinic. I thought, “Maybe that’s the path I want to take.”
In consultation with another primatologist at school, I learned about a potential career path that, given my background in medicine, would allow me to go into research and still work with nonhuman primates. I decided to start exploring the animal research path.
When I finished college, I went to work in a research laboratory at Columbia University in visual neuroscience with nonhuman primates. At that point, I had to decide whether to go to veterinary school or pursue a PhD in primatology. I decided on veterinary school, knowing I wanted to work with nonhuman primates in a research environment.
That was my goal, and here I am.
Ivy Tillman: It’s always interesting to hear about these paths because it’s rare that we have guests—or even people in our professions—who had a completely straight path. I think those experiences make your career richer and influence what you bring to where you are now.
The center has been advancing biomedical science for nearly a century. It serves as one of only seven NIH-supported national primate research centers in the country.
For listeners who may not be familiar with the center or even the network of primate research centers throughout the U.S., could either of you describe your role, the center’s role and how the work comes together to support the center’s mission?
R. Paul Johnson: That’s a great question. Thank you, Ivy.
The NIH-supported primate centers were founded in the 1960s, and their charge was to support nonhuman primate models that ultimately improve and advance human health.
They were all about establishing models. There is some primatology for primatology’s sake that is really important, and there is some work on conservation. But the primary charge is to help people conduct better research in nonhuman primates to advance NIH-supported research that improves human health.
They have gone through a number of evolutions. When they were founded, they were the regional primate research centers. In the early 2000s, there was a reevaluation of the network, and they decided to rebrand themselves as national primate research centers to emphasize the importance of supporting a national network of researchers.
That is something we do here and that all the primate centers do. About half of the research we support here is led by researchers outside Emory. That is a very important charge.
We continue to evolve. Over the past year, a number of the centers have evolved to become national biomedical research centers. That has been an official change at Tulane and Washington, and just last month our primate center was officially renamed the Emory National Biomedical Research Center.
The intention is to indicate that we support a wide range of research projects.
Nonhuman primate research is our sweet spot and an area of expertise. It takes considerable expertise and specialized resources to support high-quality, top-notch nonhuman primate research, and Joyce can talk more about those.
That is our central charge, but we also support a wide range of research projects. We conducted a survey earlier this year to see how many of our researchers are using new approach methodologies, or NAMs.
Using the broad NIH definition, including organoids and in silico modeling, about 70% of our researchers are currently employing NAMs in their research in addition to nonhuman primates. Similarly, about 70% of our researchers use human samples.
I think it is important to think of us as centers of excellence that use a whole range of research models, from in vitro studies and NAMs to rodents, nonhuman primates and human samples. We have the complete arc of biomedical research designed to ultimately advance human health.
There are seven centers across the country. We work closely together to make sure we are using best practices, and we work very closely with our colleagues at NIH to ensure that we are supporting a national group of biomedical researchers.
Ivy Tillman: Thank you for that overview. It helps clarify the work being done and its impact on people in the United States.
Joyce, can you describe the work you do at the National Biomedical Research Center now?
R. Paul Johnson: Yes. We’re still getting used to the name.
For clarity, when we say “primate centers,” there are many primate centers. In this conversation, when we use that term, because not everybody has changed over to the new name, we’re referring to the group of seven NIH-supported centers.
Joyce Cohen: In my role as a veterinarian here, I get to be part of cutting-edge research. We consult with investigators and help them create their research models and determine the best path forward. We also participate in the hands-on research involving the animals.
However, in my role, I also have oversight responsibilities and help ensure animal welfare, which is critically important.
Our mission as veterinarians is to advocate for the animals and look out for them while facilitating and supporting critical research. We do that in many forms, whether it is grant writing and figuring out the experimental model or IACUC review and being part of that process and its refinement.
It also extends to how we care for the animals. That’s why I love being at a primate center. Because we have so many animals, we have dedicated support staff in many different areas just for the animals. That includes our colony management group, which manages the large social groups at the field station and our breeding colonies, and our behavioral management team, which looks out for the welfare of every animal from a behavioral perspective.
One of the things I get to do in my role is work on the housing and facilities in which the animals live. That includes designing new and larger caging with better features geared specifically toward the needs of nonhuman primates, increasing social housing and constructing new housing facilities to improve animal welfare.
That is how we work together to support all of the missions.
The last thing I would mention is that, while our central mission is to support human health, this circles back to support veterinary and animal health as well. Medical discoveries that begin in animals and translate to humans can also translate back into veterinary medicine and treatments for companion and farm animals.
Ivy Tillman: I think that’s really important to bring up because, particularly when we have these conversations in public spaces, we don’t always think about the impact of the work you’re doing on our companion animals. My companion animal is sitting right next to me as I’m recording this podcast, so that matters for her care as well.
You touched on the oversight and infrastructure support you have. Can either of you talk about the role of the IACUC, particularly for individuals for whom this may be a new term?
What is an IACUC, and what role does it play in the research process and in strengthening the quality of research and animal welfare?
Joyce Cohen: Do you want me to start on that, Paul?
R. Paul Johnson: Yes. Why don’t you?
Joyce Cohen: For anyone who may not be aware, IACUC stands for Institutional Animal Care and Use Committee. This is a group required under the Animal Welfare Act and Public Health Service policy for institutions using animals in research.
The group consists of researchers, veterinarians, a member of the public and a nonscientific member. The constitution of the committee is expressly mandated.
Our IACUC here at Emory is required to have that representation, but we probably have more than 50 people on our committee. We have an extremely large IACUC because we are combined with the primate center and the School of Medicine.
This is the group that reviews every animal research protocol happening at the institution. We look at every procedure that is going to be done. We look at the goals of the research, the number of animals and the justification for what researchers are proposing to do, and we make sure they are using standards that the institution will support.
Ivy Tillman: You’ve talked about the different roles within the center and among the staff. How do you—or how does the center—encourage investigators, researchers, veterinarians, technicians and staff to ask difficult questions and look for ways to continually improve? What kind of culture do you create?
R. Paul Johnson: That’s a great question. Joyce and I can go back and forth on this.
First, I think you need to have a culture of collaboration and open communication.
We are a large community of diverse people, which is required to run a primate center. Just within animal resources, there are people with a range of responsibilities. On the research side, you have different roles, including principal investigators, laboratory managers and technicians. Then we have research administrators, facilities staff and others.
One important thing is making sure there are several different opportunities for an open exchange of information and that information doesn’t simply filter up to the top and then back down. You have to have communication across the hierarchy. People need to be comfortable expressing honest opinions.
Sometimes those are difficult, honest opinions, but that’s really critical. People need to be able to say, “This line of communication is not working.”
I have to give Joyce credit here. During the 12 years we’ve worked together, Joyce has often come to me and said, “This line of communication isn’t working. How about if we change it?” She says it very nicely, and she’s been right every time.
We have needed to rethink the way we constituted committees to bring the appropriate people to the table. Again, that doesn’t just mean going to the top of the pyramid. There need to be many lines crossing the pyramid where people can provide information, have conversations and express ideas.
Within that, you also need common values.
We can’t say there is one North Star for a primate center, but I think our three North Stars are providing outstanding care for the animals, supporting outstanding science and taking care of our people.
I’m mixing the metaphor by coming up with three North Stars, but we have to agree on where we want to go. As we have conversations about how to achieve those goals operationally, we have to rely on those points: taking care of our animals, supporting the science and supporting our people.
Joyce Cohen: Sometimes you hear that there is a dichotomy between the scientists and the animal resources or veterinary staff—that they are opposing forces—but that’s not the culture here.
We work together. Occasionally, we have differences of opinion, but overall, we all want to move the science forward. We all want it to be meaningful and important research with good results, and we all care tremendously about the animals and their welfare.
With those main principles, we can always come to some resolution.
Probably the most controversy or difference we might have is on the financial side—making sure we have enough money to run the center while investigators have enough money to do their science. That can create conflict.
But we all work together. We want to invest in the animals. We all want to see them in the best housing.
At a primate center, we also have experts performing some of the hands-on work, especially in infectious disease research, so sometimes researchers aren’t actually working hands-on with the animals. We’ll bring them into the animal facility to see the animals they’re working with.
You can’t not love the monkeys when you see them. They’re amazing animals.
We work really hard to make sure we’re all speaking the same language and seeing the same things so we can agree on a path forward.
Ivy Tillman: I like that. I heard words such as collaboration and transparency, as well as the three North Stars. I was actually envisioning them. I like that concept, and it’s clear what your priorities are.
Like you said, Joyce, it’s about moving the science forward.
If we think about the scientific need for the research done at the center, I want us to talk about what the center has contributed. Are there specific advancements or discoveries—scientific questions that have been answered—during your time there or even throughout the history of the center?
R. Paul Johnson: Sure. There are so many—scores of them.
I’ll make a start. If it’s OK, I’d like to highlight not just what happened here at Emory, which we will certainly emphasize, but what has happened across all seven centers because we are a consortium.
Broadly, we conduct studies in nonhuman primates when they can’t be done in another model—when they can’t be done in rodents or humans and you need a model that reflects as closely as possible what happens in humans.
That narrows the research to a handful of general areas: infectious disease, neuroscience, transplantation, regenerative medicine and stem cell therapy, and metabolic diseases. That doesn’t cover everything, but those are the big five.
Since my background is in infectious disease, I’ll start with HIV/AIDS. The contributions of primate models across the centers have been spectacular. They have contributed a huge body of knowledge to where we are now, with effective antiviral therapy and antiviral regimens that can prevent infection with essentially 100% efficacy, which is remarkable.
The initial studies at the New England Primate Research Center establishing the SIV/AIDS model in rhesus macaques were fundamental in providing rigorous evidence that primate lentiviruses can cause immunodeficiency.
We accept that as a given now, but in the mid-1980s, just after the identification of these viruses, there were still a lot of questions. You identify these viruses, but do they really cause AIDS, or are there other causes? The animal models provided rigorous evidence for that.
They also taught us a lot about how the virus damages the immune system. In particular, research in monkeys—and later validated in people—showed that the virus particularly affects gut-associated lymphoid tissue.
We often don’t think about our gut, but most of our immune cells are there. HIV and SIV, in the first two weeks of infection, wipe out 50% or more of the helper T cells in the gut. That is a huge opening salvo in the course of immunodeficiency that then plays out over years.
Those initial steps were discovered in monkeys because researchers could conduct studies that couldn’t be done in people.
Moving on to antivirals, the Washington Primate Center conducted initial studies with a drug called tenofovir that had been put on the back burner, frankly, because it was difficult to administer. The results in monkeys were so dramatic that researchers said, “We have to use this drug.”
They figured out a way to modify it and administer it orally, and it is now a mainstay of antiretroviral therapy for tens of millions of people worldwide.
The ability of antibodies to prevent infection in infants and adults has also been fundamentally altered by results in nonhuman primates.
Very recently, investigators at the California and Tulane primate centers conducted a provocative and exciting study involving a form of gene therapy. An antibody encoded by a virus called AAV can deliver the gene for that antibody to infants and could potentially provide lifelong protection against mother-to-child transmission. One shot could, in theory, prevent mother-to-child transmission.
Just this past week, studies from the Emory primate center, led with scientists at the Scripps Research Institute in California, showed that using the right combination of immunizations can lead the immune system down a path to generate antibodies capable of neutralizing a substantial number of diverse HIV isolates.
These are the elusive broadly neutralizing antibodies, which have been really difficult to produce through vaccination.
It’s a very promising result.
Again, this is my background, so I’m a little biased, but the contributions of nonhuman primates to HIV/AIDS research have been remarkable.
That is looking in the rearview mirror. Going forward, as we try to get these vaccines over the line to being effective, develop less complicated treatment regimens, explore prospects for an HIV cure, develop better antivirals and improve methods of preventing infection, results from studies in nonhuman primates will continue to be essential for the foreseeable future if we are going to end the HIV/AIDS epidemic.
And that’s just one area.
You can go to each of the seven centers and see fundamental, substantial contributions each has made in the HIV/AIDS arena.
Joyce Cohen: Do you want to mention transplantation here?
R. Paul Johnson: I was about to. That was next.
There have been some great advances in transplantation.
To transplant an organ from another individual to a person who needs a kidney transplant or another organ transplant, you have to address the fact that the immune system will recognize and reject the organ as foreign. You therefore need immunosuppressive agents to prevent rejection.
Historically, those immunosuppressive drugs have been somewhat blunt instruments. While they kept the kidney, liver or heart from being rejected, they also made people more susceptible to infection. In some cases, they have significant toxicity.
For example, one of the mainstay immunosuppressants used in kidney transplantation is cyclosporine. Cyclosporine suppresses the immune system very well, but it can also affect the kidney.
Ironically, the drug suppressing the immune system can damage the very organ it is trying to protect.
There is a very well-known transplant surgeon here at Emory, Chris Larsen, who was interested in developing a more precise way to suppress the immune system using designer molecules that block specific pathways that activate T cells.
He identified a promising strategy that worked in mice. They tried it in monkeys, and it didn’t work.
He then had to go back, working with the pharmaceutical company, to refine the candidate drug. They found one that worked very well in monkeys. It worked in people and ultimately went on to FDA approval. It is now given to patients at Emory University Hospital who undergo kidney transplantation.
The drug is called belatacept. It was the first new immunosuppressive drug approved in, I think, 10 to 20 years.
Ultimately, a follow-up comprehensive phase 3 study found that people treated with belatacept versus cyclosporine had better kidney retention rates and better survival. It affected overall mortality.
It’s a great example of this arc of research. You start with an idea. You test it in rodents. You test it in monkeys. Sometimes it’s recursive. Sometimes you find a problem and have to go back and try again. Eventually, you move on to human trials.
If we look at what would have happened without nonhuman primates, the likely story is that researchers would have moved forward with something that didn’t work in human trials. It could have failed, and that could have been the end of the story.
Instead, we have this arc of a very successful drug that is better than what had been the standard of care for kidney transplantation.
Ivy Tillman: Wow. I like that illustration and the arc from the conception of the idea to the actual impact on human health.
And, like you said, sometimes you have to go back and fix something and try again. That’s part of the scientific process.
R. Paul Johnson: That’s research.
Ivy Tillman: Yes. And we want people to understand that process.
R. Paul Johnson: It’s not a straight, linear path.
Ivy Tillman: It is not.
I’m going to shift our conversation a little bit. As we talk about scientific progress and the many accomplishments that have already been made, Paul mentioned new approach methodologies earlier in our conversation.
NAMs are increasingly part of the public conversation. How do you think about NAMs? Where do they show promise, and where do nonhuman primate models remain essential in ways that alternatives cannot replicate?
R. Paul Johnson: Great question, and it is something that, as you noted, is front of mind for all of us these days, as it should be.
There are a couple of overarching points to make first.
One is that the primate centers and researchers at primate centers have used NAMs for decades. We didn’t call them that.
Thirty years ago, for example, I published a technique for taking thymic tissue and forming what was essentially a thymic organoid.
For early precursor bone marrow cells to mature into T cells, they need a specialized environment. You can’t just put them in a petri dish in the laboratory and have them turn into T cells. They need special signals and a special environment.
We developed something 30 years ago that allowed us to study T cells that matured in a thymic environment but outside a monkey. That was a very valuable model for testing and down-selecting things before we conducted in vivo experiments.
Unfortunately, there has been a false dichotomy in some conversations between NAMs and nonhuman primates.
That’s the wrong way to think about it.
Again, we use a range of research models to answer biomedical questions. It should be an “and” rather than an “or.” It’s NAMs and nonhuman primates.
I think the current emphasis on NAMs is really critical. At this stage, they are helpful mainly in refining and reducing nonhuman primate use.
Another confounding factor in the NAMs debate is that our conversation today has focused on what we might call discovery or foundational research—trying to identify how systems work and then how therapies or vaccines could improve human health.
There is another conversation related to toxicology and the use of animal models in toxicology. That is not my area of expertise.
In many ways, I think the appropriate use of NAMs for toxicology experiments is more advanced because researchers are often asking specific questions: Does this compound irritate the skin? Does this compound cause toxicity to a particular system?
Those are specific, targeted questions.
For those of us trying to determine how a virus affects a whole organism with multiple organ systems and multiple immune cell types, we can begin to dissect that in a petri dish using NAMs. NAMs can give us very helpful information.
But we are not yet at the point where we can synthesize that information to replace a nonhuman primate model in any case I’m aware of for discovery research.
The conversation should therefore be: How do we work together? How do we use nonhuman primate NAMs and human NAMs in concert with nonhuman primate models to advance human health?
It should be an “and” question, not an “or” question.
In infectious disease, for example, there is work to identify specific molecules that can reactivate latent virus for HIV cure research. NAMs are helpful for initial screening and down-selection, but there are clear data showing significant differences between what happens in vitro—even in NAMs—and what happens in people or monkeys.
If you’re trying to screen 20 compounds, you can do some initial down-selection with NAMs, but in the vast majority of cases, they are not going to provide the final answer you need to move forward with a human clinical trial.
There is also some really interesting work underway involving respiratory models and attempts to model the lung by developing NAMs that combine respiratory epithelial cells and immune cells. The California center is doing a lot in this area.
Again, this is early-stage but very promising research. It should absolutely be supported.
But these are early days. Right now, to determine whether the results from NAMs are relevant to what happens in a whole organism, we need comparative studies in nonhuman primates to see whether they model the biology appropriately.
This is a very active area of research. As I mentioned, about 70% of our investigators are using NAMs in one way or another.
It is a really important line of research. But this should be a broad conversation about working together to advance human health rather than establishing arbitrary timelines. Science generally doesn’t work according to arbitrary timelines.
Saying we’re going to end nonhuman primate research within some arbitrary time frame isn’t how science works.
We should start from the bottom up: How do we develop better systems that we can study and determine whether they are able to reduce, refine or replace nonhuman primate models?
It needs to be a conversation. Sometimes that conversation has become a little divisive, but we want this to be a big-tent conversation.
Ivy Tillman: Exactly.
Joyce, as methods evolve and we have this “and” conversation rather than an “either/or” conversation, how do you think research oversight is evolving—or will evolve—to support both innovation and animal welfare?
Joyce Cohen: I think research oversight has always done a pretty good job of supporting both and trying to move the needle on animal welfare.
Honestly, much of that change has been driven internally by the laboratory animal community setting its own new goals and pushing regulatory bodies to change what they are asking for because these are things we want to see ourselves.
It’s definitely complementary.
As Paul was indicating, I think right now and in the near future, NAMs can certainly help reduce the number of nonhuman primates used by allowing us to prescreen and ask some early questions to refine what we’re doing in the nonhuman primate model.
I absolutely think that can begin helping with the reduction of animal use.
Ivy Tillman: As we discuss NAMs and the public discourse and interest surrounding them, I want to move into a broader conversation that we at PRIM&R are having—and continue to have—with the public as well as research ethics and oversight professionals.
That conversation is about trust, transparency and bringing the public along in our work.
What do you wish people understood more about your work, and how do you build and maintain public trust?
Joyce Cohen: I feel that, over the last 10 to 20 years, we’ve been working to improve communication and openness to gain public trust.
There had previously been a lot of risk avoidance and perhaps not enough information was shared with the public, which allowed a different narrative to be driven into people’s minds.
I think we’ve made a lot of strides in improving how we share information and getting accurate information out there, and I think that helps.
If I could impart one thing to the public, I wish people understood how much those of us working with the animals care about what we do and how much compassion there is.
We have relationships with the animals we work with, whether that’s a monkey or a mouse. We’re here doing the hands-on work because we love the animals and because we believe in the importance and value of what we do.
We want to be here to make sure it’s done right and to look out for the animals.
I also wish people understood the incredible regulatory oversight involved in what we do.
There are laws, rules, regulations, inspections and oversight governing what we do every day. We are very carefully managed, and we live up to those expectations because we really, really care about the animals.
Ivy Tillman: It’s really important.
I can attest to going to the center, seeing the interactions with the animals and leaving different.
I did not expect that. I’ve been in the biomedical research world for a long time, more so on the human research side, but I’ve worked at universities that conducted animal research.
To see the animals, understand some of the research and understand some of the behavioral research being done—and its impact on the animals as well as the long-term impact on human health—was remarkable.
To actually see the animals and those interactions really affected me.
Paul, you were going to say something?
R. Paul Johnson: Yes. I wanted to echo Joyce’s point because I had exactly the same response to that question, framed slightly differently.
I think the big surprise for many people would be how much our researchers and staff really care for the animals.
That is key in terms of openness. Again, I think it is an ongoing issue.
We receive public funds from NIH to conduct our research. We have an ethical responsibility when doing work with animals. Openness and transparency are key.
We have two campuses. The one you visited on your tour is in Lawrenceville, about 30 miles from our main campus. That is where our breeding colonies are.
We have open houses twice a year there to bring members of the immediate neighborhoods and community in to see the animals and hear from our staff and scientists about why the research is important, how we take care of the animals and the types of research we conduct.
I think another surprise for many people would be the behavioral research that takes place at the primate center and the opportunity to study the incredibly complex behavioral relationships among rhesus macaques in a large group.
We can use that as a model for stress, and there is so much we can learn from that work about how stress affects the immune system, how it affects diet and how specific biomarkers can be affected by stress.
That is another area of research I suspect many people are unaware of.
We have to continue working every day to earn and maintain public trust in the work we do here because it is important. We take it very seriously, but it can’t end there.
We have to be able to demonstrate to the broader public the high standards we have for animal research and explain why we conduct animal research.
Ivy Tillman: Absolutely.
As we begin to conclude our conversation—which I’m really enjoying, by the way, so thank you both—I’m very aware of the next generation and the conversations we have about how we prepare the next generation of oversight professionals, scientists and researchers.
If you had to give advice to someone entering one of these fields today, what would you tell them about biomedical research and the work you do?
Joyce Cohen: That’s tough.
I’ll be honest. This is a challenging time to be in science and research. I would say that people still need to feel that drive and passion and continue to come into the field.
I’m worried about the next generation of people in research and whether people are going to continue to move forward. But we’re leaders in innovation, creativity and science, and we have the infrastructure set up here. We shouldn’t lose it. We should move forward.
We also need to take the lead in animal welfare, enhancements and changing how we do things.
We need people to come into the field to continue making a difference. That’s what I would encourage people to strive to do.
Ivy Tillman: Paul?
R. Paul Johnson: I think two things.
First, from a scientific perspective, the opportunities we have now across all disciplines are unparalleled. The research tools we have now are incredible.
When I first started studying the immune system, two-color flow cytometry was really exciting. Now we have 40 or more colors. We can study the expression of thousands of genes in millions of cells.
For neuroscience research, there is the ability to acquire very complex datasets and analyze them at scale, including video-based social coding of behavior.
There are incredible opportunities right now.
Yes, there are challenges, and we shouldn’t be blind to them, but the scientific opportunities are remarkable.
The second thing is that, as we discussed at the beginning, most of us are not going to follow a linear path.
You have to find something you’re passionate about and that you really care about. It helps if you’re good at it, but the most important thing is to be passionate about it.
Then you follow the path, and that path is not always straight.
Find an area you’re excited about. Find a great mentor who is as passionate about it as you are and who provides a supportive laboratory environment that fosters excitement and creativity.
Ivy Tillman: I think those are really important words of wisdom and advice from both of you.
As we conclude, I just want to say thank you.
I was looking forward to this conversation after our visit to the center. I also think it is important to make sure the public and the professions we serve—both animal research oversight and human research oversight professionals—have access to these types of conversations.
We need to have these conversations about the importance of the work being done at this center and others throughout the country.
Thank you both for your time, and thank you for joining us today on the podcast.
Joyce Cohen: Thank you.
R. Paul Johnson: Thank you, Ivy. It’s been a pleasure.
Joining me today are two of the people who make that work possible: Dr. R. Paul Johnson, who leads the center, and Dr. Joyce Cohen, who oversees the health and welfare of the animals at the heart of this research.
Together, they represent an intersection of scientific discovery, veterinary medicine and ethical leadership that is central to advancing research responsibly. I want to take a moment to welcome Paul and Joyce to the podcast. Thank you for joining us.
R. Paul Johnson: Ivy, thank you for having us. We’re looking forward to the conversation.
Ivy Tillman: First, can you each take a moment to share a little bit about your career path? We appreciate having the chance to learn from our guests about how they developed the expertise they have.
R. Paul Johnson: I can go first. I am an infectious disease physician-scientist. My area of interest has been HIV/AIDS research. I did not go to medical school intending to be a monkey doctor.
That was not my planned career path. I graduated from medical school in 1984 and then completed my internship and residency in the mid-1980s and my infectious disease fellowship in the late 1980s. That was when the HIV/AIDS epidemic was first taking off in the U.S., and it was a time before we had effective antiretroviral treatment.
We were still figuring out a lot about the virus: what type of immune cells it infected and how it damaged the immune system. We were working to develop effective antivirals and determine whether a vaccine was possible.
My initial work started with people with HIV in Bruce Walker’s laboratory at Massachusetts General Hospital. We were looking at a particular type of cell called a killer T cell, or cytotoxic T cell. We learned a lot about those cells, but there were fundamental questions we couldn’t address in people, including what happens early in infection.
That is a really critical period of infection that was very difficult to study in humans. What would happen if you had a candidate vaccine? We weren’t ready to test anything in humans yet, so we needed an animal model.
Fortunately, there was work underway at the New England Primate Research Center at that time that established an incredibly valuable nonhuman primate model of AIDS. It has spread throughout the world and models what happens in people very well, from the cells the virus infects to the course of disease—which is a little more rapid in monkeys than in people—and its susceptibility to vaccines and antivirals.
I started working part time at the primate center, trying to extend some of the skills we had developed looking at immune responses in people with HIV and translating those to nonhuman primates.
It took off from there. I was trying to split my time between Massachusetts General Hospital and the New England Primate Research Center while also being a clinician. That was hard.
Ivy Tillman: I bet.
R. Paul Johnson: As time went on through the 1990s, I spent more and more time at the primate center and eventually focused my career there.
Fast-forward to 2014. The longtime director of the Emory primate center, Stuart Zola, decided to retire, and I was lucky enough to be selected as director. I came here in 2014 and have been having a wonderful time since then.
Ivy Tillman: Absolutely. Joyce, tell us about your career path.
Joyce Cohen: Sure. First, I have to say that I’ve worked with you for 12 years, Paul, and I’ve never actually heard that story. It was really interesting to learn that.
My career path was also not set. It took a somewhat convoluted path. I definitely was not one of those people who grew up knowing I wanted to be a veterinarian.
I was premed all the way. That was definitely my plan when I started college. It was actually a combination of two things that changed my path.
I was taking Psychology 101, and the professor was a renowned primatologist, Robert Seyfarth. He talked a lot about animal behavior and behavioral primatology. I became fascinated with it and really interested and excited.
I added anthropology as a second major because I was so interested in it, but I was still continuing on my premed path. Then, one summer in college, I was putting together my résumé while looking for a summer job. When I finished it, I looked at it and thought, “Everything I’ve ever done has been with animals. I haven’t done anything in human medicine.”
I had shadowed a veterinarian at Ocean World. I worked at the Wild Bird Center. I followed a veterinary clinic. I thought, “Maybe that’s the path I want to take.”
In consultation with another primatologist at school, I learned about a potential career path that, given my background in medicine, would allow me to go into research and still work with nonhuman primates. I decided to start exploring the animal research path.
When I finished college, I went to work in a research laboratory at Columbia University in visual neuroscience with nonhuman primates. At that point, I had to decide whether to go to veterinary school or pursue a PhD in primatology. I decided on veterinary school, knowing I wanted to work with nonhuman primates in a research environment.
That was my goal, and here I am.
Ivy Tillman: It’s always interesting to hear about these paths because it’s rare that we have guests—or even people in our professions—who had a completely straight path. I think those experiences make your career richer and influence what you bring to where you are now.
The center has been advancing biomedical science for nearly a century. It serves as one of only seven NIH-supported national primate research centers in the country.
For listeners who may not be familiar with the center or even the network of primate research centers throughout the U.S., could either of you describe your role, the center’s role and how the work comes together to support the center’s mission?
R. Paul Johnson: That’s a great question. Thank you, Ivy.
The NIH-supported primate centers were founded in the 1960s, and their charge was to support nonhuman primate models that ultimately improve and advance human health.
They were all about establishing models. There is some primatology for primatology’s sake that is really important, and there is some work on conservation. But the primary charge is to help people conduct better research in nonhuman primates to advance NIH-supported research that improves human health.
They have gone through a number of evolutions. When they were founded, they were the regional primate research centers. In the early 2000s, there was a reevaluation of the network, and they decided to rebrand themselves as national primate research centers to emphasize the importance of supporting a national network of researchers.
That is something we do here and that all the primate centers do. About half of the research we support here is led by researchers outside Emory. That is a very important charge.
We continue to evolve. Over the past year, a number of the centers have evolved to become national biomedical research centers. That has been an official change at Tulane and Washington, and just last month our primate center was officially renamed the Emory National Biomedical Research Center.
The intention is to indicate that we support a wide range of research projects.
Nonhuman primate research is our sweet spot and an area of expertise. It takes considerable expertise and specialized resources to support high-quality, top-notch nonhuman primate research, and Joyce can talk more about those.
That is our central charge, but we also support a wide range of research projects. We conducted a survey earlier this year to see how many of our researchers are using new approach methodologies, or NAMs.
Using the broad NIH definition, including organoids and in silico modeling, about 70% of our researchers are currently employing NAMs in their research in addition to nonhuman primates. Similarly, about 70% of our researchers use human samples.
I think it is important to think of us as centers of excellence that use a whole range of research models, from in vitro studies and NAMs to rodents, nonhuman primates and human samples. We have the complete arc of biomedical research designed to ultimately advance human health.
There are seven centers across the country. We work closely together to make sure we are using best practices, and we work very closely with our colleagues at NIH to ensure that we are supporting a national group of biomedical researchers.
Ivy Tillman: Thank you for that overview. It helps clarify the work being done and its impact on people in the United States.
Joyce, can you describe the work you do at the National Biomedical Research Center now?
R. Paul Johnson: Yes. We’re still getting used to the name.
For clarity, when we say “primate centers,” there are many primate centers. In this conversation, when we use that term, because not everybody has changed over to the new name, we’re referring to the group of seven NIH-supported centers.
Joyce Cohen: In my role as a veterinarian here, I get to be part of cutting-edge research. We consult with investigators and help them create their research models and determine the best path forward. We also participate in the hands-on research involving the animals.
However, in my role, I also have oversight responsibilities and help ensure animal welfare, which is critically important.
Our mission as veterinarians is to advocate for the animals and look out for them while facilitating and supporting critical research. We do that in many forms, whether it is grant writing and figuring out the experimental model or IACUC review and being part of that process and its refinement.
It also extends to how we care for the animals. That’s why I love being at a primate center. Because we have so many animals, we have dedicated support staff in many different areas just for the animals. That includes our colony management group, which manages the large social groups at the field station and our breeding colonies, and our behavioral management team, which looks out for the welfare of every animal from a behavioral perspective.
One of the things I get to do in my role is work on the housing and facilities in which the animals live. That includes designing new and larger caging with better features geared specifically toward the needs of nonhuman primates, increasing social housing and constructing new housing facilities to improve animal welfare.
That is how we work together to support all of the missions.
The last thing I would mention is that, while our central mission is to support human health, this circles back to support veterinary and animal health as well. Medical discoveries that begin in animals and translate to humans can also translate back into veterinary medicine and treatments for companion and farm animals.
Ivy Tillman: I think that’s really important to bring up because, particularly when we have these conversations in public spaces, we don’t always think about the impact of the work you’re doing on our companion animals. My companion animal is sitting right next to me as I’m recording this podcast, so that matters for her care as well.
You touched on the oversight and infrastructure support you have. Can either of you talk about the role of the IACUC, particularly for individuals for whom this may be a new term?
What is an IACUC, and what role does it play in the research process and in strengthening the quality of research and animal welfare?
Joyce Cohen: Do you want me to start on that, Paul?
R. Paul Johnson: Yes. Why don’t you?
Joyce Cohen: For anyone who may not be aware, IACUC stands for Institutional Animal Care and Use Committee. This is a group required under the Animal Welfare Act and Public Health Service policy for institutions using animals in research.
The group consists of researchers, veterinarians, a member of the public and a nonscientific member. The constitution of the committee is expressly mandated.
Our IACUC here at Emory is required to have that representation, but we probably have more than 50 people on our committee. We have an extremely large IACUC because we are combined with the primate center and the School of Medicine.
This is the group that reviews every animal research protocol happening at the institution. We look at every procedure that is going to be done. We look at the goals of the research, the number of animals and the justification for what researchers are proposing to do, and we make sure they are using standards that the institution will support.
Ivy Tillman: You’ve talked about the different roles within the center and among the staff. How do you—or how does the center—encourage investigators, researchers, veterinarians, technicians and staff to ask difficult questions and look for ways to continually improve? What kind of culture do you create?
R. Paul Johnson: That’s a great question. Joyce and I can go back and forth on this.
First, I think you need to have a culture of collaboration and open communication.
We are a large community of diverse people, which is required to run a primate center. Just within animal resources, there are people with a range of responsibilities. On the research side, you have different roles, including principal investigators, laboratory managers and technicians. Then we have research administrators, facilities staff and others.
One important thing is making sure there are several different opportunities for an open exchange of information and that information doesn’t simply filter up to the top and then back down. You have to have communication across the hierarchy. People need to be comfortable expressing honest opinions.
Sometimes those are difficult, honest opinions, but that’s really critical. People need to be able to say, “This line of communication is not working.”
I have to give Joyce credit here. During the 12 years we’ve worked together, Joyce has often come to me and said, “This line of communication isn’t working. How about if we change it?” She says it very nicely, and she’s been right every time.
We have needed to rethink the way we constituted committees to bring the appropriate people to the table. Again, that doesn’t just mean going to the top of the pyramid. There need to be many lines crossing the pyramid where people can provide information, have conversations and express ideas.
Within that, you also need common values.
We can’t say there is one North Star for a primate center, but I think our three North Stars are providing outstanding care for the animals, supporting outstanding science and taking care of our people.
I’m mixing the metaphor by coming up with three North Stars, but we have to agree on where we want to go. As we have conversations about how to achieve those goals operationally, we have to rely on those points: taking care of our animals, supporting the science and supporting our people.
Joyce Cohen: Sometimes you hear that there is a dichotomy between the scientists and the animal resources or veterinary staff—that they are opposing forces—but that’s not the culture here.
We work together. Occasionally, we have differences of opinion, but overall, we all want to move the science forward. We all want it to be meaningful and important research with good results, and we all care tremendously about the animals and their welfare.
With those main principles, we can always come to some resolution.
Probably the most controversy or difference we might have is on the financial side—making sure we have enough money to run the center while investigators have enough money to do their science. That can create conflict.
But we all work together. We want to invest in the animals. We all want to see them in the best housing.
At a primate center, we also have experts performing some of the hands-on work, especially in infectious disease research, so sometimes researchers aren’t actually working hands-on with the animals. We’ll bring them into the animal facility to see the animals they’re working with.
You can’t not love the monkeys when you see them. They’re amazing animals.
We work really hard to make sure we’re all speaking the same language and seeing the same things so we can agree on a path forward.
Ivy Tillman: I like that. I heard words such as collaboration and transparency, as well as the three North Stars. I was actually envisioning them. I like that concept, and it’s clear what your priorities are.
Like you said, Joyce, it’s about moving the science forward.
If we think about the scientific need for the research done at the center, I want us to talk about what the center has contributed. Are there specific advancements or discoveries—scientific questions that have been answered—during your time there or even throughout the history of the center?
R. Paul Johnson: Sure. There are so many—scores of them.
I’ll make a start. If it’s OK, I’d like to highlight not just what happened here at Emory, which we will certainly emphasize, but what has happened across all seven centers because we are a consortium.
Broadly, we conduct studies in nonhuman primates when they can’t be done in another model—when they can’t be done in rodents or humans and you need a model that reflects as closely as possible what happens in humans.
That narrows the research to a handful of general areas: infectious disease, neuroscience, transplantation, regenerative medicine and stem cell therapy, and metabolic diseases. That doesn’t cover everything, but those are the big five.
Since my background is in infectious disease, I’ll start with HIV/AIDS. The contributions of primate models across the centers have been spectacular. They have contributed a huge body of knowledge to where we are now, with effective antiviral therapy and antiviral regimens that can prevent infection with essentially 100% efficacy, which is remarkable.
The initial studies at the New England Primate Research Center establishing the SIV/AIDS model in rhesus macaques were fundamental in providing rigorous evidence that primate lentiviruses can cause immunodeficiency.
We accept that as a given now, but in the mid-1980s, just after the identification of these viruses, there were still a lot of questions. You identify these viruses, but do they really cause AIDS, or are there other causes? The animal models provided rigorous evidence for that.
They also taught us a lot about how the virus damages the immune system. In particular, research in monkeys—and later validated in people—showed that the virus particularly affects gut-associated lymphoid tissue.
We often don’t think about our gut, but most of our immune cells are there. HIV and SIV, in the first two weeks of infection, wipe out 50% or more of the helper T cells in the gut. That is a huge opening salvo in the course of immunodeficiency that then plays out over years.
Those initial steps were discovered in monkeys because researchers could conduct studies that couldn’t be done in people.
Moving on to antivirals, the Washington Primate Center conducted initial studies with a drug called tenofovir that had been put on the back burner, frankly, because it was difficult to administer. The results in monkeys were so dramatic that researchers said, “We have to use this drug.”
They figured out a way to modify it and administer it orally, and it is now a mainstay of antiretroviral therapy for tens of millions of people worldwide.
The ability of antibodies to prevent infection in infants and adults has also been fundamentally altered by results in nonhuman primates.
Very recently, investigators at the California and Tulane primate centers conducted a provocative and exciting study involving a form of gene therapy. An antibody encoded by a virus called AAV can deliver the gene for that antibody to infants and could potentially provide lifelong protection against mother-to-child transmission. One shot could, in theory, prevent mother-to-child transmission.
Just this past week, studies from the Emory primate center, led with scientists at the Scripps Research Institute in California, showed that using the right combination of immunizations can lead the immune system down a path to generate antibodies capable of neutralizing a substantial number of diverse HIV isolates.
These are the elusive broadly neutralizing antibodies, which have been really difficult to produce through vaccination.
It’s a very promising result.
Again, this is my background, so I’m a little biased, but the contributions of nonhuman primates to HIV/AIDS research have been remarkable.
That is looking in the rearview mirror. Going forward, as we try to get these vaccines over the line to being effective, develop less complicated treatment regimens, explore prospects for an HIV cure, develop better antivirals and improve methods of preventing infection, results from studies in nonhuman primates will continue to be essential for the foreseeable future if we are going to end the HIV/AIDS epidemic.
And that’s just one area.
You can go to each of the seven centers and see fundamental, substantial contributions each has made in the HIV/AIDS arena.
Joyce Cohen: Do you want to mention transplantation here?
R. Paul Johnson: I was about to. That was next.
There have been some great advances in transplantation.
To transplant an organ from another individual to a person who needs a kidney transplant or another organ transplant, you have to address the fact that the immune system will recognize and reject the organ as foreign. You therefore need immunosuppressive agents to prevent rejection.
Historically, those immunosuppressive drugs have been somewhat blunt instruments. While they kept the kidney, liver or heart from being rejected, they also made people more susceptible to infection. In some cases, they have significant toxicity.
For example, one of the mainstay immunosuppressants used in kidney transplantation is cyclosporine. Cyclosporine suppresses the immune system very well, but it can also affect the kidney.
Ironically, the drug suppressing the immune system can damage the very organ it is trying to protect.
There is a very well-known transplant surgeon here at Emory, Chris Larsen, who was interested in developing a more precise way to suppress the immune system using designer molecules that block specific pathways that activate T cells.
He identified a promising strategy that worked in mice. They tried it in monkeys, and it didn’t work.
He then had to go back, working with the pharmaceutical company, to refine the candidate drug. They found one that worked very well in monkeys. It worked in people and ultimately went on to FDA approval. It is now given to patients at Emory University Hospital who undergo kidney transplantation.
The drug is called belatacept. It was the first new immunosuppressive drug approved in, I think, 10 to 20 years.
Ultimately, a follow-up comprehensive phase 3 study found that people treated with belatacept versus cyclosporine had better kidney retention rates and better survival. It affected overall mortality.
It’s a great example of this arc of research. You start with an idea. You test it in rodents. You test it in monkeys. Sometimes it’s recursive. Sometimes you find a problem and have to go back and try again. Eventually, you move on to human trials.
If we look at what would have happened without nonhuman primates, the likely story is that researchers would have moved forward with something that didn’t work in human trials. It could have failed, and that could have been the end of the story.
Instead, we have this arc of a very successful drug that is better than what had been the standard of care for kidney transplantation.
Ivy Tillman: Wow. I like that illustration and the arc from the conception of the idea to the actual impact on human health.
And, like you said, sometimes you have to go back and fix something and try again. That’s part of the scientific process.
R. Paul Johnson: That’s research.
Ivy Tillman: Yes. And we want people to understand that process.
R. Paul Johnson: It’s not a straight, linear path.
Ivy Tillman: It is not.
I’m going to shift our conversation a little bit. As we talk about scientific progress and the many accomplishments that have already been made, Paul mentioned new approach methodologies earlier in our conversation.
NAMs are increasingly part of the public conversation. How do you think about NAMs? Where do they show promise, and where do nonhuman primate models remain essential in ways that alternatives cannot replicate?
R. Paul Johnson: Great question, and it is something that, as you noted, is front of mind for all of us these days, as it should be.
There are a couple of overarching points to make first.
One is that the primate centers and researchers at primate centers have used NAMs for decades. We didn’t call them that.
Thirty years ago, for example, I published a technique for taking thymic tissue and forming what was essentially a thymic organoid.
For early precursor bone marrow cells to mature into T cells, they need a specialized environment. You can’t just put them in a petri dish in the laboratory and have them turn into T cells. They need special signals and a special environment.
We developed something 30 years ago that allowed us to study T cells that matured in a thymic environment but outside a monkey. That was a very valuable model for testing and down-selecting things before we conducted in vivo experiments.
Unfortunately, there has been a false dichotomy in some conversations between NAMs and nonhuman primates.
That’s the wrong way to think about it.
Again, we use a range of research models to answer biomedical questions. It should be an “and” rather than an “or.” It’s NAMs and nonhuman primates.
I think the current emphasis on NAMs is really critical. At this stage, they are helpful mainly in refining and reducing nonhuman primate use.
Another confounding factor in the NAMs debate is that our conversation today has focused on what we might call discovery or foundational research—trying to identify how systems work and then how therapies or vaccines could improve human health.
There is another conversation related to toxicology and the use of animal models in toxicology. That is not my area of expertise.
In many ways, I think the appropriate use of NAMs for toxicology experiments is more advanced because researchers are often asking specific questions: Does this compound irritate the skin? Does this compound cause toxicity to a particular system?
Those are specific, targeted questions.
For those of us trying to determine how a virus affects a whole organism with multiple organ systems and multiple immune cell types, we can begin to dissect that in a petri dish using NAMs. NAMs can give us very helpful information.
But we are not yet at the point where we can synthesize that information to replace a nonhuman primate model in any case I’m aware of for discovery research.
The conversation should therefore be: How do we work together? How do we use nonhuman primate NAMs and human NAMs in concert with nonhuman primate models to advance human health?
It should be an “and” question, not an “or” question.
In infectious disease, for example, there is work to identify specific molecules that can reactivate latent virus for HIV cure research. NAMs are helpful for initial screening and down-selection, but there are clear data showing significant differences between what happens in vitro—even in NAMs—and what happens in people or monkeys.
If you’re trying to screen 20 compounds, you can do some initial down-selection with NAMs, but in the vast majority of cases, they are not going to provide the final answer you need to move forward with a human clinical trial.
There is also some really interesting work underway involving respiratory models and attempts to model the lung by developing NAMs that combine respiratory epithelial cells and immune cells. The California center is doing a lot in this area.
Again, this is early-stage but very promising research. It should absolutely be supported.
But these are early days. Right now, to determine whether the results from NAMs are relevant to what happens in a whole organism, we need comparative studies in nonhuman primates to see whether they model the biology appropriately.
This is a very active area of research. As I mentioned, about 70% of our investigators are using NAMs in one way or another.
It is a really important line of research. But this should be a broad conversation about working together to advance human health rather than establishing arbitrary timelines. Science generally doesn’t work according to arbitrary timelines.
Saying we’re going to end nonhuman primate research within some arbitrary time frame isn’t how science works.
We should start from the bottom up: How do we develop better systems that we can study and determine whether they are able to reduce, refine or replace nonhuman primate models?
It needs to be a conversation. Sometimes that conversation has become a little divisive, but we want this to be a big-tent conversation.
Ivy Tillman: Exactly.
Joyce, as methods evolve and we have this “and” conversation rather than an “either/or” conversation, how do you think research oversight is evolving—or will evolve—to support both innovation and animal welfare?
Joyce Cohen: I think research oversight has always done a pretty good job of supporting both and trying to move the needle on animal welfare.
Honestly, much of that change has been driven internally by the laboratory animal community setting its own new goals and pushing regulatory bodies to change what they are asking for because these are things we want to see ourselves.
It’s definitely complementary.
As Paul was indicating, I think right now and in the near future, NAMs can certainly help reduce the number of nonhuman primates used by allowing us to prescreen and ask some early questions to refine what we’re doing in the nonhuman primate model.
I absolutely think that can begin helping with the reduction of animal use.
Ivy Tillman: As we discuss NAMs and the public discourse and interest surrounding them, I want to move into a broader conversation that we at PRIM&R are having—and continue to have—with the public as well as research ethics and oversight professionals.
That conversation is about trust, transparency and bringing the public along in our work.
What do you wish people understood more about your work, and how do you build and maintain public trust?
Joyce Cohen: I feel that, over the last 10 to 20 years, we’ve been working to improve communication and openness to gain public trust.
There had previously been a lot of risk avoidance and perhaps not enough information was shared with the public, which allowed a different narrative to be driven into people’s minds.
I think we’ve made a lot of strides in improving how we share information and getting accurate information out there, and I think that helps.
If I could impart one thing to the public, I wish people understood how much those of us working with the animals care about what we do and how much compassion there is.
We have relationships with the animals we work with, whether that’s a monkey or a mouse. We’re here doing the hands-on work because we love the animals and because we believe in the importance and value of what we do.
We want to be here to make sure it’s done right and to look out for the animals.
I also wish people understood the incredible regulatory oversight involved in what we do.
There are laws, rules, regulations, inspections and oversight governing what we do every day. We are very carefully managed, and we live up to those expectations because we really, really care about the animals.
Ivy Tillman: It’s really important.
I can attest to going to the center, seeing the interactions with the animals and leaving different.
I did not expect that. I’ve been in the biomedical research world for a long time, more so on the human research side, but I’ve worked at universities that conducted animal research.
To see the animals, understand some of the research and understand some of the behavioral research being done—and its impact on the animals as well as the long-term impact on human health—was remarkable.
To actually see the animals and those interactions really affected me.
Paul, you were going to say something?
R. Paul Johnson: Yes. I wanted to echo Joyce’s point because I had exactly the same response to that question, framed slightly differently.
I think the big surprise for many people would be how much our researchers and staff really care for the animals.
That is key in terms of openness. Again, I think it is an ongoing issue.
We receive public funds from NIH to conduct our research. We have an ethical responsibility when doing work with animals. Openness and transparency are key.
We have two campuses. The one you visited on your tour is in Lawrenceville, about 30 miles from our main campus. That is where our breeding colonies are.
We have open houses twice a year there to bring members of the immediate neighborhoods and community in to see the animals and hear from our staff and scientists about why the research is important, how we take care of the animals and the types of research we conduct.
I think another surprise for many people would be the behavioral research that takes place at the primate center and the opportunity to study the incredibly complex behavioral relationships among rhesus macaques in a large group.
We can use that as a model for stress, and there is so much we can learn from that work about how stress affects the immune system, how it affects diet and how specific biomarkers can be affected by stress.
That is another area of research I suspect many people are unaware of.
We have to continue working every day to earn and maintain public trust in the work we do here because it is important. We take it very seriously, but it can’t end there.
We have to be able to demonstrate to the broader public the high standards we have for animal research and explain why we conduct animal research.
Ivy Tillman: Absolutely.
As we begin to conclude our conversation—which I’m really enjoying, by the way, so thank you both—I’m very aware of the next generation and the conversations we have about how we prepare the next generation of oversight professionals, scientists and researchers.
If you had to give advice to someone entering one of these fields today, what would you tell them about biomedical research and the work you do?
Joyce Cohen: That’s tough.
I’ll be honest. This is a challenging time to be in science and research. I would say that people still need to feel that drive and passion and continue to come into the field.
I’m worried about the next generation of people in research and whether people are going to continue to move forward. But we’re leaders in innovation, creativity and science, and we have the infrastructure set up here. We shouldn’t lose it. We should move forward.
We also need to take the lead in animal welfare, enhancements and changing how we do things.
We need people to come into the field to continue making a difference. That’s what I would encourage people to strive to do.
Ivy Tillman: Paul?
R. Paul Johnson: I think two things.
First, from a scientific perspective, the opportunities we have now across all disciplines are unparalleled. The research tools we have now are incredible.
When I first started studying the immune system, two-color flow cytometry was really exciting. Now we have 40 or more colors. We can study the expression of thousands of genes in millions of cells.
For neuroscience research, there is the ability to acquire very complex datasets and analyze them at scale, including video-based social coding of behavior.
There are incredible opportunities right now.
Yes, there are challenges, and we shouldn’t be blind to them, but the scientific opportunities are remarkable.
The second thing is that, as we discussed at the beginning, most of us are not going to follow a linear path.
You have to find something you’re passionate about and that you really care about. It helps if you’re good at it, but the most important thing is to be passionate about it.
Then you follow the path, and that path is not always straight.
Find an area you’re excited about. Find a great mentor who is as passionate about it as you are and who provides a supportive laboratory environment that fosters excitement and creativity.
Ivy Tillman: I think those are really important words of wisdom and advice from both of you.
As we conclude, I just want to say thank you.
I was looking forward to this conversation after our visit to the center. I also think it is important to make sure the public and the professions we serve—both animal research oversight and human research oversight professionals—have access to these types of conversations.
We need to have these conversations about the importance of the work being done at this center and others throughout the country.
Thank you both for your time, and thank you for joining us today on the podcast.
Joyce Cohen: Thank you.
R. Paul Johnson: Thank you, Ivy. It’s been a pleasure.