By Keith Brannon| Photography by Daymon Gardner
For more than half a century, scientists in the Tulane National Primate Research Center, (TNPRC) have battled major diseases such as AIDS and Zika virus.
Earlier this year, the National Institutes of Health awarded a $42 million, five-year grant to Tulane National Primate Research Center to continue its mission to fight diseases and improve human health through biomedical research.
The funding was a renewal of the primary base grant that supports the operation of the 54-year-old center, which employs more than 300 scientists, staff and animal care workers on a 500-acre campus in Covington, Louisiana. As part of a network of seven national primate research centers across the country, Tulane National Primate Research Center (TNPRC) is dedicated to finding cures, treatments and preventions for major infectious diseases including HIV/AIDS, Lyme disease, malaria, tuberculosis and emerging diseases like Zika.
While the center is home for a substantial number of independent investigators, it’s also a significant resource for researchers within Tulane University School of Medicine. The study of nonhuman primates is critically important for medical research, as it often precedes clinical trials in humans. Because they share more than 90 percent of our genes, nonhuman primates can demonstrate how diseases affect people unlike any other animal, computer or cell culture model.
“There’s a recognition that a lot of studies in mice don't translate as well into what would be predicted to work in humans,” says TNPRC Director and Chief Academic Officer Jay Rappaport, PhD. “And there are a lot of studies that can not be done in humans and can be done more effectively in nonhuman primates.”
Tackling Global Threats
One key area is the search for new vaccines to protect against viruses and bacteria or the so-called select agents, which are biological toxins and infectious organisms that could become public health threats. An example is Burkholderia pseudomallei (Bps), an increasingly drug-resistant bacteria that causes melioidosis, a potentially deadly disease common in Southeast Asia and other tropical climates.
Without treatment, it can cause fatal organ failure within 48 hours. Those infected can get pneumonia, skin abscesses and other symptoms similar to tuberculosis.
Bps is rare in the United States, but public health officials consider melioidosis an emerging global threat because the bacteria can live in soil well outside the countries where the disease is endemic. It’s a priority for the U.S. Department of Defense not only because it’s a danger to troops stationed overseas but also because it could be aerosolized into a bioterrorism weapon.
One Scientist's Work
Tulane microbiologist Lisa Morici, PhD, has spent more than a decade studying Bps and Burkholderia mallei, a closely related pathogen that infects animals. She worked with researchers at the primate center to develop the military’s leading vaccine candidate against the bacteria.
Lisa Morici, PhD developed a vaccine candidate for a fatal drug-resistant bacteria.
Tulane National Primate Research Center was essential for the work, she says.
“From the very beginning I wouldn't be where I am right now without the primate center — without a doubt,” says Morici, associate professor of microbiology and immunology. “The primate model, for me in particular, is very critical, because I work with select agents. I develop countermeasures for infectious agents that would never be feasible to test in a clinical trial in humans. Any work with the infectious organism had to be done at the primate center. And I think one of the keys to my success was establishing relationships early on with primate center faculty.”
Morici’s research started with a $25,000 pilot grant, and steadily grew into a $7.68 million project. She worked closely with Chad Roy, PhD, director of infectious disease aerobiology at the primate center to show that the vaccine could protect animals exposed to the pathogen in the air. Much of that work was conducted in the primate center’s level 3 Regional Biosafety Lab.
Chad Roy, PhD collaborated with Dr. Morici to test her vaccine at TNPRC.
Her vaccine is composed of outer membrane vesicles (OMVs), which are nanoparticles shed by bacteria as they grow. OMVs are also being developed as a new class of adjuvants or immune system triggers for use in next-generation vaccines.
“Outer membrane vesicles are very small particles that are shed from the surface of the bacteria, and our bodies have evolved signaling pathways to recognize these particles as a sign of a live infection. And as a result, our bodies mount a robust immune response,” she says. “Outer membrane vesicles from bacteria are very similar between different species, and they contain conserved sequences that our bodies recognize. And as a result, we can use vesicles from one bacterium to mount immune responses against it and similar bacteria. And in this sense, we can use the vesicles that we produce here in our laboratory to vaccinate against bacteria from many different clinically important pathogens.”
In January, the Defense Department awarded her more than $4 million for a three-year contract to develop a final prototype of the Bps vaccine for good manufacturing practice production.
“It’s an amazing feeling to work on something that could save lives or prevent disease,” she says. “We're excited to see the vaccine technology used in other areas. We'd like to take the platform and adapt it to other organisms like Pseudomonas aeruginosa, a drug-resistant bacterium, or perhaps salmonella or other diseases where there might still be a need. Then we can protect global populations in addition to the U.S. military.”
Exploring gene therapy and regenerative medicine
Next-generation vaccines aren’t the only breakthroughs at the School of Medicine that rely on the primate center. Bruce Bunnell, PhD, director of the Tulane Center for Stem Cell Research and Regenerative Medicine, depends on TNPRC for projects ranging from the developing stem cell therapies to treat rare genetic diseases to using regenerative medicine to replace joint cartilage.
Bruce Bunnell, PhD leads projects in gene therapy, stem cell treatments and tissue/cartilage regeneration.
“Pretty much everything that I do from a research perspective, whether it's gene therapy, stem cells or tissue engineering projects, they all have involved nonhuman primate research,” Bunnell says. “I wouldn't have the papers nor would I have some of the grants that I have without having access to the primate center. For me, it's a huge part of my research life.”
Bunnell has three major research projects ongoing at TNPRC. One of the largest is his first collaboration with the center to investigate Krabbe disease, which is a rare inherited disorder that destroys the protective coating of nerve cells in the brain and the nervous system.
“Krabbe disease is a lysosomal storage disorder. It's an inborn error in metabolism,” Bunnell says. “Humans that have Krabbe's are born with a genetic mutation such that their lysosomes, or the garbage disposal of our cells where everything goes to get degraded, don't work properly. They're missing a key enzyme such that things that normally get broken down into very small molecules can't get broken down.”
Bunnell has been testing stem-cell therapies against Krabbe’s.Years ago, primate center staff discovered the disease in rhesus monkeys in a breeding colony within the facility. TNPRC was the first to have a naturally occurring nonhuman primate model of the disease.
“We've been doing a lot of studies in nonhuman primates, where we're infusing various stem cell populations in the central nervous system to look at their ability to treat disease,” Bunnell says.
Part of the research also involves a collaboration with the University of Texas Southwestern Medical School to engineer viruses to deliver targeted gene therapy. They are making viral vectors derived from Adeno-associated virus (AAV) a non-parthenogenic virus that doesn’t illicit a strong immune response in people.
The project aims to transduce cells in hard to reach regions of the brain and central nervous system.
“It’s an approach called viral evolution, where you make libraries of different components of AAV viruses and let them recombine on their own and look at their ability to transduce cells in the brain, or to genetically engineer cells in the brain,” Bunnell says. “And that work absolutely requires nonhuman primates, because the data that we get should mimic what we see in the human system, whereas data in the mouse model will be good data, but it won't necessarily indicate what's going to happen in people.”
The technique could also work to fight Krabbe’s as it has the potential to target cells in the spinal cord and brain.
“The unique thing about Krabbe’s disease is that in the brain it effects oligodendrocytes, which are cells that produce a compound called myelin, which is like the installation on electrical wire. And so ideally, all we really need to do is get genes into the oligodendrocyte cells, and we should be able to correct that,” Bunnell says.
The difficult challenge Bunnell’s collaborator hopes to overcome is engineering vectors that are able to target specific cell types.
Bunnell is also conducting regenerative medicine research at the primate center. He is part of a project to develop an experimental graft that plastic surgeons can eventually use to regenerate a nipple and areola for complete breast restoration after cancer treatment. He is also working on a project with Dr. Zongbing You to regrow cartilage to help repair joints damaged by age and degenerative diseases.
Such advanced work is only possible using nonhuman primates, Bunnell says.
“Our field is still young and immature. To move something into a human being, there's still a lot of work that has to be done a large animal models,” he says. “Gene therapy, stem cell treatments and new tissue-engineering-based approaches are all going to have to go through nonhuman primates in order to be successful.”