By Eric Barton and Alexandra Pecharich
As a young assistant professor in the early 1980s at Johns Hopkins University’s Bloomberg School of Public Health, Tomás Guilarte would often visit an affiliated clinic to observe children undergoing therapy to chemically remove lead from their bodies.
Many were from poor neighborhoods in Baltimore, and their exposure stemmed from lead-based paint crumbling off the walls in their homes. The dwellings of the identified children were being remediated, but for the youngsters the damage was already done: diminished memory and other cognitive problems that contributed to poor performance in school. (Lead-based paints were banned for use in housing in 1978.)
Some years later, a national clinical study confirmed that the type of therapy the children had received, called chelation, successfully reduced the toxin levels in their bodies. Unfortunately, the study also reported that it did nothing to reverse learning deficits or improve school performance. The latter convinced Guilarte that new approaches were needed to help lead-poisoned children.
Guilarte went on to perform research in which he identified the molecular and cellular basis of the lead-induced impairment the children had experienced. His laboratory would be among the first to describe lead as an inhibitor of a critical brain receptor involved in learning and memory.
His work then pivoted to looking for ways to overcome the problems faced by youngsters exposed to lead at the height of their brain development. It revolved around a gene responsible for making a protein called brain-derived neurotrophic factor, or BDNF. He investigated how to boost production of that protein using laboratory rats that his team exposed to lead and whose learning deficits mimicked those of the affected youngsters.
“What we found is that in the animals that received enrichment, BDNF gene expression increased,” Guilarte says. “Enrichment” in this case was a high-quality environment, he explains. Whereas the control subjects lived in standard cages with only their basic needs met, the test group lived in larger, multiple-story cages with running wheels and toys that were changed out regularly to provide novel stimulation. (Translated into human terms, “enrichment” for affected children could mean everything from tutoring and after-school programs to the addition of computers in the home.)
As the study progressed, the results exceeded expectations. “We showed the learning deficits were reversed,” Guilarte says of the progress made by subjects in the test group. He soon came to recognize something the scientific community had largely failed to consider. While many recognized that environment could negatively impact neurological health, few seemed to understand that positive changes in physical surroundings could potentially improve the cognitive condition of sufferers. While today such a statement might seem almost intuitive, the realization back then prompted new lines of study, among them groundbreaking work by Guilarte himself.
The seasoned researcher joined FIU in 2016 as dean of the Robert Stempel College of Public Health and Social Work and quickly set about creating the Brain Behavior & the Environment (BBE) program, a research and educational center that looks at how environmental factors impact brain health.
The BBE is an emerging pre-eminent program at FIU and it is the direct result of the vision of FIU leadership to enhance science, research and education throughout the university. Since the program’s inception, Guilarte and his team of experts—all of them lured to FIU by the promise of this unique endeavor—have more than $17 million in grant funding, primarily from the National Institutes of Health.
Such substantial financial support drives home the growing need to examine both the causes as well as possible preventive and curative therapies for neurodegenerative disorders: An estimated 44 million people worldwide currently suffer from Alzheimer’s disease or a related form of dementia; an estimated 7 million to 10 million have Parkinson’s disease.
Genetics versus the environment
Among those who accepted Guilarte’s invitation to do something big is Jason Richardson. He was raised on a Mississippi farm that grew cotton, rice and soybeans. He spent more than a dozen years in agricultural work, in one capacity or another, even directing crop dusters by standing in the field with flags. The latter often resulted in his getting a direct hit of pesticide.
Today, Richardson has dedicated his career to studying just how such toxins might affect people’s health. His work, along with that of others on the team, has upended the way Alzheimer’s and Parkinson’s are studied.
For much of history, scientists believed that all neurological disorders had their basis in genetics alone. That changed in the early 1980s after a group of drug users showed up to an ER in San Francisco with symptoms similar to those of Parkinson’s disease, such as tremors and impaired balance. Months of study would confirm that neurotoxins in the chemicals they consumed had caused the loss of dopamine neurons—the root of Parkinson’s. It was a watershed discovery.
“That moment got people thinking that maybe it’s something in our environment that causes these types of diseases,” Richardson says.
Yet the new revelation would soon be ignored. In 1998 a specific gene associated with Parkinson’s—something researchers had been seeking—was formally identified, Richardson explains. That finding would go on to curtail interest in the environmental factors that lead to that particular neurodegenerative disease.
The lingering bias toward the study of genetics over environmental factors has persisted—even with the 1980s findings associated with Parkinson’s and the lead poisoning Guilarte saw in young patients—and that’s what the BBE program is up against. Yet its mission makes perfect sense: Only about 5 percent of all cases of Alzheimer’s and Parkinson’s are the result of purely genetic mutations. The other 95 percent of cases are the result of environmental factors in combination with varying degrees of genetic factors. By understanding the contribution of environmental factors and genetics, the hope is to be able to identify those at risk early on and potentially intervene or prevent disease.
And that’s exactly what Richardson and his team focus on: preventive science, figuring out what can be changed in our environment to decrease risk factors.
“What we tell people is when you’re looking at complex diseases, they don’t have just one cause,” Richardson explains. “What we do here at FIU that is very different, and we’re probably one of the only places really working on this in a multifaceted way, is look at that in-between, that gene-by-environment interaction, because that’s where the action is. Because there are multiple risk factors.”
When he says multiple risk factors, Richardson means both the lifestyle factors associated with an individual—such as quality of diet, participation in exercise, habits such as smoking and coffee drinking and even education level—as well as those things over which people often have less control, such as chemical exposure.
When it comes to the last, Richardson warns, there must be a balancing act. Not every potential toxin can, or should be, removed from use. Some pesticides make possible the world’s ability to grow enough food (or almost enough) to feed the masses. Others pose threats but have a good that outweighs the bad—such as the recognized potential harm of the synthetic insecticide DDT that nonetheless has saved millions of lives in its use as a way to control malaria.
“Risk assessment has multiple components,” says Richardson of the work of those in his field. “The hazard assessment is a component, but there is a risk-benefit ratio. There’s two sides to everything.”
Seeking therapies for Parkinson’s
Professor Kim Tieu is a leading expert on Parkinson’s, and his work has attracted millions in grant support, most recently $6.6 million from the NIH.
Tieu’s most high-profile work involves studying a protein that has potential to be a drug target for Parkinson’s.
“By using genetic and pharmacological approaches to reduce the function of this protein, we have demonstrated our therapeutic strategy in experimental models of Parkinson’s,” Tieu says. “Our new grant from the NIH will allow us to move this project one step closer from bench to bedside.”
The NIH grant supports this research as well as Tieu’s hunt for an existing medication that could stop the protein in its tracks. He is seeking to repurpose an FDA-approved drug already on the market for some other use that might also successfully counteract the protein. Tieu is collaborating with the Scripps Research Institute-Florida, which has a sample library of tens of thousands of FDA-approved drugs against which his team will screen for what he calls a “disease modifying therapy.”
That form of treatment—unlike currently available medications for Parkinson’s, which only replace the brain’s missing chemical neurotransmitter (dopamine) and often lose efficacy over time—holds the promise of preserving the function and integrity of cells. Measured scientist though he is, Tieu is hopeful that he can identify a drug suitable for a clinical trial by the conclusion of this project in eight years.
“Parkinson’s was discovered over 200 years ago and quite a bit of advances have been made over the last few decades, still not enough, but we are making progress,” he says.
Studying the effects of phosphates
Even as researchers seek to understand the pathological mechanisms underlying neurological disorders and to develop treatments, connecting the dots between environmental exposures and diseases such as Parkinson’s and Alzheimer’s remains a full-time pursuit.
Associate Professor Jeremy W. Chambers has for years worked on the basic science that supports much of the experimental work done by colleagues within the BBE program and elsewhere. His is also a type of research that policy makers consider when making decisions about public health.
“We do the basic biochemistry and cell biology,” Chambers says. “How do neurons function? How do they die? And then we incorporate environmental agents and how they could be driving some of the mechanisms that we’re looking at to better understand toxicity and disease.”
Recently, Chambers’ research has gone beyond that foundational science to the study of organophosphates, a class of compounds that can cause detrimental neurological effects. Organophosphates were used in chemical weapons by Germany in World War I and more recently in Russian counter-intelligence operations. They are also found in roughly a third of pesticides used in the United States today, including on Florida golf courses and crops.
For many years, little federal funding and few investigative efforts were dedicated to discerning the broader effects of these chemicals. But organophosphates have since been linked to millions of deaths by respiratory failure and long-standing neurological effects. Some organophosphates are outright banned in some countries, although still widely used in Asia as well as allowed in the United States, where they comprise roughly 30 percent of insecticide use. The U.S. Environmental Protection Agency recently rescinded a proposed ban on the widely used pesticide Chlorpyrifos, which has been linked to neurological damage in children.
It is the debate between science and public policy that makes Chambers’ work critical, he says. “Most of these concerns can be hashed out through a basic science understanding of how these compounds affect the function of our nervous system at the molecular level. That’s the perspective that my lab brings.”
The next generation
The BBE program is ensuring that the trend in environmental-based brain research begun by Guilarte and his team will continue well into the future by preparing the scientists who will one day take over.
Students can pursue two different specialized master’s tracks in Brain, Behavior and the Environment available in addition to a doctoral degree. Courses are devoted to topics such as environmental hazards and neurotoxicology and include components of neuroanatomy and studies of behavioral outcomes associated with toxin exposures. The big picture approach makes graduates ready to work in government health agencies, biotech and other industries, clinical jobs and academic research.
“Instead of theory being the guiding practice, we want these students to be more laboratory-oriented,” says Chambers, the researcher who is also director of the Ph.D. program. “Our students will have this unique skill set that they will be able to leverage into the next generation of neurological research.”
Maribel Saad ’18 earned a bachelor’s of science in biology from FIU and now is working toward a master’s in public health. The BBE track allows her to interact with front-line researchers.
“For me personally, it has been very interesting and fascinating because I have been able to hear first hand from top researchers about the work they have been doing,” says Saad, who took the required neurotoxicology course from Tieu, the well-funded Parkinson’s expert, who is also her advisor.
“He has been talking a lot about [the latest research] in class and discussed recent experiments. To be able to ask him questions about that subject is really helpful,” says Saad, who is still defining her own research project and values the examples of those around her.
Despite his heavy research and administrative commitments as department chair, Tieu relishes the chance to teach young people who will take up the mantle.
“Information in the textbook is sometimes outdated,” he says. “There are things that stay the same, but when it comes to research for diseases like Parkinson’s and Alzheimer’s, the field is moving quite rapidly. This is why we try to incorporate the latest technology and research into the classroom so students get access to the latest information.”
Solving the curse of neurodegenerative disease remains a painstaking process with potentially life-impacting consequences. While millions currently suffering with illness might not reap the full benefits of the work happening today, the future for others will be improved. And much of it thanks to FIU.
The BBE program has generated broad attention for the concentration of experts brought together around its mission and great excitement for what their research has discovered. Pamela J. Lein, a professor of neurotoxicology in the School of Veterinary Medicine at the University of California, Davis, labors in the same arena and welcomes the intentionality with which Tomás R. Guilarte has built his team.
“The work is complicated, and it requires a lot of different levels of expertise,” she says. “You need people who have expertise in epidemiology, people who have expertise in animal models, biostatistics and toxicology. I think he really has succeeded in bringing together some of the best minds. I think we’re all looking forward to seeing what the center comes up with.”