image: Niall Howlett, Associate Dean for Research and Graduate Education at the University of Rhode Island College of Pharmacy.
Credit: URI Communications
A rare, genetic disorder that prevents bone marrow from producing healthy blood cells and platelets, often associated with birth defects, blood disorders, and cancers in children and adolescents, has recently been discovered to also impact neurological health, prompting a novel study in the University of Rhode Island College of Pharmacy to search for treatments for Fanconi Anemia Neurological Syndrome.
Professor and Associate Dean for Research and Graduate Education Niall Howlett began studying the condition after learning about a patient with Fanconi anemia who had been doing well after having gone through a bone marrow transplant—one of the common treatments for FA, along with blood and platelet transfusions, and growth hormone therapy. But after a minor fall, the patient found he couldn’t move, despite there being no obvious physical injury.
“He hasn't walked since. There was this sudden onset of some neurological manifestation of this disease,” Howlett said, noting that some patients with FA also develop noncancerous lesions on the brain. “They're almost like these necrotic dead zones in the brain. The incidence of this has been increasing and increasing over the last couple of years.”
That is likely due to improvements in treatments for the initial ailments of Fanconi anemia, including more effective bone marrow transplants and advances in cancer treatment. Patients who rarely used to live into adulthood are now surviving into their 20s and even their 30s, uncovering the neurological conditions scientists have only recently learned about.
“It's an accelerated aging disease, so we're now seeing symptoms that we often see in the general population, typically with people in their 70s or 80s. In Fanconi anemia patients, they are maybe in their 30s,” Howlett said. “Literally in the last five years, we're seeing this new constellation of symptoms in FA patients that we would never have seen before. If you asked me 10 years ago if Fanconi anemia is a neurological disease, I would have said, ‘No, it's birth defects, bone marrow failure, cancer.’ But because patients are living longer, we now are seeing these new neurological symptoms—visual defects, hearing issues, loss of balance, cognitive decline—in a subset of patients.”
Howlett began working with Salva Regina University neuroscientist Belinda Barbagallo, performing genomics experiments using computational resources established by URI Director of Research Computing Gaurav Khanna and his team. After running multiple Fanconi anemia samples through the software, the researchers found connections between the disease and damage to neural cells. The evidence was strong enough to warrant further study into causes of the neurological damage, prompting Howlett’s $550,000 grant from the National Institutes of Health to fund his novel project.
Howlett aims to uncover the connections between FA and nervous system development, as well as nervous system decline, including neurodegeneration. To do this, Howlett and his team are using C. elegans, a microscopic, transparent roundworm, which has a well-characterized nervous system. Using fluorescence microscopy, Howlett and his team can track the development and decline of worms genetically modified to carry the FA gene mutations. He can even zoom into individual neurons and see how they may be affected by various treatments.
The researchers also perform behavioral experiments. They can observe how the worms move, for example, counting the number of times they reverse, which is a natural movement controlled by specific sets of neurons. Lower incidence of the specific movement would indicate dysfunction or degeneration of that neuron. They also place the worms in a dish with various chemicals that should either attract or repel them to see whether their sensory perception is impaired.
To measure feeding behaviors, Howlett places the worms in a petri dish coated with the bacteria they eat to measure whether there are changes in their usual feeding patterns. He will also place small amounts of bacteria around the petri dish to test the worms’ ability to find food.
“We know how many neurons there are, we know which neurons control what behavior,” Howlett said. “We can do behavioral assays to determine, for example, whether they are attracted to one specific chemical, and repelled by a different chemical. If not, that can be suggestive of a defect in a particular set of neurons. So, these behavioral assays can tell us whether specific neurons are working OK.”
Ultimately, Howlett and Barbagallo are attempting to determine why some FA patients develop neurological symptoms, and whether they can identify proteins or pathways that affect specific neurons and influence neurological behavior.
“If you identify a protein or a pathway, then you’ve got a drug target,” Howlett said. “You can then potentially treat worms with these drugs and find out if their behavior changes. The simplicity of this system is so compelling. Obviously, our nervous system is way more complex, but there are enormous similarities between the worms’ nervous system and ours. Their neurons are pretty much our neurons. If we study how those neurons work in the worm, or how they’re affected by loss of the Fanconi anemia pathway, those findings are directly transferable to what happens in humans.”