New Innovation Pipeline Helps Bring Visions to Light
Behind a single unmarked door in the basement of Morrill Science Center III are more than 6,000 of one of science’s most valuable models for studying human genetics and disease—the zebrafish. The tiny, striped members of the minnow family dart about in 200 small tanks on racks that are four rows deep.
The Jensen Lab is not a large room. There are no windows, there’s fluorescent lighting, and the air is humid, though it smells neither fresh nor stale. Large electric pumps hum in the corner. It’s an intimate place where water, and life, are in nonstop motion; there’s a constant purring.
Today, Abigail Jensen, University of Massachusetts Amherst associate professor of biology, shows me one tank in particular. In this tank, all of the zebrafish—each 3 to 4 centimeters long—have lost their zebra; their typical five uniform, pigmented, horizontal stripes are gone. Called “crystals,” these creatures are a translucent pink. I can see the outlines of their backbones and the shadows of their tiny internal organs.
“I call them crazy crystals,” says Jensen. “We’ve bred the pigments out of them—the silver, the black, and the gold. So now excessive amounts of light will penetrate the entire eyeball, even from the back.”
She reminds me that light is actually a toxic insult upon life at the cellular level, especially on cells called photoreceptors that process light in the eye. “Their eyeballs are completely clear,” she explains. She hopes the light will degenerate, or damage, the cells. “It seems weird that we are trying to get the cells to die,” says Jensen. “But we need a model to get the cells to die so that we can understand why they die and then how to keep them alive.” Learning why the cells degenerate will improve our understanding of an eye disease that affects about one out of every 8–10 thousand young Americans: Stargardt disease.
Named for Karl Stargardt—the German ophthalmologist who first described the inherited eye disorder in 1909—Stargardt disease is a disorder of the retina that causes vision loss (though generally not complete blindness) during childhood or adolescence, though in some cases it doesn’t occur until adulthood. Vision loss progresses slowly over time in most people with the disease, from normal vision to legally blind. Currently, there is no treatment to delay or cure the disease.
Thanks to a grant from the Manning Innovation Program—a recent $40,000 gift to UMass for the support of translational research projects and the transfer of breakthroughs to the marketplace—Jensen hopes she is all the closer to finding a key that will unlock some of the secrets of Stargardt disease.
Pioneering Research Program
Alumnus Paul Manning ’77 and his wife, Diane Manning, committed $1 million through their family foundation to establish the Manning Innovation Program in order to stimulate, recognize, and reward innovation. The program will foster a culture of entrepreneurship in the College of Natural Sciences and enhance the spirit of collaboration among Isenberg School of Management advisors, science and technology researchers, and industry experts.
“UMass Amherst researchers are working on some of the most important issues of our day,” says Paul Manning, who earned a bachelor of science degree in microbiology. “I couldn’t think of a better place to invest in a cutting-edge model—bringing science and business together—that can bring solutions to more people, faster.”
A Family Connection
Jensen’s research into Stargardt disease hits close to home for the Mannings. Both of the Manning sons—Bradford and Bryan—have Stargardt disease. The two brothers (both in their early 30s) now run an online clothing label called Two Blind Brothers, which donates all proceeds to the Foundation Fighting Blindness. The New York City-based store offers super soft, Braille-enhanced T-shirts and Henleys.
Their parents’ gift will provide much-needed support to Jensen and other scientists, “to enable the development of ground-breaking research from UMass toward product candidates, prototypes, and translational technology,” says Peter H. Reinhart, founding director of the UMass Institute for Applied Life Sciences, under which Jensen’s work falls. And one of those “product candidates” is the behavior of a particular gene that Jensen studies called ABCA4, the mutation of which affects the retina and is believed to be the most common cause of Stargardt disease.
The retina contains two types of light-sensing photoreceptor cells—rods and cones. Together, these cells detect light and convert it into electrical signals, which are then “seen” by the brain. Both rods and cones die away in Stargardt disease, but the cones are more strongly affected in most cases, for reasons not clearly understood.
A Scientific Black Box
“It’s a complete black box in the field,” says Jensen. “We don’t understand what program is launched or what internal program is suppressed when cells are dying.” One part of the puzzle is called the retinal pigmented epithelial cell, which plays a vital role in supporting the cones. “We know that these are compromised, and the cones and rods die right away, and that they are vital for the health of the photoreceptor cells.”
The ABCA4 gene makes a protein that normally clears away waste by-products inside the cones. In turn, cells that lack the protein accumulate waste and central vision becomes impaired, eventually leading to cellular death.
“If we identify the beginning of the process, molecularly, we can identify targets for intervention to slow down or prevent this process,” says Jensen. “One can envision ultimately ways that we could prop up that pathway using drugs or small molecules. That is, to keep them functioning in the presence of the mutation. But you can’t do anything until you identify the pathway, which is what we are trying to do.” (Think of studying the photoreceptor cells under a microscope after forcing light upon the eyes of translucent zebrafish.)
Other Disease Treatments
Discovering these pathways could lead to treatments not just for Stargardt disease, but for other retinal diseases such as retinitis pigmentosa, a severe form of retinal degeneration. “What we’ve done so far is a pretty herculean task,” says Jensen, whose senior research associate John Willoughby runs the genome editing technology called CRISPR. “We are doing all we can to combine and stress the retina as much as possible to elicit degeneration. This means combining all the mutations we can in one fish, to make this happen as fast as we can.”
While normal research focuses on a single simple recessive mutation across at most two generations, Jensen and Willoughby have combined eight different mutations in dozens of generations of fish and the number is growing. “It’s never been done before. The number of mutations we’ve made, and combinations of mutations, is insane.”
Jensen is just the first of many to be given the opportunity with Manning funds to prove her ideas in a lab and get help bringing her findings to the greater world. The next wave of scientists and business students chosen to partake in the program have begun work on a new suite of projects this fall semester.
Marrying Science and Business
Anne P. Massey, dean of the Isenberg School of Management at UMass Amherst, says the program “creates a pioneering way to harness great ideas and turn them into applicable solutions. By joining great minds in science and business, we will be able to tackle larger challenges. I’m excited to see what patents, products, and solutions will be born out of this promising program.”
College of Natural Sciences Dean Tricia Serio says, “By cultivating and mentoring high-achieving scientists and pairing them with business-minded collaborators, this program has the potential to change industries—and lives.”
Back in the Morrill lab, the researchers are putting the Manning funds to good use. Jensen says she and Willoughby have made a range of “genetic tools” to study the rods and cones. “We are set up to manipulate gene expression in photoreceptors,” says Jensen. “If we identify a pathway, we can genetically manipulate that pathway in zebrafish with our tools to test whether or not they are good targets.”
Until the Manning program, Jensen and Willoughby, who are married, have dedicated countless hours with no funding. “This support opens things up,” says Jensen. “It’s the kind of risky research that if it can’t happen at a university like UMass, it won’t happen.” Her next step is to apply for a grant from the National Eye Institute, the country’s foremost biomedical research institution. “As with much scientific research, it’s hours and hours of testing and failures” says Jensen. “It’s high risk, high payoff. If we’re successful, it’s a game changer.”