Molecular Biology, Neuroscience
The Johns Hopkins University
Dr. Nathans is also a professor of molecular biology and genetics, of neuroscience, and of ophthalmology at the Johns Hopkins University School of Medicine.
Signaling Pathways that Control Development and Disease in the Mammalian Embryo and Retina
Faced with the complexities of calculus, most high school students are content to let their teachers guide them through the course that underpins so much of science. With the encouragement of his calculus teacher, Jeremy Nathans studied at his own pace and discovered his passion for math and, ultimately, science.
“I really loved math, but I could also see early on that I wanted a connection to the real world,” Nathans says. This choice to have a connection to the real world led Nathans to pursue questions surrounding the mammalian visual system.
One of Nathans’s earliest scientific influences—aside from his father, 1978 Nobel Prize winner and HHMI investigator Daniel Nathans—was Alexander Rich at the Massachusetts Institute of Technology. “Alex was an M.D. by training, but he never practiced medicine,” Nathans says. “His broad scientific perspective made me realize that biology, chemistry, and physics combine in ways that allow you to ask very interesting questions.”
It wasn’t until he entered graduate school at Stanford University that Nathans became passionate about vision after a career-altering seminar on the mammalian visual system. “I was so struck by the beauty of the visual system that I asked my thesis advisor, David Hogness, if I could work instead on the genetics of human color vision,” he recalls.
Hogness, a molecular biologist working on fruit flies, was developing the new molecular techniques needed to probe complex genomes, including the human genome, and he appreciated that this represented an interesting scientific question.
Although humans are in many ways an unsatisfactory experimental organism, color vision is a trait that is highly developed in primates. “At the time there was a detailed understanding of human color vision at the psychological level, but little was known about its molecular basis,” says Nathans. “The time was ripe for exploring it.”
Nathans’s efforts to clone the genes for the three color-sensing receptors pushed the technological envelope. The retina contains two kinds of light-sensing cells: rods for dim light vision and cones for color vision. The cones come in three varieties, each containing one type of receptor, which respond most efficiently to red, green, or blue light. Nathans based his search for the color receptor genes on the idea that the light-absorbing receptor found in rods—rhodopsin—was similar to the color vision receptors. To test his theory, he first needed a DNA probe that would bind to the rhodopsin gene.
For two years Nathans was stuck at the first step in the process. “That’s a tough place to be. If you haven’t found what you are looking for, you don’t know if it’s a foot away or a mile away,” he says. Eventually, he succeeded in isolating the rhodopsin gene and, with additional work, the three genes coding for the color vision receptors. With the cloned genes in hand, Nathans was then able to demonstrate that variations in the color receptor genes are responsible for the common anomalies of human color vision, referred to as color blindness.
“What is really striking about the human visual system is how beautifully it works,” says Nathans. “For example, we can distinguish well over one hundred thousand distinct colors based on the relative activities of just three receptors—it’s quite amazing.”
Nathans’s interest in the mammalian visual system extends to clinically significant problems, such as retinitis pigmentosa (a degeneration of the periphery of the retina) and macular degeneration (a degeneration of the center of the retina).
“The retina is like a Ferrari—it’s a high-performance, high-maintenance organ,” Nathans says. “Many genes are required to build a retina and keep it running, and they all have to work correctly.”
Vision researchers have been trying to identify the genes responsible for inherited retinal diseases, with the goal of understanding the molecular mechanisms responsible for them. This knowledge could lead to methods to prevent and/or treat these diseases. The effort, however, is daunting, as the number of known genes and pathways continues to expand. To complement these experiments, Nathans and his coworkers have recently taken a different approach—looking for pathways that are responsible for keeping the retina healthy.
“We think it is likely that every tissue in the body has a built-in repair pathway. If you break a bone it will heal. The same is true for a cut in the skin—there is a built-in pathway that heals the wound. We thought that a general damage response would likely exist in the retina as well,” Nathans notes.
Nathans and his coworkers have shown that when the retina is damaged by light, trauma, or inherited disease, the repair pathways that spring into action are similar, and he sees this similarity as an opportunity.
“If that response could be manipulated,” Nathans says “we could potentially help people who have any of a wide variety of degenerative retinal diseases. Even if we could delay disease progression in diseases like retinitis pigmentosa or macular degeneration by a just few years,that would have an enormous impact.”
Nathans’s interest in the tissue repair response hasn’t supplanted his curiosity about how the retina develops. His lab also focuses on the Frizzled cell-surface receptors, one of which is responsible for the development of blood vessels in the retina. Defects in Frizzled signaling lead to several human retinal vascular diseases, and Nathans has been studying these diseases by genetically engineering the corresponding defects in laboratory mice.
“I am confident that a deeper understanding of the molecular mechanisms of retinal development and repair will lead to improved therapies for patients with retinal diseases,” says Nathans.