Jeremy H. Nathans, M.D., Ph. D.
Jeremy Nathans admits to being a late bloomer. The son of a Nobel Prize-winning scientist (for his work in molecular genetics), Dr. Nathans did not see science as his future until his senior year of high school. Until then, he says, "I was more interested in basketball."
That year, as a student at Baltimore's Polytechnic High School, Dr. Nathans discovered that math and science were no longer mere "fun." "They suddenly got very, very interesting," he says. "I started doing some reading in math and chemistry on my own, and I realized I didn't have to rely on what was being taught in the classroom." That discovery launched a distinguished and innovative career.
Finding a Niche
His first love was physics, but as an undergraduate at the Massachusetts Institute of Technology, he became increasingly fascinated by the life sciences and began what he describes as a "slow detour" toward biology. He graduated in 1979, with a degree in chemistry and biology.
It was as a graduate student at Stanford that Dr. Nathans first became attracted to the study of the eye and the mechanism of vision. "I heard a couple of lectures on vision as part of the medical curriculum," Dr. Nathans remembers. He was so fascinated that he "ranliterally ranstraight to the library" to learn more.
He soon discovered a particular fascination for the problems of color vision, the mechanisms of which remained obscure. It was a chance to tread new ground: the most important molecular players in this sensory function remained undiscovered.
Pinpointing Light-Absorbing Proteins
The retina contains two kinds of sensory cells: rods for black-and-white perception and cones for color. The cones come in three varieties, which respond to either red, green, or blue light. "It occurred to me," Dr. Nathans recalls, "that the recombinant DNA techniques then being developed could answer many questions about color vision, in particular the identity of the proteins that absorb different wavelengths of light. I couldn't resist it."
Dr. Nathans' research strategy was based on the thesis that the light-absorbing protein found in rodsrhodopsinwould be similar to color vision pigments. To test his theory, he designed a DNA probebased on the partial nucleic acid sequence already known for rhodopsinthat would bind to the rhodopsin gene.
"After a certain amount of sweat, we were able to identify the genes that encode each of the three pigments that absorb different colors. We got lucky," Dr. Nathans says.
Analyzing Mutant Pigment
Dr. Nathans demonstrated that most people with aberrant color visioncommonly referred to as "color blindness"have variant forms of one or another of the cone cell pigments.
In the years that have followed, Dr. Nathans has continued to focus his work on the retina, using an approach that combines neurobiology, physics, genetics, and clinical medicine. In his laboratory, he used the color pigment gene sequences to determine the sequence homology of both normal and aberrant forms of their corresponding proteins so that he could determine their biophysical propertiessuch as how their structure affects their interaction with light. He also found that many people have variations in their color pigment sequences that have small effects on their ability to distinguish colors.
Identifying the Causes of More Severe Visual Disorders
The logical extension of Dr. Nathans' interest in the mechanism of color vision was his developing interest in the genetic disorders that often cause color blindness. Although approximately 10 percent of men experience some kind of red-green color vision anomaly, complete color blindness is far less common. A mere 1 in 100,000 have the comprehensive color blindness that occurs when serious mutations occur in two out of three color vision pigments.
"Color perception works by the brain comparing the strengths of the red, green, and blue outputs," explains Dr. Nathans. "So if you lack two out of the three, you are left with shades of gray." This discovery may eventually help color-blind men who in their thirties often experience a progressive loss of sensitivity in the center of the retina, where most of the cone cells are found. Thanks to Dr. Nathans and his colleagues, our understanding of how the mutations lead to this degeneration has increased, although so far no one has identified a way to halt it.
Dr. Nathans has also identified a connection between retinitis pigmentosaa degeneration of the peripheral retinaand mutations in the rhodopsin gene. "Most of the mutant pigments are unstablethey unfold spontaneously," explains Dr. Nathans. "The unfolded protein is a mess for the cell to deal with, so over time that increases the chance that cells will die. Rods and cones don't regenerate, so if you lose them, that's it."
The Retina as Mini-Brain
Today, Dr. Nathans' retina research is driven by an even more ambitious curiosity. "I'm really interested in how the human brain is built and how it works. That is a mighty tall order, but it is also the biggest challenge for modern biology. The only way to approach such a huge problem is to pick it apart into small enough pieces that you can design an experiment and get yourself an answer."
Learning more about the retina may help him find the answers to his questions. "The retina is not just a sensor, like a camera; it is a mini-brain that processes an image in a number of ways. By studying how the retina develops during embryogenesis, you can study how the brain is builthow embryonic cells make the right connections and are programmed to become the mature cells they ultimately become."
Best of all, says Dr. Nathans, "you can get a sense of how the genetic blueprint for making cells evolved. And you can study genetic differences in individuals and between species, and how these differences affect function."
Dr. Nathans continues to help us see how intricateand how miraculousour eyes can be.
© 2013 Howard Hughes Medical Institute. A philanthropy serving society through biomedical research and science education.