How the human eye perceives light has been the lifework of Jeremy Nathans. While still an M.D./Ph.D. student at the Stanford University School of Medicine, Nathans was the first to isolate the human genes responsible for color vision and to discover how changes in these genes can cause colorblindness. From that extraordinary start, Nathans went on to Johns Hopkins as a Howard Hughes Medical Institute investigator where he and his team identified the genes and mechanisms responsible for inherited eye diseases affecting thousands of people. Nathans’s work has also focused on molecular pathways involved in development and function, and their staggeringly complex interactions. Throughout his career, Nathans’s ability to connect genes to mechanisms to physiology has revealed new insights into disease, development, and the fundamental biology of our powerful sense of sight.
They say beauty is in the eye of the beholder, but for Jeremy Nathans, beauty is in the eye. “Vision can provide information about objects that are centimeters away, when we thread a sewing needle, or that are trillions of kilometers away, when we look at the stars,” he explains. “Our visual system can capture movements occurring in less than a second, and it can operate effectively on moonless nights and sunny afternoons—environments that differ by one million fold in light intensity.” Having spent nearly 40 years working to understand vision, Nathans is still struck by the extraordinary physiology and exquisite mechanisms of the human eye.
After growing up in Baltimore, the son of a Johns Hopkins University biomedical scientist and a lawyer, Nathans earned his undergraduate degree at the Massachusetts Institute of Technology before enrolling in Stanford University’s M.D./Ph.D. program in 1979. At the time, he didn’t have a clear idea of what research topic to pursue, but after hearing professors Denis Baylor and Lubert Stryer describe their research on light detection, Nathans recalls, “I was captivated by the elegance of their experiments and the extraordinary performance of the eye.” For a required assignment to sketch out a theoretical research project, he proposed a novel approach to identifying the molecular basis of human color vision. For most students, this homework was just an exercise in scientific thinking and writing, but for Nathans, it became the launchpad for his life’s work. His proposal was so exceptional that it is still held up as a model for all incoming Stanford graduate students.
At Stanford, Nathans accomplished exactly what he proposed. He used a partial sequence of the black and white vision protein, called rhodopsin, to isolate the rhodopsin gene and then he used the rhodopsin gene as probe to identify the related genes for color vision. This two-step strategy, which was technically challenging with the methods available at that time, led Nathans to the genes that encode the red, green, and blue color detectors in the eye, known as opsins. By isolating these genes, he had also isolated, for the first time, genes for an important class of signaling proteins called G-protein coupled receptors. He went on to show that people who are red/green colorblind have variations in their red and green color-detecting genes. His work showed how those changes lead to alterations in the structure of the color-detecting molecules that change their properties. Nathans also showed that the genes responsible for red and green color detection are located on the X-chromosome. This discovery explained why red/green colorblindness is more common in men, who, unlike women, do not carry a second X-chromosome that contains a backup copy of the genes.
“It is very rare that a graduate student can open up an entire field of research. And even more unusual to do it on their own in the lab—that’s exactly what Jeremy did,” Lubert Stryer says of Nathans. Following his Ph.D. thesis, Nathans earned his M.D. and then completed a brief postdoctoral fellowship at the biotechnology company Genentech, before starting his own lab in 1988 as a Howard Hughes Medical Institute investigator and faculty member at Johns Hopkins Medical School. He has been at Hopkins ever since.
When he set up his new lab, Nathans broadened his research to include retinal diseases as well as retinal cell biology and biochemistry. He and his team found that the most common form of the inherited retinal degenerative disease, retinitis pigmentosa, is caused by gene mutations that prevent the rhodopsin protein from assembling normally, making it difficult for the protein to reach its correct location in cells. They also identified defects responsible for Stargardt disease and vitelliform macular dystrophy. Understanding these retinal diseases at the molecular level may one day provide an opportunity for targeted treatments.
Another strand of Nathans’s research focuses on elucidating the functions of a family of proteins called Frizzled receptors, first identified in fruit flies and named for the appearance of misoriented hairs on flies carrying mutated versions of the genes. Encoded by ten genes in mammals, including humans, Frizzled proteins are master regulators of embryonic development, helping to shape the nervous system, blood vessels, kidneys, and hair. In 1996, Nathans and his collaborators discovered that Frizzled receptors bind to Wnt proteins, key players in embryonic development. The team later showed that defects in the Wnt/Frizzled signaling pathway result in problems with blood vessel development in the eye, revealing a shared mechanism behind two hereditary eye disorders.
Much of Nathans’s research has only been possible because of novel tools and techniques that he pioneered in his lab. One recent innovation allowed lab members to visualize and manipulate single cells in the brains of mice. They used this technique to trace, for the first time, the complex branching patterns of the brain’s largest neurons. Visualizing the complexity of these and other neurons is relevant to understanding their unusually high susceptibility to neurodegeneration, as seen in Alzheimer’s disease.
Nathans is also renowned as a teacher and a science communicator. His Johns Hopkins graduate school course, “Great Experiments in Biology,” is one of the most popular on campus. Nathans has produced public outreach videos and web-based lectures aimed at high school and college students, and has been recognized with all three of Johns Hopkins’s major teaching awards.
Among his many scientific honors are the 2019 Helen Keller Prize for Vision Research (shared with King-Wai Yau), the 2016 Beckman-Argyros Award, the 2013 Lifetime Achievement Award in Biomedical Science from Stanford Medical School, the 2009 Edward Scolnick Prize in Neuroscience from the McGovern Institute at MIT, and the 2008 Champalimaud Award for Vision Research (shared with King-Wai Yau). Nathans has also been elected to the National Academy of Sciences, the National Academy of Medicine, and the American Academy of Arts and Sciences.
The study of human vision traces its origins to the pioneering work of scientific giants such as Isaac Newton, Thomas Young, James Clerk Maxwell, and Hermann von Helmholtz. By standing on the shoulders of those giants and applying the new technologies of molecular genetics, Jeremy Nathans has been able to answer age-old questions about how the human eye develops and functions.
Information as of March 2020