When David Eisenberg’s father brought home an incubator of worms for his son to grow on chocolate bars, the busy pediatrician nurtured his son’s lifelong love of science. The pair attempted to petrify eggs and sterilize the worms with ultraviolet light. While none of these experiments proved earth-shattering at the time, they did spark Eisenberg’s insatiable curiosity.
“It was mostly play science,” says Eisenberg, whose work focuses on understanding the structural basis for the protein misbehavior characteristic of many neurodegenerative disorders. “But it really got me interested in science. Of course, my father was hoping that I would follow him into medicine.”
As an undergraduate at Harvard University, Eisenberg started on a somewhat different path. He came under the tutelage of protein scientist John Edsall, who encouraged him to explore computational and physical sciences in addition to the biochemical sciences. “Every time I had the chance to take a class in something like literature, John would say 'Look at this course in mathematics or quantum physics,'” Eisenberg laughs. “He had an M.D., but he urged me to go into fundamental science because he thought it was the key to making progress in medicine.”
Nonetheless, Eisenberg entered Harvard Medical School with the thought of becoming a physician. Unwilling to give up basic science he took a leave of absence to get a Ph.D. at Oxford University in England and never looked back. “At first my dad was disappointed, but when he saw that my intention was to work in medical science if not medicine, he was somewhat assuaged.”
Eisenberg began his research career studying the intricacies of protein structure and how proteins bind to one another. However, as the story about the role of aberrant proteins in neurodegenerative diseases began to unfold in the literature, Eisenberg's interest was roused. “If I was ever going to have anything to contribute to medicine this was going to be the area,” he recalls thinking. “These diseases encompass fundamental scientific questions with important medical implications.”
Abnormally folded proteins are found in at least 20 devastating diseases, including Alzheimer’s, Parkinson’s, and Creutzfeldt-Jakob diseases. In each disorder, a different protein transforms into a misfolded version and aggregates into threads known as amyloid fibrils. In some diseases such as Creutzfeldt-Jakob, the misbehaving protein, known as a prion, not only misfolds but is also infectious.
Setting their sights on understanding how misfolded proteins aggregate into amyloid fibrils, Eisenberg and his lab attempted to identify which portions of the protein are responsible for creating the fibril. By analyzing a yeast prion protein called Sup35, his group discovered that a seven–amino acid peptide segment of the Sup35 prion could form fibrils. That was the easy part.
“The difficulty came when we attempted to crystallize it and determine its atomic structure,” Eisenberg says. “The protein tends to form fibrils and that negates forming crystals.”
His student at the time, Melinda Balbirnie, eventually coaxed the peptides into crystals, only to discover that they are so tiny—somewhere between 30,000 and 50,000 times smaller than the crystals scientists normally work with—that common methods of crystallographic analysis failed to provide a clear image. It wasn’t until the group collaborated with Christian Riekel, a crystallographer at the European Synchrotron Radiation Facility in Grenoble, France, that the group was able to get a close look at the crystals.
“Christian had developed an x-ray camera that could image these miniscule crystals,” says Eisenberg. “It took several trips to France to finally get the crystal structure solved. But, seeing the structure itself was such a surprise.”
The small peptides had formed a structure that looked like a tightly bound zipper. Instead of gently associating with each other, the molecules interdigitated like the teeth of a zipper. The tightly bound structure of this peptide crystal helps to explain why amyloid fibrils are so difficult to break apart.
Although fibril formation is often associated with disease, recent evidence indicates that smaller collections of misfolded protein known as oligomers may be the truly toxic form. Eisenberg believes understanding the structure of these oligomers is critical to making significant progress in developing new therapies for these neurodegenerative diseases.
“To treat these diseases, or even just delay the onset of symptoms, we may need to interfere with the oligomer,” says Eisenberg, whose lab is trying to characterize the protein oligomers.
“Amyloid diseases and prion diseases are a natural fit for me because they are protein-folding problems and the diseases are so devastating,” Eisenberg says when considering his career. “They may be some of the most important diseases to society when you take into account the projected numbers of people who will develop Alzheimer’s and those who will need to care for them.”