KEVIN EGGAN: STEPS TOWARDS STEMMING DISEASE
September 14th, 2005
Used only for research and medical applications, therapeutic cloning is fundamentally different from reproductive cloning. Both begin with the same approach: scientists insert an adult cell nucleus into an egg whose own nucleus as been removed. For mysterious reasons, the adult nucleus reverts to an embryonic state, prompting the egg to divide as if it were naturally fertilized. But there the similarity stops—in reproductive cloning, the egg is placed into the uterus of a living female to make a baby whose genetic makeup matches that of the adult cell donor. Eggan and the vast majority of scientists reject reproductive cloning of humans as unacceptable. With therapeutic cloning, the embryo never leaves the petri dish—instead, scientists use it as a source of stem cells, which they harvest for a variety of uses.
Eggan says his research goals at Harvard are twofold: One is to understand how nuclear transplantation actually works. And the other is to make stem cells that carry genes for specific diseases. He hopes to use these cells to study neurodegenerative illnesses like Parkinson’s disease, Lou Gehrig’s disease, and Alzheimer’s. Additional efforts to make pancreatic beta cells with genes for type 1 diabetes are being pursued collaboratively with MCB Professor Doug Melton.
Disease lines of embryonic stem cells are made with adult cell nuclei taken from patient donors who have a given illness. Like normal stem cells, these diseased varieties can form any type of adult cell in the body. Ideally, scientists will use them to create the tissue cells affected by the donor’s illness, for instance, the dopaminergic neurons affected by Parkinson’s disease. By watching how the diseased tissue cells deviate from normal development, it may be possible to derive insights into the genetic roots of the disease and its symptoms.
Opponents of therapeutic cloning claim the technique is unethical because it creates life merely to destroy it for science. But Eggan counters that in his view, preimplantation embryos derived for research don’t have the same moral status that we do. "[Opponents’] views are based on religious convictions and faith and we must respect their opinions even if we disagree with them," he says. "However, I would argue that we also have a moral obligation to help those with debilitating diseases."
A Normal Upbringing
Eggan’s path to Harvard began in Normal, Illinois, the town where he was born 31 years ago. After completing a bachelor’s degree in microbiology from the University of Illinois, he applied to medical school, was accepted, but deferred in favor of a two-year research stint at the National Institutes of Health, where he studied RNase H in S. cervisiae.
The NIH experience cemented a growing desire to pursue research full time. Eggan eventually decided against a career in medicine, choosing instead to pursue a PhD at the Massachusetts Institute of Technology, which—much to his surprise, he says—accepted him for fall entry in 1998.
At MIT, Eggan studied with Rudolph Jaenisch, a pioneer in cloning biology. It was a heady time in the field, he says. The first animal ever cloned—a sheep known worldwide as Dolly—had been created two years before at the Rosslin Institute in Scotland. The first cloned mouse, named Cumulina, was created the summer before Eggan entered graduate school. Eggan says he was fascinated by cloning. "I thought it was remarkable that you could take a committed adult cell, put it into an egg, and release the constraints that normally keep it from forming other types of cells," he says. "That’s a fundamentally interesting process with implications for how cell state and identity are regulated at the molecular level."
Working with Jaenisch, Eggan began to explore this process and also the more ominous finding that cloned animals often develop abnormally, with organ defects and immunological problems. His efforts led to key discoveries about the genetic and epigenetic factors that modulate fetal growth during embryogenesis. Using transcriptional profiling, Eggan also found evidence of major differences in gene expression in cloned and normal mice. These findings contributed to the science of cloning, he says, and also to the debate over whether it’s a good idea to clone people. "And we were, of course, able to say that absolutely this is not a good idea," he concludes.
After finishing his PhD in 2002, Eggan split his time between a postdoc with Jaenisch and a collaborative project with Richard Axel, a Nobel Prize–winning scientist at the Howard Hughes Medical Institute. Axel and Eggan simultaneously investigated two persistent issues in biology: The first was whether animals could be cloned from the genes of the most terminally differentiated cells, for instance neurons, which don’t divide further after being formed. The other was a long-standing question in the science of smell: namely, why olfactory neurons in the nose express just one out of roughly 1,000 possible odor receptors. To study these questions, Eggan used olfactory neurons with a given receptor to clone mice. In so doing, he showed that such a feat was possible, and he also produced an animal model that could help determine if odor receptor choice is governed by some irreversible change in DNA. Studies with these mice ultimately showed that olfactory neurons have no irreversible DNA perturbation, and that odor receptor choice among these cells is influenced by some other, unknown mechanism.
Arrival at Harvard
In August 2004, Eggan came to Harvard to begin a junior fellowship. His current research, he says, extends the work he began here last year. In a major effort, Eggan is trying to understand how adult cells revert to embryonic states after nuclear transfer.
Two methods are being applied: In the first, he compares transcriptional profiles of cloned embryos. "This allows us to ask questions like, when do adult genes get turned off and when do embryonic genes get turned on?" he explains. "We’re also asking if there are obvious changes in the process that might be interesting with respect to abnormalities in cloned animals and cloning efficiencies." In a second approach, Eggan and his colleagues are fusing human embryonic stem cells to adult cells. The goal of these experiments is to determine if embryonic features can be transferred to adult cells via this process. Preliminary studies with human skin cells indicate they can. Eggan and Chad Cowen—a postdoc in Melton’s laboratory—have shown that all somatic genes in the adult skin cell are turned off in the fusion hybrid.
The other major focus of his work—making disease lines of embryonic stem cells—is also ongoing. Eggan says these cells could help overcome fundamental barriers in disease research. By the time disease strikes an individual, the affected cell type is often obliterated, Eggan explains. "And [unlike stem cells], patients aren’t a renewable, replicable resource," he adds. Disease-specific stem cells, on the other hand, offer numerous opportunities to study genetic pathways and drug intervention strategies. "These cells give us unlimited amounts of material that we currently don’t have. We could study disease mechanisms and drug screens. We’ll be doing a lot of this collaboratively, and that’s another reason that I’m excited to be here."
Looking forward, Eggan says he feels good about the future and anticipates ample synergy between his laboratory and others at MCB. Existing collaborations with Melton will continue, as new ones, for instance studies of Lou Gehrig’s disease with Tom Maniatis, emerge. "I’ve got the good fortune to start my career at one of the premier biology departments in the world," Eggan says. "I also appreciate that Harvard has really stepped forward to back this research despite the controversy. We have an atmosphere here that is thoughtfully and carefully supported, and this gives us opportunities that aren’t present in many other places."