Now 80, a Ph.D. and professor emerita in the Miller School of Medicine’s Department of Psychiatry and Behavioral Sciences, Egeland appears to have achieved her goal. She and collaborators at three other institutions have identified what may be the molecular pathway underlying bipolar I (manic depressive) disorder (BPI), a breakthrough that could lead to better drugs for treating BPI, as well as depression and other related mood disorders. Their findings have been published online in Nature Molecular Psychiatry.
The research involves the relationship between BPI and a rare genetic dwarfism, Ellis van-Creveld (EvC) syndrome, through a signaling pathway known as sonic hedgehog. EvC results from mutations that disrupt this pathway, and showed that the pathway plays a role in the development of BPI.
The foundation for the recent discovery was built during decades of longitudinal field research conducted by Egeland and her staff, who ascertained and diagnosed both EvC and BPI among Old Order Amish families in Pennsylvania. These two medical conditions were inherited (co-segregated) together, and both were prevalent in a few large families. However, no Amish person with EvC was ever reported with BPI disorder. The current team of researchers believes the reason is that the pathway disruption by EvC confers protections against BPI. This raises the hope for new drug treatments that may similarly affect the sonic hedgehog pathway.
“No one doubts that BPI has an important, disease-causing genetic component,” said Edward I. Ginns, M.D., Ph.D., professor of psychiatry at the University of Massachusetts Medical School, a neurologist and geneticist, and lead author of the current study. “In our search for the causes of BPI, this is a paradigm-changing discovery that could lead to better treatments. There are drugs already in clinical trials for other medical conditions that target sonic hedgehog protein signaling, and they may also hold promise for treating BPI.”
The current findings were supported as far back as 1998 in an article in the Proceedings of the National Academy of Sciences, in which Ginns, who was lead author, and a group of co-authors, including Egeland, provided the first evidence for protective genes for bipolar disorder on chromosome 4, where the gene for EvC was mapped and another gene located that relates to the sonic hedgehog molecular pathway.
BPI, the most serious form of bipolar affective disorder, is a common psychiatric illness characterized by recurrent swings from periods of high energy and mania to those of low energy and sadness. During manic episodes, patients have a reduced need for sleep, are more talkative and restless and with a mood ranging from happy to irritable. Poorly made decisions and resulting rash behaviors are common, with little regard for the consequences.
Cycles of depression may include crying, slowed thinking and concentration, and poor eye contact, with limited social contacts and pessimism. Patients suffering from BPI (mania or depression) have a higher risk for suicide (especially among males) and self-harm, an issue of increasing public concern. Although there is no cure, it can be managed so that patients can have better control of their bipolar symptoms. Treatment can include therapy and antipsychotic or mood-stabilizing medications.
The prevalence of BPI among the Old Order Amish is no different from non-Amish populations, and the bipolar symptoms and response to treatment are the same as for non-Amish patients. The Amish are, however, an ideal population for genetic studies such as Egeland’s, because a limited gene pool means a common shared heredity.
Egeland was introduced to the Amish community in 1960, and her earliest published research about EvC dwarfism was in 1964 (Bulletin of The Johns Hopkins Hospital). After cases were ascertained and certified, she traced each one back to detect a common progenitor (pioneer family line) introducing this condition. The resulting family tree (pedigree) and a large EvC sample laid the initial foundation for the latest findings. “I never would have predicted that my research would extend over half a century,” she said.
In 1976, Egeland launched National Institute of Mental Health-funded research called the Amish Study at the University of Miami to explore major affective disorders among the same Amish settlements. She developed methods for systematic ascertainment of cases, diagnostic evaluations and establishment of DNA and cell lines. When a progenitor trace was done for each certified case of BPI disorder, it unexpectedly revealed the same pioneer as discovered earlier for EvC dwarfism.
“It is gratifying to know that a number of the early Amish Study research findings provided the building blocks for our current findings,” said Egeland, “and it is exciting to retrieve retired file materials, dust them off and celebrate their renewed relevance.”
Despite the new findings, much work lies ahead for the researchers, as they don’t know exactly what changes occur along the sonic hedgehog pathway — which involves more than a dozen other molecules and interacts with more than 100 other genes — that lead to BPI. Still, said Ginns, “Even though the symptoms of BPI can be quite varied and complicated, the underlying genetics might actually have a more simple cause than we could have imagined.”
Although Egeland “officially” retired in 2006, she has continued to work full-time on the Amish Study, and she looks forward to further explorations by Ginns and co-investigator Marzena Galdzicka, Ph.D., at the University of Massachusetts Medical School. She offered some thoughts gleaned from her long experience with the Amish, who opened their world to her because she treated them as partners in the research, and not simply as subjects and patients.
“The Amish population provides a natural human laboratory unique in the United States, and I have been privileged to work with them,” she said. “A key requirement for longitudinal research is having the ability to make difficult mid-course corrections, even when others advise that it is premature to do so. I was told, for example, that it was premature to abandon conventional blood markers in order to embrace the new DNA technology. I have rejected words like ‘premature’ and ‘impossible’ at every step in my career. That’s why the Amish Study was the first in the world to go to the molecular level for a common psychiatric condition (Nature, 1987).
“Science isn’t just a Petri dish; it’s about asking hard questions, and it’s all I ever wanted to do. If you believe in the importance of the questions you are asking, then you have to stay the course.”
Miller School of Medicine