Virginia Lee & John Trojanowski on the Protein Road Map to Alzheimer's

Special Topic of Alzheimer's Disease Interview, December 2011

Virginia Lee and John Trojanowski

In our Special Topics analysis of Alzheimer's Disease research over the past decade, the work of Dr. Virginia M.-Y. Lee ranks at #2 by total cites and #8 by total papers, based on 217 papers cited a total of 13,693 times, and the work of Dr. John Q. Trojanowski ranks at #3 by total cites and #6 by total papers, based on 239 papers cited a total of 13,237 times.

Lee and Trojanowski both rank among the top 1% of researchers in the fields of Neuroscience & Behavior, Clinical Medicine, and Biology & Biochemistry in. In Neuroscience & Behavior, they both rank in the top 20. They were also featured in ScienceWatch.com's Hottest Research of 2007-2008 analysis.

Lee and Trojanowski form a rather unusual research team: they are both professional and personal partners. Together, they run the Center for Neurodegenerative Disease Research (CNDR) at the University of Pennsylvania Perelman School of Medicine in Philadelphia. Lee serves at the CNDR's Director and Trojanowski as its Co-Director.

Lee is also the John H. Ware 3rd Professor in Alzheimer's Research, Professor of Pathology and Laboratory Medicine, and Co-Director of the Marian S. Ware Center for Alzheimer's Drug Discovery Program. Trojanowski, meanwhile, is also Professor of Pathology and Laboratory Medicine, and serves as the William Maul Measey-Truman G. Schnabel, Jr. M.D. Professor of Geriatric Medicine and Gerontology, as well as Director of the Institute on Aging, Alzheimer's Disease Core Center, and Penn Udall Center for Parkinson's Research.

Earlier this year, ScienceWatch.com Editor Jennifer Minnick met with the two researchers at their office to talk about their work.


Collaborating at Home and at Work

Married since 1979, Lee and Trojanowski got their first taste of professional collaboration in 1982. They enjoyed working together so much they each decided to change the course of their careers and collaborate full-time. As Trojanowski explains, "We thought it was a lot of fun to collaborate as life partners, as well as to collaborate as lab partners, and it worked very well. We both immediately realized that if we were to pursue other science in the future, we needed something we could do together that would be a career's worth of work—we didn't want to just work on something together for a year or two. We asked ourselves, what could we put our heart and souls into over the long haul that would make a difference, that would address an enormous public health problem?"

They chose Alzheimer's disease. Neither knew much about it—no one knew much about it in the 1980s. But with the Baby Boomer generation getting older, both could see the writing on the wall in terms of where Alzheimer's demographics were heading. Lee's skills as a biochemist and cell biologist and Trojanowski's as a neuropathologist and neuroanatomist complemented each other perfectly for the problem set of Alzheimer's, something that continues to be true to this day.

"We thought it was a lot of fun to collaborate as life partners, as well as to collaborate as lab partners, and it worked very well."
–John Trojanowski

Of course, they needed a team: those who could do basic studies and animal models, those who could bring in the patients, physicians, neurologists, geneticists, etc. The group of people eventually came together to form the CNDR.

What's interesting is that Lee and Trojanowski were actually advised against this course of action when they were first debating it. "The advice we were given when we said we wanted to work on Alzheimer's was it'll wreck your career," Trojanowski reveals, "It's such a swamp, nothing is known about it. They said, 'Virginia the research you're doing now is great; John, yours is great too, and if you change course and go into Alzheimer's your career will go down the tubes.' Almost every senior faculty member at Penn we asked, i.e. those who were in the senior positions that we are now in our careers, told us as very young faculty, 'whatever you do, don't work on Alzheimer's.'"

Lee and Trojanowski, however, ignored the advice, and over the years the impact of their research has proven that they were right to follow their instincts.

Proteins: The Road Map to Disease

The list of highly cited papers for Lee and Trojanowski in our analysis is a mix of reviews, consensus papers, and methods papers, along with what Lee calls "true discovery" papers. These are the papers that introduce something truly new to the field, something that everyone wants to cite and talk about.

For Lee, one of the biggest "true discovery" papers is their 1991 Science report on the purification of the tau protein from Alzheimer's disease paired helical filaments that form neurofibrillary tangles, one of the two hallmark lesions of Alzheimer's disease (Lee VMY, et al., "A68—a major subunit of paired helical filaments and derivatized forms of normal-tau," 251[4994]: 675-8, 8 February 1991), which currently has over 1,000 cites in Clarivate Analytics Web of Science®.

"Almost every senior faculty member at Penn we asked, i.e. those who were in the senior positions that we are now in our careers, told us as very young faculty, 'whatever you do, don't work on Alzheimer's.'"
–John Trojanowski

"When we got started, I was working on a group of brain proteins that form normal neurofilaments that are very abundant in neurons, and so at that time, it was thought that these might possibly be the disease proteins in Alzheimer tangles, but that turned out not to be the case, so, we asked then what forms these tangles?" recalls Lee. "We wanted to collaborate, and identify the proteins that form the abnormal filaments in Alzheimer's disease tangles, and we decided to go after this—to try to purify the tangles.

"When we started, Glenner and Wong had already identified the beta-amyloid peptide that forms Alzheimer's disease amyloid or senile plaques, and so people were just starting to wonder about the tangles: could the protein be tau? Using brains we had collected in our center, we were able to demonstrate that Alzheimer tangles indeed were formed by abnormal tau proteins."

Trojanowski continues, "There were many people who had pointed to tau as a candidate, but it was our partnership that led to our success by combining the neuropathology with Virginia's ingenious development of a way to isolate the paired helical filaments that form neurofibrillary tangles and then sequence these pathological structures to show that the building blocks of these filaments were tau.

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