Virginia Lee & John Trojanowski on the Protein Road Map to Alzheimer's
Special Topic of Alzheimer's Disease Interview, December 2011
When asked to sum up their major contributions to the field, Trojanowski says, "We solved the structure of three lesions—tau in tangles, alpha-synuclein in Lewy bodies, and TDP-43 in the inclusions of amyotrophic lateral sclerosis (Lou Gehrig's disease) and frontotemporal degeneration. So we like to think one of our major contributions to the field of neurodegenerative diseases is putting a molecular face on these pathology structures that have been known for many, many years, but without information on their building blocks.
"Having a molecular specificity is so critical to every next step of solving these diseases because once you have a name, i.e. the protein identity of the building blocks of neurodegenerative disease pathologies, you know what it will be doing, and then it is possible to create a roadmap for targeted drug discovery for these disorders.
"This is like finding the agent that causes AIDS. Before the AIDS virus was found, people had all sorts of wild theories about why gay men and drug abusers were getting this disease, but the discovery that AIDS is caused by a viral infection changed the whole landscape because it became clear what the drug target was. Not that you'll immediately find your drug target, but this is the beginning of this process!"
"…we like to think one of our major contributions to the field of neurodegenerative diseases is putting a molecular face on these pathology structures that have been known for many, many years, but without information on their building blocks."
–John Trojanowski
Lee continues, "When we study a protein that underlies a neurodegenerative disease, we study the normal function and the abnormal, deleterious properties that the pathological form of the protein acquires in the disease state. And John and I recognized, back in the beginning of our work together, that to understand these diseases you really have to start with the human brain. In those days when we started out, in the 1980s, the science people were doing at the time was not very rigorous for a number of reasons including a very small 'tool kit' for discovery research. There was a lot of room for Ph.D.'s like me and John to contribute.
"I think that now it's dramatically different in that there are so many people getting into research on human diseases, especially neurodegenerative diseases, but sometimes they forget to directly study human disease samples like the brains of Alzheimer patients. And so they have limited understanding of what exactly the disease is all about. So now I'm telling young faculty and postdocs, 'don't forget to study the human brain, especially from patients with the disease in which you are interested!'"
Trojanowski concurs. "With the proteins that have been identified, you can go to yeast or worms or flies and create many models for research, but people then don't bring their models back for comparison with authentic human disease and say, 'does this model really look like the real disease, i.e. in people?' Virginia tells young faculty when they ask for advice on pursuing their interest in neurodegenerative diseases to keep looking at the human brain and learning about it, and make sure you connect your laboratory science to the real world, to the human disease. So whether you're studying bodily fluids, DNA, brain imaging, or other things you know, there's all sorts of things going on that Ph.D.'s can get involved with and strengthen other aspects of their research. It's good advice."
The Importance of Biomarkers
One of the other successful areas of Alzheimer's research that CNDR is doing is Alzheimer's and Parkinson's biomarker research. The first Alzheimer's biomarker work Lee and Trojanowski did was in 1995 when the reported that the cerebrospinal fluid tau levels increased in living Alzheimer's patients. Thus, when Trojanowski was invited to join the Alzheimer's Disease Neuroimaging Initiative (ADNI) in 2003, he accepted. Lee acts as a consultant on the project, and Trojanowski co-leads the biomarker core of ADNI at Penn with his colleague Dr. Leslie M. Shaw.
"With Alzheimer's, you have a whole head full of plaque, tangle, Lewy body, and TDP-43 pathology that needs treatment options, and those options have to address both the plaques and the tangles in all Alzheimer patients, as well as Lewy body and TDP-43 pathology in a large subset of Alzheimer patients."
–Virginia Lee
"ADNI is one of the largest and most successful public-private partnerships aimed at solving a biomedical problem, in this case, biomarkers for Alzheimer's disease," Trojanowski explains. "No single entity, no single company, no single university can solve these problems alone. It's one of the most exciting and thrilling aspects of research I work on and it's very important—biomarkers can help with early diagnosis, or testing drugs for clinical trials, determining which patients should be on which drugs, etc."
The biomarker work done by the CNDR led directly to the founding of Avid Pharmaceuticals by one of Lee and Trojanowski's M.D./Ph.D. students, Dan Skovronsky. Trojanowski describes it as a wonderful success story for a young investigator. Skovronsky did his Ph.D. work with Virginia and was training in neuropathology under Trojanowski, when he did some of the original work on an Alzheimer imaging ligand under Lee's supervision.
This work, first published in Proceedings of the National Academy of Sciences of the United States of America in 2000 (Skovronsky DM, et al., "In vivo detection of amyloid plaques in a mouse model of Alzheimer's disease," 97[13]: 7609-14, 20 June 2000), was a proof-of-concept that an imaging compound, now called AV45, could bind to A-beta amyloid in the brains of transgenic mice that were engineered to form Alzheimer-like A-beta amyloid plaques.
"Dan founded the company as a trainee, raised $70 million as a 36-year-old entrepreneur—didn't do a postdoc, just left his training here, founded his company, and advanced the imaging ligand to the point where he was able to show that AV45 was very sensitive for detecting A-beta amyloid plaques in living people," Trojanowski explains, "Avid, the company he launched, was recently bought by Eli Lilly, Inc. for $800 million. So that's a good example of how government funding from the National Institutes of Health not only can lead to improvements in how we diagnose Alzheimer's disease and help patients, but also create new jobs."