Distinguished Investigator

A conversation with Mayo Clinic's Matt Farrer, Ph.D.

Unraveling the genetic mysteries of Parkinson's disease

JACKSONVILLE, Fla. — Matthew Farrer, Ph.D., a molecular geneticist who specializes in Parkinson's disease, was recently named the 2008 Distinguished Investigator at Mayo Clinic in Jacksonville. At age 40, Dr. Farrer, is one of the youngest investigators to have reached Distinguished Investigator status. The award, he says, is humbling, but more importantly, he hopes it will result in more interest in genetic research and Parkinson's disease.

"It's humbling, but to be honest for me it's not about award but instead, it's about recognition of the scientific approach that's important. Parkinson's disease was long held to be a sporadic disease driven by environmental causes, but through molecular genetic insights, we've been able to develop models and novel molecular therapies. The templates we've developed could be applied to any disease," he said.

Dr. Farrer has been with Mayo Clinic in Jacksonville since 1997 when he arrived from St. Mary's Hospital in London. There he trained and worked alongside some of the most notable geneticists in the United Kingdom: Bob Williamson, Steve Brown, Lizzy Fisher John Hardy, Anna Kessling and Pete Scambler.

He was born in a pub in England in 1968. His father was a builder and moved the family often between jobs in England and Australia. By the time Dr. Farrer was 16, he attended about eight different schools. "It was sink or swim, you know," he said. But there's a lot to be said for moving around — it builds character, Dr. Farrer said. His interest in neuroscience arose in his youth when he spent time with his mother who worked in a psychiatric hospital.

"I eventually ended up doing a degree in biochemistry and my Ph.D. dissertation on the genetics of Down syndrome. I was interested in cognition and in thinking about Down syndrome as a complex genetic trait. People with Down syndrome have three copies of chromosome 21 instead of two, which means they have about 386 extra genes. These extra copies contribute to the phenotypes such as congenital heart defects, leukemia and age–associated dementia in some patients. From a scientific point of view it provides a window into the molecular genetic etiology of a truly complex disease," he said.

Q. How did the study of Down syndrome lead to your work in human genetics?

A. I was interested in how different combinations of extra normal copies of genes contribute to the increase in the prevalence of conditions that make up Down syndrome. My training is in the genetic dissection of complex traits and that's how I ended up getting interested in Parkinson's disease.

Q. I understand that St. Mary's was an exciting hotbed for research in genetics?

A. Yes, I was very fortunate in getting a research assistant position and Ph.D. at St. Mary's Hospital. At that time, I had no idea of the reputation of the place and of the pioneering research going on there. There was a big effort to try and map genes for cystic fibrosis, Duchene's muscular dystrophy, Friedreich's ataxia, DiGeorge syndrome, Huntington's disease, Alzheimer's disease and prion (Kuru, Creutzfeld–Jacob and mad cow) disorders. Many of the people and players who ended up doing these discoveries came through Mary's at one time or another. Many of the leading lights of modern day human molecular genetics were at Mary's. It was a wonderfully exciting, intellectual environment to work in.

Q. How do you define Parkinson's disease?

A. People generally think of Parkinson's disease as a movement disorder, but even though having impaired motor function is the predominant symptom, it's more than that. Often other symptoms, such as Lewy pathology in the gut, cardiac denervation, sleep disorders, excessive salivation and constipation appear 20 years before they develop any motor signs. It's a syndrome and all of these signs are part of the syndrome. For the most part, these non–motor features are not amenable to present day drug therapies. So now I am using Parkinson's disease as a model to look at the symptoms of the disease in an effort to develop therapies that would benefit all of those features.

Q. Years ago, it was assumed that Parkinson's was an environmental disease unrelated to genetics. Did you have a hard time convincing people otherwise?

A. Oh, yes. I was told that I was wasting my time and that there was no genetics in Parkinson's. The skeptics were quickly proved wrong when soon after the first gene for Parkinson's was published. From a genetics point of view, any organism that has DNA is genetically predisposed to health and disease. Although Parkinson's for the most part is not considered a heritable trait, it doesn't mean to say that genetics aren't important and that genetics can't be used to identify risk factors for the disease and that molecular insights can't then be used as tool or rationale to develop new drugs. And so, that's what I started championing.

Q. Between 1994 and January 2009 you've published 221 articles on subjects ranging from congenital heart defects published early in your career, to Parkinson's disease today. Of these, which are your key findings?

A. There have been a few. In 2003, we mapped the gene defect for Lewy body dementia to chromosome four. This finding was published in Science. We found that these patients have four copies of alpha–synuclein gene locus (SNCA) whereas you and I have two. They have twice as much and they develop this devastating condition. Of course, it's a big clue in solving this illness. This was one of the eureka moments of the year.

To have a definitive post–mortem diagnosis of Parkinson's disease, you have to have Lewy body pathology. The antibodies to alpha–synuclein (a major Lewy body component) have become the hallmark reagent to define this pathology in Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. This shows you how even rare genetic findings can really change the field. Since then, we have identified many families with three and four copies of SNCA. The insightful discovery is that people with four copies of the gene get the disease in their 30s, whereas people with three copies get the disease in their 70s. There is a relationship between copy number, age of onset, as well as the rate of decline and co–morbidities, like dementia.

Q. So the Synuclein gene is an important part of solving this puzzle?

A. Yes, the synuclein gene also turns out to be a universal risk factor for all Parkinson's disease. We've done studies in more than 20 different populations around the globe and we've seen the same effect. We still haven't pinned down the precise molecular mechanism, but SNCA genetics highlights a difference between patients and control subjects.

Now we know that having too much synuclein is the problem, if we can lower the amount of synuclein, perhaps we can stop disease progression? Hopefully we may even 'cure' the disease in asymptomatic individuals who are destined to get it. The therapy we're now developing may be efficacious in any disease with Lewy bodies as a major feature, such as Lewy body dementia.

Q. You've also published work on the leucine–rich repeat kinase 2 gene. How is this gene significant?

A. In 2002, a new linkage was reported in a Japanese pedigree known as the Sagamihara kindred, to a region on chromosome 12. We confirmed the linkage in families from the U.S. and Europe and started a sequencing effort with Tom Gasser, my research collaborator in Germany, to identify the mutant gene. We found two mutations in two very large family pedigrees in which the gene is dominantly inherited. This means that half of every generation gets the disease. We didn't realize then how important a discovery this would become.

Q. You're also associated with the discovery of another gene mutation. How was it significant?

A. The Lrrk2 G2019S mutation is arguably the most important genetic discovery in Parkinson's disease to date. By genetic segregation analysis in many Norwegian families, we showed G2019S was pathogenic. Jan Aasly, my good collaborator in Trondheim, Norway made this possible. Surprisingly we showed that all of the individuals and families with the G2019S mutation — whether they are in Norway, Ireland, Poland, the U.S. or living on the outskirts of the Sahara desert — are part of the same ancient family. These individuals are all ancestrally related.

The highest frequency of this mutation is from the Maghrabe in northern Africa. In this region, one in three people who require treatment for Parkinson's disease have a Lrrk2 G2019S mutation. I am now working with colleagues in Tunisia to describe the natural history of Lrrk2 G2019S in Parkinson's disease. What are the earliest features and signs? How does the disease progress? Can these features be used biomarkers of disease onset or progression? Most, but not all people with a G2019S mutation get the disease and we're trying to find out why that is.

Q. You were formally trained in the genetic analysis of human complex traits, but have become a professor of molecular neuroscience. Does your work begin and end in the lab?

A. Fortunately no. My horizons have broadened and deepened. I'm not just a human geneticist. My interest is in translating molecular insights into molecular therapeutics for patients. I really want to turn genetic discoveries into novel, potent therapeutics. For the last four or five years I've been developing the lab around finding out what disease proteins actually do, to identify the pathways in which they are central and to create model systems and functional assays.

Q. We often here the phrases 'personalized medicine' and 'bench to beside.' Can you talk about your work in that context?

A. Lrrk2 G2019S is a good example. Not only can a DNA test help with a diagnosis, but we've used the mutant gene to make mouse models of the disease. We want to understand Lrrk2's function. The G2019S mutation likely activates the protein in a constitutive way so that it doesn't turn off when it should. The pharmaceutical industry considers Lrrk2 and the G2019S mutation druggable targets. They have also become motivated to develop new treatments for Parkinson's disease based on these molecular insights, which is a fantastic development.

Q. What has been a key support to you during your career?

A. Well, you can be as brilliant as you like, but what's important is having a team effort — a network and support. It's not necessarily about knowing the answers, but knowing who might know and having a relationship with them so that you can ask. And that's what really helped me in my career.

One of the things the Mayo fellows in Jacksonville do really well, is they focus on key themes in research. Everybody here works on neurodegeneration in one form or another. It's very powerful because it gives you that critical mass of investigators and expertise, yet it doesn't dilute the effort.

Q. What does the future hold for Parkinson's research?

A. New revelations are made in this field in the lab every year and at a remarkable pace. We will continue our work with a view toward clinical trials of molecular therapeutics. I am optimistic that our mission to halt the disease will be accomplished.

— Reprinted with permission from Inside Mayo Clinic Research