A seminal finding in Huntington’s disease steered David Fischer’s career toward finding solutions to this complex condition
Dr. David Fisher, PhD remembers well the day he decided to pursue neuroscience. It was when the gene for Huntington’s Disease (HD), an inherited, fatal neurodegenerative disorder, was isolated in 1993 by a collaborative research group. The gene, called huntingtin, culminated a decade-long detective story.
Fisher had just begun his PhD in molecular genetics at Leiden University in The Netherlands, and reading about the genetic discovery amounted to a kind of epiphany for him. He decided to pursue neuroscience and neurological diseases. Today, Huntington’s disease remains one of his main focuses at Charles River Laboratories, where he currently serves as Executive Science Director.
“The huntingtin gene had such a peculiar mutation at the time,” says Fischer. “Of course, now there are more diseases caused by repeat expansions in the gene, but then it was really one of the first clear molecular signatures that was 100% linked to the onset of disease.”
Knowing the single mutation that triggers a fatal condition doesn’t automatically lead to ways of reversing it. HD is aggressive, brutal, and complex. People with the disease lose their ability to walk and experience delusions, memory loss, and confusion. Twenty-five years after the amazing discovery of the gene, scientists are still on the hunt for how to find drugs to treat HD. Fischer is confident they will be successful, however, buoyed by a promising new drug injected into cerebrospinal fluid that suppresses the production of the huntingtin protein in the brain of HD patients.
Fischer joined Charles River in 2014 through the acquisition of the services division from Galapagos, which he had joined in 2005. During these years he has taken a leadership role in a number of early-stage drug discovery programs in rare and orphan disease indications, including Cystic Fibrosis, HD, ALS, Usher III Syndrome, and Duchenne Muscular Dystrophy, and additional indications such as metabolic diseases, oncology, Alzheimer’s, and Parkinson’s Disease. The work has sparked several preclinical candidates. He brings expertise in complex and primary cell-based assays, including iPSC and hESC models and human primary cell models and their application for drug discovery and functional genomics.
Fischer also holds an undergraduate degree in chemistry from Leiden. During six years of post-doctoral fellowships at the Netherlands Institute for Neuroscience in Amsterdam (an Institute of the Royal Netherlands Academy of Arts and Sciences) and the Free University Amsterdam he focused on neurodegenerative diseases, in particular Alzheimer’s and HD. David also mentored two graduate students at the University of Amsterdam and at Leiden University. He has published over 60 peer-reviewed papers and patent applications.
Eureka: When HTT was isolated, the possibilities must have seemed incredible to scientists.
DF: Yeah. And then of course we’re still more than 25 years forward and we haven’t yet solved that disease. But we’ll get there, I think. When the gene for cystic fibrosis was cloned around the same time as huntingtin, people were assuming, okay, within a couple of years we will have solved CF. And we are finally here with drugs for 90% of CF patients. But it took much longer than we thought. So genetics are great, they really give us deep insight, but it isn’t an immediate road to success.
Eureka: Why has it been so hard to move the needle with Huntington’s?
DF: We still don’t really understand what the link is between that mutation and the onset of disease. It’s different from cystic fibrosis, where the mutation immediately causes symptoms. There’s this build-up of mucus in lungs, and the children can have problems with their digestive tracts. Compare that to Huntington’s, where the mutation is there from birth, but a typical patient will not have any symptoms until they’re 45-ish. So there are many steps between that mutation and the clinical symptoms, and then finally the neuronal dysfunction and degeneration of neurons in patients, and we still don’t understand that.
Eureka: Can you describe a “Eureka Moment” in your career?
DF: It was before the full human genome was sequenced. There were all these EST [expressed sequencing tag] libraries around, not annotated at all. Nobody knew what those genes or fragments of genes were. I remember I ran a bioinformatics tool—it was not a BLAST search because BLAST was not yet invented—to look for homology in a certain protein in that EST library. Computing power was a lot less than it is today, so you had to run those queries overnight. The next morning there was one hit, and it was clear that the computer had picked up homology. If you looked at the protein sequence, it did make sense. So you could find genes just by searching with a clever algorithm.
Eureka: How exciting! What did you do when you observed this?
DF: Well of course you need to confirm that is truly a gene. You need to find out where it maps on the human genome, and raise antibodies to make sure the protein is expressed where you think it should be. So definitely it is the beginning of a lot of work.
Eureka: What would you like to do if you were not a scientist?
DF: I don’t know. I think that a scientist is so much higher up the ladder than the next choice it’s going to be difficult.
Eureka: What kind of music do you listen to when you are in the lab?
DF: Classical music. String quartets are good for working.
Eureka: What composers do you favor?
DF: Haydn, Beethoven. Sorry, I’m very old-fashioned.
Eureka: No it’s all right. I would have been more surprised to hear that you listen to punk rock. Where do you get your science news?
DF: I think, again, that I’m a bit old-fashioned. I read journals like Science, Nature and Cell. I browse through those every week.
Eureka: Are you the only scientist in your family?
DF: No, my sister is also in biomedical research and my father is a chemist.
Eureka: Lastly, who are your research heroes?
DF: Probably those guys that figured out the genetic code. Not just the structure of DNA but actually how the cell reads the information in the DNA and makes it into proteins. That wasn’t just a single person, of course. It’s a significant number of people, who after the Second World War pulled this off over the course of 25, 30 years. If you just look at the technologies they had to work with back then to decipher the genetic code and understand how to make mRNA and you needed tRNA [transfer RNA] to make the protein. You would be able to do that more quickly today, but back then they didn’t have fancy sequencing or mass spectrometry. They had to do everything by hand.
Eureka: Amazing the painstaking work that went into decoding genes.
DF: Yes, and it has brought us so many opportunities for drug discovery.