Steven Perrin, recently named chief scientific officer of the ALS Therapy Development Institute (ALS TDI) in Cambridge, Mass., didn’t start out to be a scientist, although his interest in science goes back a long way. (MDA and the TDI recently formed a partnership to support a three-year, $36 million project to identify biochemical targets in ALS. Read story here.)
By the time Perrin, now 42, graduated from Bishop Guertin High School in Nashua, N.H., in 1983, he already knew where his strengths lay — in math, biology and chemistry. Not surprisingly, he decided to become a doctor, entering the premed program at Boston College in 1983.
But four years later, with a bachelor’s degree in biology, Perrin decided to work in a laboratory instead of going straight to medical school. He took a job as a research technician at Boston’s Brigham and Women’s Hospital, extracting DNA from patients’ tissue samples.
The program also involved some clinical training. “We started doing clinical rotations in oncology [cancer] clinics,” he recalls. “I was working with kids and young adults with hematologic malignancies, and I felt it wasn’t the career direction in which I wanted to go.”
Moving away from medicine, he entered graduate school at Boston University in 1991, earning a doctorate in biochemistry four years later.
At the time, he remembers, analyzing the activity (“expression”) of 10 genes at a time was considered high throughput. “If someone had asked me to survey a whole genome [all genes],” he says, “I would have laughed.”
The technology that would make such feats possible, however, was on the horizon. In 1995, just as Perrin was finishing his doctoral program, scientists at Stanford (Calif.) University published a paper describing “a high-capacity system to monitor the expression of many genes in parallel.”
This system, known as microarray technology, ushered in a new age, in which thousands of genes would eventually be examined simultaneously, at first for their levels of expression; and later on, for their composition.
About that time, the pharmaceutical company Hoechst Marion Roussel opened one of the first pharmaceutical genomics centers, in Cambridge, Mass. “At the time my academic lab was doing gene analysis the old-fashioned way,” Perrin says. “Hoechst Marion Roussel wanted to set up high throughput technology.”
Perrin was hired to get the job done. In those days, he says, “there were no commercial software programs for computational analysis. We hired mathematicians and statisticians to develop custom software to analyze gene expression data.”
Eventually, Hoechst Marion Roussel merged with other companies and ended up employing 90,000 people at 27 sites around the world, and Perrin was spending a great deal of time traveling. At the same time, he felt his career was becoming too focused on technology alone, and he wanted to get back to integrating it with biology.
In 2000, he left and joined Biogen, another Cambridge, Mass., firm. “They had only 3,000 people, all in Cambridge. They didn’t yet have gene expression profiling in 2000, so I had to set it up from scratch. But by this time the technologies were more mature, and we did it much more quickly.”
A three-pronged approach
At the TDI, Perrin plans to use genetics, the analysis of genetic variance; genomics, the analysis of gene expression; and proteomics, the analysis of protein levels and functions, to sort out the ALS disease process.
His team will examine tissue samples from ALS patients and multiple mouse models of neurodegeneration, moving beyond the commonly studied SOD1 G93A mouse, which has a specific ALS-causing mutation in the SOD1 gene. A very small percentage of human patients have this familial form of ALS.
A unified ALS hypothesis
Perrin says he has a hypothesis about ALS that originates with the SOD1 mutant mouse model but that he believes doesn’t end there.
“I think mutant SOD1 ends up being a sticky protein that gloms onto structures in the cell, such as mitochondria, the endoplasmic reticulum and the axonal transport machinery,” he says, referring to parts of nerve cells that produce energy and move compounds from one point to another.
“My hypothesis is that it’s the same for sporadic [nonfamilial] ALS. A sticky protein makes cells unhappy; the cell doesn’t know what to do; microglia [cells of the immune system] get activated; and motor neurons die.
The question is, for sporadic ALS, what’s the protein? And, do you have to understand the mutated proteins, or is there a strategy to help motor neurons deal with sticky or misfolded proteins by regulating some other pathway?”
Perrin, of course, hopes there is.
“This is the first time that we’re taking an unbiased, comprehensive approach to ALS disease biology,” he says. “We’ll tackle it on a scale that hasn’t been described for ALS, or for any disease.”