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Like Father, Like Son

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Long before the “proteome,” Leigh and Norman Anderson stepped in tandem to the beat of the proteomics drum

By John S. MacNeil

 

In the annals of science, it is not uncommon for parents and children to work together: Leigh Anderson, an early proteomics advocate, thought he’d found the perfect prototype for his lifelong collaboration with his father in Lawrence Bragg and his father William, who together won a Nobel prize in 1915. But as Leigh later learned from his thesis advisor Max Perutz, after jointly figuring out how to use x-ray crystallography to decipher the structures of biological molecules, the Braggs “hated each other for the rest of their lives,” says Anderson.

For Leigh, 53, and his father Norman, 84, who began working together when Leigh was a teenager and his father a scientist at Oak Ridge National Laboratory, collaborating seems to have been a pleasure. Former and current colleagues say the two always work in tandem, not in a hierarchy. “They feed off each other,” says Carol Giometti, who worked with the Andersons for seven years at Argonne National Laboratory. “They can talk science 24 hours a day.”

At Oak Ridge, Norman led an effort to isolate trace amounts of viruses that might be associated with cancer. Teenage Leigh tagged along to the lab on Saturdays, where he helped his father develop zonal centrifuges for isolating viruses — a lifelong interest of Norman’s. Taking advantage of monthly auctions of outdated electronics and other laboratory equipment at seven cents a pound, Leigh built his own lab in his parents’ basement.

One result of his early indoctrination in biology, Leigh says, is that he developed the “particular personal defect” of avoiding biology classes. “The last actual class I took in biology was in the 9th grade,” he says. While an undergraduate at Yale he majored in physics, but spent senior year studying how to image biological molecules with a field ion microscope. His experimental background won him admission to three of the most prestigious biology graduate programs: at MIT, Harvard, and the University of Cambridge.

Having spent a childhood summer in the UK and been moved by a sophomore year trip to Europe (Charlemagne’s statue at Notre Dame inspired the handlebar mustache that is still his trademark), Leigh opted for Cambridge, where he lucked out with a place in Max Perutz’s group in the MRC Laboratory of Molecular Biology. His thesis examined how hemoglobin flip-flopped between its two conformations by freezing intermediate structures and studying them with x-ray crystallography. Cambridge, he says, was a ball: “Socially, being an American living in England means that you can get away with anything, but also that lab at that time [had] the largest concentration of smart people that may ever have been in biology.”

Upon departing Cambridge in 1975, Leigh joined his father at the Medical University of South Carolina, where Norman was studying plasma proteins. Soon after, Leigh discovered Patrick O’Farrell’s groundbreaking 1975 paper describing how 2D gels could separate complex mixtures of proteins, and returned briefly to Cambridge to set up a 2D gel separations system in Sydney Brenner’s lab. Then he took off for Nairobi, Kenya, to help grad school colleague Terry Pearson set up a 2D gel system at the International Laboratory on Research for Animal Diseases.

In proteomics, the Andersons found a raison d’etre. Envisioning a project to apply 2D gel technology to the systematic study of human genetic mutations, DOE awarded father and son money in 1976 to start a small group at Argonne National Laboratory. There they designed much in the way of new technology for 2D gel analysis, including what became the Iso-Dalt large format second dimension electrophoresis system, a version of which is still sold by Amersham Biosciences. Carol Giometti, whom the Andersons hired as a post-doc, says Leigh took a keen interest in the informatics behind 2D gel image analysis, but that it was often hard to distinguish which of the pair came up with an idea first. Colleagues also attribute to the Andersons a unique ability to bring together a talented team: at Argonne the 15-strong group routinely discussed scientific questions over lunch together, Giometti says.

By the late ’70s, Leigh had begun contacting lawmakers in Washington about funding a large-scale database of protein information collected from a wide variety of human tissues. Armed with the Human Protein Index concept, Leigh met with various government agents, including Senator Alan Cranston, then Democratic majority whip. But with the change in administration in 1980, the idea stalled in the corridors of the Capitol.

So the Andersons broke out on their own. In 1985, the pair took up residence outside DC — more out of business necessity than proximity to lawmakers, Leigh admits. “We started the company in Maryland because the only person we knew with business experience lived there,” he says. With the help of Bob Stevenson, a former Union Carbide exec, Large Scale Biology was born.

For the next 14 years, LSBC survived on contract-research agreements with numerous pharma companies and technology development grants from NIH and NIST. With help from about a dozen employees, the duo continued to build their expertise in automating and analyzing 2D gel separations; in the meantime, well-funded efforts to sequence the human genome progressed rapidly. By the late ’90s, it looked like the genome sequence, combined with advances in biological mass spectrometry, would make the Andersons’ dream for a human protein index finally feasible.

By 1999, the Andersons decided it was time to expand, and LSBC merged with Biosource Technologies, a Vacaville, Calif.-based company with a technology for expressing proteins in transgenic tobacco plants. Following a 2000 IPO that raised almost $91 million, LSBC laid out plans for identifying disease-related proteins through its Human Protein Index proteomics platform, and expressing them in plants for use as therapeutics or as reagents for protein microarrays. At the time, it seemed likely LSBC could rapidly identify and bring to market protein therapeutics along the lines of Amgen’s Aranesp, a formulation of erythropoietin.

But, says Leigh, “It turns out you need more than [$90 million] to do something truly ambitious.” Big pharma never bought into proteomics, and Wall Street’s focus on therapeutics forced many proteomics companies away from discovery research. “If I had to do it over, I’d just focus on plasma and diagnostics [from the start],” adds Leigh. When it became clear last summer that LSBC could no longer afford to support the kind of diagnostics-oriented research that interested the Andersons, they took a hiatus from the business world.

Today, Leigh and Norman are once again collaborating. Through the Plasma Proteome Institute, a nonprofit entity they established late last summer, Norman has returned to his lifelong interest in separating and identifying viruses, and Leigh is developing methods for adapting proteomics technology to what he thinks is its optimal application: diagnostics. The Andersons aren’t sure where their funding will eventually come from, but for the moment they’re enjoying the less competitive environment outside of commercial biotech. “When you have the luxury to step back, you can see the whole sequence of what needs to be done,” says Leigh.

In the short term, that means Leigh is working to devise a platform that marries the sensitivity of protein mass spectrometry with the reproducibility of contemporary diagnostics tests. The goal: assemble several hundred proteins indicative of disease, and routinely identify them in patients’ plasma. Norman, meanwhile, is working with plasma in his own way: he’s designed a series of experiments for isolating all the viruses found in human plasma, with the goal of identifying a potentially dangerous virus — such as SARS — before it becomes widespread.

Who’s writing the checks? “We are the major funders,” says Leigh. Once the Plasma Proteome Institute has collected the initial proof-of-concept data, he adds, outside funding should follow. In the meantime, father and son are enjoying the freedom to act on their passion. “It cuts through all the red tape — if you want something you just call up and use your credit card,” Leigh says. “We’ve waited our whole lives for this.”

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