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Pawson Hopes Signal Transduction Will Bear Fruit for MDS Proteomics

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AT A GLANCE

NAME: Tony Pawson

AGE: 49

POSITION: Senior Scientist, Samuel Lunenfeld Research Institute, Mount Sinai Hospital; and Professor, Department of Molecular and Medical Genetics, University of Toronto.

PRIOR EXPERIENCE: Developed new models for signal transduction based on interacting protein domains, and co-founded MDS Proteomics in 1999.

Tony Pawson first got turned on to biology in high school, thanks to a “fabulous” teacher, he said. It’s a good thing, too, because the co-founder of MDS Proteomics and signal transduction researcher at the Samuel Lunenfeld Research Institute in Toronto has contributed his fair share towards understanding the basic networks underpinning cellular biology.

But unlike other researchers now enveloped in the field of proteomics, Pawson’s contributions didn’t come through inventing new approaches to separating proteins or new algorithms for identifying them with mass spectrometry. Instead, he has used various gene and protein analysis techniques to painstakingly build up an expertise in signal transduction, and applied his results on a proteome-wide scale.

To do this, Pawson first shipped off to the University of Cambridge in 1970, where the Kent native studied biochemistry. There, partly because he was habitually late for lectures, he managed to avoid learning the dogma of early 1970s-era molecular biology — that was fortunate, he said, because his creativity of thought would otherwise have suffered. But Pawson enjoyed the subject, and on the recommendation of his advisor, Tim Hunt, joined Alan Smith’s group in 1973 at the Imperial Cancer Research Fund, as it was then known, at the University of London.

 

Starting with Retroviral Oncogenes

Under Smith, Pawson began studying the genes encoded by retroviruses, in particular the retroviral Src oncogene and its function. Although the modern tools of cell biology had yet to be invented, Pawson used viruses to infect cells with oncogenes like Src, in the hope of understanding how normal cells become malignant. After writing his thesis on the gene expression of an oncogenic retrovirus and earning his PhD in 1976, Pawson moved to the University of California, Berkeley, to take a postdoc in Steven Martin’s lab, where he continued his work with retroviral oncogenes.

It was during this time that Pawson’s curiosity was piqued by an observation that was to shape his research interests from then on: that when the Src gene of Rous sarcoma virus, and other oncogenes like it, are expressed in vertebrate cells, the protein affects just about every aspect of cellular behavior, from gene expression and cytoskeletal architecture to metabolism and growth control. “That suggested to me that everything in the cell is connected, that the cell isn’t a bunch of separate little bits doing their own thing, but that there must be some sort of fundamental integrating mechanism,” he said. “Otherwise how could a single protein have such a profound effect on everything that goes on in the cell, turning it from a normal cell to a cancer cell in one fell swoop?”

 

Then Moving to Vancouver

By 1981, when it came time to wrap up his post-doc and look for a job, Pawson knew he wanted to stay in North America, so when the University of British Columbia offered him an assistant professorship, he took it. “I was keen to stay on the West Coast, and quite frankly [UBC] was the first to offer me a job,” he said. “Plus Vancouver looked attractive — it’s a beautiful city.”

There Pawson began setting up his lab to study the oncogenic variants of tyrosine kinases and how they induce the malignant transformation of cells, a line of inquiry that he had begun following while a member of Martin’s lab at Berkeley. In addition, Pawson said he had the luck to become acquainted with Michael Smith, a fellow researcher at UBC, who developed the method of site-directed mutagenesis, a technique that at the time only a few labs in the world had the expertise to carry out. Pawson used the method to make specific mutations in activated oncogenic tyrosine kinases, and discovered that tyrosine kinases interacted with other cellular proteins through a domain not involved in its previously characterized catalytic activity.

Nowadays this idea seems almost elementary, Pawson said, but at the time it was quite radical. Pawson’s theories led him to create a model for how tyrosine kinases interacted with other proteins through this new domain, which he termed the SH2 domain. By 1990, he had refined this idea, and was able to show that the SH2 domain actually binds to phosphotyrosine-containing sequences. Pawson proposed that related mechanisms applied to other receptors as well.

By this point, Pawson had moved to the Samuel Lunenfeld Research Institute, an arm of the Mt. Sinai Hospital, which he had joined as one of the founding faculty members in 1985. Pawson said his reasons for moving were many, but primarily he saw an opportunity to come in on the ground floor of a new, clinical research-oriented institution with strong ties to the molecular and structural biology community in Toronto.

“There are certain times when scientists move, and one time is [after] you get your assistant professorship and you’re [at an institution] for four or five years,” Pawson said. “If you do well and you think you’re on to something important, you start to wonder, ‘Am I in the right place to carry this forward?’ It seemed at UBC I was going to do a lot of teaching, and there wasn’t really anyone there who knew a lot about signal transduction, or the kinds of things I was interested in [aside from Michael Smith].”

 

Moving to Proteomics at the Lunenfeld

Aided by fellow Lunenfeld scientists such as Janet Rossant, who was involved with gene targeting in mice, Pawson expanded his research into signal transduction and began demonstrating that the cell uses interaction domains such as SH2 in numerous different contexts. “That’s what led us into the proteomics aspect of things,” he said. “Our argument was that a significant aspect of cellular behavior is organized through protein interactions, and if you want to know how cells are organized on a global scale, one way to address that is to look more comprehensively at how proteins interact one with another.”

But the transition to proteomics had other roots as well. By the late 1990s Pawson had built up his group’s expertise in structural and yeast cell biology to help study signal transduction, and upon the completion of the sequencing of the yeast genome, the yeast researchers began looking for other avenues of inquiry. “The yeast guys started to panic, saying, ‘What do we do next?’ We realized that mass spectrometry was going to be an important new technique to look at proteins, and we realized one of the world’s leading mass spectrometry manufacturers and developers, MDS Sciex, was in Toronto.”

Once Pawson’s group hooked up with MDS Sciex, and with generous funding from the Canadian government to get Pawson’s proteomics group off the ground, the two parties began to think they could apply mass spectrometry more generally to decipher cell function. The goal, they realized, was to apply Pawson’s signal transduction research to finding drug targets and learning how drugs interacted with proteins in cells. With impetus from both MDS and Pawson, MDS Proteomics was born in September, 1999.

As a co-founder, Pawson provided the original scientific foundation for the company, and helped recruit and train MDSP’s initial scientific team. As the company has matured over the last three years, Pawson has taken more of an advisory role, although his lab still transfers a significant amount of scientific innovation to MDSP. “The company now has its own identity, and is less dependent on us, but it still benefits from the innovation we contribute,” Pawson said.

Although Pawson said he’s still “extremely involved” with MDSP, he also plans to turn his attention to new applications of his research into signal transduction, including treating diseased cells by rewiring their cell signaling circuitry, and studying the signaling processes involved in the nervous system. “The problem is that when you’re lucky enough to discover something that is of general significance, then you’re left with a lot of things you could work on [as well],” he said.

“I’ve been accused of being unfocused quite often because we work on way too many things, but that’s because it’s exciting.”

— JSM

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