The Search Magazine Article October 01, 2013

The questioner: profile of Ken Paigen

Kangaroo, whale, naked mole rat, Tasmanian devil, Thomson's gazelle, rhinoceros. Mouse. Human. The engine of evolution, which powers the astounding variety of mammalian life, is genetic recombination. And the mammalian genome comes equipped with a toolkit of proteins designed to work on that engine.

Ken Paigen wants to figure out how the tools work.

With his beard, glasses, twinkling dark eyes and shock of curly gray hair, Paigen has the classic scientist "look." In fact, he has an international reputation as a scientist's scientist: the quiet voice in the back of a packed lecture hall asking the question all the other researchers wish they'd thought of.

Paigen was The Jackson Laboratory's director (the role now designated president and CEO) from 1989 to 2003. Since then he has moved back to the research bench as a JAX professor and executive research fellow.

In late 2009 Paigen's laboratory published a paper in the journal Science showing that a protein known as PRDM9 turns certain locations on chromosomes into "hotspots" of genetic recombination activity during the first moments of reproduction. It was a hot moment for hotspots: Two other research groups, publishing in the same issue of the journal, identified PRDM9 as important in both mouse and human genetic recombination.

Paigen is the principal investigator of a five-year, $8.2 million grant from the National Institute of General Medical Sciences of the National Institutes of Health. Together with JAX collaborators Petko Petkov, Ph.D., Mary Ann Handel, Ph.D., Matt Hibbs, Ph.D., and Greg Carter, Ph.D., he is exploring the key mechanisms for how PRDM9 reshuffles DNA during meiosis, the process by which egg and sperm divide their respective complements of chromosomes in half, providing one set each to the offspring.

"Defects in meiosis can result in infertility or subsequent embryonic loss," Paigen says. "Actually, up to half of all human pregnancies go awry due to spontaneous abortions or developmental defects. Those losses, which usually go unnoticed, are in large part the consequence of failures of genetic recombination process."

As challenges to human health go, Paigen says, "humans generally do fine at having babies. But meiosis is simply one of the most fundamental biological processes; there's a lot we don't know about it and science is about investigating the unknown. There's a need to question and explore how the world works, and you learn later on what the practical applications are.

"As Einstein said, 'What use is a baby until it grows up?'"

PRDM9 belongs to a family of proteins known as zinc finger proteins, which recognize specific sequences in DNA and regulate their function. Paigen notes that there are more than 800 zinc finger proteins in the human and mouse genomes.

A human is born with a complete set of chromosomes in every cell, with about 20,000 genes turning on and off to orchestrate changes in gene expression, and thereby the physiological changes that occur throughout a lifetime as shaped by environment (diet, exercise, sun exposure and so on). Zinc finger proteins are the cellular tools that enable these gene expression changes as a baby grows its first tooth, learns to swim, goes through puberty, gains the freshman 15 and finishes a first marathon at age 85.

"Approximately one out of every 25 genes codes for a zinc finger protein," Paigen says, "but the rules governing how they recognize specific DNA sequences are still obscure. While PRDM9 appears to function only during meiosis, it provides an exceptional opportunity to expand our understanding of those rules."

Path to research

Paigen was born in 1927 at Hunts Point Hospital in the Bronx, N.Y. "I had a normal, middle-class upbringing," he says. "Father was a dentist, Mother stayed at home with my older sister and me."

What he calls the "formative educational experience of his life" started in the fourth grade, when he was selected to attend the Speyer School, an early experiment in magnet schools for students with high IQs, as well as a separate program for students with IQs under 90.

"Each semester we had to write a book detailing what we had learned about a given subject," he recounts. "One of our teachers was interested in antiques, and at the age of 11 I could tell you the difference between Chippendale and Hepplewhite furniture, though I couldn't possibly do it today."

Paigen's academic aptitude got him into the Bronx High School of Science and on to Johns Hopkins University as a pre-med student, in keeping with his father's wishes that he become a physician. "When I started college I didn't know there was such a thing as a Ph.D.," he says. "In my senior year we got a new professor who taught a course in cellular physiology (which nowadays would be called cell biology). I fell in love with it, and I found out you could actually become a scientist. Much to my father's distress, I got accepted as a graduate student at Caltech."

Paigen describes the job market for scientists facing him in 1950, after earning his Ph.D. in biochemistry, as "utterly and totally abysmal." But at last, after two post-doctoral stints, Paigen heard that the new Roswell Park Memorial Institute (now Roswell Park Cancer Institute) was looking for faculty, and he landed his first academic job there without even having to interview for it. Over his 27 years at Roswell Park, he would become the chair of the department of molecular biology.

Paigen and his wife, JAX Professor Beverly Paigen, Ph.D., faced some tumultuous times at Roswell Park and eventually decided to move to U.C. Berkeley, Ken becoming the chair of the department of genetics and Beverly a scientist in the Children's Hospital Research Institute. "The University was a great place," Paigen says. "We had flowers in our garden every day of the year, we had a sailboat in the Berkeley marina and went sailing on San Francisco Bay, we attended all the performances of the dance theater and the repertory theater, and we went skiing in Tahoe. But after seven years I was invited to become the director of The Jackson Laboratory."

Trial by fire

For Paigen, joining The Jackson Laboratory in 1989 was a kind of trial by fire. After a visit to the Laboratory on May 10 of that year, having agreed to take the director's post in October, he returned to Bangor International Airport to drop off his rental car and fly home. A note was waiting for him at the rental car desk: "The Lab is on fire."

"I presumed this was a fire in a wastepaper basket," Paigen says, but then he decided it must be a serious situation, got back into the rental car and drove back to Bar Harbor.

"There's a place on Route 3 in Trenton, Maine," he recounts, "as you approach Mount Desert Island, where you make a turn and see the island's mountains for the first time. I could see an enormous plume of smoke. It looked like a volcano. And when I got to the Lab there was chaos."

A fast-spreading fire had started in Mouse Room 4 in the Laboratory's mouse production facility. A few weeks earlier, Paigen had read an account of the Exxon-Valdez oil spill disaster in the New York Times. The article had detailed the errors in leadership, planning and communication that had exacerbated the problems caused by the spill, lessons Paigen kept in mind during the rescue process.

"As of that day I stepped into the director's job," he says, adding with a laugh, "I don't remember what I did with that airline ticket."

This major milestone in JAX history coincided with a turning point in mammalian genetics. The late 1980s brought the advent of gene transfer technology—the ability to engineer changes in a mouse genome in order to develop better models of human disease. The laboratory mouse was about to become the primary platform for genetics research, and The Jackson Laboratory was poised to take an even larger role in the international biomedical research community.

Paigen headed to Capitol Hill to convince the U.S. Congress that The Jackson Laboratory needed not only to rebuild, but to expand. With the Laboratory's counsel, Ken Trevett, and lobbying consultants Lloyd Mees and Susan Geiger, the JAX team met with members of Congress and made their case for funding.

Former U.S. Sen. George J. Mitchell of Maine recalls the effort: "I worked closely with Ken and other Jackson Lab supporters to obtain funding that was crucial to rebuilding the lab. It is in times of crisis that leaders are most severely tested, and the aftermath of the fire was a crisis. Ken was at all times strong and visionary, as he successfully led the effort. It was a pleasure for me to help restore the Lab, an important part of our economy on Mount Desert Island and a national treasure in medical advancement."

Growth and opportunity

During Paigen's tenure as director, the Laboratory saw a doubling in its staff, from 548 to 1,162 employees, and its operating budget, from $25.4 million to $50.4 million. And the institution's role as the international hub of mammalian genetics also grew, with the expansion of the Mouse Genome Informatics research databases and distribution of hundreds of new mouse models of human disease to laboratories around the world.

JAX Chairman Emeritus David Shaw had helped to recruit Paigen as director. "As chair of the board of trustees, I was grateful to be associated with such a talented and passionate director, and was only sorry that Ken's sailing days occasionally suffered from the heavy workload of historic opportunity, change and exponential growth. Ken is deeply committed to realizing the potential of genetics to improve human health and wellbeing. That commitment has been inspirational to me and many others associated with the Lab."

Paigen and JAX took a leadership role in settling one of the key research controversies of the past two decades. In the late 1990s, Harvard University obtained patents on a transgenic mouse capable of developing a human cancer. E. I. DuPont de Nemours & Co., which funded the development of the so-called "OncoMouse," retained intellectual property rights to the patent and sought to restrict the Laboratory's ability to distribute the mice. Working with Harold Varmus, M.D., the Nobel laureate who was then director of the National Institutes of Health, Paigen engineered an agreement whereby academic researchers had free access to the OncoMouse.

"Ken put the legal talents and immense prestige of The Jackson Laboratory on the line in this important cause," Varmus states. "And while we never completely voided the patent, he injected a high moral standard into the debate in support of what we now call ‘open science,' a notion that underwrites more recent movements towards open access to the scientific literature and the greater use of research data. He was and is a proud warrior in such battles, showing others how to advocate for sensible policies that improve the conduct of science. JAX is justifiably proud of him!"

Now well into his ninth decade, Paigen shows no signs of slowing down. "After all these years I continue to be amazed by what happens in basic research. You start out studying one thing, like genetic recombination, and suddenly find your work is relevant to a host of subjects you weren't even thinking about when you started. It's one of the things that makes you want to come to work every morning."

JAX Professor Emeritus John Eppig, Ph.D., Paigen's longtime friend and colleague, comments, "When Ken joined the Lab, it was great to finally have a director who could ask the key questions no matter who was presenting their work. He still does."