Medical Pioneers

Dr. Peter J. Quesenberry envisions a time when patients will be rejuvenated by their own stem cells

08/11/2002

BY G. WAYNE MILLER
Journal Staff Writer

PROVIDENCE -- To reach the Center For Stem Cell Biology, you travel a serpentine course along hallways and stairs to a secluded wing of Roger Williams Medical Center. The door is always locked, and visitors must use the phone to gain entrance. A member of the staff will then escort you in.

Once admitted, you proceed down a long corridor lined with laboratories. Turn right at the end, and you arrive at the office of Dr. Peter J. Quesenberry, the center's director. Early morning is a good time to catch him.

Chances are, Quesenberry will be smiling, or telling funny stories, or laughing mischievously: he finds amusement in many places, including the skeptics of his sometimes-unconventional ideas. He likely will be wearing a rumpled suit, and with his wire-rimmed glasses, thinning hair, and imperfect posture, he conjures up the image of an English professor -- a Faulkner scholar, one might guess. Quesenberry indeed revers literature, and one of his many pursuits is writing a novel. But it is on the outposts of medical science that Quesenberry stakes his claim.

At age 64, Quesenberry is at the height of a career that has made him an authority on blood, cancer, cell biology, immunology, and bone-marrow transplantation. He lectures around the world and the abbreviated list of his articles and books runs to nearly 50 pages. Quesenberry has been a professor of medicine at Harvard, Tufts, and other esteemed medical schools for three decades, and the grants he's won total tens of millions of dollars.

Journal photo / Connie Grosch CELL SIGHTING: Assisted by Dr. Brian E. Moore, a research fellow, Dr. Peter J. Quesenberry looks at a cross-section of a mouse brain, at the Center For Stem Cell Biology, at Roger Williams Medical Center.

The research involves adult stem cells, which are present in the bone marrow and elsewhere in the body. If the hypothesis Quesenberry and others around the world are testing proves true, doctors someday will be able to direct these cells to regenerate damaged or dead tissue. People suffering from cancer, stroke, multiple sclerosis, Alzheimer's and Parkinson's diseases, cirrhosis of the liver, cardiac disease, and a multitude of other ailments would benefit. Since many of these conditions are age-related, mankind would move closer to the ancient dream of a fountain of youth.

This research is controversial, although not because of the cells involved. Unlike experiments with stem cells derived from embryos (which have the potential to develop into fetuses and then babies), adult stem cells can be extracted from consenting people, a process that raises few religious or ethical issues. The controversy involves Quesenberry's theory, which would turn dogma upside down. Generations of doctors have been taught that the role of adult stem cells is to stay inside bone marrow and manufacture new blood cells -- not mysteriously transform into a disease-fighting magic bullet.

"Most people get comfortable with their own understanding of things," Quesenberry said. "I think that is universal. Most people don't like major changes, don't you think? And a major change in dogma potentially threatens the significance of things that have been done by [other] people."

But threats can help advance science, and Quesenberry delights not only in challenging the conventional wisdom but also in tweaking the skeptics. Undeterred by their doubts, he worries only that their dissent will impede his funding.

"The naysayers are saying this is crazy, sloppy science," Quesenberry said. "This is very exciting. It should be: 'Go full-tilt, find out if you're right or wrong -- support this thing full-tilt and really go after it.' "

Which is what Dr. Q. is doing behind a locked door off Chalkstone Avenue in Providence, R.I.

'That's pretty! That's nice!'
One recent morning, Quesenberry left his office and went to one of his labs. He entered a tiny, windowless room, where Dr. Brian E. Moore, a research fellow, had prepared slides for him to examine under an uncommonly exquisite German microscope. Quesenberry sat, removed his glasses, put his eyes to the machine, and began hunting for cells.

"Is this the brain?" he said.

Moore confirmed that it was a cross-section of a mouse brain. Mice and humans share many of the same genes, making the animals suitable research subjects -- although Quesenberry must leave their direct handling to assistants, since he is highly allergic to rodents. ("They're getting their revenge!" a doctor on Quesenberry's staff quipped.)

Quesenberry maneuvered the slide under the microscope. "I'm not seeing much," he said. He was not annoyed, only stating fact. In science, patience is a virtue.

Quesenberry continued exploring until he found something to his liking. "There's a good positive cell," he said.

Moore fiddled with a computer, linked to the microscope, until a phosphorescent circle of green against a shadowy blue background appeared on the monitor. It looked like a view of the cosmos through some powerful new telescope.

"Look at the green there," Quesenberry said. "See it? You can see the fluorescence coming through."

"Let me bring down the exposure," Moore said. He wanted a digital photograph of the cell. The $250,000 microscope and computer setup can also create rotating three-dimensional images, useful to illustrate Quesenberry's lectures and presentations at conferences.

"There you go," said Quesenberry. "That's pretty! That's nice!"

This experiment really began five years ago, when scientists in Osaka, Japan, inserted a gene from a jellyfish into fertilized mouse eggs. The gene carried instructions for producing green fluorescent protein (GFP), which makes the jellyfish glow in the dark.

As hoped, cells making up the mice born from the eggs also glowed a ghostly green (unmistakably so when exposed to ultraviolet light) -- and the offspring of that first generation of genetically altered mice were also luminous, which confirmed the gene had been permanently transferred. The new strain was a breakthrough. Now scientists seeking to track the movement of cells from one animal inside another had a reliable tool for identification.

Quesenberry uses GFP mice grown in Bar Harbor, Maine, home of The Jackson Laboratory, a leading breeder of research animals. Several weeks before he examined slides, his assistants euthanized the mice using a humane technique, then harvested the marrow from inside their bones. Meanwhile, another group of mice -- ones lacking the GFP gene -- received radiation to their brains. The scientists then injected marrow from the GFP mice into the veins of their irradiated brethren -- the "patients" -- and waited.

The hope was that stem cells from the donor mice would circulate through the patient mice's blood systems, home in on the brain, recognize the injury, and respond by producing new brain cells -- in other words, be a magic bullet. Since the patient mice did not have the GFP gene, any green cells found in their brains must have been derived from the donor stem cells.

But green cannot confirm the specific cell type, only its origin in the donor mouse. Several types of brain cells (including neurons) exist, and the brain is fed by blood vessels, composed of yet other types of cell. There is also the possibility that a green cell could be a stray blood cell from the donor marrow. And a green cell could be "artifact" -- scientific slang for something not easily identifiable. So while Quesenberry and Moore believed they were finding neurons, they cautioned that further tests were needed.

And more work will be needed before they would attempt trials in humans. No one yet knows precisely how stem cells function normally, never mind how they might best be coaxed into fighting disease.

Still, the morning's results excited Quesenberry. Moore had stained the specimens with a dye that attaches to neurons, and as Quesenberry continued his hunt, he found several green cells tinged with red.

"Look at this!" he said. "You can see the red right on the edge of the cell. Take a look here. That's pretty neat. I think that we can say that is a positive: a neuronal-type cell."

"Definitely," said Moore.

But a moment later, a mystery -- and a reminder that nature sheds its secrets reluctantly.

"See the very nice green in these dark spaces?" Quesenberry said. "What are those? Kind of looks like a blood vessel, doesn't it. But there are so many of those. I don't think the mouse brain should have so many."

A résumé thicker than some magazines
Quesenberry is the son of a Wall Street lawyer whose German ancestors settled in Virginia generations ago. (Quesenberry is the anglicization of a German name.) He grew up on Long Island, where he was co-captain of his high school football team. He wanted to play football professionally, but his weight, about 165 pounds, ended those aspirations. He earned varsity letters in soccer and lacrosse at the University of Virginia, and, thinking he might be a writer, he majored in English. He also took enough science and math courses to qualify for admission to medical school. Becoming a doctor, he said, was his "fallback" career plan.

He did not enjoy his first year at the University of Virginia Medical School, but he began to find passion for medicine in his second. Interested in surgery, he went to Vietnam as a Navy medical officer -- and soon decided he did not want to pass his days in an operating room. Hematology (the study of blood) and, later, oncology (the study of cancer) fascinated him.

After extensive training in Boston, Quesenberry joined the faculty of Tufts Medical School and, later, the Harvard Medical School. In 1979, he returned to the University of Virginia, where he was professor of medicine, professor of otolaryngology (the ear, nose and throat specialty), and chief of the Division of Hematology/Oncology. In 1993, he left for the University of Massachusetts Medical Center in Worcester, where he was director of the Cancer Center and professor of cell biology. When he lost his director's title in an administrative shuffle that accompanied a hospital merger, he decided to leave. Quesenberry is not arrogant, but he does not enjoy being slighted. And a man with a résumé thicker than some magazines has options.

Quesenberry received several offers, but decided to stay in New England; his family was rooted here, and the research fellows and staff on whom he relies were unlikely to leave the region. Seeking to enhance its role as a leading cancer treatment and research center, Roger Williams, an independent hospital, lured him to Rhode Island with the promise of heading the Center For Stem Cell Biology, freedom to pursue his research, and a professorship at Boston University, with which Roger Williams is affiliated. Quesenberry also maintains a clinical practice, which provides additional income and the opportunity to treat patients -- a lab-to-ward link that Quesenberry considers vital if research is to bear true fruit. He has been in Providence since January 2001.

With his pedigree, Quesenberry could easily hold a position at a major pharmaceutical or biotechnology corporation. He could have a company car, a corner office, and stock options worth millions. But research, not money, has motivated him throughout his long career.

"When you go into a corporate environment, you're going to be restricted," Quesenberry said. "What usually happens is people love it there the first couple of years -- they've got a lot of resources and money, a beautiful office, all that crap. Then what happens in the third or fourth year or so, the suits will come in and say: 'Well, we think you should maybe go this other direction. Or, now we want you to focus just on this -- the development of a money-making drug.' "

Quesenberry lives on the East Side with his wife, Marilyn, a nurse and landscape designer. One of their children, Preston James, is entering his final year at Yale Law School, and the other, Matthew Isaac, will be a fourth-year student at the University of Massachusetts Medical School.

In what passes for spare time, Quesenberry enjoys baseball: raised a New York Yankees fan, he now follows the Red Sox, too, a contradiction in allegiances that makes him a novelty in New England. He reads the professional literature, of course, but also voraciously outside his field: "I always try to have a good detective novel," he said. And he is writing his own novel. A murder mystery, it involves a large pharmaceutical company, gangsters, and the discovery of two decapitated dog heads in a Mercedes -- an echo of Mario Puzo's The Godfather.

Quesenberry came from an affluent family and his profession has certainly not left him wanting, but he is no materialist. Asked what kind of car he drives, he said: "A Chrysler -- it's got about 100,000 miles on it." And the model? "It's a Chrysler. I don't pay much attention to it." The year? "Probably '93, '94, something like that." For the record, he noted that his car is red.

'Say they clone him'
Photographs of Quesenberry's wife and two children adorn his office, and one bookshelf is filled with past issues of scientific journals, including Experimental Hematology, of which he was editor for most of a decade. Another shelf has a copy of PCs for Dummies, near a volume entitled Molecular Biology and Differentiation of Megakarocytes. Next to a small aquarium, several of Quesenberry's awards are displayed. "You hang around long enough, they give you something!" he said, laughing.

Quesenberry cracked a smile again when a visitor drew attention to the print of Ted Williams that hangs on his wall. What did the doctor think of the controversy surrounding Williams's son's decision to have the body of the great baseball player frozen, in hopes of someday returning? "Say they clone him," Quesenberry said. "His clone's probably going to hit .240 and be a bad fielder!'

Between research and lecturing one day this summer, Quesenberry was joined in his office by three of his disciples: Dr. Mehrdad Abedi, who is of Iranian descent; Dr. Jean-Francois Lambert, who is Swiss; and Dr. Gerald A. Colvin, an American. The three moved with Quesenberry from the University of Massachusetts, along with lab manager and research project leaders Christina I. McAuliffe and Mark S. Dooner, whose first job, a big one, was to get the new Center for Stem Cell Biology up and running.

The doctor and his young scientists were discussing a passage in a hematology book they are writing together. Quesenberry's colleagues had just finished the pages at hand, about a blood disorder known as polycythemia. The point was how to best diagnose the ailment, which is rarely seen.

Line by line, Quesenberry critiqued the passage. He chuckled when he got to a phrase describing a "careful" exam. Wouldn't that erroneously imply that some exams should be careless? he said.

Colvin struck the word "careful."

Further on, Quesenberry got hung up on a recommendation for a test known as a serum EPO: as an early diagnostic tool, an EPO would be unnecessary, Quesenberry declared.

"I don't buy it," he said. "It's likely to be confusing."

Quesenberry's colleagues begged to differ; they had not pulled the recommendation out of thin air, but read it in respected medical texts. Abedi left his boss's office and returned with one such text a moment later. It was Harrison's 15th Edition Principles of Internal Medicine -- a 2,629-page volume that is the gold standard of the field.

Abedi opened to the chapter on polycythemia and confirmed the recommendation. Quesenberry was unpersuaded. He implied that the chapter's authors did not see enough polycythemia cases to speak with absolute authority.

Colvin struck the recommendation.

Later that day, Quesenberry left his lab to attend a ceremony honoring the Adele R. Decof Foundation for its $2-million gift to Roger Williams' Cancer Center. Polycythemia was still on his mind. Spotting Chief of Medicine Dr. Alan B. Weitberg, an eminent physician in his own right, Quesenberry asked what initial steps he would take in a suspected case of polycythemia. Weitberg named several tests, but EPO was not on his list.

"There!" said Quesenberry. "I'm vindicated!"

But EPO had become something of an obsession. In conversations with other colleagues over the next week, Quesenberry could not resist giving his quiz.

'A silly mantra'
Earlier this year, Quesenberry submitted a paper to Blood, the Journal of the American Society of Hematology, a publication read by everyone of significance in the field. Co-authored with Colvin and Lambert, "The Chiaroscuro Stem Cell: A Unified Stem Cell Theory" proposed a new model that helps explain how stem cells can become magic bullets.

"This is not the standard dogma of many investigators in the field," the paper began.

And thus was born a controversy, hardly Quesenberry's first.

Through the process of peer review, articles submitted for publication in authoritative journals are screened by members of the editorial board. Quesenberry's reviewers were scathing, as these things go.

"I believe the authors go too far in discrediting the established concept. . ." wrote one, "and in so doing they throw the baby out with the bath water." Wrote the other: "This review is highly speculative and provides little data to support the authors' theory . . ."

And both reviewers took offense at Quesenberry's characterization of some of his critics as old-fashioned thinkers who recite "a silly mantra." Such a dismissal, one reviewer said, brought Quesenberry's credibility into question.

Quesenberry was amused. He had intended a little fun, although not for fun's sake alone; controversy, he believes, can get scientists rethinking, which can ultimately advance science. "You should have a little juice in these things," he said, "although sometimes it causes me trouble!"

In the end, Quesenberry agreed to drop the silly mantra reference and make other changes. But he did not back down from his central, as-yet-unproved thesis -- and in answering the reviewers' critiques, he could not resist another jab. Quesenberry wrote: "I can't help but quote Freeman Dyson here: 'For any speculation which does not at first glance look crazy, there is no hope.' " Dyson is a distinguished British-born physicist, and his musings on extraterrestrial life have made him controversial in some circles.

After the revisions, Quesenberry's paper was accepted for publication, and the 64-year-old scientist continued with his research. Along with similar work at the National Institutes of Health, Duke University, the University of Minnesota, and elsewhere, evidence for a magic bullet grows.

Quesenberry envisions a time when patients with all manner of disease will check into a hospital, be treated, and go home rejuvenated by stem cells. And that time could be near: he has already completed the preliminary design of a 24-bed tissue-restoration unit for Roger Williams Medical Center, and he hopes to open a smaller version as early as next year.

There is, of course, the possibility that Quesenberry and like-minded scientists elsewhere will be proved dreamers -- and "silly mantra" will come to describe their position, not the naysayers'. Dogma could be truth.

Quesenberry acknowledges this. "We may be wrong," he concedes.

But he believes that he is right, and that excites him.

"I'm fascinated with the basic mechanism of how cells make cells," he said. "The idea that we can understand something, turn it around, and cure a disease -- that's pretty satisfactory. That gets me going."