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Promise and Progress - The Coffey Way

Transforming Prostate Cancer
Issue No. 2013

The Coffey Way

By: Valerie Matthews-Mehl
Date: January 3, 2013


Coffey Teaching
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Don Coffey Teaching

Donald Coffey was raised in the hills of Bristol, Tennessee in the 1930s.  His father ran a service station.  Neither of his parents finished high school.  He struggled in school himself—repeated grades, was asked to leave his first college, and was rejected by 20 graduate schools. He never heard of Johns Hopkins or Baltimore, and never knew a doctor or anyone with cancer, but after praying and meditating, he had what he describes as an overwhelming desire to study cancer. The unlikely journey that brought him to Johns Hopkins was far from easy, but as Johns Hopkins leadership would soon recognize, one of academia’s worst students was an astute learner and even better teacher. Coffey became one of Johns Hopkins foremost experts in prostate cancer and one of its most sought after professors.

In more than 50 years at Johns Hopkins, Coffey has racked up a long list of accomplishments. Many of the accolades are as unconventional as the man. He served as acting chair of the Department of Pharmacology without ever taking a course in pharmacology.  With no medical degree, he helped found the Cancer Center in 1973 with its first director Albert Owens and then ran it in 1987, and served as President of the American Association of Cancer Research from 1997 to 1998.  The jovial, spectacled, southern-speaking Ben Franklin look alike is a one-of-a-kind, and his story is as much about cancer research as it is about the human spirit.

The early research of Donald Coffey was in many ways the bedrock on which modern genetic and epigenetic discoveries at Johns Hopkins were built.  In 1974, he turned the research world upside down challenging the popular thought on how DNA was copied. At the time, little was understood about DNA and genes. Most researchers were interested in understanding what it was and what was recorded on it. Not surprising, Coffey had a different idea.  He was interested in the structure of the tape and how it was organized in the nucleus. He decided to look at the core of the nucleus. It was a revolutionary idea. Most scientists believed there was nothing inside the core. 

Popular thought was that there was no single place in the cell where DNA was copied.  Instead, scientists hypothesized that DNA was like a tape and was replicated by a moving recording head, of sorts, which ran along the stationary tape. Coffey disagreed. He believed the core of the nucleus was where DNA was copied and that the tape-like DNA strands, a yard long, were coiled tightly inside the cell nucleus.   

For those born in the digital era, the tape cassette and recorder analogy seems outdated, but one has to remember this research was occurring in the 1970s.

With a $500,000 no-strings-attached cancer research grant from Bristol Myers, Coffey brought together two young up-and-coming unknowns in the field of cancer research, Drew Pardoll, an M.D.-Ph.D. student, and Bert Vogelstein, who Coffey calls the only true genius he’s ever met.

Pardoll theorized that rather than using one mobile recording head, the DNA tape was instead copied at thousands of fixed sites along what they dubbed the nuclear matrix. Coffey explains, “The nucleus has a skeleton to it.  That’s the nuclear matrix.  Attached to that skeleton are recording heads, the machinery that replicates DNA. The DNA is organized in thousands of loops moving through these heads.”  Vogelstein used a series of calculations, which Coffey describes as too complex to translate, and showed that Pardoll’s model could work. Coffey recognized that a doubting scientific community would not believe it unless they could see it, so they showed what all of it looked like through pictures and scale models.  Coffey recalls, “Ken Pienta and I went to Sears and bought a jigsaw, and we built an award-winning scale model 175 feet long of a relaxed single loop of DNA magnified 25 million times.”  Another scale model, this one just four feet long, was constructed to illustrate the super-coiled loops of DNA.

What does all of this have to do with cancer?  For that, Coffey, the professor known for using Slinkys, soap bubbles, soda cans, and 175-foot long replica of a DNA loop to illustrate a point, turns to the cassette recorder.  He pops an audiocassette tape into a tape player and pleasing sounds of Johann Strauss’ Blue Danube waltz begin to play. Without warning, it is interrupted by the Rolling Stones singing Get Off of My Cloud.  Unexpectedly, the tape begins once again to play Blue Danube.  “This is cancer,” says Coffey.   “Cancer is like your body’s genetic tape playing the wrong song at the wrong time,” explains Coffey.  “The tape is all mixed up and contains errors. Cancer is a problem of uncontrolled cell growth and differentiation, and I want to know what tape is played and when.  Pieces of the tape are in wrong place, and there are errors in what is playing.  Songs are played at the wrong time. Embryonic songs are played when they should have been turned off.”

Of course, understanding what is on the tape and how it is played has been one of the greatest scientific contributions of Johns Hopkins.  Coffey’s students Vogelstein and Pardoll became world-renowned scientists in their field; Vogelstein as the most frequently cited researcher in all of medicine for his work revealing the genetic blueprint for cancer and Pardoll for his work in figuring out how cancer cells evade the immune system. As for the tightly coiled loops of DNA, Kimmel Cancer Center investigator and leading epigenetics experts Stephen Baylin and William Nelson showed that the coils and loops touch and interact with many gene sites, creating a structure that turns off tumor suppressor genes.

Still, at the time of their discovery, the notion of a matrix was met with skepticism. “It was amazing how these young people here could prove this stuff against the greatest labs in the world,” says Coffey.  Suddenly scientists at MIT and Princeton were doing similar experiments.

Coffey was not blindly enamored of the work that came from more prestigious academic institutions nor was he disregarding of the observations of everyday folks who learned their trade on the job and not in the classroom. He was as comfortable conversing with the janitor as he was with the CEO. This not only made him a fine human being but also a stellar scientist.  Coffey was interested in solving problems, and he was not someone motivated by notoriety or celebrity. 

He tells of a job he had when he was in college working as a chemist for the North American Rayon Company in Tennessee. They were having a problem with lines that carried acid used in the production of rayon.  The acid would back up and spill all over the floor.  Coffey was charged with finding out what was causing the problem.  He talked to everyone he could think of, including Big John, a laborer who worked in the basement of the building. Big John tipped him off to a vibration in a machine that started about 20 minutes before the breakdowns occurred. This observation led Coffey to the cause of the problem. 

Coffey believed that to find answers, one first had to ask the right questions. “He liked to gather everyone’s ideas.  He made people feel like no idea would ever be looked at as being stupid,” recalls Pardoll.

Coffey and Big John became instant legends at the North American Rayon Company, and his boss there, a Johns Hopkins alumnus, inspired him to go to Baltimore. He boss told Coffey, “You’ll have to work your way in, but they’ll take care of you. When you hit the ball they don’t care who you are.”

“I was a C student from East Tennessee State University, and now I was planning to go to Johns Hopkins,” says Coffey. (Before Tennessee State, he attended Kings College. The college president suggested he leave after hiring a plane to drop political leaflets, some of which got wet and dangerously fell to the earth like a cinder block. Years later, Kings College gave him an honorary doctorate.)

Coffey discussed it with his wife Eula, and they agreed they should move to Baltimore.  By day, Coffey worked at Westinghouse designing radar antennas.  In the evening he took classes and got his foot in the laboratory door by washing glassware for graduate students.  After receiving a glowing reference from his former employer at North American Rayon, the School of Medicine hired him to work evenings in the urology lab.  A year later, in 1959, with no graduate degree, he was named the acting director of the Brady Urological Research Laboratory.  “The starting salary was $5,000.  I was making $18,000 at Westinghouse, but I knew I wanted to do cancer research.”  After a year of running the lab, he was accepted to the School of Medicine’s graduate program in Physiological Chemistry. 

Coffey earned his Ph.D. at 33.  By then, he had already been a chemist, an engineer, a laboratory director, and prostate cancer researcher. Everybody wanted him, and Professor Paul Talalay hired him to the Pharmacology Department faculty.  Soon thereafter, Professor William Scott invited him to join the faculty of the Urology Department.  Coffey’s meteoric rise from his self-described role as “chief bottle washer” to become the Catherine Iola and J. Smith Michael Distinguished Professor of Urology; professor of Oncology, Pharmacology and Molecular Sciences, and Pathology; and a member of the professional staff of the Applied Physics Laboratory seemed right out of a Hollywood movie.

In fact, despite his academic struggles, Coffey was a perfect fit for Johns Hopkins.  He believed that much could be learned if people from different disciplines would just get together and talk about a problem. “People like to visualize a disease as one thing wrong.  Like, there’s a wire loose in car, but it’s never just one wire in a car.  By the same reasoning, it takes multiple steps to form a cancer cell.  There’s an aging phenomenon associated with it, a genetic phenomenon, and a whole bunch of environmental and epigenetic factors.  Man, I hate to tell you how often people from all those different fields don’t get together in science,” says Coffey. 

For Coffey, neither the classroom nor the laboratory ever closed.  In the hallways of the Brady, in his office over high tea, or in a conference room, Coffey could be found fostering collaborations and inspiring innovative ideas about cancer.  It was not unusual for these discussions to last long after business hours.  The next morning, equations and notes jotted across blackboards were evidence to the lively discussions that had occurred the night before.

Coffey, who suffers from dyslexia, profoundly understands that everyone learns differently.  The disorder that caused him to struggle as a student helped make him one of the world’s greatest teachers.

Among his many revered lessons is what he calls the “Real Final Exam.” In it, he extols several time-tested principles:

“If you find something to be true, what does it imply?  Often we don’t need more experiments.  We need more critical thinking about the results.”

“Generate more than one concept to explain your data, then give all the possibilities your equal attention and effort.  Your pet idea will usually turn out to be just that.” 

“Don’t assume anything you can’t prove.”

“The experiment that doesn’t come out the way you think it should is the only experiment that is really going to teach you something new.”

“When discoveries are made, give everyone credit.  You were probably not the first one to study the problem, nor will you be the last.”

In fact, the last one is a favorite of Coffey’s who sometimes seems to espouse credit for everyone but himself.  Back at North American Rayon Company, though he put all of the pieces together to solve the acid line problem, he quickly redirected credit to Big John and secured him a sizeable raise. He talks willingly and with pride about the accomplished researchers and clinicians who have come through his laboratory. Rightfully so, as the list reads like a who’s who in cancer.  In addition to Vogelstein and Pardoll, it includes Kimmel Cancer Center Director William Nelson, Urology Director Alan Partin, Radiation Oncology and Molecular Radiation Science Director Ted DeWeese, and Prostate Cancer Foundation President and CEO Jonathan Simons, to name just a few.

Coffey continues to patrol the hallways of Johns Hopkins in search of new talent.  He has a simple formula for finding the best and brightest.  He asks people. It could be other professors or students, or even patients.  He asks them, who is the smartest?  Who is the best?  Then, he recruits these rising stars to the fight against cancer.  As the list of his recruits attests, the formula is one that works. 

Coffey turned 80 on October 10, but age has done little to quell his quest for knowledge.  His most recent research examines the shared traits between bacteria and cancer cells.  Coffey and his collaborators believe that cancer cells, like bacteria, rely on communication and “social networking” to survive and thrive within the body.  Cancer cells and bacteria use chemicals and gene pathways to override controls that tell cells how to behave, he says. He hopes that better understanding the social behavior of cancer cells—intricate cell-to-cell communication they use to grow, spread, and evade treatments—will inspire new therapeutic approaches. 

Coffey was also part of a team that used a testicular cancer model to prove that cancer cells that are exposed to heat are easier to kill with anticancer drugs and radiation therapy.  They showed that even advanced cancers that have spread to other parts of the body could be reined in with heat.  To develop it clinically, Coffey, Radiation Oncology Director Ted DeWeese, and scientists Robert Ivkof, Shawn Lupold, and Prakash Kulkarni3 are using small antibodies that attach to iron particles which, in turn, naturally attach to cancer cells throughout the body.  When exposed to alternating magnetic fields, the iron particles vibrate enough to heat up the cancer cells so they become more vulnerable to therapies.   

Coffey says these discoveries have led to a new fascination with temperature. In terms of personalized medicine, Coffey points out, temperature, as fever, is one the of primary measurements used to determine whether someone is sick—and he ticks off a multitude of questions: “I am trying to understand temperature and the scientific and evolutionary reason for the precise body temperature of 98.6°. Why is it not 87° or 103°, and why does a chicken egg hatch at approximately 100°? Why is a hurricane caused by only a few degrees change in ocean surface temperature? Why does a flame form in a precise structure on a candle?  And why does a woman's temperature go up a few degrees when she ovulates? Why is the sex of an alligator and turtle decided at precisely 100°?  And why does a man's sperm not survive body temperature? Why do snowflakes form such interesting patterns? How does life form against the second law of thermodynamics of increased entropy and heat? How can this heat and temperature be used to cure infections and to treat cancer and to germinate acorns and to form the precise tree line on the mountain?”

While the answers to these questions may, for the time being, remain a mystery, one thing is certain. In the inquisitive mind of Donald Coffey, nothing changes but the birthday. His enthusiastic and continuing quest for knowledge promises to bring Johns Hopkins and the world more unexpected discoveries, unusual props, and riveting lectures.

 

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