Laura Benzaquen and Jose Halperin have found that a common antifungal agent, clotrimazole, inhibits cell proliferation. The drug is now being tested as a treatment for a wide variety of diseases. The miracle of seeing a cell divide-of "like" so exquisitely and accurately producing "like"-can turn into a horrifying sight when the dividing goes on relentlessly. This uncontrolled dividing of cells is the hallmark of a multitude of diseases, from atherosclerosis to cancer.
Harvard Medical School researchers have found an agent that may be able to control this unwanted cell proliferation. In the June 1 issue of Nature Medicine, they report that clotrimazole, a common drug for fungal infections, inhibits the division of cancerous and noncancerous cells, both in vitro and in animals. This work suggests that clotrimazole (CLT) may be useful for treating tumors and a variety of other ailments, such as rheumatoid arthritis and atherosclerosis, that involve abnormal cell proliferation.
"Many human pathologies involve cell proliferation, both benign and malignant. So we are not just talking about cancers," says Jose Halperin, HMS associate professor of medicine who led the research. "The spectrum of possibilities for a relatively low-toxicity and high-potency inhibitor of cell proliferation is tremendous."
CLT has been safely used, and sold over the counter, for many years to treat commonplace fungal infections, such as athlete's foot and vaginal yeast infections. Moreover, the dose of CLT that inhibits cell proliferation is similar to dosage levels prescribed for fungal infections.
The discovery of clotrimazole's hidden properties as a potent inhibitor of cell proliferation was not just a matter of serendipity. For years, Halperin and his colleagues in the Laboratory for Membrane Transport have been studying the movement of ions across channels in the membrane of the cell. They were especially interested in a channel that allows potassium to move across the cell membrane. This channel appears to be regulated-opened and closed-by the rise and fall of calcium ions inside the cell.
The researchers had a hunch that the opening of these channels, known as calcium-activated potassium channels, might be a crucial step in cell division. If so, then blocking them-preventing them from opening-should prevent the cell from proliferating. But they couldn't prove this hypothesis because they had no effective way of blocking the calcium-activated potassium channels.
Then, a few years ago, they came across a report showing that calcium-activated potassium channels in red blood cells could be inhibited by clotrimazole (the report didn't say anything about clotrimazole inhibiting cell proliferation). The researchers decided to see if clotrimazole could stop cells from dividing.
They began by introducing clotrimazole to a variety of normal human cells-including fibroblasts and smooth muscle cells-grown in culture. They then exposed the CLT-treated cells to growth factor. Normally, growth factors trigger cells to divide. But the CLT-treated cells just sat there.
These two slides compare the lung of a mouse treated with clotrimazole (right) with the lung of a mouse notreated with the antifungal agent (left). Metastatic tumors appear as dark grey circles, which are readily apparent in the untreated mouse. The lung of the treated mouse, in this instance, appears to be free of tumors.
"We found that clotrimazole had a very potent dose- dependent inhibitory effect on growth-factor-stimulated cell growth," says Laura Benzaquen, a clinical fellow in medicine at Beth Israel Hospital and lead author of the study.
Interestingly, when they stopped treating the cells with CLT, the cells would appear to recover their normal ability to divide in response to growth factor, suggesting that the drug does not destroy the cell or its components.
The HMS researchers then repeated the in-vitro experiment, this time using a wide variety of cancer cells, including very aggressive human melanoma cells, colon cancer cells and lung cancer cells. "And all cancer cells tested so far have been stopped with clotrimazole," says Halperin.
"We're focusing now on applications that will be treating very important diseases, diseases that have a tremendous impact on public health." --Jose Halperin
Finally, they tested CLT in mice. To perform this test, they chose a virulent strain of skin cancer cells developed by Randolph Byers, who was, at the time, HMS assistant professor of pathology. Byers, who is now at Boston University Medical School, had cultured a line of very aggressive skin cancer cells, called MMRR, that metastasize only to the lungs. This made it easy to monitor the spread of cancer cells.
Halperin and his collaborators took the cultured MMRR cells and injected them into the tail veins of mice whose immune systems had been destroyed. They then injected CLT subcutaneously in one half of the mice. In the other half, they injected a placebo. The results were stunning. The control animals had, on average, 40 distinct cancerous growths in the lungs. The mice given daily injections of CLT had, on average, fewer than eight metastases in the lungs.
Although exciting, the results were also puzzling. "We couldn't believe that just inhibiting the calcium-activated potassium channels would be enough to produce such dramatic results," Halperin says.
In a series of experiments, the HMS researchers subsequently found that CLT also depletes the cell's storage of calcium. Normally, calcium levels are under tight control in the cell. Most calcium is stored away in a cell compartment known as the endoplasmic reticulum. When the cell is exposed to a growth factor, these stores of calcium are released into the cytoplasm. The calcium is then either quickly pumped out of the cell through the cell membrane, or returned to the reservoirs in the endoplasmic reticulum.
The system is very tightly regulated, Halperin says. If the calcium stored in the reservoirs does not return to its normal levels, channels in the cell membrane open and let in more calcium.
CLT interferes with this storage system, the HMS researchers discovered. It draws calcium from the endoplasmic reticulum, but then blocks the channels that normally open to restore the calcium reservoirs in the endoplasmic reticulum.
Thus, the researchers believe CLT may be working on at least three fronts to inhibit the early stages of cell division. First, it is depleting the intracellular calcium stores. Second, it is blocking the restoring of calcium in the endoplasmic reticulum. Third, it is blocking the calcium- activated channels that allow potassium to enter and leave the cell.
"It's the combination that appears to be so powerful in inhibiting cell proliferation," says Halperin.
Whether CLT will inhibit cell proliferation in humans remains to be seen. The drug is being tested in independent clinical trials at Harvard's affiliated hospitals as a treatment for a wide variety of proliferative diseases, both cancerous and noncancerous. Among the noncancerous diseases being tested are nonmalignant, proliferative skin disorders such as psoriasis and actinic keratosis. Soon they will start trials for vascular proliferative diseases such as atherosclerosis.
Sheffield Medical Technologies, a pharmaceutical technology management company based in New York, has obtained the licensing rights to develop clotrimazole and its analogs as anti-proliferative agents.
--Misia Landau
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The clotrimazole research was performed by Halperin, Benzaquen, Byers and Carlo Brugnara, associate professor of pathology at Children's Hospital.
Healy was chosen by President George Bush in 1991 to head the NIH. During her tenure, she launched the Women's Health Initiative, a $625 million effort to study the causes, prevention and cures of diseases that affect women. She established the Shannon awards to provide funding for creative, innovative approaches to biomedical research. She also established a laboratory for human genetics at the NIH.
A cardiologist by training, she directed research programs at Johns Hopkins University School of Medicine and at The Cleveland Clinic Foundation prior to assuming the NIH post. Healy graduated from Harvard Medical School in 1970, and is a member of the Board of Overseers of Harvard College.
END
Brown, 28, received a bachelor's degree in English at Williams College. Before coming to HMS, he worked at a number of miscellaneous jobs, including stints as a newspaper reporter, a busboy, an EKG technician and an English teacher.
It was while teaching seventh and eighth graders that he began to write poetry. Now he uses writing as a way to keep his "creative" side alive while in medical school. Says Brown: "Medical school is like being in a swamp. It's a wonderful swamp, but it's easy to lose that part of yourself."
The following is Brown's poem that won first place.
Timepiece
I came upon the watch you gave me
At the bottom of the dresser drawer,
Still obstinately chopping one moment from another
To a musty audience of old ticket stubs,
Half-chewed pencils, bits of string,
An assortment of anti-fungal medication
And a scattering of vagrant coins
Caught here and kept for a time
From their journey from pocket to pocket.
Few things we engineer we want to last
Like watches do, to be this sure and steady,
To drag us wrist-first
From door to door
As if we would be lost without them,
Pounding their battery-powered rhythms
Into our echoing souls
Until we know the minute and the hour
Of every arrival, delay, and departure
Through the stale concourses of our lives.
And though I have long since forsaken
This one for another, more waterproof,
One that I can wear into the shower,
I have not forgotten that small scratch
From the boulder in the Adirondacks,
The flecks of white paint from your garage,
A faint smudge that might be suntan lotion
From our Sunday afternoons upon the beach,
And the holes that gape from the worn leather band,
One for my wrist, and one for yours.
--David W. Brown
"How can these kids compete?" asks Reede, now the director of the Minority Faculty Development (MFD) Program at Harvard Medical School. "How can you compete if you don't have the equipment? And you don't have the texts? And you don't have the teachers?"
Joan Reede: "I think all of this stems from my working in environments where I saw what happened when [students] don't have [educational opportunities]."
Since coming to HMS in 1989, Reede has worked to give
these public school students the opportunities they deserve.
She is attempting, through a variety of programs, to enhance
the science education they receive, to excite the students
about a career in biomedicine, and to give them the
confidence they'll need to reach their goals.
"The question is: What can we do to help put the balance in? And you can say that we can just give money, but money alone is not the answer," says Reede.
As director of the MFD program, Reede has targeted three levels of the "pipeline" for making a scientist: teacher development, curriculum development and student development. In collaboration with HMS colleagues, she has helped create a program that, starting this summer, will train high school teachers. She has developed a neuroscience curriculum intended to make students curious about the workings of the brain. And she has helped establish a summer program that brings minority high school students into laboratories on the quad.
At the heart of Reede's work is the curriculum development. In January 1993, Reede embarked on a pilot television program, with the help of HMS neuroscientists David Potter and Edwin Furshpan, that involved 70 high school science teachers in five states. The program, funded by Harcourt General, was a series of five, 90 minute, interactive broadcasts designed to see if teachers thought the case-based learning utilized in the New Pathway could be tailored for use in their anatomy, biology and physiology classes.
"The overwhelming response was, 'Yes,'" says Reede, who took the teachers' comments and turned the program into a video to be used in individual classrooms.
"She's always thinking, always creating, trying to think of some way to creatively engage young kids," says Furshpan, the Robert Henry Pfeiffer Professor of Neurobiology.
Furshpan and Potter worked with Reede on the series and, later, the classroom video. Together they developed the case, titled "Mary's Mystery," featured in the video. The case presents a 17-year-old girl who has had a seizure in the park after leaving a party. Mary's story unravels through "911" type re-enactment scenes, interviews with the health care professionals that work with Mary, and short lectures on the brain given by Potter and Furshpan.
"There's hardly anybody who is uninterested in a medical case," says Potter, the Robert Winthrop Professor of Neurobiology. "You start with a real case, with a real person who is suffering and has a problem. And then you use that in a context in which you learn something."
Furshpan adds: "One of the things that 'Mary's Mystery' does is not simply teach neuroscience. It brings up psychosocial issues related to health. It tries to bring up questions of health care delivery."
Edwin Furshpan and David Potter have worked with Joan Reede on the program. Says Potter: "Each of us became what we are now because some devoted teacher decided that we were valuable to the future, and [put] time in on us."
This neuroscience curriculum also includes materials for hands-on exercises. Students are given brain images generated by MRIs and computer tomography scans. They are asked to point out the different structures visible on the slides. They also are given penlights to check each other's pupillary light reflexes.
"The students love that, and they are enormously involved," says Furshpan. "And then they're probably willing to sit and listen to David and me drone on about the reflex pathway involved in this."
With funding from Harvard Mahoney Neuroscience Institute, the curriculum has now been introduced to seven science classes in Boston, Cambridge, Brookline and Randolph. Reaction from the students involved has been positive. "They came away from their participation in the program with a feeling that they had a role in medicine-that there was a place for them too," Reede says.
Also, in early May, Reede, Furshpan and Potter presented their work with "Mary's Mystery" to high school teachers at the annual meeting of the Massachusetts Association of Science Supervisors in Marlborough. For Reede, this feedback from the teachers is essential. "They know how to teach. They know about their classroom. They know what's needed in secondary education."
Despite the teachers' enthusiasm about the curriculum, the future of the program is in doubt because of a lack of funding.
In the meantime, the three will launch the "Teacher's Institute" this summer. The institute, funded by Howard Hughes Medical Institute, will bring 10 teachers from Boston and Cambridge to HMS for a week of lessons on neuroscience. These teachers will be introduced to "Mary's Mystery," and thus problem-based learning. Site visits to HMS' affiliated hospitals have been planned, and the teachers will have a chance to investigate HMS' labs.
They also will work with Potter and Furshpan to flush out a new neuroscience case to be used in high schools. "The teachers presumably are coming because they hope to learn from almighty Harvard Medical School a lot of important things about teaching," says Potter. "Sitting here at almighty Harvard Medical School, we're looking forward to learning from teachers how we can actually do it right."
But to concentrate on just the teachers would be remiss in her responsibilities to the students, says Reede. "You've got these teachers who are up on the latest things, and they have all this wonderful curriculum, and they get these kids all excited, but where do these kids go?"
That's where "Project Success" fits in. Project Success is a program that places minority high school students interested in biomedicine in HMS' laboratories for eight weeks during the summer. This year, the third year the program has been offered, 10 area students will have an opportunity to do research. The program is sponsored by the National Institutes of Health.
With all of her work in these three areas, Reede's mission is clear: improve the educational foundation from which the students will launch, and instill them with hope and confidence that they can, in fact, fly.
Her reward? She speaks of the day last summer when the Project Success students presented their research to HMS deans and faculty. "They were wonderful. I sat there with tears coming down my face," she recalls. "You walk away and say, 'God, this was a good day.'"
--Rachel A. Streit
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The HMS group gave lectures on topics ranging from attention deficit disorder to new developments in obstetrics and gynecology.
"It has a cascade effect," said Susan Pauker, assistant clinical professor of pediatrics. "When you teach teachers, they in turn teach their students, and [the students] bring home their new knowledge to family and friends. You expand your actual teaching hours."
The HMS "troop" was organized by Eleanor Shore, dean for faculty affairs. "I had hoped to give [the teachers] access to some of the most interesting things in medicine and science going on right now-because their enthusiasm transmits to the students."
In addition to Pauker, the HMS presenters were Susan Arnold, instructor in obstetrics, gynecology and reproductive biology; Edwin Furshpan, the Robert Henry Pfeiffer Professor of Neurobiology; Ned Hallowell, instructor in psychiatry; Beverly Merz, editor of the Women's Health Watch; Thomas O'Brien, associate professor of medicine; David Potter, the Robert Winthrop Professor of Neurobiology; Joan Reede, director of the Minority Faculty Development Program; Patricia Thomas, editor of the Harvard Health Letter; and Margaret Waterman, lecturer on medical education.
END
The idea of upgrading physical medicine and rehabilitation to departmental level was first proposed a decade ago. It will help the medical school in its efforts to recruit a physician to head physical medicine and rehabilitation, and aid in faculty development in this rapidly maturing field. The change also should help insure better training of students in this discipline, and attract clinical funding.
The faculty council also heard a report by Richard Kitz, faculty dean for clinical affairs, on guidelines for faculty compensation and practice plans. In September, a task force on faculty compensation made recommendations that would establish limits on indirect as well as direct compensation. Department heads at the affiliated institutions will be required to draft compensation plans for their faculty and for themselves, which will then be reviewed by an oversight committee.
Kitz said that the practice plans should provide sufficient support for teaching and research. It has been suggested that the practice plans contribute 20 percent of their income for these purposes.
Ellen Rothman
Mount Success was our nemesis. We were tired, hungry, and
sweaty after hiking in the Adirondack Mountains all day.
Nine of my Harvard Medical School colleagues and I were
attempting to reach the summit of the 3,300-foot peak of
Mount Success before nightfall. We failed.
The irony of the situation was not lost on us.
When I arrived at Harvard Medical School last summer, I was eagerly anticipating a pass/fail, relaxed academic atmosphere, but dreading the fabled work load and stress of medical school, and feeling intimidated by the potential brilliance of my classmates.
As I settled into reality over the course of the year, my second two concerns dissipated as I adjusted to the course load and became friends with my peers. The reality shock came from the high stress that low-pressure academics can elicit. Particularly among students like us who are used to achieving "success."
There have been rumors circulating about my class in particular, especially at exam time. "I heard that our class is the most stressed-out class that has come through in at least the last five years." This description of our class has been attributed to everyone from someone's friend's tutor to Holmes Society Master Dan Goodenough.
After preparing for a pass/fail exam by a marathon week of studying, I was commenting to my friend how overzealous our continuous vigil in the library seemed for a pass/fail exam. I never studied this hard for an exam that was graded in college. "I know I'm going to pass. That's not the issue," he said. "I just want to pass with dignity."
That comment is not particular to my friend. I have heard several variations on the same theme, including, "Yes, but I want to pass well." We all joke about the "Super P" for the student who passes extraordinarily well. And yet, we all strive for it.
No matter how inconsequential each exam may be and no matter how forgiving the administration, we expect ourselves to surmount and to succeed. For many of us, it is not enough to just pass.
At an open forum recently, one of my classmates voiced her frustration about failing a block final. "Why is it that no one talks about failing a test? I saw the curve. There are 10 more people down there with me. This is not something we should be ashamed of." In medical school, where we break some of the most ingrained social mores, failure is the ultimate taboo.
We are constantly scrutinizing ourselves to maintain a safe distance from even the risk of failure. In a curriculum with no requirements, conversation is constantly punctuated by, "Are you going to learn that?"; "What have you read?"; and "Do you think that's important?"
Not only do we doubt ourselves, but we even question the New Pathway and the learning process itself. People are constantly concerned that we do not learn enough facts and basic science. Most of us have heard stories of disparaging remarks about our scientific grounding by clinicians during the rotations. We all joke about reading Harrison's, the 2,000-page tome of medicine, cover to cover. Rumor has it that one of our classmates actually has.
This collective doubt is contagious. One of my friends came away from tutorial feeling frustrated and stressed after their discussion about the New Pathway. They had voiced the usual nagging doubts about the "quantity" of our education. My friend, who is generally pleased with our education, said, "Well, maybe I'm not learning enough. Maybe I'm not going to be a good doctor. But I guess I'm just going to have to trust that Harvard knew what they were doing when they picked me," she said.
Medicine itself rewards and requires this constant self- evaluation and desire to succeed. The glamor of medicine is the ability to save. According to this mystique that is only partially grounded in reality, we will be able to heal people suffering from self-induced diseases like cirrhosis and lung cancer. We will be able to rescue other people from a genetically predetermined fate. We will understand the human body, the enigma of life. In turn, patients will look to us to provide a dramatic, and even daring, escape from fate.
Yet, at the same time, we ourselves must be above human fallacy. We must surmount fatigue and eradicate oversight and error. Our mistakes and failures can have catastrophic consequences.
Of course, this idealized vision of medicine and health care is exaggerated and aggrandizing. Nonetheless, the pressure can be overwhelming.
In a recent pathology lab, our instructor was displaying someone's internal organs that were riddled with the mealy, yellow tumors of lymphoma. "You must be extremely careful when palpating potential tumors in your patients," he said. "You may dislodge loosely associated cells which can then produce new metastases." It is overwhelming to think that even my innocent touch can have deadly consequences.
Perfection. Medicine expects it. We demand it. We failed in our first attempt at Mount Success. We will quest for the summit for the rest of our lives.
--Ellen Rothman
Editor's Note: Ellen Rothman is completing her first year at Harvard Medical School. Her column, "On Becoming a Doctor," appears in every other issue of FOCUS.
"There was a lot of shifting going on at that point. Until then, if you were a biochemist or molecular biologist, you might study the same [organism] your whole life," says Jonathan Beckwith, American Cancer Society Professor of Microbiology and Molecular Genetics at Harvard Medical School. "But in the late '60s, with all the new developments-and even more so in the '70s-it was almost the opposite. If you stayed with [the same organism], you were disdained."
Beckwith has stuck with the same organism, a single- cell bacteria known as E. coli, for 35 years. Beckwith's long-term association with E. coli-far from breeding contempt-has produced a wide range of genetic discoveries, from the discovery of the genetic element that turns genes on to the cloning of the first gene in 1969.
Nor have Beckwith's discoveries been restricted to the domain of genetics. Over the past two decades, he has used the tools of bacterial genetics to answer a whole series of questions about how cells work, and, in particular, how proteins are transported inside and outside of the cell-questions untouched by geneticists until Beckwith tackled them. He also has led the way in using genetics to address the question of how proteins are folded in the cell.
"It's stuff that everybody would like to be doing. Somehow he manages to attack problems others would like to," says Joe Pogliano, a research assistant in Beckwith's lab, adding that Beckwith's success lies to a great extent in his ability to focus on the bigger picture. "Jon likes to think big. He won't spend time chasing out little details. Something he's really good at is defining what's important and what's not."
Beckwith's sense of the big picture has drawn him outside the lab and into the realm of politics. Over the past 25 years, he has been actively involved-through various political organizations and activities-in raising people's awareness of the ethical and social issues surrounding genetic research. Though he has done it from the security of a tenured position at HMS, these activities have, at times, put him in direct opposition with his close scientific colleagues.
"The important thing about Jon is that he put himself outside of his [scientific community] for a political purpose," says Richard Lewontin, Harvard University professor of zoology. "I think it took more determination-more willingness to distance himself from his close scientific community-than [other politically active scientists] who were outsiders to that community."
What drew Beckwith into the world of science in the first place was a mixture of talent and luck. The son of an English teacher and a businessman, Beckwith was not fated to become a biologist. "It wasn't like I had a burning interest in science from a very young age," he says.
As an undergraduate at Harvard, Beckwith was good at science-he majored in chemistry-but not terribly enthusiastic about it. Even as a graduate student in biochemistry, he was "looking for something to get excited about."
"That was the first flash of real excitement that I remember having," says Beckwith. It wasn't just the idea that genes are turned on and off, but also the way Jacob and Monod came up with the idea that caught Beckwith's imagination. "Just the way of thinking-and, obviously, the intuition and imagination that went into their work-was something that I hadn't seen before," says Beckwith.
Beckwith decided that he wanted to work with Jacob in Paris. He had already visited the city while chasing his future wife, Barbara, through Europe. Numerous strolls along the Seine, endless hours talking in cafes, visits to the French countryside-all of these cast a spell. "I knew I had to get back," he says.
But Jacob's lab was a hot place to be in 1960 and competition to get in was stiff. Beckwith applied and was rejected. "I think that I didn't have anything that particularly appealed to him at that point," says Beckwith.
Indeed, it would be three years before Beckwith would have something special that would get him into Jacob's lab. In the meantime, he went to work first with Arthur Pardee, now HMS professor of biology and chemistry and molecular pharmacology, emeritus, and then with Bill Hayes, now head of the microbial genetics research unit at Hammersmith Hospital in London.
As the year in London was drawing to a close, with his fellowship money running out-and having been rejected a second time by Jacob-Beckwith applied for jobs in the United States and didn't get any. "I had no money for the following year. I didn't know what I was going to do," he recounts.
In the midst of this uncertainty, Beckwith's thoughts returned to work he had done in Pardee's lab on the question of how genes get turned on in E. coli. (It was in Pardee's lab that Beckwith first started working on the tiny creature.) Beckwith was following up on a suggestion by Jacob and Monod as to where the "on switch" for a particular set of genes, known as the lac operon, might lie when he came across a puzzling finding. Deleting the supposed on switch apparently turned the lac genes on.
"A lot of science is about asking the right questions." --Jonathan Beckwith
"This was inconsistent with their model that this was an essential site for transcription. Because if you delete the essential site, you should knock out the ability [to turn genes on]," says Beckwith.
At first, he didn't know what to make of the anomaly, and he didn't think to question Jacob and Monod's belief that the supposed on switch was, in fact, an on switch. "Their intuition had been so good over the years that if they intuited something, everybody else took it on faith that that was correct," Beckwith says. "The great Jacob and Monod had shown this, and it must be right."
It was only in the waning months of his postdoctoral work in London-with no job prospects and, perhaps, with nothing to lose-that Beckwith began questioning his most basic assumptions. Turning over the anomalous results in his mind, Beckwith realized that the supposed on switch was, in fact, controlling the translation of messenger RNA into proteins-and not the transcription of DNA. Deleting this region had the effect of turning on the genes because the deletion was removing any restraints on the translation process.
But the effect on Beckwith's faltering career was, without a doubt, positive. Beckwith was invited to work in the labs of Brenner and of Jacob. He also was offered a faculty position at Harvard. He accepted all three-an embarrassment of riches by today's academic standards.
By the time Beckwith arrived in Paris, Jacob was turning his attention away from genetics to the question of how organisms develop, but his lab was full of lively postdocs still focused on genetics. Beckwith would exchange reprints and ideas with them across the lunchtable-spread with champignons and saucissons from the local epicerie-or over drinks at sidewalk cafes. And occasionally even in the laboratoire.
One of these freewheeling exchanges led to a technique for isolating genes. This technique-which essentially uses viruses to snatch genes from a chromosome-came about as the result of a serendipitous collaboration between Beckwith and his officemate Ethan Signer.
"Why I still like what we're doing [in the lab] is that our work does involve a lot of time spent talking about how we are going to do an experiment." --Jonathan Beckwith
Beckwith had been developing a method for moving around the lac genes to any place he wanted in the chromosome. Signer, who is now professor of biology at Massachusetts Institute of Technology, had been studying how viruses pick up genes. "So one day [Ethan] said, 'We should see if my virus will pick up your lac genes, now that they're in this convenient place.' And they did," Beckwith recalls.
Indeed, Beckwith would use the method to isolate the first gene, the lac z gene, when he came to HMS-a truly novel achievement in the pre-recombinant-DNA mid-'60s era. "I don't think that people were thinking about purifying genes then," he says.
Indeed, Beckwith's primary aim when he first arrived at HMS in 1965 was to go back and find the mysterious on switch of the lac genes. Using a combination of techniques-including a new technique that Beckwith designed for monitoring the activity of different genes-he and his colleagues succeeded in isolating the on switch, or promoter.
As it turned out, this discovery raised a new challenge, one that threw something of a wrench into his career. One of the things he learned about the lac promoter is that it does not work alone. Instead, it requires other agents-RNA polymerase and a DNA-binding protein-to help it turn on the lac genes. To figure out how the lac promoter and these other agents interact required using biochemical techniques for studying the DNA-binding qualities of proteins-a skill that Beckwith lacked.
"It was a little bit frustrating to go so far with the work in terms of the ideas and not be able to follow it through to do that kind of biochemistry," says Beckwith. He faced a decision. Either he could collaborate with people who had the expertise, or he could gain the expertise himself.
After a couple of failed collaborative ventures, Beckwith decided to take a break. "This was actually an important transition point for me," he says. Not only had he been running a lab full time, he had become very involved in a variety of political activities and organizations.
"Jon was doing the 'terrible' thing-I mean he was [cloning DNA] in microorganisms-and that's what people were screamingly afraid of. So he really had to face up to that," says Lewontin.
The press conference attracted an enormous amount of publicity, as did a speech Beckwith gave a few months later to the Society of Microbiologists. Beckwith had won the prestigious Eli Lilly Award, and in his acceptance talk, he announced that he would give the prize money to the Black Panther movement.
"I got attacked by some people pretty strongly," he says, adding that he also received a great deal of support from students.
Being in the public limelight had an important effect on Beckwith. "Because I had to confront these issues, I was forced to try and really understand [the social and political issues] I was talking about."
In his spare time, Jonathan Beckwith loves to explore the canyons of the Southwest.
Beckwith became extremely active in exploring issues of genetic
research and broader social issues, both in the organization
"Science for the People" and in local protests.
"Jon put an immense amount of time and energy into Science for the People. Some people took a lot more responsiblity than others and worked harder and nudged other people. And Jon is that sort of person. And he deserves immense credit for that," says Lewontin.
In the fall of 1970, Beckwith decided to take a sabbatical. "I was actually burned-out from a combination of keeping a lab going and doing this [political] work," he says. He went to Italy, to a colleague's lab, where he tried his hand at purifying DNA. "I was a dead loss, a total failure," he says. A family illness called him back to the United States after only four months, but, by then, Beckwith had made a decision.
"I think what I must have done was decide that genetics was my forte and what I enjoyed doing," Beckwith says. So, while many geneticists were switching to new methods-and to other organisms-in order to study gene regulation, Beckwith decided to stick with E. coli and to look for new kinds of problems that could use genetic input.
He became intrigued by a whole new set of questions. One of these was the puzzle of how cell membranes are generated. Another was how membranes export proteins. These questions had previously lain in the province of cell biology.
Beckwith found that he could approach these with the same techinques he had used-and, in some cases, invented-to study how genes are regulated. For example, he and his colleagues could use the classic genetic method of selecting for mutant bacteria-in this case they looked for a whole variety of mutants that were defective in getting proteins out of the cell
. "The idea was that genes code for various parts of the machinery in the cell that gets proteins out," Beckwith says, adding that mutations in each gene would impair the cell's ability to secrete proteins.
To sort out the various mutations, Beckwith and his colleagues employed the same technique he used to identify the promoter. This technique, known as gene fusion, consists of attaching a gene with a clearly identifiable product onto one whose function is in question. So far, Beckwith and his colleagues have used this technique to identify five of the six genes known to be responsible for secreting proteins in bacteria.
"That basically opened up the major research that we've done for years and still continue, at least in part. But it took us some time before we recognized the full extent of the power of what we had," Beckwith says.
Having isolated the secretory genes, called sec genes, Beckwith and his colleagues will now try to purify the proteins and to figure out how they interact. Beyond that lies the question of how proteins get across the cell membrane.
Beckwith spends a great deal of time in his lab, where he thrives on troubleshooting with students. He encourages in students the same intuition and imagination that drew him to genetics.
"He leads [class] discussions a little bit the way he runs the lab-encouraging people to be creative. Maybe that's why there have been so many breakthroughs in his lab-he allows people to be creative and think on their own," Pogliano says.
--Misia Landau
"It's two worlds. And in the middle a whole array of fascinating things," said Judith Messerle, Countway librarian.
The Countway Library celebrated its 30th birthday May 23 with an open house that featured talks, computer demonstrations and an exhibit of portraits of medical and science luminaries by the renowned photographer Yousuf Karsh. The anniversary provided an occasion for the library to detail its plans for the future, which include a $10 million renovation. There also are plans to make the contents of the library-and of other libraries around the world-more accessible to Countway users.
"I want the Countway to play a role in teaching people [how to find] their way in the new information network," said Paul S. Russell, chair of the joint library committee.
The Countway Library actually represents the confluence of two formerly independent libraries, a Harvard library housing collections from the medical school, dental school, and school of public health, and the Boston Medical Library. Before the merger, the BML-which was established last century-was far ahead of the Harvard library in terms of medical collections. But it was struggling with a mounting pile of uninventoried and uncatalogued periodicals and books that had become a financial burden.
Although the idea for a merger between the BML and Harvard libraries met initial opposition by other local medical schools, the merger eventually went through in 1961. A building for the joined collections was completed in 1965, thanks to a major contribution by Sandra Countway in memory of her brother Francis, who was president of Lever Brothers Soap Company. The Countway Library is open to members of Harvard Medical School, Harvard School of Dental Medicine, Harvard School of Public Health, the BML and also to students and faculties in other local medical schools.
Over the past 30 years, the Countway has increased its collections and, at the same time, has tried to make them more accessible to its users through computer data bases and educational sessions. But now-with more than 60,000 volumes waiting to be inventoried and catalogued-the Countway finds itself in the same predicament that the BML did more than 30 years ago. The enormous wealth of the collections has placed a financial burden on the library. At the same time, the physical condition of the building is deteriorating.
The $10 million renovation will include improvements to the Countway's infrastructure as well as its interior. The reading room will be expanded. And a "knowledge lab" will be established that will "guide users in plumbing the depth and breadth of the expanding world of computerized [and nontraditional forms of] biomedical knowledge," Messerle said.
--Misia Landau
Key to Institutions:
BIH-Beth Israel Hosp.
BWH-Brigham & Women's Hosp.
CBR-Center for Blood Research
CH-Cambridge Hopsital
CHMC-Children's Hosp.
DFCI-Dana Farber Cancer Inst.
FDC-Forsyth Dental Center
HMS-Harvard Medical School
HSPH-Harvard School of Public Health
JBCC-Judge Baker Children's Center
JDC-Joslin Diabetes Clinic
MAH-Mt. Auburn Hosp.
MGH-Mass. General Hosp.
MMHC-Mass. Mental Health Ce.
MH-McLean Hosp
NEDH-New Eng. Deaconess Hosp.
SERI-Schepens Eye Research Inst
SRH-Spaulding Rehab. Hosp
CALENDAR JUNE 14-27
WEDNESDAY, JUNE 14
Bart Chernow
Sinai Hospital
Anesthesia & Critical Care Grand Rounds:
Pharmacologic Approach to Circulatory Shock
7 am, Sherman Aud.,
BIH
J. Vincent Poblete
NEDH
Plastic & Reconstructive Surgery Grand Rounds:
The Residency Summarized
7-8 am, CRI, 2nd Fl., NEDH
Robert Leffert
MGH
Shoulder Rounds:
Case Presentations
7:30-8:30 am, Lower Amp., Clinics 1,
MGH
Cynthia Morton,
Mary Norton & Louise Wilkins-Haug
BWH
Ob/Gyn Grand Rounds:
Updates in Prenatal Diagnosis From the Antenatal Diagnostic
Center
7:30-8:30 am, Duncan Reid Conf. Rm., BWH
Adrienne Lara-Fuller BIH
Ob/Gyn Grand Rounds:
Resident Talk
8-9 am, Riesman Lecture Hall, BIH
Peter Mowschenson
BIH
Surgical Grand Rounds:
Controversies in Ileo-Anal Pouch Surgery
8:15 am, Joslin Aud.,
NEDH
Steve Threlkeld
MGH
Infectious Disease Conference:
New Directions in the Therapy of CMV Infections
Albert Ko
MGH
Nonadherence in Treatment of Tuberculosis
8:15 am, Bigelow 8 Conf. Rm., MGH
James Kasser &
Barbara Philipp
CHMC
Pediatric Practice Seminar:
Office Orthopedics (An Opportunity to Bone Up on the Topic)
10:30 am, Carnegie Classroom, CHMC
Marlene Rabinovitch Hospital for Sick Children, Toronto
Fyler Lecture/Medical Grand Rounds:
Pulmonary Hypertension
Noon-1 pm, Enders Aud., CHMC
Martin Schwartz, Scripps Inst.
Seminar in Molecular Pathology:
Regulation of Cell Growth and Intracellular Signaling
Pathways by Integrins
1 pm, 1st Fl. Conf. Rm., Research North,
BIH
Samuel Miller
MGH
Bacterial Virulence Seminar:
Salmonella-Secreted Proteins and Signaling to Epithelia
4:30 pm, 2nd Fl. Conf. Rm., Channing Lab, 180 Longwood Ave.
THURSDAY, JUNE 15
Michael Roizen, MGH
Anesthesia Lecture:
Preoperative Assessment - What Is Necessary to Do?
8 am, Clinics 3, MGH
Thomas Smith, BWH
Medical Grand Rounds:
Inotropic vs. Neurohormonal Modulation in the Management of
Heart Failure-New Insights and Clinical Implications
8-9 am, Shriners Burns Aud., MGH
John Fromson, Mass. Medical Society
Medical Grand Rounds:
Physician Psychoactive Substance Use - Identification,
Intervention, Treatment and Prevention
8:15 am, Hurwitz Aud., MAH
MGH Gyn Residents
Gynecology Grand Rounds:
Roast of the Professors
8:30-9:30 am, Meigs Conf. Rm., Vincent 228, MGH
Lisa Lerner
MGH
Clinicopathological Conference:
Case Records of the MGH
11 am, Ether Dome, Bulfinch 4, MGH
Michael Robertson DFCI
Bone Marrow Transplant Conference:
IL-12 - Basic Biology and Clinical Applications
Noon-1 pm, Dana 1820, DFCI
Ronald Shouten
MGH
Psychiatry Grand Rounds:
Patterns of Behavior in Perpetrators of Domestic Violence
Noon-1 pm, Ether Dome, MGH
Elizabeth Ginsburg BWH
Continuing Medical Education Seminar:
Premenstrual Syndrome
12:15 pm, 5th Fl. Conf. Rm., ACC, BWH, 850 Boylston St.
Marcello Pagano HSPH
Newborn Epidemiology and Health Policy Conference:
The Use of Statistical Methods in Neonatal Research
1:30 pm, 5th Fl. Conf. Rm., BWH,
221 Longwood Ave.
Richard Shannon B/WRVA
Cardiovascular Grand Rounds:
Mechanisms in the Pathogenesis of Dilated Cardiomyopathy
3-4 pm, Duncan Reid Conf. Rm., BWH
FRIDAY, JUNE 16
In Sup Choi & Christopher Ogilvy MGH
Cerebrovascular Conference
7-9 am, Gray 2 Reading Rm., MGH
Alan Saven, Scripps Clinic
Hematology/Oncology Grand Rounds:
Lympho-Proliferative Disorders
8-9 am, Trustman Board Rm., BIH
Barbara Coffey
MH
Academic Conference:
Tourette's Disorder - Neurobiology and Clinical
Phenomenology
Film-Twitch and Shout
11 am-1 pm, Pierce Hall, MH
Jerome Gross
MGH
Spaulding Grand Rounds:
Amphibian Regeneration and Mammalian Wound Repair - Links
and Loose Ends
11 am, Conf. Rms. 8A & 8B, SRH
David Borsook
MGH
Psychopharmacology Conference:
IL-1 and the Hypothalamus - A Review
Noon-1 pm, Walcott Rm. 1, MGH
Arnold Relman
BWH
Medical Grand Rounds:
Future of Medical Practice
Noon, Bornstein Amp., BWH
Robert Cardiff
UC/Davis
Cancer Center Seminar:
Human Breast Cancer and the Amazing World of Transgenes
12:15 pm, 7th Fl. Aud., MGH East
Hiroshi Maruta
Royal Melbourne Hospital
Cardiovascular Research Seminar:
Anti RAS Tumor Suppressors - GTPase Domain of p190 and
SH3/Inter-SH2 Domains of p85
12:15 pm, Rm. 4501,
MGH East
SATURDAY, JUNE 17
Raj Goyal
BIH
Surgical Grand Rounds:
Esophageal Motility Disorders
9-10 am, Riesman Lecture Hall, BIH
MONDAY, JUNE 19
Christopher Chow & Mark Lucarelli, MEEI
Retina Service Residents' Conference
8-9 am, Sloane Teaching Rm., MEEI
Penny Jeggo, U/Sussex
Molecular & Cellular Toxicology Seminar:
Genes Involved in DNA Repair and V(D)J Recombinations
11:30 am-12:30 pm, Kresge 502, HSPH
Daniel Tenen, BIH
Hematology/Oncology Research Seminar:
The Role of the PU.1 Transcription Factor in Myeloid
Development Regulation of Multiple Growth Factor Receptors
Noon-1 pm, Duncan Reid Conf. Rm., BWH
Marjorie Debnam, CH
Medical Grand Rounds:
Morbidity and Mortality
Noon, Lecture Hall, CH
Eli Newberger, CHMC
Family Violence Seminar:
The Context of Family Violence - The Transformation of the
American Family and Dilemmas of Policy and Practice
12:30-2 pm, 57 Binney St. #3, CHMC
TUESDAY, JUNE 20
David Bates, BWH
Medical Grand Rounds:
Improving the Efficiency and Quality With Information
Systems
8 am, Joslin Aud., NEDH
Harry Papazian, BIH
Primary Care Seminar:
Foot Pain
8-9 am, Riesman Lecture Hall, BIH
Richard Brown & Steven Loring, HSPH
Physiology Seminar:
Sucking Physiology - Morphology and Mechanics of the
Elephant's Respiratory System
9:30 am, Rm. 202, Bldg. 2, HSPH
Carolyn Compton MGH
GI Grand Rounds:
Update on the Pathological Classifications of Gastritis
11 am, GI Library, Jackson 7, MGH
Marc Homer, Tufts
Radiology Grand Rounds:
Malpractice Issues in Mammography
12:30 pm, Main Amp., BWH
Janethe Pena, SERI
SERI Seminar:
Alternative Splicing of Elastin mRNA in Human Optic Nerve
Heads
1 pm, Taft Conf. Rm., SERI
Ian Sanderson, MGH
GI Research Seminar:
Dietary Factors and Enterocyte Gene Expression
4 pm, GI Library, Jackson 7, MGH
Patricia Hibberd
HMS
Division on Aging Seminar:
Viral Infections in the Elderly - What's New?
4:30-5:30 pm, Trustman Board Rm., ST-208,
BIH
FRIDAY, JUNE 21
Steven Goldring NEDH
Plastic & Reconstructive Surgery Grand Rounds:
Silicone Breast Implants and Connective Tissue Disease
7-8 am, CRI, 2nd Fl., NEDH
Hank Simms, Rhode Island Hosp.
Anesthesia & Critical Care Grand Rounds:
ARDS - An Update
7 am, Riesman Lecture Hall, BIH
Allan Sutin, BWH
Anesthesia Grand Rounds:
Newborn Resuscitation
7 am, Anesthesia Lecture Hall, BWH
Robert Leffert
MGH
Shoulder Rounds:
Case Presentations
7:30-8:30 am, Lower Amp., Clinics 1, MGH
Gerard Ostheimer BWH
Anesthesia Grand Rounds:
Legal Issues in Obstetric Anesthesia
8 am, Anesthesia Lecture Hall, BWH
Members of the Faculty
Ob/Gyn Grand Rounds:
Research Day
8-9 am, Riesman Lecture Hall, BIH
Jane Weeks, DFCI
Surgical Grand Rounds:
The Outcomes Research Movement - Is There a Role for the
Academic Medical Centers?
8:15 am, Joslin Aud.,
NEDH
Kate Ruoff, MGH
Infectious Disease Clinical Microbiology Conference:
Anaerobic Bacteria
8:30 am, Bigelow 8 Conf. Rm., MGH
Vincent Chiang & Andrew Powel
CHMC
Medical Grand Rounds:
Cases From the Wards - Graduation
Noon-1 pm, Enders Aud., CHMC
Peter Daniolos, Ava Penman & Cindy Tellingator, CH
Psychiatry Grand Rounds:
The Loss of a Parent Through the Eyes of a Child and a
Clinician - The Impact of HIV on the Family and Caregivers
12:30-2 pm, Macht Aud., CH
John Sedivy, Yale
Molecular Biology Seminar:
Gene Targeting in Somatic Cells - Genetic Analysis of C-myc
12:30 pm, Wellman 11 Conf. Rm., MGH
David Rosmarin
HMS
Law & Psychiatry Seminar:
Damned if You Do, Damned if You Don't - Medical/Legal Issues
in Mental Health Managed Care
6:30-8:00 pm, Hackett Rm., Bulfinch 3,
MGH
THURSDAY, JUNE 22
Richard Bohmer & Charles Boucher, MGH
Medical Grand Rounds:
Clinical Process Improvement
8-9 am, Shriners Burns Aud., MGH
Jeffrey Cooper
MGH
Anesthesia Lecture:
Anesthesia Simulation - Expensive Toy or Breakthrough
Technology
8 am, Clinics 3, MGH
Johnathan Lord &
Anne Arundel
General Health System
Nursing/Medical Grand Rounds:
Principles and Possibilities When Re-engineering Clinical
Care
8:15 am, Hurwitz Aud., MAH
David Berck & Ricardo Sainz de la Cuesta MGH
Gynecology Grand Rounds:
Morbidity and Mortality Rounds
8:30-9:30 am, Meigs Conf. Rm., Vincent 228, MGH
John Woodall
B/WRVA
Mental Health and Behavioral Sciences Clinical Case
Conference
10:30 am-Noon, LRC, Brockton VA
Leslie Ottinger
MGH
Clinicopathological Conference:
Case Records of the MGH
11 am, Ether Dome, Bulfinch 4, MGH
Dennis Willerford, MGH
Bone Marrow Transplant Conference:
Characterization of Progenitor Populations Mobilized by
Cytokines
Noon-1 pm, Dana 1820, DFCI
Troyen Brennan
HSPH
Newborn Epidemiology and Health Policy Conference:
Ethical Issues Arising in Neonatal Clinical Research
1:30 pm, 5th Fl. Conf. Rm., BWH,
221 Longwood Ave.
Joseph Horwitz, UCLA
Broadhurst Foundation Lecture:
Structure and Function of Alpha Crystallin
4 pm, Taft Conf. Rm., SERI
Michael Joseph, MEEI & Norbert Liebsch MGH
Skull Base Tumor Meeting:
Case Presentations
6-7 pm, Orr Conf. Rm., Cox 2, MGH
FRIDAY, JUNE 23
In Sup Choi & Christopher Ogilvy MGH
Cerebrovascular Conference
7-9 am, Gray 2 Reading Rm., MGH
John Glasby, UCLA
Hematology/Oncology Grand Rounds
8-9 am, Trustman Board Rm., BIH
Seda Ebrahimi-Keshishian
MH
Academic Conference:
Understanding Eating Disorders
11 am-Noon, Pierce Hall, MH
Richard Masters, MGH
Spaulding Grand Rounds:
Dermatologic Potpourri
11 am, Conf. Rms. 8A & 8B, SRH
Mitchell Fink, BIH
Research North Seminar:
Pathological Derangements of Intestinal Epithelial
Permeability
2:30-3:30 pm, Research North, BIH
MONDAY, JUNE 26
Ira Mintzer, CH
Medical Grand Rounds:
Alcoholism Update
Noon, Lecture Hall, CH
Carolyn Moore Newberger , CHMC
Family Violence Seminar:
Professionals' Replication of Coercive Family Dynamics - A
Cautionary Tale
12:30-2 pm, 57 Binney St. #3, CHMC
TUESDAY, JUNE 27
Hasan Bazari
MGH
Medical Grand Rounds:
Cholesterol Emboli Syndrome
8 am, Joslin Aud., NEDH
Robert Shmerling
BIH
Primary Care Seminar:
Use of Diagnostic Tests in Rheumatic Diseases
8-9 am, Riesman Lecture Hall, BIH
Barbara Nath, MGH
GI Grand Rounds:
Biliary Manometry
11 am, GI Library, Jackson 7, MGH
Arthur Mercurio
NEDH
GI Research Seminar:
Function and Regulation of Integrin-Laminin Receptors in
Human Cancers
4 pm, GI Library, Jackson 7, MGH
John Anderson
HMS
Division on Aging Seminar:
Comfort Measures Only - Bioethics Policy Development in a
Community Teaching Hospital
4:30-5:30 pm, Trustman Board Rm., BIH
Roger Packer
U/Virginia
Frommer Memorial Lecture in Neuro-Oncology:
Medulloblastoma - Current Advances and the Future
4:30 pm, Bornstein Amp., BWH
