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Delivering Progress to Patients
Festival Session Features Bench-to-Bedside Success Stories

By Carla Garnett

Photos by Ernie Branson

On the Front Page...

What goes around comes around. That adage could be the principle upon which much of NIH's research is based. As if to prove the point, NIH's 16th annual Research Festival devoted one of its plenary sessions to tracing three success stories from bench to bedside and back.


Dr. Barry Hoffer
"I'd like to welcome everybody to the plenary session 'Bench to Bedside' and perhaps also bedside back to bench," said NIDA scientific director Dr. Barry Hoffer, who cochaired the 2002 Research Festival organizing committee and moderated the session held in the Natcher Center on Oct. 17. "One of the true strengths of the intramural research program at the National Institutes of Health is the close association between basic science, and clinical science and clinical research. Not only is there physical proximity between the clinical research infrastructure at the Clinical Center and basic science laboratories, but also many of the individuals who are carrying out cutting-edge basic research are involved in clinical research as well. This uniquely positions the intramural research program to be an organization at the forefront of translational research, that is, taking findings from the laboratory, bringing them to the clinic and also taking insights from the clinic and bringing them back to the laboratory."

Timing May Be Everything

Looking back over the 26-year period from 1976 to 2002, Dr. Judith Rapoport, chief of the Child Psychiatry Branch in NIMH's Division of Intramural Research Programs, said a confluence of circumstances led to the success she and her team accomplished on obsessive-compulsive disorder (OCD).

"This brought back a wonderful period in which research on a little-known disorder in psychiatry and what happened from clinical research and clinical observations led to some very interesting and useful laboratory work," she said. "I've titled this 'Bedside to Bench,' but it has certainly reverberated many times since."

Rapoport explained that despite the fact that the term obsessive-compulsive has become part of cultural vernacular and is often used jokingly in reference to benign habits, OCD is actually a severe and chronic disorder that interferes in a major way with daily functioning.

It was while studying OCD in the late 1970s, Rapoport recalls, that several concurrent events propelled her research forward: The first epidemiologic report of psychiatric disorders in the U.S. found that a larger than expected percentage (2-3 percent instead of .01 percent) of Americans met criteria for OCD. Anecdotal evidence from Spain and England reported that in depressed patients with OCD, the antidepressant drug clomipramine seemed to benefit both disorders. Clomipramine was no longer being systematically tested, however.

NIMH's Dr. Judith Rapoport, NCI's Dr. Steven Rosenberg (c) and NIDCD director Dr. James Battey offered words of wisdom about basic, clinical and extramural research during the NIH Research Festival.

"A lot of things happened around the same time," Rapoport remembered, "and for something to work this well in a project, timing may be one of the most important things." Also around then, her group began a clinical study of young people with OCD; the publicity following a radio interview with one of the study participants opened the floodgates for calls from OCD patients. Next came Rapoport's book, The Boy Who Couldn't Stop Washing, which — to her surprise — made the New York Times bestseller list and prompted Rapoport to hit the talk-show circuit.

"That was a fascinating experience — both scientifically and otherwise," she recalled. "With the enormous media exposure, we started getting responses to these studies in groups where hundreds of people would phone in. That immediately — and in a terribly efficient way — led to a series of studies on a number of disorders we'd never considered before that had in common non-useful excessive behaviors."

While studying one of those related disorders — trichotillomania (the compulsion to pull out one's hair) — Rapoport's group ended up developing the first animal model of OCD. Hearing of her work with trichotillomania, a veterinarian approached her team about Labrador retrievers diagnosed with canine acral lick dermatitis, which causes dogs to lick their fur until bald patches and ulcers appear. As a result, Rapoport admitted that her group "conducted the only clinical animal study in the history of NIH."

The success of the OCD work surpassed all expectation, and is validated by its widespread adoption by peers in other fields of study.

"Five years before we started," Rapoport said, "there were no papers on OCD. Now there are at least 250 papers on the diagnosis, treatment and neurobiology of the disorder."

In addition, scientists at NIH produced the first brain-imaging studies for OCD, and an OCD subspecialty now exists. There are about 500 treatment clinics specifically for OCD across the U.S. and nearly 75 percent of patients treated with some combination of therapy derived from this work have a significant degree of positive change.

"Obsessive-compulsive disorder is now claimed by our neurology colleagues as well as our psychiatry colleagues," Rapoport concluded. "In summary, the NIH studies did a series of firsts with bewildering speed, even to the investigators. We showed that (OCD) was common, we showed there were effective treatments, we showed — first with anatomic then with functional studies — that there was dysfunctional circuitry, we developed the first animal model, and perhaps most importantly, we've seen the development of new immunosuppressant treatments under the current leadership of Dr. Susan Swedo at the NIMH."

If At First You Don't Succeed...

Dr. Steven Rosenberg, chief of surgery at NCI, has every right to be frustrated. Despite his best attempts to develop new treatments for people with invasive cancers, many of his patients still die. However, many of his patients survive longer than predicted, and many others are cured entirely. And that, he said, is the purpose of NIH research.

"Cancer is a curable disease today in about half of all individuals who develop it," Rosenberg said. "We have three effective treatments — surgery, radiation therapy and chemotherapy — that will cure patients and allow them to live out their normal lifespans. The problem we face in modern medicine is the remarkable incidence of this disease."

Last year in the U.S. alone, he noted, there were more than 1,200,000 new cases of invasive cancer; thus, the half of patients who could not be cured accounted for over 530,000 deaths.

Rosenberg discusses immunotherapy.

Rosenberg explained the need to develop treatment options for those patients whose disease does not respond to standard methods. One option, he said, could be immunotherapy, a treatment that "doesn't use an external force like a scalpel, radiation beam or drug, but rather attempts to alter the body's own natural defenses to fight the disease. The body recognizes a cancer as foreign, we now realize, but not foreign enough to reject it. The goal of immunotherapy is to see if we can enhance the body's defenses to fight off the invading cancer."

He also put human faces on the research, describing the medical histories of Michele, a 28-year-old wife and mother of a 7-year-old, and Andy, a 16-year-old high school senior. Both came to NIH with invasive skin tumors that had resisted all other treatments.

Through a series of slides, Rosenberg showed the tremendous success with interleukin 2, which stimulates the patient's immune system to destroy tumor cells. Of all melanoma patients whose tumors disappeared completely, no recurrences have been seen in 80 percent up to 15 years after treatment.

As of 2001, among 409 patients with widespread metastatic melanoma treated since 1985 in the Clinical Center, about 7 percent undergo a complete regression; another 9 percent undergo at least a 50 percent regression of all of their disease. Regression appears to be permanent.

"Is complete regression possible? The answer is yes," said Rosenberg. "But it only happens in a small percentage of patients."

Such treatments did not prove permanent for Michele and did not reduce Andy's tumors at all.

Over a period of 13 years, Michele would undergo several procedures at NIH to resect tumors, identify anti-cancer antigens and boost her body's natural ability to fight cancer. She died at age 41, but not before seeing her little girl grow up, marry and deliver Michele's first grandchild. For Andy, Rosenberg's team was forced again and again to return to the drawing board. None of the immunotherapy options that had been effective in other patients were having any effect at all on the young man's tumors. At the lowest point, Andy dropped out of school, was bedridden and needed painkillers. As a final option — part of a compassionate therapy agreement — Rosenberg's team tried another tumor-fighting combination. Remarkably, the new mixture completely eliminated the tumors and Andy, cancer-free for more than 2 years, returned to college. Immunotherapy investigators learned quite a bit from Michele's and Andy's illnesses, but adding to the knowledge base is not what satisfied Rosenberg.

"We understand a lot at the molecular level that the patients have taught us," he said, "but our goal is certainly not only to understand the underlying biology, but also to use this information to develop a better treatment, to take this bench research back to the bedside. As Sophocles stated more than 2,000 years ago, 'What profits wisdom when there is nothing to be done?'...The point of this symposium is to emphasize the importance of taking basic scientific findings from the laboratory to patients in desperate need of new treatments for their disease."

Sweet Sound of Synergy

Imagine hearing a "ping" and being glad to have your son tell you it's just the microwave oven. That's what a cochlear implant has done for Donna Sorkin, who struggled with hearing loss for most of her life and lost most of her ability to hear at age 35. A guest of NIDCD director Dr. James Battey, Sorkin was invited to discuss her journey from barely noticeable hearing impairment to profound hearing loss, and back.

"The cochlear implant could only be developed after there were many basic breakthroughs," said Battey, giving a brief background of the device, from concept to reality. "This is a truly multidisciplinary endeavor, where anatomists together with physicists and engineers were needed to figure all the things that were needed to develop a clinically useful cochlear implant."

Donna Sorkin, who uses a cochlear implant, said sounds most people with normal hearing take for granted — such as the ping of a microwave oven — were foreign, but welcome, to her ears after she received her implant. Battey (l) invited Sorkin to tell her NIH success story at a recent plenary session.

The effort to develop the device spanned dozens of years and garnered both private and public funding; NINDS (NINDB, on early grants) and NIDCD supported grantees working on the implant, which was not without its detractors.

"In the early going most auditory researchers did not believe the cochlear implant would ever be of benefit to patients," Battey said. "(This is) yet another example where conventional wisdom proved to be wrong. Most auditory researchers in the early 1980s did not believe that this device could ever work clinically."

Important hallmarks began in electronics with the development of the transistor in the 1940s. By 1957 the first implant had been placed in a patient, who could then detect sound but not understand speech. In 1965, NINDB grantee Blair Simmons and colleagues at Stanford University developed an implant that allowed a patient to distinguish between sound frequencies, providing the basis for speech recognition. NIH grantees showed in 1975 that determining the correct levels of electrochemical stimulation was crucial to prevent damage to the auditory system.

In 1989 and 1991, dramatic advances in speech recognition were developed by NIH-supported biomedical engineers. Today, about 50,000 people worldwide use cochlear implants, which have become the treatment of choice for postlingually deaf adults and an option for deaf babies.

Battey emphasizes the importance of rehabilitation following cochlear implant surgery. In one of three NIH success stories presented during a plenary session of the 2002 Research Festival, the development of cochlear implants was hailed as a multidisciplinary, public-private accomplishment that surprised its early critics.

During her talk, Sorkin — now vice president for consumer affairs at Cochlear, which manufactures the implants — summarized 40 years of her hearing tests, which since elementary school days had showed mild hearing loss but by age 27 reflected rapidly diminishing hearing. She began to have difficulty keeping up in meetings, hearing the soundtrack at movies and communicating by telephone. By age 35, she had a profound hearing loss that was difficult to correct with a hearing aid. She required captioning for meetings, and worried about stopping work completely. She decided to pursue the possibility of having surgery for an implant, if only to augment her lipreading ability. More than 3 years after surgery and rehabilitation, Sorkin's hearing is nearly back to where she began — equivalent to mild hearing loss.

"This was the result of a lot of research that had been funded by NIH," she said. "People often ask me what the sound is like, if it's as I remember. The answer is that it's really very good sound. Voices that I remember from the time before I lost my hearing, voices of my friends and family sound very much as I remembered them. I enjoy music. It's not exactly the way I remember music to be, but it's an enjoyable experience. Using the telephone was a watershed. I think sometimes we forget how important using the telephone is in your life. For me that was the ultimate."

On average, adults with the implant require 3 to 5 years following surgery before achieving their optimal hearing, Battey said, emphasizing the importance of rehabilitation. Asked about the years-long delay before hearing is recovered, he said investigators have a theory: "We believe the answer is in two words. Neural plasticity. The brain learns again to interpret the input as meaningful speech, much in the way that the brain learned that same process over not a dissimilar period when you're a young child. The cochlear implant story is an enormous testament to technology, but it's an even bigger testament to the phenomenal plasticity of the nervous system."

NIH's 16th Annual Research Festival Includes Multiple Poster Sessions

Photos byRich McManus

Jeannine Botos of NCI's Laboratory of Receptor Biology and Gene Expression points out details of her work on "Cellular Processing of Progesterone Receptor in Mouse Mammary Adenocarcinoma Cells" to Bradley Scroggins, also of NCI. Her poster was one of hundreds on display at NIH's 16th annual Research Festival.

Tadashi Yamashita (l) explains his work on "Enhanced Insulin Sensitivity in Mice Lacking Ganglioside GM3."

Dzung H. Nguyen (r) answers questions on his work with D.D. Taub on "Inhibition of Chemokine Receptor Function by Microbial Cholesterol Oxidase and Sphingomyelinase."

Assia Derfoul (l) gets an explanation of Qi Wang's poster on "Interaction of Corepressors with Agonist and Antagonist Complexes of Glucocorticoid Receptors."

NCI's Matt Garin views poster with NICHD's Meg Cooley (c) and Lauren Axelrod.

Susan Leitman of the Clinical Center's department of transfusion medicine explains a protocol to treat hemochromatosis (HH) subjects with phlebotomy. The blood derived from these subjects constitutes 10 percent of the blood transfused to CC patients, she said. "The subjects are thrilled not to have their blood discarded," said Leitman, who would like to see the day when all infants are routinely screened for HH.

NCI's Paris K. Ponder (r) shows a guest her work on helping youngsters quit smoking tobacco.

Nurses (from l) Margie Lloyd, April Powers, Colleen Ternisky, Susan Marden and Julie Gumowski proudly show their poster, "Does Structured Intermittent Therapy in HIV Patients Improve Symptom Distress and Health-related Quality of Life?"

NIMH's E. Anne Riley stands by her poster on the Schizophrenia Program.

Zhen-Dan Shi of NCI-Frederick stands by his poster "Design and Synthesis of a Novel Macrocycle that Exhibits High Grb2 SH2 Domain-binding Affinity."

Gitanjali Saluja (r) of NICHD shares her work on "Childhood Injuries and Adult Supervision: Results of a Retrospective Study," with institute colleagues Margaret Hillier (l) and Courtney Johnson.

NCI's Terrence R. Burke (l) shows his poster on potential new anticancer therapeutics to NIMH's Jon Marsh.

On Thursday of Research Festival week, a tent outside the Natcher Bldg. was the site of a free lunch catered by a number of local restaurants, and which featured live music.

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