In 1904, a handful of businessmen and physicians noted an increase in the number of cancer deaths in Philadelphia, so they created the American Oncologic Hospital. Little did they know that a century later what they established would have a resounding worldwide effect on cancer research and treatment.
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The centers research spans basic, clinical, and prevention programs, as well as community outreach. There is a long history of strength in basic science, noted Young. For example, in 1960 the late David Hungerford, M.D., at the Institute for Cancer Research and Peter Nowell, M.D., at the University of Pennsylvania discovered the first genetic abnormalitythe Philadelphia chromosometo be associated with human cancer. The centers clinical emphasis began to grow in the 1980s after the National Cancer Act was passed in 1974, when Fox Chase became one of the first comprehensive cancer centers. Since 1980, the number of new cancer patients treated there annually has risen from 738 to 6,500 in 2003.
As Fox Chase celebrates its centennial, some of its top scientists recalled the qualities of the institution that have made it a research powerhouse. On top of Fox Chases lengthy list of scientific awards and achievementsincluding a Nobel Prize in Medicine, a Lasker Clinical Research Award, and election of a half-dozen members to the National Academy of Sciencesresearchers and clinicians all emphasize the collegial and multidisciplinary atmosphere at the cancer center as key to what they have accomplished.
Mosaic Mouse
Beatrice Mintz, Ph.D., senior member and the Jack Schultz Chair in Basic Science, pointed to the influence of two people: Timothy R. Talbot Jr., M.D., director from 1957 to 1977, and Jack Schultz, Ph.D., senior member and founding head of what was then the Division of Biology. Their quiet encouragement, she said, set the tone of the institution and fostered an appreciation of originality and quality over mere productivity. She added that the supportive environment and independence afforded her since her arrival in 1960 were what freed her to undertake important but difficult research problems of her own choosing.
Mintzs work started with the development of the first mosaic or chimeric mammal, a mouse produced by amalgamating embryo stem cells from two genetically different mouse strains. This now allowed for the experimental study of developmental changes resulting from genetic diseases in whole animals throughout their life span. Extending this work, Mintz and colleagues substituted stem cells from malignant mouse teratocarcinomas in place of one of the two embryo stem cell strains. Within the resulting chimeric animals, cells from the tumor had become normal and contributed, along with the embryo cells, to all tissues, and even to the reproductive cells. Offspring of the chimera included descendants of stem cells originating in a malignant tumor. This represented the first clear reversal of a malignancy and was attributed to changes in the function of genes in the tumor stem cells in their new environment.
Mintzs laboratory went on to establish the first cell culture line of totipotent stem cells from a mouse teratocarcinoma, ultimately making it possible to engineer new mouse models of specific genetic diseases. At about the same time, Mintzs laboratory was the first to demonstrate another, more direct, means of producing mice with a specific genetic change of interest. By injecting DNA into an early embryo, they showed that it could be stably incorporated into the genetic material of cells growing and differentiating into a transgenic animal. All these experiments showed there was a great deal of flexibility in the fate of cells and provided new ways to study genetic diseases.
Serendipitous SCID Mouse
Mintzs mosaics are not the only famous mice to come from Fox Chase. In the late 1970s, researchers there decided to establish specific pathogen-free strains so that latent infections would not be a problem for future research. Melvin Bosma, Ph.D., senior member, and colleagues discovered by chance that members of one specific pathogen-free strain had severe combined immune deficiency (SCID). In a routine check of serum samples sent to his laboratory from the off-site facility where the breeding took place, the investigators ran across mice that did not type for an immunoglobulin allotype of interest. "We assumed we were dealing with a genetic contamination," recalled Bosma, but when they typed the mice for another immunoglobulin allotype, the animals lacked that as well.
"The point is that we ended up with some mice with neither allotype and we thought that was most strange," said Bosma. "And then we quickly looked to see if they had any immunoglobulin at all, and they lacked all of the major isotypes." Bosma and colleagues later found the mice lacked both B- and T-cell immunity and that the defect was heritable, enabling them to establish a colony of SCID mice. Fox Chase freely distributed the mice to other researchers, and now 20 years later roughly 175,000 SCID mice are distributed worldwide through five licensee companies.
Because SCID mice have no lymphoid immunity and cannot reject foreign transplants, they have been used as recipients of human tissue and cells to study such diseases as cancer and AIDS. SCID mice also serve as a model for studying normal and abnormal lymphocyte differentiation. "It was a chance observation which we didnt let go of," remembered Bosma. "We went one step further, and were awfully glad that we did."
Population Emphasis
Over the last 40 years, Fox Chase has pioneered a population approach to cancer treatment and prevention. In addition to setting up one of the first family cancer risk assessment programs more than 10 years ago, one of Fox Chases most distinguished claims to fame has been a substantial contribution to the worldwide decrease of people susceptible to liver cancer.
The hepatitis B virus was first identified at Fox Chase in 1967 by distinguished scientist Baruch Blumberg, M.D., Ph.D., and colleagues. This earned Blumberg the 1976 Nobel Prize in medicine or physiology (shared with Carleton Gajdusek). A vaccine for hepatitis B, invented at Fox Chase, was developed in conjunction with Merck Pharmaceuticals. It was the first vaccine that could claim to be capable of preventing a human cancer. Liver cancer caused by chronic hepatitis B is one of the five leading causes of cancer deaths worldwide.
"The work on hepatitis B and its relation to primary cancer of the liver and the invention of the vaccine has had a major impact on the formation of the preventive oncology program at Fox Chase," said Blumberg. "According to the [Centers for Disease Control and Prevention], next to the program for the cessation of cigarette smoking, the vaccination program against hepatitis B virus is the major interventional cancer prevention program in the world today. It has had a profound effect on the incidence of primary cancer of the liver."
In the Trenches
In addition to being at the nexus of key translational biomedical discoveries, Fox Chases clinical programs have long been innovative users of technology to fight cancer.
Inventive use of radiation therapy has been a constant theme over the last 100 years. For example, the American Oncologic Hospital was using radium in patient care soon after its discovery by Marie Curie early last century. More recently, in the early 1990s, Fox Chase developed the CT simulator, a technique that allows physicians to integrate CT imaging with radiation therapy planning. "This is now used across the country and has a great impact in how radiation therapy is used," said Benjamin Movsas, M.D., vice chair of the Radiation Oncology Department. "We are now pioneering applying IMRT, intensity-modulated radiation therapy, in which the intensity of radiation can be modulated within the radiation field to more precisely focus on a patients tumor." This, Movsas said, will allow the radiation dose to be tailored and the side effects minimized.
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