Dr. Barnett (Barney) Rosenberg, a former Biophysics Professor at Michigan State University (MSU) and co-discoverer (with Loretta Van Camp) and developer of the globally important anticancer drug, cisplatin, died on Saturday, August 8, 2009 at the age of 82, following a protracted and debilitating illness. He is survived by his wife, Ritta, and his two children, Tina and Paul. He was a veteran of World War II.
In 1963, Barney and his laboratory technician, Loretta Van Camp, initiated the research that led to the discovery of cisplatin. While the idea was wholly conceived by Barney, Loretta Van Camp carried out all the experimental work. Their goal was to examine the effect(s) of an electric field on dividing E. coli bacteria, the impetus apparently being two-fold: (1) to provide students with a biologically-oriented project (i.e., implement the “bio” in biophysics) and (2) to address a speculative notion held at the time that a magnetic component might be operating in mitosis. Barney addressed this notion in a talk given at the Sheraton Hotel in NY. He noted the visual similarity of the pattern characteristic of the separation of chromosomes in the telophase of mammalian cell division and that of the lines of force between the poles of a magnet. From this, he reasoned that cell division might be affected (coupled) by the magnetic component of an electrical field. As numerous accounts of the serendipitous discovery of cisplatin have reported, these investigators set up a continuous culture apparatus containing E. coli bacteria in a protein-free (Medium C) culture medium. Two platinum foil electrodes, connected to a sonic generator and immersed in the culture medium, were used to generate the electric field. Shortly after the field was generated, a key observation was made—the bacteria had undergone filamentous growth. Dr. Rosenberg knew instantly that cell division was inhibited, but not cell growth, facilitating the filaments to reach lengths of up to 300 times their normal length. Dr. Rosenberg also fully understood what the implications of this observation were.
James E. Trosko, Distinguished MSU Professor of Pediatrics and Human Development, was a graduate student at MSU working on his Ph.D. in the Biology Research Building during the time period (1961–1963) when Barney began this research. He recalls that Barney remarked to a group of biology graduate students before he started the historic bacterial experiments that “I am going to cure cancer”. Apparently, Barney had recently attended a seminar that inspired this comment. As a theoretician, Barney had no equipment of his own and had to borrow all the equipment needed to do the critical experiments. Dr. Trosko also recalls that he was present in the lab on the very day that the key discovery was made. On this day, Trosko was the first to arrive at the Biology Research Building and opened the lab door to the room where the bacterial experiment was in progress. An overpowering stench, emanating from the continuous culture apparatus (chemostat), permeated the room and building. He saw the bacterial mess which Barney later dubbed “spaghetti-like”. As Professor Trosko recalls, when Barney arrived later in the morning and saw the “spaghetti-like” filamentous growth, he exclaimed, “I've just cured cancer”. Previous accounts of the discovery of cisplatin state that Rosenberg's research was not cancer-oriented. With a witness to the key experiment, the discovery takes on a new perspective.
After reproducing the bacterial filamentation results many times (including experiments in which the electric field strength was varied), the investigators were still left with the dilemma: what was the causative agent? Barney realized that the causative agent might be a useful anticancer agent, if they could identify it. Many investigations aimed at identifying the causative agent ensued. One afternoon in the Fall of 1964, Tom Krigas, a chemistry graduate student, working part-time for Dr. Rosenberg, came to my lab to discuss what might be causing the filamentation. Having assisted in an analytical chemistry course in which students used Pt crucibles in doing their gravimetric analyses and learned about the conditions under which Pt metal would react chemically, this experience provided the basis for my suggestion to Tom that perhaps the Pt electrodes were undergoing electrolysis and that the electrolytic products might be the agents responsible for the filamentation. Tom relayed this hypothesis to Dr. Rosenberg and, subsequently, the search centered on looking for chemical agents that might be produced in the culture medium as a result of electrolysis and the consequent reactions of the “hot” platinum ions with Cl− and NH3 in the culture medium. Independent synthesis of all the possible Pt(II&IV) complexes containing only Cl− and/or NH3 and the testing of these for induction of filamentation led to the conclusion that cisplatin was the most effective agent in inducting filamentation. In 1968, Barney made what he later called the “purely intuitive jump” and tested cisplatin in mice in which Sarcoma 180 solid tumor had been implanted seven days earlier. This test was a stiff challenge because instead of treating the mice on the day after the tumor was implanted (standard protocol at the time), Rosenberg and Van Camp waited until the tumor had grown to about 1 g in weight (from an initial 50 mg fragment). The results were dramatic, producing a high percentage of complete “cures”. Barney presented the results to the National Cancer Institute (NCI), who verified the potent antitumor activity of cisplatin. He also established collaborations with other laboratories, most notably with the Chester Beatty Institute in London. The promising test results with cisplatin brought in NIH grant support and support by three precious metal companies.
Although cisplatin was approved by the Federal Drug Administration (FDA), there was considerable reluctance by pharmaceutical companies to license/market the drug despite the fact that all the initial clinical studies were underwritten by the NCI. This reluctance underscored the feeling and skepticism that pharmacologists had about the likelihood that metal complexes could have useful biological activity. In this regard, Barney visited almost every major pharmaceutical company in the world trying to interest them in licensing cisplatin. The valiant efforts of Archie Perstayko and Stanley Crooke finally convinced Bristol-Myers to license cisplatin (and later carboplatin) from MSU.
The impact of the discovery of cisplatin has been nothing short of phenomenal. By all measures, cisplatin is the most important anticancer drug ever developed. It has saved countless thousands of lives of cancer patients. It is effective against a spectrum of human tumors, particularly testicular cancer (against which it is essentially 100% curative if the cancer is detected early), early stage ovarian cancer, lung (non-small cell lung cancer—the type that smokers develop), head and neck, and advanced bladder cancer.
In 1999, the results of three clinical studies found that cisplatin reduced death rates from cervical cancer by up to 50 percent when combined with radiation. These results, published in the New England Journal of Medicine, were so definitive that the NCI contacted oncologists world-wide before the findings were published and urged them to implement the treatment. This was only the fifth time in the history of the NCI that this occurred. Just two days before Rosenberg's death, Great Britain's National Institute for Health and Clinical Excellence published an article that said cisplatin, when combined with a chemotherapeutic drug known as Alitma, was especially effective in fighting certain types of lung cancer.
The impact of the discovery is not simply limited to cancer chemotherapy. The success of cisplatin as a chemotherapeutic drug entity has brought about the realization that selected metal complexes can elicit potent and selective activity. Clearly, it has led to a renaissance in the area we now call bioinorganic chemistry.
For MSU, Cisplatin brought in hundreds of millions of dollars in royalties (including carboplatin) to enhance their endowment and fund various research and educational programs.
Working in Barney's lab was an enriching experience. Dr. Professor Bernhard Lippert, who worked as a post-doctoral student in Barney's lab from 1974–1976, has stated, “Barney was able to convey to his students and coworkers, to the NIH and other agencies an excitement about research”. He did not micro-manage his students, mainly post-doctoral students, but rather trusted in their abilities and provided them with a maximum amount of freedom to do research. If a student needed help or wished to discuss an issue, Barney was available (albeit arriving late in the morning). The international flavor of his lab was a cultural experience for the typical American student. At any given time, a very diverse group of students, representing at least a half-dozen countries, were working in the Rosenberg lab. We were also fortunate to have had the opportunity to meet a diverse group of internationally known scientists who were visiting Barney's lab and to travel abroad to present papers at international meetings.
• Aging research
• Development of anticancer/antiviral activity of a protozoan protein (Barrogen)
• Exploring tRNA levels in a single cell via microcapillary electrophoresis (as an extension of his aging work)
• Study of the induction of cancer propensity from cosmic ray exposure in previous generations
• Microwave detection of brain activity (for triage on the battlefield)
• Partial development of a rapid, portable heart rate variability detector
• Aspirin as an endorphin inducer
• Fish herding using minute amounts of chemical attractants
• Investigation as to whether bacteria could be isolated that converted coal to methane
• Exploration of the possible role of oxidized cholesterol in arterial wall compliance
• Theoretical exploration of the origin of the constancy of charge and mass in fundamental sub-atomic particles.
Of these projects, the development of Barrogen was a long-term project that involved the whole Institute, led to publications, patents, clinical trials in cancer, and external testing in viral models partially supported by the National Institute of Allergy and Infectious Diseases (NIAID).
Indeed, Barney Rosenberg has had a long and distinguished career. He is author or co-author of 155 publications, discoverer or co-discoverer on many patents, and has been the recipient of sixteen awards, including the Cain Memorial Award from the American Association of Cancer Research (1983), the prestigious Charles F. Kettering Prize given by the General Motors Cancer Research Foundation (1984), and the Galileo Galilei Medal (University of Padua, Italy, 1987). Although hopeful and certainly deserving, he never received what many scientists thought was his inevitable big prize—the Nobel Prize.
We have lost a great friend and outstanding scientist. His contributions to society will live in perpetuity.
James D. Hoeschele
Assistant Professor Emeritus, MSU, and Cancer Research Fellow in Dr. Rosenberg's Lab, 1970–1972
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