In remembrance of Barnett Rosenberg

This remembrance pays tribute to Dr. Barnett Rosenberg, a personal friend, mentor, and brilliant scientist “whose curiosity, imagination and persistence led to the discovery and development of cisplatin” [G. A. Petsko, A Christmas Carol, Genome Biology, 2001, 3(1)] described by many as perhaps, the most important anticancer drug ever discovered.

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.

Biographical history

Originally from New York City, Barney earned a B.S. degree in physics from Brooklyn College (1948), and both master's (1950) and doctorate (1955) degrees in physics from New York University. [Barney did his Ph.D. with Professor Paul H. Kallman, a student under Dr. Albert Einstein. Barney was very proud to be the academic grandson of his hero, Albert Einstein.] A short stint at Westinghouse Electric Corporation (1956–1958) as a senior research scientist was followed by research at NYU (1958–1961) as a research scientist. On October 1,1961, Barney officially joined MSU, having been recruited by Dr. Leroy Augenstein, with whom he jointly founded the Biophysics Department. Originally a research department, the Biophysics Department was later disbanded and Barney became a faculty member in the Chemistry Department. Barney's research at MSU focused on several areas (predominantly and most notably platinum cancer chemotherapy) from 1961 until the early eighties, at which time he took a leave of absence from MSU to start his own research institute, the Barros Research Institute, in Holt, MI. Barney officially retired from MSU on January 1, 1997.

Recollections on the discovery of cisplatin

Barney's research at MSU initially focused on the conductance in proteins and vision research involving rhodopsin and carotenoids. Barney's group particularly relished the idea of the carotenoid work because carotenoids were extracted from the shell of boiled lobsters, the meat from which had no research value and thus was given to and happily eaten by the staff.

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.

Impact of the discovery of cisplatin

In 1971, cisplatin entered clinical trials in the U. S. at several locations. An international platinum symposium held in Oxford in 1973 was looming as a sort of cisplatin showdown, because clinicians using cisplatin were confronted with dose-limiting kidney toxicity that they had never experienced previously with any other anticancer drug and for which no amelioration was known. This crisis nearly ended the use of cisplatin as an antitumor drug. Fortunately, the astounding results of Dr. Lawrence Einhorn and his team at Indiana University School of Medicine in treating testicular cancer, for which no known effective anticancer drug was available at the time, saved cisplatin from failure and assured that cisplatin would be approved by the FDA, as it was in 1978. The development of the mannitol diuresis procedure ameliorated drug-related kidney toxicity and promoted wider and safer use of cisplatin.

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.

Dr. Rosenberg—the person

Barney was a kind, gentle and non-pretentious person. Despite his stature and significant achievements, he was gracious and showed respect to everyone. As his students will attest, he was extremely bright and valued and encouraged thinking. In an interview published in the Deroit Free Press on December 2, 1984, he stated that if he walked into the lab and found a student sitting at his desk with his feet propped up on his desk, he would not get upset that he was not working at the lab bench. Rather, he would be happy that he was thinking, an activity which Barney thought was the epitome of why a student was attending the University. Barney indeed was a thinker and his thoughts were voiced freely at international platinum meetings. By his own admission, his knowledge of chemistry was weak, but his comments, however unrealistic, would stimulate discussion and challenge his colleagues to think about ideas/hypotheses that he would propose.

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.

Rosenberg's research-post cisplatin

Barney's research interests were diverse in nature and after twenty years of research in the platinum area, he abandoned this area to focus on other areas of interest. His projects were always aimed at improving the human condition says David Juckett, who obtained his Ph.D. under Barney’s supervision in the Biophysics Department. He always liked to “break ground” in new areas where no one else was working. The list of projects that Barney initiated at the Barros Research Institute includes:

• 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

Acknowledgements

David A. Juckett and John W. Judge, researchers at Barros Research Institute, contributed to this article.

---