Focus
Student Scene
February 25, 2002
 Jan Schmollinger Photo by Jeff Cleary |
A Laureate's Lesson: Ideas Outshine Data
The lecturer told his audience that after the vaccination "the subcutaneously injected tumors grow slowly and, in the absence of vascularization, they show significant interior necrosis." What may sound like last Wednesday's Harvard Immunology Seminar Series was a talk delivered at Amsterdam University on June 1, 1908. The presenting scientist was Paul Ehrlich, a physician by training who had pursued laboratory research from an early point in his career. On that summer day almost one hundred years ago, Ehrlich had chosen to inform his Dutch colleagues about "the current state of carcinoma research."My principal investigator had heard from a colleague that an article by Paul Ehrlich mentioned the concept of tumor surveillance for the first time. Since the transcript of the lecture was entirely written in German, Ehrlich's mother tongue, he turned to me for a translation. Before this task, my knowledge of Ehrlich's work had been spotty at best. After going over the first paragraphs, however, I was quite surprised how similar the described experiments sounded to the ears of today's scientists.
Turn-of-the-Century Cancer Vaccines
Ehrlich had gathered a large collection of mouse strains and spontaneous murine tumors and was examining under what conditions transplanted tumors would grow in the recipients. Later, he injected less aggressive tumors in order to protect the mice from subsequent challenges with a variety of tumors. Ehrlich made the unexpected observation that the initial injection protected the mice to a certain degree even if the challenge consisted of cells of a different tumor type. In this series of experiments, he noted that an aggressive tumor type, which usually attracted blood vessels, would now lack vascularization, grow more slowly, and display necrosis. In other words, Ehrlich was experimenting with a crude cancer vaccine that prevented angiogenesis, a topic that could not be more up to date.From today's point of view, the knowledge that Ehrlich and his peers possessed was minimal. Serious immunological research was in its humble beginnings with a very rudimentary understanding of the cell types that mediate protection of the host organism. The most important diagnostic tool was the microscope, and it may come as no surprise that one of Ehrlich's first interests was the improvement of staining procedures for bacteria and tissue samples.
Even in hindsight the achievements are impressive. In addition to his above-mentioned work, the cigar-smoking scientist established a method for the standardization of antisera, which were an important reagent to cure diphtheria in those days. Instead of remaining in lucrative antisera research, Ehrlich continued to change fields. His laboratory pioneered pharmacological high-throughput screenings and chemotherapy. In order to fight infectious diseases such as trypanosomiasis and syphilis, he and his Japanese collaborators screened hundreds of chemical substances at the Royal Institute of Experimental Therapy in Frankfurt. The group discovered that several organic arsenic compounds had the capacity to kill the syphilis-causing bacteria and, after initial opposition, these substances were used in patients. This discovery came 20 years before Alexander Fleming carried out the initial experiments that lead to the isolation of the antibiotic penicillin.
Data Deluge
The theoretical contributions made by the Nobel laureate, who shared the prize in 1908 with Ilya Ilyich Mechnikov of the Institut Pasteur, are still worthwhile reading. The incomplete understanding of immunology in the early years of the 20th century occasionally lead Ehrlich astray, but most of his thoughts were well ahead of his time. Ehrlich elegantly argued against fellow scientists who saw microbes as the primary reason of tumor formation. Furthermore, he stated that immunity against cancer must be mediated by "cellular forces" that keep tumors in check--a concept now known as tumor surveillance.With service facilities that provide 600 base pairs of clear sequence and DNA array chips that allow us to simultaneously compare the expression level of thousands of genes, it is hard to imagine lab research at the beginning of the last century. Sometimes I wonder whether today's flood of data occasionally clouds our vision. Careful observation and analysis allowed Ehrlich and his colleagues to make the most out of their modest amount of data.
--Jan Schmollinger, an HMS research associate in medicine at the Dana-Farber Cancer Institute