GOOD FOR THE VIRUS, BAD FOR THE HOST - THE STORY OF REVERSE TRANSCRIPTASE
Howard Temin and David Baltimore (right)
Editorial comment: At a time when viruses occupy the psyche of the world’s population, the Editors thought it would be interesting to look back into the history of viruses. More specifically, this is a story of 2 men whose research took our understanding of viruses into the stratosphere. It is a story of encouragement for anyone who has spent long hours on a research project only to have the paper rejected. Finally, it emphasizes that the cure of modern infectious diseases and ultimately of cancer, will largely take place in the laboratory, not in the clinic.
1970 was a turbulent year in the United States. Antiwar demonstrations culminated in the shooting deaths of 4 students at Kent State University in Ohio, during a student protest. At the same time research performed by Howard Temin and David Baltimore, whose labs were separated by 850 miles, were to have a profound and lasting effect on the field of molecular biology. “The simultaneous reports of RNA-dependent DNA polymerase – soon to be renamed reverse transcriptase – from the two laboratories led to rapid conceptual advances in our thinking about virus replication, the genetic basis of cancer and mechanisms of eukaryotic gene expression.” (Coffin and Fan, 2016)
There are currently 7 viruses that cause human cancer. They include the Epstein-Barr Virus (Hodgkin‘s Disease, nasopharyngeal carcinoma, Burkitt’s Lymphoma), Human Papillomavirus 16 and 18 (cervical, anal, oropharyngeal, penile carcinomas), Kaposi’s Sarcoma-Associated Herpesvirus (Kaposi’s sarcoma, primary effusion lymphoma, multicentric Castleman’s disease), Hepatitis B and C Virus (hepatocellular carcinoma), HTLV-1 (T-Cell leukemia) and, Merkel Cell Polyomavirus (Merkel cell carcinoma).The first cancers found to be transmitted by viruses (then called filtered extracts) were leukemia (1907) and sarcoma (1911) in chickens. They were both discovered by Peyton Rous while at Rockefeller University. In 1961 the viruses (now identified as retroviruses) were found to contain RNA and henceforth these retroviruses were called RNA tumor viruses. For his work, Rous was awarded the Nobel Prize 50 years later. Descendants of Rous’s viruses later played a pivotal role in the illumination of the origin on oncogenes and the discovery of reverse transcriptase (RT).
In 1960, Howard Temin, then at the University of Wisconsin, developed what he termed the “provirus theory”. At that time there was a central dogma in molecular biology. It stated that genetic information is encoded and stored in DNA and from there encodes RNA and then to protein. Temin’s provirus theory however, stated that both virus replication and viral-induced cancer from the Rous sarcoma virus, an RNA virus, is replicated via a DNA intermediate. The thought of copying RNA into DNA was considered heresy and a paper submitted by Temin for publication, suggesting the provirus theory, was quickly and unceremoniously rejected. (There are at least 8 other papers rejected which later resulted in Nobel Prizes for the authors, including Krebs paper on the “citric acid cycle, the Krebs’s Cycle”).
Temin’s interest in biology dates to his student years. He spent summers in a special biology program at the Jackson Laboratories in Bar Harbor Maine. He received his undergraduate degree from Swarthmore College and then to Caltech for graduate school. It was here that he joined the laboratory of Renato Dulbecco who was later to share a Nobel Prize with Temin and Baltimore in 1975. In his last predoctoral paper in 1960, Temin noted that different strains of Roux Sarcoma Viruses (RSV) resulted in different shaped tumors in chickens. He wondered whether “…RSV could contribute to genetic information directly to the cell”? On the strength of his studies at Caltech, he was recruited to the McArdle Laboratory for Cancer Research at the University of Wisconsin (UW). It was at UW, where he was to spend the rest of his career, that Temin developed his provirus hypothesis.
David Baltimore also attended Swarthmore College. He developed an interest in virology in graduate school at MIT from which he shortly transferred to Rockefeller University. In 1965, also working with Dulbecco at Albert Einstein School of Medicine, he honed his skills while working on poliovirus. He established his first independent lab while at the Salk Institute. He made his final move back to MIT in 1968.
In 1970, Temin and Baltimore independently and simultaneously described RNA-dependent DNA polymerase activity in RNA tumor viruses (later called reverse transcriptase by an editorial writer in Nature). Their labs both demonstrated that DNA-dependent DNA polymerase is present within the retroviral virions (fully formed virus outside of the host cell) and that the exogenous RNA template can be copied into their complementary DNA. The articles by Temin and Baltimore were published back to back in the same issue of Nature, in 1970. Both papers can be seen in their original form at these links: Termin and Baltimore. Note how brief the articles are, articles that have had a major impact on molecular biology.
The articles were published 10 years since Temin had first described his provirus theory which was met with ridicule and calls of heresy. Temin persisted. Howard Temin, David Baltimore, and Renaldo Dulbecco (their mentor) shared a Nobel Prize in Physiology or Medicine in 1975, only five short years from their milestone publications.
Howard Temin’s comments at the Nobel Prize banquet are particularly noteworthy. “This prize is an honor for all virologists, especially molecular virologists and those working with tumor viruses, for although the Nobel prize is awarded to individuals, we realize that science is a communal effort – what we have accomplished has rested on the achievements of others, and the future and practical significance of our work will also be determined by the achievements of others.” Howard Temin