Extraordinary Payoff from Investment in Basic Research on Weird Viruses
A century of basic scientific research on retroviruses was required for the current advances in cancer and HIV prevention, diagnosis, and treatment and gene therapy to be achieved. Furthermore, our understanding of normal cell growth, human development, genetics, and evolution would be immensely impoverished if it were not for scientists pursuing their curiosity about peculiar animal viruses for over 100 years. Finally, numerous valuable technologies and commercial products have emerged from studies investigating how retroviruses are transmitted.
The viruses that are now known as the avian sarcoma and leukosis viruses were discovered in 1908 and 1911. It was remarkable that birds could get cancer from a virus, but it was just an interesting finding at the time; cancer in humans or other mammals did not seem to be transmissible. Indeed, Peyton Rous, who reported the evidence for the existence of the Rous sarcoma virus in 1911 only received the Nobel Prize in Physiology or Medicine for his discovery in 1966!
The mouse mammary tumor virus was reported in 1936, whereas the first mouse leukemia virus was discovered in 1957. These findings were followed by the identification of other avian and mouse as well as cat and monkey cancer-causing viruses in the following decades. The study of these viruses provided an understanding of how DNA damage by exposure to X-ray radiation could produce cancer. Also, slow viral infections in mammals (now know to be caused by lentiviruses) were observed. Still there were no analogous viruses in humans; how “relevant” could the investigation of these viruses be?
The provirus hypothesis of Howard Temin provided a challenge to the simplest statement of the Central Dogma of Molecular Biology (the flow of genetic information in a cell goes from DNA to RNA to protein). The hypothesis was largely accepted when Temin and others demonstrated that RNA tumor virus particles contained reverse transcriptase (copying RNA into DNA—the reverse of normal cellular transcription) activity in 1970 (this time it only took five years for Temin and the others to win the Nobel Prize). Still there were no analogous viruses in humans; how “relevant” could the investigation of these viruses be?
It was then recognized that the genes in these viruses, (whose name was changing from RNA tumor viruses to retroviruses (retro—genetic information flow was backwards from RNA to DNA)) that caused cancer had highly similar analogues (called homologues) in normal cellular genetic material and that they played a role both in cancer (when mutated or improperly regulated) and normal growth control. The discovery of these viral and cellular oncogenes propelled cancer research forward. Still there were no analogous viruses in humans.
It wasn’t until 1979 that the first human retrovirus was discovered. This finding was followed a few years later by the identification of the lentivirus (a type of retrovirus) human immunodeficiency virus (HIV) as the cause of AIDS. Although there was an initial delay in the recognition of the seriousness of the AIDS epidemic the miraculous treatments for HIV were developed remarkably rapidly. None of this progress could have been achieved without the decades of research on viruses that at the time did not have human analogues.
Finally it should be recognized that the study of retroviruses provided the foundation for a ubiquitous technology for copying and analyzing RNA sequences, an understanding of how the human placenta forms, and insight into the origin of nearly 50% of the human genome. Modern gene therapy originated with retroviruses as the vehicles for gene delivery. It is likely that there will continue to be payback from the investment in retrovirus research for unraveling the mysteries of other human conditions.
The productiveness of retroviral research is illustrative of how the best practice of science transpires. Pursuit of intellectual curiosity, relentless investigation of the peculiar, “relevance” emerging unexpectedly—these are the seeds of scientific success. Medical advances are the flowers. If the seeds are not watered with public appreciation and financial support, no flowers will bloom.
The historical account in this article is indebted to the chapter by Peter K Vogt, “Historical Introduction to the General Properties of Retroviruses.” In: Coffin JM, Hughes SH, Varmus HE, editors. Retroviruses. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 1997.
David A. Sanders is an associate professor in the Department of Biological Sciences at Purdue University.