In 1970, everybody knew, or believed they did, how the flow of genetic information in a cell works. The Central Dogma of genetics dictated that DNA is transcribed into RNA which is translated into amino acids that form proteins, in that direction and that direction only. When, in the early 1960s, a gifted young researcher named Howard Temin declared on the basis of his studies of Rous sarcoma virus that there exists a mechanism by which the Central Dogma flows in the reverse direction, that viral RNA is translated into DNA which is then spliced into the host’s own DNA, his ideas were declared rank heresy. There his ideas remained until, in that fateful year of 1970, a viral enzyme was discovered whose entire job it was to transcribe DNA from RNA.
The Central Dogma was shattered, and the era of retroviral research had begun. This branch of science studies RNA-based viruses, the mechanisms by which they copy their genetic material into DNA and insert it into the host DNA, the stages by which that DNA harnesses cellular machinery to make new virus building blocks, and the ultimate fate of that DNA across the life cycles of cells and the passing of generations as it mutates and remains locked into our genetic code as endogenous viral DNA. Few people have contributed so steadily yet diversely to ferreting out the closely-held secrets of retroviral behavior as Dr. Anna Marie Skalka (b. 1938).
Born in Brooklyn in an apartment above a pizza shop to an Austrian immigrant father whose name was changed to Edward at Ellis Island by an immigration official who felt there were too many Heinrichs in the country already, and a French-Spanish mother from Puerto Rico who had been orphaned at five, Anna Marie Sturn was not the son her parents had wanted, but her intelligence and natural curiosity overcame her father’s early disappointment, and the two were soon fast forest-tromping companions.
In school, Sturn skipped two grades on the strength of her natural gifts, and later at Grover Cleveland High School she was placed in small, advanced classes thanks to the school’s track system. She spent her summers interning at Pfizer, where both of her parents worked and where she learned some commercial laboratory basics and, perhaps more importantly, saw firsthand that scientists could be just as warm, normal, and fun-loving as anybody else in their pursuit of nature’s truths.
Sturn applied for and won a scholarship that provided funds for her to attend any Long Island college of her choosing, and she selected Adelphi College, a former women’s college where she majored in biology and minored in art while waiting for the decisive influence that would determine her life’s course. She believed she had found it in the mentorship of herpetologist Bayard Brattstrom, but in her junior year a DNA extraction lab fired her with the desire to better know this only recently decoded molecule.
She decided to put off marriage to army veteran Rudolph Skalka in order to attend graduate school, first at Yale, and later at New York University’s Department of Microbiology, where she studied the role that histones (the proteins around which DNA wraps itself in the nucleus) play in inhibiting DNA synthesis. In 1963 she moved with her department chair to Albert Einstein College for Medicine, where her colleagues included future reverse transcriptase co-discoverer David Baltimore. Here she finished up her thesis, and was awarded her PhD in 1964.
Few people have contributed so steadily yet diversely to ferreting out the closely-held secrets of retroviral behavior as Dr. Anna Marie Skalka.
After hearing a lecture by Alan Campbell about the behavior of bacteriophage lambda (bacteriophages are viruses that attack bacteria), Sturn (now Skalka after her 1960 marriage) wrote to a member of the famous Phage Group at Cold Spring Harbor, inquiring if there might be work there for her. There was, and in late 1964 she joined the Genetics Unit where she was set to work investigating some intriguing features of lambda DNA which led her to the discovery of how genes were asymmetrically grouped on the lambda genome, and why those genes were asymmetrically transcribed into mRNA over time. She also hypothesized a “rolling press” model for the continuous synthesis of linear viral DNA from circular DNA templates, but hesitated to write up her results, which allowed David Dressler and Walter Gilbert to win acclaim when they independently suggested their influential “Rolling Circle” model in 1968.
1968 was also the year that Skalka was contacted to join a new fundamental science research unit at Hoffman-La Roche, to be called the Roche Institute of Molecular Biology (RIMB), an institute funded by the outrageous profitability of the company’s signature product, Valium. Skalka would remain here until 1987, happy to to be able to set her own research agenda without simultaneously having to teach classes, as she would have had to in an academic position. She continued her work on phage lambda, discovering the stages of lambda DNA replication (an early stage that produces circular DNA and a later that produces multi-copy long strands), the co-opting of the host cell’s repair genes during viral DNA replication, and a new model for how replication, repair, and recombination mechanisms interweave in the lambda DNA replication process.
The early 1970s saw the retrovirus revolution, and Skalka, after years of studying the DNA-based lambda phage, was ready to join the ranks of those investigating these exciting new RNA based viruses. Unfortunately, the year after she decided on her change of field, the 1975 Asilomar Conference organized by Stanford geneticist Paul Berg drew up self-policing guidelines for experiments with potentially hazardous DNA that meant Skalka could not get to work right away on the avian sarcoma and leukosis viruses she had targeted for study. So, she took some time studying the genes that code for ribosomal RNA in chickens. This type of RNA plays an enzymatic role in the formation of amino acid chains in the ribosome, and the new techniques her lab developed in cloning it would prove useful in the retroviral work she and her colleagues would undertake in the 1980s.
That work established important links between the behavior of retroviruses and that of transposons – those mobile sections of our DNA posited by Barbara McClintock two decades prior. Retroviral DNA, it turns out, enjoys partaking in transposon-like leaping activity, making mRNA copies of itself that then splice genetic information into random sections of our DNA. Approximately eight percent of our genetic code is made up of the results of these labors of ancient “retrotransposons,” most of it having long since mutated into harmless genetic dead weight, while some of it has been harnessed by our own cells to play key roles in the regulation of our native DNA.
In 1983, Skalka was asked to form and lead a new department at Hoffman-LaRoche, to be focused on the study of oncogenes, and in particular to elucidate the role retroviruses play in transporting cancer-promoting genes from organism to organism. Her book, The Oncogene Handbook, co-authored with Tom Curran and E. Premkumar Reddy, was an early and indispensable compilation of all the known cancer-causing genes carried by retroviruses. In 1985, her department was relocated back to the RIMB, where she had the title of Chair of the Department of Molecular Oncology, from which position she was headhunted to take over as director of the Fox Chase Cancer Center, a role she filled until 2008. During her time at Fox Chase, she oversaw the discovery of crucial new information about the functioning of viral integrases, the enzymes which stitch viral DNA into host DNA, which has allowed us to develop therapies that, by inhibiting viral integrase, drive a stake into the heart of the viral life cycle.
For most students of biology, however, it is not this long list of exciting discoveries that her name brings to mind, but rather something on the order of the phrase, “Yo, can you hand me my Skalka?” Skalka, a popular short-hand for her 2000 textbook Principles of Virology (co-authored with Flint, Racaniello, and Rall), has remained a standard during two decades of rapid change, and has earned a place on the bookshelf of every molecular biologist thanks to its regular and exhaustive updating and famous clarity of expression. And so, the figure who entered the RIMB to avoid teaching has ironically become one of the most important figures in the teaching of her field, a reputation that has only increased with the release in 2018 of her popular science book Discovering Retroviruses: Beacons in the Biosphere.
For four decades now Dr. Anna Marie Skalka has pulled retroviruses from the totally opaque shadow realm they inhabited prior to 1970, and has shone an illuminating light through her over 200 published papers on virtually every aspect of their existence, from how and when they replicate to how they integrate, how they use our cellular machinery to their advantage to how they depend on particular metallic ions for their function, and how they mutate to how they have made themselves at home in our nuclei over the course of tens of millions of years. Because of her, we can better fight those retroviruses that mean us harm, and better understand those that we have come to depend on through the long course of biological time. She has given us our viral past, and ensured for us a hopeful anti-viral future, and if there is anything more American than the story of a daughter of immigrants born above a pizza shop rising on the strength of her brains to accomplish all of that, I don’t know what it might be.
FURTHER READING: Dr. Anna Marie Skalka’s book Discovering Retroviruses is a great read that covers the history of viral research and goes into lovely but clear detail about the role retroviruses play in carrying cancer-causing genes, and their connections with transposable elements. She has also written a brief 25-or-so page memoir of her life and work for the Annual Review of Virology, “Finding, Conducting, and Nurturing Science: A Virologist’s Memoir”, which can be found here.
Lead image credit: Photo provided by Dr. Anna Marie Skalka. It is published on Women You Should Know with Dr. Skalka’s express permission. Photo taken at the Fox Chase Cancer Center by Joe Hurley.