Editor's note: This is the first in an occasional series about key people and discoveries at the University of Pennsylvania's Perelman School of Medicine, this year marking its 250th anniversary.
Fifty years ago, most scientists dismissed the idea that cancer could be seeded by the same kind of germ as colds and the flu.
Not Gertrude and Werner Henle, husband-and-wife virologists at the University of Pennsylvania School of Medicine and Children's Hospital of Philadelphia.
With original thinking, dogged dedication, and considerable luck, they made important discoveries about the Epstein-Barr virus, a microbe that remains an international research focus.
The Henles linked EBV to infectious mononucleosis, the fatigue-inducing illness that is still a bane of U.S. college campuses. Then they established EBV's role in two rare malignancies, Burkitt's lymphoma and nasopharyngeal cancer, that are endemic in parts of Africa and Asia.
They did all this and more before molecular technology transformed the young field of virology.
"When I do my teaching, I always tell my students, 'You don't need fancy technology.' The Henles did everything with an old-fashioned microscope," said Jay Levy, a cancer researcher at the University of California, San Francisco.
Levy worked for the Henles while an intern at the Hospital of the University of Pennsylvania. He later codiscovered the AIDS virus.
Werner and Gertrude, fondly called Brigitte, met at their alma mater, the University of Heidelberg, as the Nazis were rising in Germany.
Werner's grandfather, the famous anatomist Jacob Henle, was a Jew. So after Werner earned his medical degree in 1936, he left for the United States to teach microbiology at Penn. Gertrude arrived a year later, and they married that same day.
They were, Levy recalled, "inseparable" and "complementary," with Gertrude's outgoing, outspoken personality balanced by Werner's thoughtful, methodical ways.
"Brigitte, a prolific reader, would burst into the laboratory with new ideas, inspired by new reports in journals," Levy wrote in a eulogy after she died in 2006, 19 years after her husband. "Werner would mull over the possibilities, and then together they executed systematic experiments to evaluate their hypotheses."
In the lab they set up at Children's Hospital, the Henles proved the effectiveness of vaccines for influenza and mumps, and showed how certain blood antibodies could suppress infectious hepatitis A virus. They pioneered virology research techniques and worked with scientists worldwide to amass an indispensable collection of blood serum samples.
The couple, who had no children of their own, profoundly influenced their many proteges, including Harald zur Hausen, who won a 2008 Nobel Prize for linking the human papillomavirus to cervical cancer.
In correspondence now archived in the U.S. National Library of Medicine, zur Hausen told the Henles what leaving Germany to work for them in the mid-1960s meant: "I find it the most important decision I made in my scientific life, although I certainly was not aware of it at the time."
Unlike his contemporaries in the 1960s, British pathologist Anthony Epstein not only believed the iconoclastic idea that human tumor viruses existed, he was determined to find one, according to the book Cancer Virus: The Story of Epstein-Barr Virus, published last year.
Epstein and his research assistant, Yvonne Barr, focused on Burkitt's lymphoma, a newly recognized cancer that caused a disfiguring jaw tumor and was a leading killer of children in equatorial Africa.
Epstein managed to grow the lymphoma cells in lab dishes and used an electron microscope to see virus particles in the malignant cells. But that was a long way from meeting the criteria for proving a causal link. (Those criteria were first described by Henle's grandfather Jacob, then refined by Jacob's student Robert Koch.)
In 1965, Epstein turned for help to his friends and colleagues Gertrude and Werner Henle.
Over the next decade, the Henles' team unraveled the mysteries of what turned out to be a paradoxical, novel viral pathogen. The researchers showed that infection with the virus, which they christened Epstein-Barr, could turn normal human white blood cells into ones growing immortally, a hallmark of cancer cells. The team - more precisely, zur Hausen - showed that the virus could slip its DNA into a healthy cell's genome and stay there, inactive but persistent.
This latent infection helped explain how the virus ducked the immune system and how - if given genetic or environmental cues, or maybe both - it could hobble the host's DNA and promote cancer.
The latency also fit with the Henles' shocking discovery that EBV infection was ubiquitous. By measuring antibodies (a sign of immune response) to the virus in their ever-growing collection of blood samples, they concluded that by adulthood, the vast majority of humans have a dormant infection.
With that realization, they searched far and wide to identify a disease that EBV caused in the affluent Western world.
They found the answer by serendipity. Their lab technician Elaine Hutkin regularly donated blood to be used as a negative control in EBV experiments because she had no antibodies to the virus. One day in 1967, she called in sick. She had the classic signs of a fresh case of infectious mononucleosis - fever, swollen glands, sore throat.
A blood test revealed she was also, for the first time ever, highly positive for antibodies to EBV.
The Henles' "major discoveries . . . greatly influenced how the EBV story developed over the following decades," declares Cancer Virus, coauthored by the EBV researcher Dorothy Crawford.
EBV continues to fascinate and frustrate scientists. It is now known to cause five types of malignancy, including gastric cancer. Mounting evidence links it to multiple sclerosis, an autoimmune disease that, like mononucleosis, is far more common in developed than poor countries.
Because of EBV's unusual biology, it has defied efforts to develop a vaccine. But with recent discoveries about its molecular mechanisms, work is underway, notably at the Wistar Institute in Philadelphia, to develop a drug that would treat EBV cancers by selectively disabling a viral protein.