An Interview with Professor Manuel Varela: Francis Peyton Rous and the Relationship between Viruses and Cancer

Jul 11, 2019 by

Francis Peyton Rous

Michael F. Shaughnessy –

1) The name Francis Peyton Rous seems to be synonymous with viruses and cancer. Where was he born and where did he study initially?

Dr. Peyton Rous was an American pathologist, virologist, and biomedical scientist who was the first investigator to show, in 1911, that cancer was caused by a virus. For this work he was awarded the Nobel Prize in 1966 in medicine or physiology. His discovery greatly contributed to the advancements of certain biomedical fields such as cell biology, molecular biology, pathology, virology, and tumor biology.

Dr. Rous was born on the 5th day of October, in the year 1879, in Baltimore, Maryland, U.S., to parents Charles Rous and Frances Anderson Wood. In 1890, when Rous was 11 years old, Charles passed away suddenly, leaving Frances widowed with three children, Francis Peyton being the oldest of the three. The widow, now of meager means, chose to live in Baltimore, Maryland, for the benefit of the education for her young children. She, thus, placed them in the Baltimore public school system.

As a child, he was an aspiring naturalist with an interest in botany. One story pertaining to these interests was that young Rous had participated in a flower classifying contest, with a new microscope as first prize, but had run afoul of the prize committee with his non-classical nomenclature for a fern, losing the contest.

He graduated high school in Baltimore, earning scholarships to partially pay for his tuition. To help pay for his higher education as an undergraduate student at Johns Hopkins, in Baltimore, Maryland, he took a job as a writer for a local newspaper, the Baltimore Sun, in which he wrote about flowers, on a monthly basis. He took his B.A. undergraduate degree, in 1900, from the University at Johns Hopkins, concentrating in the natural sciences.

Next, he enrolled in medical school at Johns Hopkins. Unfortunately, during his second year of medical school he had acquired a serious infection while conducting an autopsy, and the infection developed into a tubercular inflammatory condition involving an axillary gland. The infected tissue was removed surgically, but convalescence required a significantly prolonged duration for a full recovery. Rous returned to medical school afterwards and took courses with prominent medical faculty, such as the famous Dr. William Osler, who was well known for having refined medical school curricula. Rous took his medical doctorate degree, an M.D., in 1905.

As an intern at Johns Hopkins, Dr. Rous made the realization that practicing medicine as a physician was not for him, and he subsequently switched to a research mode, focusing on pathology as his discipline of choice. Thus, he pursued advanced studies, in 1907, as a post-graduate assistant in the laboratory of Prof. Alfred S. Warthin, who was situated in Ann Arbor, Michigan.  He then studied pathology for a year in the laboratory of Prof. Schmorl, in Dresden, Germany. During this interim Dr. Rous had acquired a case of tuberculosis, taking more time for recovery in the Adirondacks, as presumably prescribed by his doctors. In 1909, against the advice of several of his colleagues, however, Dr. Rous moved to the research laboratory of Prof. Simon Flexner at the Rockefeller Institute, in New York, where he focused on studying cancer biology. Dr. Rous continued to work at the Rockefeller Institute for the remainder of his life. 

2) There seems to be a relationship between certain forms of cancer and certain viruses. How did he initially learn about this?

In 1911, Dr. Rous was the very first scientific investigator to show that a virus can cause cancer. His work on this front soon began after his arrival to the Rockefeller Institute. A regional farmer came the Institute with a Plymouth Rock hen that had had a rather large, irregularly-shaped globular-like mass on its breast. Dr. Rous biopsied the breast mass by excising it from the chicken and then examined the specimen under the microscope. Based on its visual properties in the scope, Dr. Rous confirmed the diagnosis that the chicken’s breast mass was a so-called spindle cell sarcoma, a breast cancer of the chicken.

Next, Dr. Rous took the chicken breast sarcoma tissue and minced the cancerous cells apart from each other, making a tumor “soup.” He then injected the minced sarcoma cell soup into several healthy chickens without any sign of tumors. Soon, a spindle cell sarcoma, a cancer, emerged in various locations throughout one the injected chickens. The new tumors grew rapidly and soon killed the chicken.

He was able to transfer solid sarcoma tissue from chicken to chicken, each new bird growing breast cancer with every passage of tumor material. It was briefly noticed that the tumors grew more aggressively with each succeeding passage, from chicken to chicken. The results had been the first recorded instance of a so-called transmission of solid chicken tumors between chickens, and Dr. Rous published the work, in 1910.

Next, Dr. Rous hypothesized that the transmissibility of the sarcomas between chicken could be accomplished without the need for intact cancer cells. Thus, Dr. Rous excised sarcoma tissue from chickens with the breast cancer, just as he had before, except that this time he broke open the sarcoma cells, thus, gaining access to the internal cellular contents, the cytoplasm, of the sarcoma cells.  Next, he applied the cytoplasmic contents of the sarcoma, now called cell-free material, and passed it through a specialized filter for catching bacteria, called the Berkefeld ultrafilter. The filter’s tiny pores permit agents that are smaller than most of the bacteria to go through the filter, agents like perhaps viruses.

The cytoplasmic sarcoma-based material that went through the tiny pores of the filter was now referred to as a “cell-free filtrate.”  It was composed of internal cellular material, from the insides of the tumor cells. No intact tumor cells were present—it was cell free! Next, Dr. Rous injected the so-called cell-free filtrate from the chicken sarcoma into new healthy chickens. The injected chickens grew tumors, without tumor cells! 

Dr. Rous published the shocking new work, in 1911.

Interestingly, a similar type of cell-free filtrate result had been previously observed with bird leukemia, in 1908, by Drs. Ellerman and Bang, but at the time it was not realized by anyone that leukemia was also a disease of cancer. However, the idea that a virus might cause cancer was not new. The notion for a viral-causation of cancer had first been proposed by Dr. Amedee Borrel, in 1903.

Dr. Rous’ papers, however, were the first to provide evidence in favor of the hypothesis that a solid tumor could be caused by a virus. We now know that many microbes can cause cancer.

3) It seems imperative that science look at causality- and whether cancer is caused by some bacteria in the air or some virus- why is this important?

Amongst the well-known causes of cancer, such as inheritability and exposure to mutagens, another causative agent for cancer concerns a group of assorted microbes.

With respect to the genetic versus the mutagenic causations, the implicated human genes may overlap.  For example, the tumor-suppressing genes, such as p53, BRCA1, etc., can be affected in which mutagenic variations account for enhanced tumorigenesis and which may, in turn, lead to carcinogenesis, if a “second mutational hit” occurs. Regarding the environmentally influenced carcinogens, many of these types of cancer cases are actually preventable. For example, avoidance of smoking (most important), plus proper dieting, obesity control, consistent exercise, moderate alcohol intake, protection from radiation and ultra-violet light exposures, minimization of exposure to occupational carcinogens, and prevention of exposure to oncogenic microbes, all can play important roles in reducing chances of cancer in humans.

Regarding microbial causes of cancer, there are various bacteria, viruses, and others known to have influential roles.

Certain species bacteria are thought to be associated with cancer. One well-studied example is the Gram-negative and twisted helical-shaped Helicobacter pylori bacterium, which not only causes stomach ulcers but is known to be associated with enhanced propensity for gastric carcinoma, known also as stomach cancer. Additionally, a pathogenic version of Escherichia coli, a Gram-negative bacterium and new strain called NC101, is linked to colorectal cancer, known also as colon cancer. Another Gram-negative bacterium that is apparently connected to colon cancer is called Bacteroides fragilis, by using a toxin called BFT (for Bacteroides fragilis toxin) to do so. A Gram-positive bacterium called Enterococcus faecalis, has been strongly implicated in adenocarcinoma, a cancer of glandular tissue like the pancreas or the colon.

With respect to the viruses there are two main classes of viruses, in general, that are known to be carcinogenic. The first of these tumorigenic classes are the DNA viruses. There are several families of these DNA oncogenic viruses. One such DNA virus family is called the Hepadnaviridae. An individual oncogenic member of this viral family includes the notorious Hepatitis B virus, a known causer of liver cancer, called hepatocellular carcinoma.

A second DNA family of viruses is called Herpesviridae. Oncogenic members of this family include the Epstein-Barr virus, which can cause Burkitt’s lymphoma, a cancer of a certain type of white blood cell called the B-lymphocytes. Another DNA virus member of the Herpesviridae family is called human herpesvirus (HHV), and one prime example is the HHV-8 strain, which is known to cause Kaposi’s sarcoma, a form of cancer of the skin and lymph nodes. A third DNA virus group is called the Papillomaviridae family. While there are hundreds of members in this family, a certain few are serious causers of the vast majority of the human cervical and uterine cancers, such as human papilloma virus strains 16 (HPV-16) and 18 (HPV-18).

The second class of tumor-causing viruses are the RNA viruses. Under this umbrella that are associated with cancer, there are several RNA viral families. The first RNA virus family is called the Flaviviridae family. An important oncogenic member within this family includes the Hepatitis C virus, another causative microbial agent of liver cancer, again, called the hepatocellular carcinoma. A second RNA family of oncogenic viruses is called Retroviridae. Two important members of this viral family are the human T-cell leukemia virus type I (HTLV-1), which causes adult T-cell leukemia and lymphoma, and the human immunodeficiency virus (HIV), which is associated indirectly by suppressing the immune system and allowing human herpes strain number 8 to cause Kaposi’s sarcoma. A third member of the Retroviridae family is the Rous sarcoma virus, known to cause chicken sarcoma.

4) What is a Rous sarcoma virus? (See below) 

The Rous sarcoma itself refers to the chicken-based breast cancer that Dr. Rous originally studied. These tumors are characterized by uncontrollable growth of the chicken breast cells.

The microbe that causes the sarcoma, the Rous sarcoma virus, is an RNA-based retrovirus. The virus has an internal single-stranded, (+)-sense RNA molecule for its genome, with a surrounding capsid protein for protection, and which is, in turn, covered by a lipid-based envelope. The Rous sarcoma virus transforms normal cells into tumorigenic tissue. The oncogenic mechanism for this transformation takes place as soon as the virus infects the normal target cell.

Once the RNA is in place, inside the cell, a viral enzyme called reverse transcriptase uses it as a template to make a double-stranded version of viral DNA molecule! The Rous sarcoma virus inserts its DNA version of the genome into the nucleus of the normal host cell!

Then, incredibly, the viral DNA version insidiously inserts itself into the genome of the chicken breast cell!  The viral DNA insertion brings along with it a brand new gene that’s not known to the chicken. The inserted gene is called v-Src (pronounced “vee-sark”), and its better known as one of several oncogenes.  These oncogenes are cancer-causing genes. The Src protein was discovered to be a tyrosine kinase, an enzyme that phosphorylates tyrosine amino acids and serves to transform cells. Thus, modulation of the Src system results in enhanced and uncontrollable growth properties in cells, producing tumors. This breakthrough led to the discovery of numerous other oncogenes.

5) Apparently, it took the scientific community about 40 years- to truly acknowledge and recognize his work. What were the issues here? (Some say this was the longest “incubation period” for a Nobel Prize.) 

Dr. Rous’ works were published in 1910 and 1911. He showed that cancer was transmissible and that a filterable cell-free extract produced chicken sarcomas. Dr. Rous himself was somewhat leery at first of the very idea that a virus could cause cancer, as is evident by the fact that in his two papers, he did not mention the term “virus.” Instead, he was careful to refer to the cancer causing virus as a “filterable agent” or a “cell-free filtrate.” At the time, such wording could tacitly be taken as “code” for virus. Such terminology had been used to justify the discovery of bacteriophages, i.e., viruses that infected bacteria.

The careful wording by Dr. Rous, however, did not fool many of the investigators at the time, and it did not discourage his critics, either. Such naysayers invoked the doctrine of Virchow, who had clearly stated that cancer had its cause from the insides of cancer cells, not from the outside! Therefore, they mistakenly thought that microbes (they were outside the cell!) could not cause cancer.

Thus, disbelief was widespread, and Rous was taken to task. First, his critics charged that Rous’ “sarcomas” were not actually cancers.  That is, they believed that Dr. Rous’ tumors were not tumors! The unbelievers pointed to his methods. Perhaps, they said, Dr. Rous has made terrible errors in his techniques! The suggested that maybe his filtrates had no viruses but some other yet undiscovered sarcoma-causing carcinogen? They even suggested that perhaps Dr. Rous’ chicken sarcoma viruses were laboratory mutants!

Whatever the case, his detractors were absolutely sure that the cancer cause was not viral. Scientific disbelief in the idea that cancer could be caused by a virus was strong, publically-professed in scientific conferences, and, as you pointed out, long-lasting, with such stern skepticism languishing well into the late 1950s!

6) Warts and rabbits- how do they figure into the picture? 

Because Dr. Rous had so brazenly implicated that viruses might have a causative effect on cancer, he was met with widespread skepticism, which was enough to effectively discourage him from pursing the matter for decades. The warts and rabbits that you referred to were the other factors that encouraged Dr. Rous to re-examine the matter.

Several of Dr. Rous’ contemporaries, led by Dr. Richard Shope, had discovered the tumor-causing papilloma viruses which he had observed to cause rabbit warts! They had prepared tissue extracts from the warts of certain cottontail rabbits, filtered the extracts, and then applied the material to test rabbits. They recorded the observation of newly formed warts on the test rabbits! 

Encouraged by these promising studies, in 1935, Dr. Rous, working with Joseph Beard, then proceeded to demonstrate a potential for causing tumors on rabbit skin after chronic infection with the so-called cottontail rabbit papillomavirus. This particular virus was DNA-based, as opposed to the RNA-based Rous sarcoma virus. The DNA work, however, ultimately led to the discovery, in the 1960s, of the human papillomaviruses as a cause of human cancer. Thus, the idea that viruses could cause cancer was finally gaining widespread acceptance.

7) What have I neglected to ask?

In 1915, when Dr. Rous was 36 years old, he married Marion Eckford de Kay, and the couple had three children together, all girls. Family life in the Rous household has been described as a happy one, with plenty of yearly vacations, each often lasting two months. Gardening and fishing were hobbies that occupied Dr. Rous and family. Vacations were, however, also working ones, in which Dr. Rous was known to take along manuscripts for review as he was a devoted editor of the prestigious Journal of Experimental Medicine.

One biographer has noted that Dr. Rous frequently experienced serious bouts of insomnia. Thus, a common practice he adopted was to keep a notepad handy on his bedside table along with a specialized pencil that had a light-fixture attached to it, in order jot down any research ideas he might think up during the middle of his countless sleepless nights.

He officially retired in 1945, but continued to work at Rockefeller University, spending close to 60 years total there. It is recorded that well into his twilight years he regularly walked to and from the laboratory, a full 15 blocks from home, each day!  On the 16th day of February, in the year 1970, Dr. Peyton Rous passed away, at the age of 90, of abdominal cancer. 

For additional study and review:

How to cure Rous Sarcoma – YouTube www.youtube.com How to cure Rous Sarcoma Francis Peyton Rous: “In 1911, as a pathologist he made his seminal observation, that a malignant tumor (specifically, a sarcoma) gr…
How to cure Rous Sarcoma – YouTube www.youtube.com How to cure Rous Sarcoma Francis Peyton Rous: “In 1911, as a pathologist he made his seminal observation, that a malignant tumor (specifically, a sarcoma) gr…
How to cure Rous Sarcoma – YouTube www.youtube.com How to cure Rous Sarcoma Francis Peyton Rous: “In 1911, as a pathologist he made his seminal observation, that a malignant
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