By Dr. Kathleen T. Ruddy
Proving that a virus causes cancer in humans is a woefully convoluted process, guaranteed to drive the sane mad. To propose, as does the National Breast Cancer Coalition, that simply by deploying $200,000 to what is essentially a mine-sweeping operation to look for evidence of viral DNA in human breast tumors, and that finding viral DNA will be proof sufficient of causation, is misleading, or more precisely, delusional. Let me explain.
In the beginning, there was ignorance. No one had any idea what caused cancer. Thousands of years went by, and still no one had a clue. A few hundred years ago, it was observed that chimney sweeps (usually young boys who were small enough to slide up and down the chimneys) had a very high incidence of cancer of the scrotum compared to the rest of the men in the population. Cancer of the scrotum has nothing to do with a virus, but this early observation was the first historical clue that something – in this case, soot – was causally related to a specific cancer.
At the beginning of the 20th century, Peyton Rous (working at the Rockefeller Institute in New York City) discovered that if he injected cell-free fluid taken from a tumor arising in the muscle of a chicken into the leg of a perfectly normal chicken, a fresh and equally malignant tumor would soon grow. Rous knew then that there must be a virus in that tumor, a virus capable of infecting another animal and producing a similar tumor. Indeed, Rous had discovered the first cancer virus, now called Rous sarcoma virus, and he couldn’t even see it! Microscopes were too weak then to see anything smaller than a bacteria. It would be 30 years before anyone had a microscope powerful enough to see Rous’s sarcoma virus. Nevertheless, like a faithful Christian, Rous believed he had fingered the first cancer virus. And he had.
Exactly no one believed him. A few years later, maybe two or three scientists peaked out from behind a thick black curtain and wondered, What if it’s true? But everyone else thought he had lost his mind. They were not the least bit interested in his data, for his idea seemed so absurd that who cared what his data looked like? The vast majority of his scientific colleagues believed he was just plain wrong, and probably feeble-minded too. In fact, during a meeting of the first version of the American Cancer Society, it was proclaimed in no uncertain terms that there was no such thing as a tumor virus. Fair warning to all who dared to cross that line.
Why was there so much skepticism, nay, frank hostility to the idea that a virus (or any infectious agent) might play a role in the formation of cancer? That’s pretty easy to answer. You see, cancers arise slowly and tend to grow slowly, while the majority of infectious diseases tend to come on rapidly and are usually quite readily traceable from one sick person to another. Right? One person has a cold, goes to work, and three days later, four others at work come down with a cold. Think of how fast the flu spreads, or small pox, or chicken pox, etc. But cancer? Does cancer ever look like it spreads through a population like the measles? No. So the idea that cancer might be caused by a virus seemed bizarre. It didn’t fit with clinical observations and known mechanisms of disease causation or spread.
And then there is the problem of finding the suspected cancer virus in the tumor. It can be very hard to do. Sometimes a cancer virus does its dirty work and flees the scene of the crime. The pathologist peers down the microscope at a sample of tumor and sees no viruses anywhere in the vicinity. This also makes it hard to prove that a virus causes cancer.
But things get even trickier when there is a suspicion that a virus which is very common in the population, like the herpes virus, is thought to cause cancer. If a virus as ubiquitous as the herpes virus infects just about everyone in the population at some point in time, but only a few people ever develop the cancer thought to be related to that herpes virus, well you’ve got a job proving the causal link between the two. Why would only some people get cancer when everyone is infected? Again, explaining these discrepancies is a chore and a burden for the scientist who wants to argue that virus A causes cancer B.
To make matters flat out confusing, there is the added knowledge that other co-factors may influence the propensity of a virus to cause cancer. For decades after scientists began to believe that perhaps there might be such a thing as a cancer virus, there was still the problem of identifying other agents, chemicals, and co-carcinogens that might play a role in amplifying the cancer-causing action of a virus. For instance, it took about two decades to discover that the virus that causes breast cancer in mice requires the presence of estrogen to really get going. Both male and female mice are equally and as readily infected with the breast cancer virus, but only the females get breast cancer. Why? Because the breast cancer virus possesses a segment of its genetic material that is sensitive to estrogen and grows in its presence. Without estrogen to stimulate it, the mouse breast cancer virus remains dormant.
And, finally, there is the problem that some viruses may enter the cell, appear to be innocent bystanders, and yet trigger distant mutations in the DNA – they’re just in the neighborhood minding their own business, but as capable of transforming a normal cell into a malignancy as any virus that comes into the cell with oncogenes blasting, like the human papilloma virus.
O.K., so now you know how hard it is to find a tumor virus, nail it as a cancer suspect, and prove to scientific colleagues that what you’ve handcuffed in your laboratory is a real McCoy cancer virus. And, yet, despite the difficulty we are now certain that six viruses cause cancer in humans. There are surely more: scientists believe that at least 20% of all human cancers are caused by tumor viruses. Well then, how do scientists prove that a virus causes a cancer in humans? After all, you certainly can’t take a putative tumor virus and conduct a randomized clinical trial in which you infect half the volunteers with the cancer virus and give the other half a placebo and then follow the group to see who gets cancer and who does not. So, if they cannot do it directly, how do scientists prove that a virus causes cancer in humans.
In 1982, as research into tumor viruses became its own branch on the Tree of Knowledge, eight criteria were put forth for proving that a virus causes cancer in humans. They are:
1. Patients with the cancer have a higher incidence of antibodies to the virus than healthy subjects.
2. Antibodies to the cancer virus are higher in cancer patients than in healthy subjects.
3. The presence of antibodies to the virus precedes the onset of the cancer.
4. The virus is found only in the tumor and not in normal surrounding tissue.
5. In the laboratory, the virus is shown to transform normal, healthy cells into malignant tumors.
6. In the laboratory, the virus produces tumors in animals.
7. Scientists can detect DNA of the tumor virus in tumors grown in laboratory animals.
8. Preventing infection by the tumor virus, such as with a vaccine, prevents the malignancy.
Let’s refer to #8 immediately. The vaccine against the human papilloma virus now used to prevent cervical cancer is an example of the final step required to prove that a virus causes cancer in humans.
As regards the human breast cancer virus, found by Dr. Beatriz Pogo in ~40% of human breast cancer specimens she examined in 1995, the slow journey toward final proof continues. Of the eight criteria that must be met to prove that a virus causes cancer in humans, six have been met with regard to the human mammary tumor virus.
There are only two steps left to obtain final proof: #3 and #8. Actually, as soon as #3 is fulfilled – that is, demonstrating that infection (as documented by the presence of viral antibodies in the bloodstream of volunteers) precedes onset of cancer and increases the risk for it – is the next big thing to do. Once that is done, a vaccine against the virus can be made and used to fulfill #8 – showing that vaccination against the virus prevents breast cancer.
This is a long blog to say it’s a long slog getting from the question of a breast cancer virus to a vaccine that prevents it. But, indeed, we are getting close. And there’s no need to start over from the beginning, as some would suggest we do. Let’s go from where we are, hovering over #3: develop a reliable blood test to document infection with the breast cancer virus and then follow a group of healthy volunteers to see who develops antibodies to the virus – a sure sign of infection – and who does not. And then ask the question, Does becoming infected with this tumor virus precede the onset of breast cancer and increase the risk for it?
Given that there is converging data that suggest 40-75% of all human breast cancer may be related to the same virus that unequivocally causes breast cancer in mice, I suggest we should devote that portion of our breast cancer research dollars trying to nail this murder suspect: convict or acquit, but don’t ignore.
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