Do Germs Cause Cancer?

[Guest guest]

FORBES

November 15, 1999

Do Germs Cause Cancer?

By Philip E. Ross

Tantalizing evidence has surfaced that bugs could play a significant role in

creating chronic illnesses like heart disease, cancer and schizophrenia. If

so, our fixation on genes and environment as causes of disease is in many

cases leading us down the wrong paths to treatments.

IN 1983 BARRY MARSHALL, AN INTERNIST FROM PERTH, Western Australia,

discovered that a spiral bacterium called Helicobacter pylori causes most

stomach ulcers. It turns out it also causes most cases of stomach cancer.

His discovery was a monumental step forward in medicine, taking patients

from the realm of palliative treatments that left them ill into the

territory of cures. Now doctors test ulcer patients for the bacterium and

treat those who have it with powerful doses of antibiotics like Omeprazole,

Clarithromycin and Amoxicillin.

The nagging question is why it took so long for doctors to accept Marshall's

discovery. For years the medical establishment laughed off Marshall's

theory, even after he demonstrated it by drinking H. pylori and giving

himself ulcers, and even after other labs replicated his experimental

results. Although that had happened by 1986, " they didn't start treating for

H. pylori for another nine years, " Marshall says, still amazed by it all.

" Hundreds, even thousands of people must have died from ulcers who wouldn't

have. " Could the medical establishment be making the same mistake about

other chronic diseases -- such killers as heart disease, cancer, diabetes,

multiple sclerosis and Alzheimer's? It is taken as a given among both

doctors and scientific researchers that the causes of these ailments are

genetic or environmental or both. That's where almost all of the research

money is going. We're spending at least $2 billion a year looking for genes

that cause cancer, Alzheimer's, heart disease and obesity. A large part of

the $150 billion a year this country spends fighting pollution is aimed at

removing trace toxins that are suspected of contributing to cancer. There is

no question that genes and environment contribute to chronic diseases. But

what if bugs start the process for some or many of these diseases? Are we

perhaps looking in the wrong places for cures and preventive measures? Is it

possible that, for some future generation of patients, cancer, Alzheimer's

or obesity will be attacked with a vaccine? The question is not as

far-fetched as it seems. Consider the matter of cervical cancer, which every

year is diagnosed in perhaps 179,000 American women and kills 4,200. The

evidence that there is something infectious about this disease goes back a

long way -- to 1832. It was then that Rigoni Stern noted that celibate women

almost never came down with this cancer. (He compared incidence of the

disease in nunneries with incidence in the general population.) The

observation came long before Louis Pasteur even elucidated the germ theory

of disease, and it went nowhere for 151 years.

Then in 1983 -- coincidentally the year that Barry Marshall made his

medicine-shattering discovery about ulcers -- Harald zur Hausen of the

German Cancer Research Center in Heidelberg proved that human papilloma

virus could cause cervical cancer. It has since become clear that the virus

is to blame for virtually all cases of this cancer. It is still true that

genes and environment play a role in this killer.

But there is no question that preventing the viral infection would all but

eliminate the cancer.

The medical establishment didn't welcome zur Hausen's theory. " To convince

scientists, as well as pharmaceutical companies, took a long time, " he says

with a sigh. What a tragedy. Imagine that the germ theory of cervical cancer

had caught on in Pasteur's day and that scientists spent the next century

striving to find a vaccine against the virus. We might have won this part of

the war on cancer by now.

The germ theory has had an irregular string of victories in medicine. In

1854 an astute doctor noted a pattern in cholera cases that made it clear a

waterborne pathogen was the cause; in 1865 ph Lister cut mortality by

keeping operating rooms antiseptic; in the 1890s it dawned on the world that

malaria, far from being due to the " bad air " that its name implies, was due

to bugs. The early successes were followed by a long stretch in this century

when there weren't many stunning surprises regarding the connection of

infectious agents to disease. After all, it doesn't take a genius to see

that measles spreads. Making the connection when there is a long lag time

between infection and disease, though, is hard. Cervical cancer comes 30

years after a woman contracts the virus from a perfectly healthy man, and it

doesn't develop in every woman who gets the virus.

The science of infectious disease may be moving faster now. We have new

tools for distinguishing microbes, for finding subtle clues to cryptic

infections and for devising antimicrobial drugs that might, by ameliorating

an illness, show that it must therefore be infectious in origin.

Could heart disease be related to a slow-moving infectious agent? No

question that heredity and diet play a role in the clogging of arteries. But

maybe a bug starts the inflammatory process that swells the lining of an

artery. Some circumstantial evidence points to Chlamydia pneumoniae, a

common denizen of the lower respiratory tract.

Pfizer, Hoechst n Roussel, and Abbott Laboratories are each testing

proprietary antibiotics against the bacterium in the hope that the drugs

will reduce heart attack rates.

Hoechst is also testing whether a war against C. pneumoniae can help asthma

patients. Zur Hausen says an experimental vaccine against human papilloma

virus -- and thus cervical cancer -- may reach the market within three

years. It might also be effective against nonmelanoma skin cancer, which zur

Hausen has recently linked to the same virus.

Other diseases, at earlier stages of investigation, are on the list of

suspects for infectious causation. Among them: breast and ovarian cancers,

multiple sclerosis, juvenile diabetes, reactive arthritis, Alzheimer's, even

obesity, and the list grows by the year. " There have been many, and there

will be more, for when you look, you find, " says Fauci, the famed

National Institutes of Health virologist. Fifteen years ago, he notes, most

doctors doubted that viruses played any role in cancer; now the consensus is

that they cause around 20% of cases. " And it will turn out to be a lot more

than that, " Fauci says. " People talk about our bodies' exposure to

pesticides and chemicals -- they're nothing compared to microbes, " says

Parsonnet, an infectious diseases specialist at Stanford University

Medical School. " Your gut is loaded with bacteria; your genitourinary tract,

your skin, your mouth, your eyes. Our bodies contain at least ten times more

microbial cells than human ones -- we are walking petri dishes, more microbe

than man -- and our relationship to microbes may be responsible for a huge

amount of disease. " When the prevalence of a disease is highly localized,

you can tease out the microbial actors all the more easily. That was true of

Burkitt's lymphoma, rare everywhere but in Africa, where it is the leading

cause of cancer death in children. It turns out the cancer develops only if

you are simultaneously infected with Epstein-Barr virus (a ubiquitous bug

best known for causing mononucleosis) and malaria, which in its severest

form is mainly found in Africa.

Another local detective story was recently reported in the British Journal

of Cancer. ish researchers found that a cluster of cases of childhood

leukemia was heavily weighted with children who had recently moved to the

area. That statistical clue is evidence of an infectious cause.

When no clear pattern of infection can be seen on the disease map of the

world or in special populations, then it can be tough to demonstrate that a

given germ, even if found often in the tissues of patients, is the cause of

their ailments.

The best example of such a hard case is C. pneumoniae and heart disease. The

bacterium is found more often in the plaque that hardens arteries than in

corresponding places in people whose arteries are clear. Is the bug a

culprit or a bystander? Serious people doubt that it is a culprit.

Ridker of Brigham & Woman's Hospital in Boston says it's no surprise to find

Chlamydia in the inflamed tissue surrounding plaque. These bacteria live

inside white blood cells -- that's how they evade the rest of the immune

system -- and when the white cells rush off to help orchestrate the

inflammation, the Chlamydia could just be hitching a ride. Nor is it a

surprise that people who have already had heart attacks have a lot of

Chlamydia antibodies -- such people are weakened, and thus more likely to

get infections. He said his group at Harvard followed healthy people for

years and found that the ratio level of their antibodies to Chlamydia did

not predict their risk of having a heart attack.

Proponents of the other side of the debate say that our tools for measuring

infection were designed to detect acute infections, where the immune

response is very strong. They may not work on low-level, chronic infections

that hide from the immune system in white blood cells or other sanctuaries.

They also argue that lab animals fed a high-fat diet could develop

atherosclerosis faster if they were also infected with C. pneumoniae. " There

are many things that can cause inflammation, " says Dunne, director

of clinical studies for infectious diseases at Pfizer. " But I think it is

likely that infection is driving the atherosclerotic process. " In a

3,500-patient study due to end late next year, Pfizer is giving three-month

courses of its Zithromax antibiotic to half the patients and placebos to the

other half. If it works, maybe we'll all end up taking the pills.

Firm evidence connecting bugs to chronic diseases once thought to be wholly

environmental or genetic is still pretty scarce. But there is some

fascinating evidence -- or speculation, perhaps we should say -- from the

budding field of Darwinian medicine. The reasoning is as follows. A chronic

ailment like schizophrenia or cancer cannot be genetic in origin, because it

confers a disadvantage in the competition to reproduce. If schizophrenics

are even a bit less likely to have children than sane people, then the

schizophrenia gene should die out over time. Indeed, it takes just a slight

evolutionary unfitness -- a 1% drag on reproduction -- for a moderately rare

gene to become extremely rare over the course of a few thousand years of

human evolution. So if you see a disease that has afflicted mankind for a

long time and confers any evolutionary disadvantage, you should suspect a

bug.

Ewald, a professor of biology at Amherst College, is the pioneer of

this view of microbial disease. He came to the field from evolutionary

biology proper -- in his case, the study of birds. He shifted his focus when

a bad case of diarrhea had him wondering what the damned germ could possibly

be getting out of his misery. Answer: the chance to spread itself into the

water supply.

Purify the water, as we have done in this country for generations, and you

break the chain of infection. Ewald wondered what would happen then -- could

the guilty microbe evolve into a more benign form, in an attempt to linger

longer in the host? Theory said that it should, and practice has confirmed

that it does. " The second most successful vaccine of all time is the one

against diphtheria, because they made the vaccine from the bacteria's

toxin, " Ewald says. " Not on purpose -- they just noticed that the toxin

makes a great antigen [target for the immune system to attack]. The

organisms in the wake of that vaccine are as mild as can be -- people are

getting the diphtheria organism all the time without knowing it. " The crude

Darwinian approach practiced by prior generations of doctors assumed that

all germs evolved to coexist happily with their hosts, Ewald notes, not

considering that bugs could easily evolve the other way, toward nastier

disease. He thinks such a swing toward virulence explains the terrible

influenza pandemic of 1919, which killed more people than World War I.

Normally, flu, like any other disease transmitted through the air, requires

a more-or-less ambulatory host. You can feel bad, of course, but not so bad

that you stay home in bed, where you can't cough on strangers. Change the

equation, and you may well change the virus (one of the most mutable known).

Ewald thinks that conditions on the Western Front aided this process,

shoving what was perhaps a worse-than-usual bug in a truly diabolical

direction.

Soldiers with flu would have been stuck in their trenches until practically

keeling over. These bad cases would get sent to a clinic, where their

uncommonly intense infections would spread to others. The sickest of that

bunch would then be removed to hospitals further back, and the process of

selection would continue. Result, according to Ewald: the most virulent

strain of flu ever seen. About 20 million died.

Selection effects also explain why the infections acquired in hospitals are

so tough, Ewald says. Hospital workers spread germs from patient to patient,

carrying strains that, because they prostrate a patient, would not have

succeeded in spreading in the general population. Mosquitoes do much the

same thing; they make deadly infections more feasible on the evolutionary

plane.

A chronic infection, which goes on for an entire lifetime, would tend to

spread in a different manner. It might travel via sexual contact, or from

mother to child at birth, or during nursing. Because new hosts don't crop up

very often in these scenarios, such a bug couldn't be all that virulent --

it has to keep its host alive (and perhaps feeling good and looking

marriageable)to maximize its own chances of getting into another host.

" Evolutionary theory leads me to conclude that sexually transmitted

pathogens cause a lot more problems than we are yet aware of, " Ewald says.

" They must survive a long time in the host, hidden from the immune system;

the only ones that survive will have figured out that trick. They may hold

down their damage in the short run, but chances are that in the long run

they'll muck something up. One way to reproduce is to stay inside the cell,

wait until it divides, and divide with it -- HTLV [the AIDS virus] and human

papilloma virus do that. But how to get the cell to divide? By mucking up

its mechanism, and that moves you one stage closer to cancer. " So maybe

there are lots of slow-acting infectious agents that, for their own

evolutionary purposes, lurk inside our cells and cause havoc over long

periods. If that is the case, it is time to repeal the four postulates of

Koch. This famous 19th-century bacteriologist set a high standard for

proving that a disease is caused by a microbe.

First, he demanded, find epidemiological statistics consistent with

infection; then isolate the suspected causative organism; then produce the

same disease in an experimental animal by injecting the organism; then

retrieve the organism from the animal. The rules worked for acute diseases.

But with cryptic infections lasting decades, involving organisms that are

often hard to culture in test tubes or in animals and that affect people

very differently because of the intercession of genes and behavior, the

chain of causation can get unmanageably complex. In the new realm of chronic

disease, declares Ewald, you should start off assuming that a microbe is not

merely a possible villain, but the likeliest one.

Ewald credits this sharpening of his thesis to his unorthodox collaborator,

M. Cochran, a Ph.D. in physics who researches optics for the

military and works on evolutionary biology as an avocation. " I consider him

a genius, " Ewald says.

Ewald first crossed paths with Cochran a couple of years back, when Ewald

served as one of the three referees for a paper Cochran had submitted to a

scientific journal. Cochran argued -- and still does -- that homosexuality

probably has to be infectious in origin because it is widespread, of ancient

duration and very bad for the reproductive success of the affected person.

Any gene for the behavior, therefore, should have become very rare long ago.

The other two referees were appalled; Ewald was intrigued, although he, too,

rejected the paper on technical grounds. In his notes to the author he

offered to collaborate with him on similar research topics.

So far they have published two academic papers; others are forthcoming.

Applied to the matter of homosexuality, Cochran's view of genes and germs is

rank speculation and without practical application anyway.

But it is useful if only as a mental exercise that leads to a change in

thinking about disease causation. Ewald and Cochran argue that researchers

should at least give germs equal standing with other unproved theories when

they tackle ailments like psychosis and diabetes. Cochran sums up the new

germ theory this way: " Big, old diseases have to be infectious. "

Schizophrenia is very common -- 1% of the population has it -- widespread,

ancient and costly from a Darwinian point of view.

Heredity clearly plays some role in susceptibility to the affliction.

Could that be the whole explanation? Defenders of the pure-gene view have to

come up with some way around the matter of reproductive fitness. They argue

that the underlying factors for the disease may have provided our Stone Age

ancestors with some unspecified advantage in surviving to adulthood. But

Cochran says there is no particular reason to believe this story. " Besides,

it's so bad for your fitness it should have disappeared very, very recently,

let alone a long time ago -- things move fast when you have fitness

differential that big, " he says. He cites, as an example of recent

evolution, the steep decline in the frequency of the gene for sickle-cell

anemia among African-Americans, compared with what you'd expect to find,

given the percentage of their African ancestry and the prevalence of the

gene in Africa. There is a simple reason why the sickle-cell gene has not

disappeared in Africa; people born with one copy of this gene have only

slight anemia, but they do have an increased ability to survive malaria

infections. Thus, offsetting the genetic pull toward elimination of the

gene -- namely, that children born with two copies of the gene die young in

Africa -- is an evolutionary pull in favor of the gene. " The gene for

sickle-cell anemia provides a very expensive defense against malaria -- it

kills children born with two copies of it -- and in America you have no such

threat to defend against, " Cochran notes. " If it started out with a gene

frequency of 20%, the highest you get in Africa, and you put it in a

nonmalarial area, it should drop to a third that in ten generations. This

changes fast. " If schizophrenia imposes a similar cost, and offers no

offsetting gain, why hasn't the genetic propensity to get it dropped to the

low, low level you'd expect to find from random mutations? Could it be that

it's caused by a bug? Remember that it's hard for humans to outevolve

microbes, given that microbes go through more generations in a day than we

do in a century.

The first of Koch's demanding postulates has already been satisfied for

schizophrenia: It turns out to be significantly more common in children born

in winter months, when infections are most common, even though symptoms do

not normally develop until late adolescence. Many have sought a microbe

perpetrator, without success, but Cochran can at least spin a plausible

scenario. " Maybe an infection cuts back on certain connections among neurons

in the brain of the newborn, and later, in late adolescence, when many

connections are pruned back, you find that you're a quart low, " he says.

" The same is true of postpolio syndrome -- you recover from paralysis, and

then, in your late 60s, you're short of motor neurons. " Following this line

of reasoning, Ewald and Cochran began to question a tenet of Darwinian

medicine that argued that we get chronic illnesses today because our bodies

are adapted to Stone Age environments. Back then, any gene that helped get

us from birth through reproductive age would have been favored even if that

same gene imposed health disadvantages at age 60.

But in the view of Ewald and Cochran, that argument, while important, cannot

be the whole story. " We see a lot of old people who are doing well in old

age, and that suggests that there is enough genetic variability for

evolution to work with, " Cochran notes. " Suppose you get hit by a falling

boulder and grandpa takes in your kids and raises them, and suppose there's

a famine, and a certain percent of the people are going to die. The question

is, who? Having a grandfather around could help just enough to make the

difference. " And if your grandchild survives, so do your genes.

Does this mean that our inherited genes and the environment we now enjoy

don't matter? Not at all -- it only means that they are not necessarily more

important than microbes. As zur Hausen points out, everyone with cervical

cancer has the human papilloma virus, but not everyone with the virus

develops the cancer. What's more, women infected with human papilloma virus

are more likely to progress to cervical cancer if they smoke.

No modern illness is more often attributed to Stone Age genes in a Jet Age

body than obesity; yet even here, certain microbes may be the real problem.

Five different viruses have been implicated in obesity in animals, and

one -- adenovirus 36 -- has been found in both humans and animals.

Nikhil Dhurandhar, an obesity specialist at Wayne State University,

discovered the virus originally in chickens, who were getting fat before

dying of their illness. He found that in chickens, rodents and monkeys,

adenovirus 36 caused increases in body fat and -- peculiarly enough --

decreases in the level of cholesterol and triglycerides in the blood.

He found that antibodies to the virus showed up five times more often in the

obese people than in lean ones from the same states (Florida, Wisconsin and

New York). On top of that, the obese people who have been infected by the

virus had lower cholesterol and triglyceride levels than the other obese

people did. The National Institutes of Health is funding a three-year

investigation.

A confirmation of Dr. Dhurandhar's theory would suggest that we are barking

up the wrong tree in obesity treatments. Instead of filling people up with

phentermine and fenfluramine, maybe we should be looking for a vaccine or an

antiviral drug.

What's the payoff if this new way of looking at chronic illness proves

correct? First off, it would explain a number of medical puzzles. We know

that poorer, less-educated people suffer from more infections; this could be

why they have more heart disease and cancer, even after you take into

account smoking and other risk factors.

Second, it could suggest new places to look for the causes of old diseases.

For example, there ought to be a lot more sexually transmitted microbes than

we know about, and many dismissed as benign may turn out to be pernicious.

We could even reexamine our study of the human genome to find whether subtle

genetic variations affect our resistance to particular infections.

Scientists now think they know what protease precipitates Alzheimer's. They

don't yet know what gives rise to this enzyme or how to respond with a

treatment. It could be that a protease inhibitor will prevent the disease;

or it could be that an antimicrobial will be the answer.

The new germ theory of disease suggests new priorities in drug research. The

challenge of AIDS has shown us how far science can go in devising

antivirals, if the will is there. Maybe we will want to develop more

antivirals against what have until now seemed to be innocuous acute

infections but may well turn out to be the precursors of long-term disease.

Work on a vaccine against Epstein-Barr virus has so far been motivated by a

desire to head off mononucleosis; maybe the work would have gone faster if

we'd known the virus also causes cancer. Maybe specialists in all diseases

should consider the possibility that germs could be the problem. " From when

I was in medical school until now, we've made very little advance in

understanding high blood pressure, " says Barry Marshall. " Millions of people

are taking medication every day of their life to control this problem, yet

it's quite possible somebody could make a breakthrough tomorrow, just as I

did with H. pylori, and explain it. "

[Guest guest]

,

Please e-mail me your eight page 'Treatments for six illnesses'. Thank you.

Jeff