FEATURE ARTICLE from POPULAR SCIENCE, 4-01, By Gunjan Sinha
See the full article with pictures at http://www.popsci.com/scitech/features/sick/index.html
The AIDS example
blood vessel disease
Schizophrenia, Alzheimer's and Squamous-Cell Carcinoma
``What Makes You Sick? It Isn't What You Think.
Infectious microbes are to blame for cancer, heart disease, and most other ailments, says controversial biologist Paul Ewald.
On a blustery and frigid evening in early December, Professor Paul Ewald is huddled inside an auditorium with a group of 30 Amherst College students.
It's the last day of classes, and as part of their final project for "Seminar in Evolution," the students are presenting data suggesting that almost every disease under the sun -- including common killers such as heart disease and cancer -- might be caused by bacteria, viruses, or other infectious organisms.
Ewald, an evolutionary biologist whose book "Plague Time" about this very subject had recently been released, sits attentively in the front row with his legs casually crossed ...
One student points to the clustering of multiple sclerosis cases as evidence that the disease might be caused by something infectious. Another suggests the seasonal variation in births of autistic children is a reason to suspect that an infection during pregnancy induces the disease.
If I hadn't just spent the entire day with Ewald, I would have found the presentations almost laughable. Like most students of science, I was taught that statistical associations are soft science: They can't prove cause and effect. But that's exactly the kind of thinking that Ewald is out to dispel.
In "Plague Time," Ewald argues that the majority of chronic diseases -- any disease that progresses gradually over time -- are caused by infections. Just because you haven't proven cause and effect is no reason to ignore the data, he says.
To back up his arguments, Ewald goes beyond curious associations such as those found for multiple sclerosis and autism, and argues his case from an evolutionary point of view: Diseases such as cancer, heart disease, and even schizophrenia and obsessive-compulsive disorder are too common to be caused primarily by bad genes, Ewald claims.
Natural selection, he says, should have weeded those genes out of the population long ago. Instead, some genes might merely be making people more susceptible to infectious organisms, which are the true culprits of chronic disease ...
But Ewald is more like a lone wolf than the leader of a pack. While some scientists, such as famed virologist Robert Gallo (the co-discoverer of the AIDS virus), agree in part with some of Ewald's ideas, others of equal stature are downright dismissive ...
"Much of it is flagrant nonsense," says Robert Weinberg, ... a cancer researcher at the Whitehead Institute of Biomedical Research in Cambridge, Massachusetts ...
As Weinberg points out, the average life expectancy of humans today is much higher than in the past. Until recently, most people didn't live long enough to get diseases like cancer and Alzheimer's. "Traditionally, human life was 30 or 40 years," Weinberg argues," and there was not any selective pressure against a genetic defect that manifested itself at the age of 60 or 70."
Ewald counters that there is no evidence proving that at least some of our ancestors didn't live to be old. "One must not look at average ages but rather at whether a substantial part of the population lived to be 60 or 70."
Besides, Ewald adds, similar skepticism was leveled against the now-famous Barry Marshall -- an Australian doctor who finally, despite much guffawing and finger-pointing from his peers, proved in 1984 that a bacterium called Helicobacter pylori causes most peptic ulcers.
Marshall's theory challenged widely held and seemingly unassailable notions that ulcers were primarily caused by stress.
[Worse than ridicule is the autoimmune disease disinformation campaign -- perhaps sponsored by organizations who want to cut costs by denying treatment with antibiotics.
Any mammal would have a selective disadvantage if it tended to destroy itself when invaded by micro-organisms. The increasing number of people who are color blind to various degrees can be pointed to as an example of the survival of defects, but this does not apply to our response to parasites:
Humans have substantially reduced their chances of coming in contact with macro - predators such as tigers; and this security has been with us for at least 10,000 years -- plenty of time for the effect to show itself of no penalty for not being able to distinguish green from yellow.
This is not the case with micro - predators. Polio, diphtheria, syphillis, tuberculosis, and HIV have wrecked havoc on us within the last hundred years. For every smallpox we put down, it seems that ten more species of pathogens rise in its place.
It was only in the 19th century that the germ theory of disease began to be accepted; and, even today, genetic tendencies and environmental stresses are the preferred explanations. In the 19th century, for example, doctors at the University of Vienna hospital had their collegue Semmelweis fired because he cut the maternity death rate of one mother for every eight admissions to one in thirty by having the staff on his ward wash their hands. (See "Plague Time" p. 17)]
However controversial, Ewald's ideas do have scientific legs to stand on. In the past few decades, a handful of cancers have been unquestionably linked to infections.
Take the case of cervical cancer and the human papilloma virus (HPV), for example. The Centers for Disease Control reports that the sexually transmitted virus is responsible for as much as 93 percent of all cases of cervical cancer.
But because most women infected with HPV never develop cervical cancer (the CDC estimates that 20 million Americans carry the virus), and the cancer takes years to kick in -- characteristics very uncharacteristic of infectious disease -- figuring out the connection took years.
"Over 100 years ago," Ewald explains, "people noticed that the frequency of cervical cancer was higher in prostitutes, and also that there were couples with penile and cervical cancer. But people didn't accept an infectious cause until the organism was identified over a century later."
Also pegged as cancer culprits are a herpes virus that causes Kaposi's sarcoma, a human T-cell leukemia virus (HTLV 1) responsible for a rare form of leukemia, and hepatitis viruses that cause liver cancer.
These and other viruses are responsible for between 15 and 20 percent of all cancers. The rest, say most scientists, can be blamed on rogue genes and non-infectious environmental factors such as diet and smoking.
Ewald, however, is convinced that evidence from other cancers, including those of the breast, will soon tip the scales in favor of infectious causes ...
Despite the lack of data proving a cause-and-effect relationship, scientists shouldn't disregard the possibility of an infectious cause, says Ewald.
Take the case of HTLV 1, which causes a rare form of leukemia prevalent in western Japan. The virus can be transmitted sexually or via mother's milk. People typically don't develop the cancer until 50 or 60 years after they've been infected, and some infected people never develop leukemia.
"It's not like chicken pox or some other organism that follows the established rules of infection," says Ewald, "and because it's transmitted in families, people could mistakenly assume it's hereditary."
Like HTLV 1, an infectious organism may be causing breast cancer but operating too cryptically to be detected with the tools available.
AIDS researcher Gallo, who also discovered HTLV 1, agrees: "Sure, there may be a breast cancer microbe, difficult to find, present rarely or occasionally, which in the right circumstances contributes to breast cancer, but that's still a very open issue."
Ewald argues that, from an evolutionary perspective, breast cancer is simply too common in the population for it to be caused by rogue genes.
His reasoning, backed up by mathematical calculations, goes something like this: Older people are still subject to natural selection after they stop reproducing because they pass on their care and wisdom to their children and grandchildren (as in some societies where grandmothers are responsible for preparing food). So a child without a grandparent will presumably be less "fit" than a child with a grandparent.
Over many generations, children with grandparents will prevail over children without grandparents (whose genes presumably made them more vulnerable to disease).
Ewald applies the same rationale to Alzheimer's and cardiovascular disease. Studies have shown that people with a gene called APO E4 appear to be more susceptible to both diseases.
But Ewald argues that a faulty gene is too prevalent (between 10 and 50 percent of a given population carries APO E4) to have been conserved through evolution, and that it is merely making people more susceptible to infection.
An airborne bacterium that infects the respiratory system, Chlamydia pneumoniae, may be one of the real culprits.
People with E4 are much more likely to be infected by Chlamydia, and several studies have confirmed the bug's presence in the fatty lesions associated with coronary artery disease.
But it's difficult to discern whether the organism initiates the disease, exacerbates the disease, or is even contributing at all.
[In "Plague Time", Professor Ewald, p. 109, writes concerning a Finnish study: "... 70 percent of the samples from heart attack patients had antibodies to Chlamydia [pneumoniae]. This percentage was significantly higher than the percentage in the control serums from people who had not had heart attacks."
Is it possible that all the deaths in recorded history from bubonic plague are miniscule compared to the people who are dying right now from heart disease due to chronic bacterial infection?]
Chlamydia's role in Alzheimer's disease is much more tenuous. In 1998, microbiologist Alan Hudson reported that he had found the bug in 22 out of 23 brains of Alzheimer's patients, whereas only one out of 25 normal brains tested positive.
"I couldn't believe my eyes, so I spent three years using every tool known to man confirming that the organism was really there, before going public with it," recalls Hudson ...
Although Hudson and Ewald have become close collaborators, one can't help but wonder whether it was mutual professional interest that truly drew them together, or their shared experience of being treated like pariahs by the medical establishment.
A self-described "gene jockey," Hudson has spent his career studying how genes enable organisms to do what they do. He stumbled onto the Alzheimer's research through a former colleague when he was at the Philadelphia College of Osteopathic Medicine.
When Hudson submitted his Alzheimer's work to a journal for publication, the editors sent it out for peer review, as is standard practice among all journals. "The Chlamydia reviewers said `publish the thing,' the Alzheimer's people hated it," he says.
The journal initially rejected the paper, and it was only after some reviewers pressured the journal that they finally published it.
Hudson's experience is all too common in a field where arguments over scientific ideas can devolve into something akin to turf war ...
Just as the medical establishment ridiculed Barry Marshall and his germ theory of ulcers, says Ewald, scientists who have spent a lifetime studying the genetic basis of disease are of course going to reject alternative explanations. "They've simply got too much invested in existing theories," he argues.
Nevertheless, researchers are working to confirm Hudson's findings. As of this writing, a group based in the Netherlands has also found an association between Alzheimer's and C. pneumoniae, as has Chlamydia expert James Mahoney at McMaster University in Hamilton, Ontario.
One of the problems, says Hudson, is that identifying the organism is very difficult and the slightest deviation in established protocol can throw off results.
As for Ewald's evolutionary argument, most scientists agree that grandparents do contribute to fitness -- the question is how much. Evolutionary arguments don't prove cause and effect.
To this, Ewald responds: "We always have to keep on the table the various hypotheses, even though we don't see direct evidence of them. One can never jump to the conclusion that infection is not important just because we find genes and environment are important."
"In most cases there's little evidence to exclude infectious causation of chronic disease. That kind of thinking has been responsible for a lot of death over the past 40 years." ''
FEATURE ARTICLE from POPULAR SCIENCE, 3-01, By Gunjan Sinha
See the full article with pictures at http://www.popsci.com/exclusive/apr2001/taming.html
``Despite efforts to stem the AIDS death toll in Africa, there were 3.8 million new infections last year and the tide of new cases shows little sign of slowing down.
But what if there were a way to manipulate the virus so that infection was no longer a death sentence?
What if instead, like herpes, it became a chronic infection that occasionally caused some health problems that could be remedied by medication?
The idea isn't as far-fetched as is seems, says evolutionary biologist Paul Ewald, a professor at Amherst College in Massachusetts.
Microbes evolve in response to their environment in ways that foster their own survival. In terms of a sexually transmitted microbe like the AIDS virus, evolutionary theory posits that when sexually transmitted pathogens find themselves in populations where people have fewer sexual partners, benign strains or species prevail.
Understanding why this is the case requires getting inside the mind of the virus, so to speak: Say you're an HIV virus. Each time you replicate, your progeny is a little different. Depending on the environment, some die off while others thrive.
Now suppose that environment entailed a society where people rarely switch sexual partners. The progeny causing the most sudden and severe illness would die with their host, never getting a chance to be passed on.
But in sexually promiscuous cultures where a virus has lots of opportunities to be passed on, there is no selective pressure against the more virulent progeny and they will thrive too.
Changing sexual behavior in ways that reduce transmission of the virus by either using condoms or remaining with the same partner not only slows down transmission, says Ewald, but also alters the evolution of the virus itself.
This has already played out in Africa with one strain of HIV. In Senegal where potential for transmission is relatively low, the HIV-2 strain tends to be less virulent than it is in the Ivory Coast and Guinea-Bisseau, where potential for sexual transmission is higher.
It's an idea that's not well appreciated by many public health professionals but has far-reaching implications, says Ewald, especially in some African countries where virulent strains are rampant.
Travelers carry those strains elsewhere and so controlling the virus's evolution should be in everyone's interest. "HIV doesn't look like its going to disappear anytime soon so having a benign form of the virus be more prevalent would certainly be the lesser of two evils." ''
NEWS ARTICLE from THE LOS ANGELES TIMES, 4-2-01, By JANE E. ALLEN
``Chronic infections tied to clogged arteries
Recurrent infections of the sinuses, lungs and urinary tract increase the risk of clogged arteries, a new study has found, bolstering the theory that heart attacks and strokes have infectious origins.
Of 826 Italian men and women involved in the five-year study, those who had suffered from common chronic infections were about three times more likely to develop new fatty deposits in the principal artery carrying blood to the brain.
"Our study provides further strong evidence that chronic infection increases the overall risk of blood vessel disease," said lead author Dr. Stefan Kiechl, a neurology professor at Innsbruck University Clinic in Austria.
Kiechl and his colleagues from Austria and Italy focused on changes in the carotid artery but also detected similar changes in other blood vessels, such as those of the heart.
They think the same process is at work in arteries of the neck, heart and legs. Problems occur when pieces of the fatty deposits break off and lodge in a blood vessel, cutting off blood supply and causing a heart attack or stroke ...
In the study, blood levels of C-reactive protein, a key indicator of inflammation often used to assess heart-attack risk, were elevated among people who had suffered chronic infections. The subjects studied were 40 to 79 and received ultrasound scans of carotid artery in 1990 and 1995.
"This is yet another piece of evidence implicating the potential role of inflammation and infection in atherosclerosis," said Dr. P.K. Shah, cardiology chairman at Cedars-Sinai Medical Center in Los Angeles. He noted that the study also found a worsening of existing plaque, not just accumulation of new plaque ...''
NEWS ARTICLE from REUTERS, 4-9-01
``Retroviruses Implicated in the Pathogenesis of Schizophrenia
Retroviruses may play a role in the development of schizophrenia in some individuals, scientists from the US and Germany report in the April 10th issue of Proceedings of the National Academy of Sciences.
In the report, Dr. Robert H. Yolken, of Johns Hopkins School of Medicine, in Baltimore, and colleagues say that they have identified retroviral RNA in the cerebrospinal fluid from 29% of patients with recent-onset schizophrenia and from 5% of patients with chronic schizophrenia.
The majority of the nucleotide sequences present in the schizophrenic patients belonged either to the human endogenous retroviral (HERV)-W family or to the murine leukemia retrovirus family. Frontal cortex tissue obtained postmortem from schizophrenics also showed differential up-regulation of the HERV-W family of retroviruses.
In contrast, no retroviral sequences were present in CSF in any of the normal control subjects or in controls with noninflammatory neurologic illnesses ...
"... most retroviruses can be activated by a number of environmental factors, including infection with other viruses such as herpesviruses," Dr. Yolken [said].
In a clinical trial about to begin in the Baltimore area, Dr. Yolken and his colleagues will study the treatment of herpesvirus infections as a way of suppressing retroviral transcription and hence the symptoms of schizophrenia ... ''
Proc Natl Acad Sci USA, 2001;98:4293-4294,4634-4639.
NEWS ARTICLE from REUTERS, 4-12-01
``HPV-16 a Possible Risk Factor for Squamous-Cell Carcinoma of the Head and Neck
Results of a nested case-control study suggest that infection with human papillomavirus type 16 (HPV-16) may be a risk factor for squamous-cell carcinoma of the head and neck.
Dr. Jon Mork of National Hospital in Oslo, Norway, and a multicenter European team report the finding in the April 12th  issue of the New England Journal of Medicine.
They analyzed serum samples for antibodies against HPV types 16, 18, 33 and 73 from 292 patients who developed squamous-cell carcinoma of the head and neck an average of 9.4 years after enrollment, as well as from 1568 matched control subjects.
The researchers also measured serum cotinine levels, a marker of smoking, and used polymerase chain reaction (PCR) analysis to look for HPV DNA in tumor tissue samples from 160 of the cancer patients.
Dr. Mork's team detected HPV-16 DNA in 50% of oropharyngeal cancers and 14% of tongue cancers. After adjustment for smoking, HPV-16 seropositivity was associated with a 2.2 excess risk of squamous-cell carcinoma of the head and neck, the team reports ... ''
N Engl J Med 2001;344:1125-1131.
NEWS ARTICLE from THE PLAIN DEALER, 4-16-01, By JOHN MANGELS
[Alzheimer's linked to brain cells' attempt to divide]
`` "Be fruitful and multiply."
The biblical decree doesn't apply to the brain's 100 billion nerve cells, which, unlike their cellular brethren elsewhere in the body, are programmed never to reproduce. If they could, spinal cord and head injuries might heal themselves.
But something about Alzheimer's disease overcomes that cellular inhibition - to a point. Scientists at Case Western Reserve University and University Hospitals have found that rogue neurons in the brains of Alzheimer's patients ignore their own commandment and try to replicate themselves, with devastating consequences.
The affected brain cells start the complex job of splitting in two, only to inexplicably grind to a halt partway through the process.
Stuck with a toxic extra copy of the genetic material they had intended to pass along to their offspring, the now overloaded and grossly damaged cells linger for months, their vital communication links to nearby neurons slowly withering.
The brain cells' eventual demise, the researchers believe, is due to the excess genetic baggage they're carrying from their ill-fated attempt to spawn. It is a novel explanation for the advancing siege of cell death that robs Alzheimer's patients of memory and sanity ...
Karl Herrup, the CWRU/UH neuroscientist who led the research published yesterday [4-15-01] in the Journal of Neuroscience, [said] "Neurons are highly resistant to division. But what this disease tells us is . . . you can eventually just override the control circuits and drive these cells to divide. And they get to make that mistake only once." ...
Nerve cells in the brain and spinal cord [normally] don't go through this division process, however. Scientists don't know why. A theory is that their thicket of up to 10,000 connections with other neurons - forming a network that carries the signals of thought and movement - would make duplication too hard.
The upshot is that the supply of neurons we're born with is all that we get. Snuff out a cluster of brain cells in a stroke or sever your spinal cord in a fall and there won't be any replacements coming along.
But something [infection?] pushes neurons in the brains of Alzheimer's patients to take a stab at dividing, Herrup and colleagues David Geldmacher and Yan Yang found. Their team and others previously had discovered hints that that might be the case, in the form of proteins that cells usually make when they divide.
Herrup's team wanted direct evidence, though, and they got it by examining hundreds of nerve cells from the brains of seven Alzheimer's patients and four people without the disease. The neurons came from areas of the brain that are known to be hit hard by the disease, where up to 80 percent of neurons die.
The scientists used tiny glowing probes that latch onto a cell's genetic material. A normal human cell should have two copies, one each from our parents. A cell preparing to divide should have four sets, so it can relay two to its offspring.
Under high-powered microscopes, the researchers saw four fluorescent green dots in the neurons from the Alzheimer's patients - a sure sign the cells were trying to divide, in spite of their embedded instructions not to.
Having even one too many chromosomes can cause disastrous results, such as the mental impairment of Down syndrome. So Herrup thinks that having an entire extra set of 24 chromosomes is such an imbalance that it eventually kills the nerve cell.
What tempts neurons to make this ruinous try at reproduction, and what freezes the process at the worst possible time? No one is sure, although a plausible idea for the trigger is that the brain cells are trying to mimic their counterparts elsewhere in the body, which multiply in response to some kind of alarm [possibly triggered by spirochetes feeding on the neurons?] ... ''