November 20, 1998

Prophets Under Siege
A Vitamin for the Ages
Science the Barbizon Hotel
A Media Frenzy
Celebrity Science

Prophets Under Siege

Last week the Wall Street Journal  ran a story that served to cool down a hot theory.

In May the New York Times  reported on its front page that Judah Folkman, the scientific heavyweight of Children's Hospital of Boston and Harvard Medical School, had found a way to cure cancer in mice. The way the story was written and played left the reader thinking that a human cure can't be far behind.

For the past quarter century Folkman has been studying tumor angiogenesis, the generation of blood vessels that feed the tumor, keep it growing and carry its nascent progeny on the first leg of their journey to vital organs, where the real damage is done.

Most cancer researchers try to figure out ways to kill cancer cells head-on when surgery is not an option. Over the years they have tried variations of two approaches: supplementing the tumor's diet with various poisons and causing lethal mutations in its DNA through ionizing radiation. More recently they have sent in high-powered "hit men" via the immune system and now are trying to bring genetic switches to bear.

Almost from the start, Folkman has spurned convention and championed the strategy of mass starvation. Like vampires, tumors need a steady supply of blood to get along. No blood, no growth, no future.

Two agents developed in Folkman's laboratory, endostatin and angiostatin, apparently deprived large tumors in mice of their blood supply, causing them to vanish.

In science, the term "apparently" is operative in such circumstances until the initial report can be confirmed by reproducing the experiment, usually several times.

The Journal  reported that other investigators, including competitors, have found reproducing Folkman's work tough going. Some wonder if he has "promised too much too soon" in his drive to advance his theories.

Folkman isn't taking it sitting down. He has issued a statement in which he maintains that "regression of mouse tumors in mice has been reproduced multiple times in our laboratory" and in "other laboratories" using purified endostatin. His group plans to assist researchers at the National Cancer Institute(NCI) and "teach them the proper techniques" so that they can successfully reproduce the experiments, too.

Folkman was honored at a surgical conference in the Twin Cities a couple of months ago. His talk was beamed from downtown Minneapolis to Mayo Auditorium, where a scattered audience watched it on the big screen.

Folkman went to some length in praising members of his research team and the work of several collaborators, work that fits in nicely with what he has been trying to show all these years: Tumors have basic needs to fill before they can kill. If these needs aren't met, tumors remain dormant or disappear.

Up on the screen went data from recent autopsy studies. The number of dormant tumors in healthy or "cancer free" individuals is much higher that previously believed. Folkman didn't need to say it. More of us than we thought are carrying the seeds of our destruction.

But is Folkman right? Or is his just another pet theory destined for oblivion?

A Vitamin for the Ages

"Our day will come" goes the lyric to a 60s hit single.

For me as a practicing nonscientist who has inveigled his way into the temple of science and consorted with its high priesthood, that day was last month. What moved me was a story that ran the Oct. 26th edition of USA Today.

    Folic acid has become the darling of nutrition
    researchers. The unassuming B vitamin, found in
    abundance in orange juice, spinach and other leafy
    green vegetables, chicken liver and beans has long
    been overshadowed by sexier nutrients.... Until
    now.

"Folate is probably the vitamin of the 21st century," said one of the experts interviewed for the story.

The bullet points:

• "The National Institutes of Health are funding research, including clinical studies to investigate the nutrient's possible role in the prevention of cardiovascular disease and colon cancer."

• "The March of Dimes just kicked off a three-year, $10 million public health education campaign for folic acid in hopes of reducing the incidence of neural tube defects in the USA by at least 30% by 2001."

• "This year, the Food and Drug Administration began to require folic acid fortification of enriched foods such as breads, flours, pastas and rice. And breakfast cereal makers can add folic acid to products."

And there's more.

"Folic acid boost could save 50,000 lives a year" ran a headline in a CNN Interactive story. BBC Online Network weighed in: "Researchers have found a direct link between low levels of two vitamins - B12 and folic acid - and the onset of Alzheimer's disease." And the Washington Post: "Multivitamins May Prevent Cancer. Study suggests large benefit, probably due to folic acid in daily supplements."

What's all this fuss about folic acid? Is this for real? Did anybody see it coming? And what does it have to do with Judah Folkman?

Science at the Barbizon Hotel

The opulent oak-paneled meeting rooms of New York's Barbizon Hotel are gone now, casualties of a major renovation.

But Friday afternoon, December 14, 1984, one of them hosted a news conference in which a University of Minnesota scientist explained what he had found that was being reported in the AAAS journal Science.

Dressed in a dark suit and holding a pointer, Jorge J. Yunis, professor of laboratory medicine and pathology and a leading geneticist, took the elite of science journalism on a brief journey along the length of a chromosome.

Chromosomes are the X-shaped bodies in the nucleus of the cell that contain the DNA. In 1969 Torbjorn Caspersson at the Karolinska Institute in Sweden found that certain stains caused chromosomes to show light and dark lateral bands along their length.

For a long time chromosome researchers could see only about 250 total bands for the entire complement of human chromosomes. Yunis pioneered high-resolution chromosome banding. Through manipulation of the cell cycle and sudden impact (he'd drop cells on to a slide from a height of 6 feet), chromosomes were induced to deliver up to a thousand bands to the trained eye.

The more chromosome bands you can see, the easier it is to spot breaks, rearrangements, duplications and other defects in the chromosomes.

Yunis placed his pointer next to a band on a chromosome where a break and rearrangement had occurred in the tumor cells of a patient with lymphoma. An oncogene or cancer gene had been found at the break. Then he explained that he had been able to recreate the break in the patient's healthy cells by depriving them of folic acid.

Folic acid is the only vitamin that operates directly on genes. Cells need it to make thymidine, a precursor molecule to DNA. If you try to grow cells without folic acid in the cell media, or if you treat them with chemotherapeutic agents designed to interfere with folate metabolism, their chromosomes begin to display characteristic breaks, even rearrangements, some involving different chromosomes.

In his paper in Science, "Constitutive Fragile Sites and Cancer" (226: 1199-1204), Yunis reported that chromosomal breaks induced by folic acid deprivation were indistinguishable under the microscope from those found in the tumor cells of patients with leukemia, lymphoma, and some solid tumors. He called these breaks "fragile sites" and in a news release suggested that they could form the basis of blood test that could determine who might be predisposed to cancer.

He also implied that folic acid might be important in preventing cancer -- by keeping chromosomes intact.

That is, a simple vitamin might help keep our genes together. Not molecules like Folkman's endostatin and angiostatin that require a lot of delicate tweaking by structural biologists and biochemists. A simple B-vitamin, discovered in spinach in 1945, and readily available in foods our mothers insisted we finish before we left the dinner table. Also readily available at any drug store. And no company to make a killing.

Was it too good to be true?

A Media Frenzy

Celebrity Science

Judah Folkman's career, according to the Wall Street Journal article, "seems to illustrate an inherent tension within modern-day, high-stakes medical science: the conflict between the advisability of great caution in reporting data and the need to sell projects to sponsors so the promising research can continue."

It's hard to argue with that neat summary. But ours is an age of unparalleled mass marketing and celebrityhood seeking. The temples of science are not immune from the conflicts that may result. Self-promotion is the way you get your ideas in front of the public. Even biomedical ethicists do it.

I myself, a practicing nonscientist, experienced an internal conflict during the time I was a top scientist's right-hand man. Journalists are trained to be healthy skeptics, yet I was completely in the camp of the "possibility" that this might be the way it works.

The theory had so many of the right ingredients: basic science, clinical science, DNA mechanisms, diet and nutrition, carcinogenesis, human evolution. I swallowed it whole, did a lot of leg work in the biomedical library to shore it up, gave my advice when asked (yes, you should include your parallel analysis of the great apes in the paper), and then helped pitch it to the news media.

Today, 14 years later, folic acid is under full sail. The distinguished Bruce Ames at Berkeley is on board. In his online CV, under nutritional factors in cancer and aging, he writes: "We have shown that folate deficiency breaks chromosomes...." Now his group is investigating a reported high frequency of folate deficiency and brain damage.

Edward Giovannucci and his colleagues at the Harvard School of Public Health recently reported that high intake of folate "may reduce the risk of colon cancer" based on their study of nearly 89,000 nurses. Epidemiology is on board.

New York Times health columnist Jane Brody is on board. The vitamin peddlers are on board, too. But they claim they always were. Science is just playing catch-up.

No one really knows whether folic acid, chromosome damage, and cancer and other diseases are all connected.

But something is going on here. Folic acid is at the center of it. And in the end a scientific prophet may be vindicated.

    --William Hoffman    hoffm003@tc.umn.edu