The sunshine cure

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I wrote this feature for Nature Medicine after receiving a poorly-written email extolling vitamin D’s benefits. The writer was so impassioned, though, that I was intrigued. This ran in the April 2007 issue. You can view a pdf version of the article here.

Could ten minutes of sunlight a day be all that’s needed to fight multiple sclerosis, cancer and tuberculosis? Apoorva Mandavilli discovers the growing interest in vitamin D’s many virtues.

sunshine2Long before antibiotics turned tuberculosis (TB) into a curable disease, a Danish scientist  found an unusual way to treat it. In 1895 Niels Ryberg Finsen, then just 35, discovered that light from an electric arc lamp cured most people with TB of the skin. Over the following six years, he successfully treated 804 patients.

Nobody understood how the treatment worked, and the condition, lupus vulgaris, was relatively rare. But TB was such a fearsome scourge at the time that Finsen’s discovery won him the 1903 Nobel Prize in Physiology or Medicine. It also began the trend of sending those sick with TB to recover in sanatoriums housed in sunny locales.

It’s only now, more than a century later, that scientists are beginning to understand why Finsen’s method worked.

“It had to be through vitamin D,” says Barry Bloom, dean of the Harvard School of Public Health.

Last year, Bloom and his colleagues published evidence suggesting that vitamin D, made in response to sunlight, stimulates the production of a compound in the body called cathelicidin, which can kill various viruses and bacteria, including the TB microbe (Science 311, 1770– 1773; 2006).

It’s not often that you hear scientists of Bloom’s caliber extolling the virtues of a vitamin; that’s more commonly associated with over-anxious parents or ardent fans of alternative medicine.

Vitamin D may be best known for its role in harnessing calcium from the diet to build strong bones. But Bloom’s report is one of several in the past few years published in top journals— including the New England Journal of Medicine, Journal of the American Medical Association and Nature Immunology—that suggest a far meatier role for the vitamin in the body’s defense against diseases such as tuberculosis, multiple sclerosis (MS) and cancer.

“I think there’s an emerging mainstream acceptance of vitamin D as an immune- regulating factor,” says Eugene Butcher, professor of pathology at Stanford University. “The only people who are going to be skeptical of it are people who haven’t bothered to read the literature in the last five years.”

Latitude gradient

A list of vitamin D’s supposed benefits is sure to make most scientists skeptical. Apart from building bones, vitamin D is thought to boost muscle strength, help heal psoriasis, and prevent MS, hormone-dependent cancers and type-1 diabetes.

The strongest evidence available is perhaps for the vitamin’s protective role in MS. Several studies have documented a dramatic ‘sunshine belt’ across the center of the globe: MS is rarer near the equator and more common in northern regions, where ultraviolet light from the sun is less intense.

“There’s a very, very strong latitude ingredient,” says Alberto Ascherio, associate professor of nutrition and epidemiology at Harvard University. In the US, for example, the incidence of MS is up to four-fold higher in the northwest than in the southeast, he notes.

In mouse models, mice that get little vitamin D succumb faster to the disease; give them vitamin D and the symptoms diminish. Even in people, those with highest blood levels of vitamin D appear to have the lowest risk of MS (JAMA 296, 2832–2838; 2006). In 2004, a study of 187,500 nurses showed that women who get at least 400 international units (IUs)—the current daily recommended dose—of vitamin D per day have a 40% lower risk of developing MS (Neurology 13, 60–65; 2004). Researchers are testing whether high doses of vitamin D can ease MS symptoms in people as they do in mice.

Latitude also seems to play a role in the incidence of hormone-dependent cancers. “There is a fair bit of epidemiological data showing that places with less sunshine have higher rates of cancer,” says David Feldman, professor of medicine at Stanford University and the editor of a 1,300-page treatise on the substance.

The effect is almost certainly because of vitamin D, Feldman says. “People tend to think it can’t do all these things when it’s a vitamin,” notes Feldman. “It’s not a vitamin, it’s a hormone.”

Based on a meta analysis of 63 studies, taking 1,000 IUs daily cuts the risk of colon cancer by 50% and of breast and ovarian cancers by 30% (Am. J. Pub. Health 96, 252–261; 2006). In vitro and in animal models, there is strong evidence that vitamin D stops cancer cells from proliferating and induces them to commit suicide.

In human trials, Feldman’s team has shown that escalating doses of calcitriol, the active form of the vitamin, slows the progression of prostate cancers. In a separate trial of men with advanced prostate cancer, an enormous weekly dose of calcitriol—about 50 times the normal amount—extended survival by nine months (Anticancer Res. 26, 2647–2651; 2006). Several trials testing higher doses of the substance against prostate cancer are under way.

Black and white

Vitamin D’s role in tuberculosis is both its oldest and most recent success story. With his electric lamp, Finsen had stumbled on to something that Bloom and his colleagues say can explain why the incidence of TB in African Americans is about eight times higher than in whites.

In mice, TB bacteria and other microbes are killed by producing nitric oxide in macrophages, the scavenger cells of the immune system. Humans rely on a different mechanism, and it’s now clear that that method depends on vitamin D, Bloom says.

The researchers discovered this phenomenon partly by accident. In comparing macrophages that can kill the TB microbe with dendritic cells that cannot, they found two stark differences: macrophages carry a receptor for vitamin D and an enzyme that converts the inactive form of the vitamin into the active form.

Infection with the TB bacterium spikes the levels of both of these, stimulating the production of vitamin D and, in turn, the antimicrobial protein cathelicidin. Their findings also explain why mice, which are nocturnal animals, would have evolved a completely different way to fight the bacteria.

African Americans have been known to have significantly lower blood levels of vitamin D because melanin filters out ultraviolet light. In their study, Bloom and his colleagues found that macrophages cultured in serum provided by African Americans produced 63% less cathelicidin than when cultured in serum from whites. This might explain why African Americans—and perhaps dark-skinned Indians—have higher rates of TB.

“How do you write a paper when everybody says race doesn’t matter and here you have a subject where blacks have more TB and it has to do with the color of the skin and nothing else?” asks Bloom. “I thought that was pretty challenging.” Bloom says scientists are planning to test vitamin D supplements in TB trials in Africa.

In a separate study in March, Butcher and his colleagues published results showing that in response to sunlight-induced vitamin D, immune cells travel to protect the outer layers of the skin from infections (Nat. Immunol. 8, 285–293; 2007).

“Those papers suggest that that the immune system is making its own vitamin D,” says Margherita Cantorna, associate professor of molecular immunology at Penn State.

Scientists have known for more than 20 years that most immune cells have receptors for vitamin D. Cantorna says 
that vitamin D directly or indirectly regulates
T-cell development
and function. In
animal models, it has
been shown to control the immune
response by stimulating cells that
dampen the immune system and inhibiting those that increase inflammation.

“By regulating one T-cell type in one direction and another T-cell type in another direction, it’s shaping the immune response to a particular antigen,” she says. “But we don’t know a ton about how it all fits together.”

Flu factor

As winter gives way to summer in the coming months, the number of people who succumb to the flu virus will drop about a 100-fold. That seasonality has been known since Hippocrates’ time, but why winter should bring flu epidemics has remained an enduring mystery.

There are a myriad theories: that people huddle indoors in the winter, swapping infected breaths; that catching a chill makes people more susceptible to the virus; that the virus itself is more stable in the wintry air—but all in the end are “pretty unsatisfying theories,” says Scott Dowell, director of the US Centers for Disease Control and Prevention’s Global Disease Protection Program. “Something that we don’t totally understand makes the flu go away.”

Some researchers have suggested that the seasonal stimulus could be vitamin D.

“It’s one of these things that is provocative and testable and it should be tested,” says Dowell. “There are lots of things proposed as beneficial effects of vitamins that don’t hold up eventually.”

Testing vitamin D’s true value is easier said than done. Because it is not a new substance, there is little interest from companies, which have the money to fund large-scale trials.

“No company is going to come along and say let’s do a double-blind clinical trial of vitamin D,” notes Michael Zasloff, director of surgical immunology at Georgetown University. “It’s not something anyone is going to make money outof.”

It might be easier just to stand in the sun.

Vitamin D is the only vitamin that is naturally made in the body—but only in response to the sun’s ultraviolet B rays. In fact, the emerging importance of the vitamin may be reason enough to hold off on the sunscreen, at least for a few minutes a day.

There are only few other natural sources of vitamin D: fatty fish, shitake mushrooms and reindeer meat. “Not many people are on that particular diet,” notes George Ebers, professor of neurology at the University of Oxford.

An eight-ounce glass of fortified milk in the US contains just 100 IUs. Ten minutes of the summer sun, in contrast, can produce far more than 400 IUs, the recommended daily intake.

That varies with the intensity of the sun, of course, and with the skin color of the person exposed. Thanks to long winters, longer working hours and an over-zealous fear of skin cancer, most people in the world don’t have high enough blood levels of vitamin D, which has led to a troubling resurgence of rickets, particularly among African Americans. Older people generally harbor even lower amounts.

Even among women taking prenatal supplements, more than 80% of African- American women and nearly half of white women tested at delivery had levels of vitamin D that were too low (J. Nutr. 137, 447–452; 2007).

To see the vitamin’s beneficial effects in cancer and autoimmune diseases, the daily intake should be boosted to about 1,000 IUs and perhaps double that for an elderly, dark- skinned woman. “It’s pretty clear that the recommendations should be higher,” says Cantorna. Experts in the US and elsewhere are debating how high those recommended levels should be.

Several of the scientists interviewed for this article say that since discovering vitamin D’s benefits through their research, they have on their own begun taking about 1,000 IUs every day. And, in the meantime, adds Zasloff, “stay in the sunlight!”

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