B Vitamins: They're Complex
By studying folate and vitamin B12, researchers are unraveling some of our body's most fundamental biochemical pathways.
Compared to a molecule of DNA – say, human chromosome 1, made of some 10 billion intricately twisted atoms – a folate molecule is plain and simple. Also known as folic acid or vitamin B9, it consists of just 51 atoms. The public health message around it is also rather mundane. Just eat normal food and, thanks to a national fortification program, you’ll almost certainly get enough. What more could there possibly be to say about this unassuming little nutrient?
Actually, quite a lot. Despite folate’s simplicity – or maybe because of it – the molecule is key to many of the body’s most important chemical reactions. Without folate, cells cannot divide and DNA cannot be made, repaired, or regulated by the fundamental process known as methylation, for which folate supplies a single but essential carbon atom. Emerging genomics research is untangling differences in the way people process folate and its biochemical cousin B12, which is necessary for its breakdown. Those differences may underlie a wide swath of diseases, from the birth defect known as spina bifida to the dementia that often comes with old age. As nutrients, folate and B12 fall into the “nurture” category. But our need for them unquestionably shapes our nature.
In 1926, three scientists found they could successfully treat one group of patients, albeit with an unappetizing “drug”: half a pound of raw, ground-up liver.
Biomedical researchers realized that folate and B12 were critical to health even before they had figured out their chemical structures. The discovery of both vitamins started with puzzling and often fatal cases of anemia, or pathologically low red blood cell production. In 1926, three scientists found they could successfully treat one group of patients, albeit with an unappetizing “drug”: half a pound of raw, ground-up liver. Two years later, a young doctor named Lucy Wills traveled to the slums of Bombay to investigate a different type of anemia afflicting malnourished pregnant women. Wills fed the women Marmite, a salty yeast paste that allowed their bodies to ramp up blood cell production. She named the mysterious, then-unknown nutrient in Marmite “Wills factor.” In 1941, it was isolated from spinach and renamed folic acid. In 1948, the secret ingredient in the raw liver was isolated, too: B12.
Today, the biochemistry of folate is well described, as is its interplay with other B vitamins. Some of the genes that drive the biochemistry are also well known. The most extensively studied is MTHFR, which is also a central player in some forms of cancer. It makes an enzyme needed to break folate down into a useful form.
The team asked some 2,500 Irish students to give blood samples and fill out questionnaires on their medical histories and daily diets
But B vitamin metabolism is far too complex to be controlled by just one stretch of DNA. To get a more complete picture of how genes regulate the body’s folate and B12 stores – and how those genes may differ from person to person – scientists need to perform genome-wide scans. They have discovered some surprises in the process thus far, says Lawrence Brody, a senior investigator at the National Human Genome Research Institute, including a link with a gene that “on the face of it doesn’t seem to have anything to do” with B vitamins. Geneticists working in this area are a little like Wills in 1928 – they can see they’re onto something important. They just haven’t yet figured out exactly what it is.
Brody is one of the scientists unraveling the genetics of B vitamin use. For one recent study, he teamed up with James Mills from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and John Scott and Anne Molloy of Trinity College, Ireland. The team asked some 2,500 Irish students to give blood samples and fill out questionnaires on their medical histories and daily diets. Team members then analyzed the blood samples, measuring metabolites formed by pathways that require or are controlled by B vitamins. Then, the team cross-referenced the metabolite levels and diet histories with hundreds of thousands of spots in each subject’s genome to see if specific genes appeared to control any of the metabolite levels. Brody’s team is still analyzing the results but, he says, two already jump out.
First, there’s that mystery gene few people would have connected to B vitamins before genome-wide studies fingered it. It is called FUT2, and it makes a protein that attaches sugar molecules to other proteins. (The association has now been replicated at least three times – it’s real.) Although much experimentation is still needed, some scientists believe one version of the gene may prevent the overgrowth of stomach bacteria that can interfere with B12 absorption.
Ultimately what you’d want to do is predict whether people will become B12-deficient
Second, says Brody, his study has found a host of other genes that “control a whole family of metabolites” in the folate and B12 pathway. Because the biochemistry of B vitamin pathways is well documented, Brody’s team can scientifically connect the dots between some of those genes and study the way they interact with each other. That has enabled the team to explain more of the “heritability” – or the proportion of individual differences within a group that are driven by genetics – than many other genome-wide studies have been able to do.
Next, Brody plans to study the same biochemical pathway in a different group of people: the elderly. “As people get older, their chances of having B12 deficiency go up,” he explains. “Their ability to absorb B12 from food decreases with age.” That is partly because proteins that carry B12 through the gastrointestinal tract refuse to let go of it when they should. But it’s unclear how many or which genes influence the process. So Brody hopes to find out – and to see if there’s any overlap with the B metabolism genes he has found in his college-aged subjects.
Once the answers are in hand, they could help doctors prevent many common disorders linked to B12 and folate deficiencies in the elderly, including depression, cognitive decline, and, of course, anemia. “Ultimately what you’d want to do is predict whether people will become B12-deficient – determining if your lab test results are ‘normal’ will be based on your genotype,” Brody says. Using genetics to predict people’s risk of a complex disorder is tricky, especially with a trait highly influenced by environmental factors. But Brody notes that doctors already order millions of tests for B12 deficiency each year. Even a little more precision in predicting the behavior of these tiny molecules, he says, “would be a big help.”
Mary Carmichael is a science writer based in Boston, Massachusetts.
(1) Genomics in Action: Lawrence C. Brody, Ph.D. National Human Genome Research Institute.
(2) An Introduction to B Vitamins. Harvard School of Public Health.
(3) Genome-wide Predictors of Metabolites. Human Molecular Genetics.