The Question of How

I’m sorry that it has been awhile since my last post, but my research has demanded more attention lately. I’ve seen something interesting in my project, so I’ve been working on understanding what exactly happened. I am trying to answer the question of how.

This question of how is important, but it often goes unanswered in science and biomedicine.

The prevention of neural tube defects is an example of the question of how going unanswered. Neural tube defects, or NTDs, are caused when the developmental processes of neural tube closure go awry. The neural tube becomes the brain and spinal cord, so a fully functional nervous system depends on the tube forming properly. Neural tube closure is a complex process, and is very prone to error. The prevalence of neural tube defects in the United States is estimated as 1 in every 1000 live births. This is not a trivial number.

NTDs include anencephaly, which is when the head region fails to close. This defect is invariable lethal, since the brain fails to form. Another defect is spina bifida, which results when the posterior region of the neural tube fails to close. Spina bifida is not fatal, but results in paralysis of the legs and lower spine.

In 1964, a researcher first discovered that many women with births complicated by NTDs had a deficiency in a chemical called folate. Folate is essential for many biochemical processes, including synthesizing nucleotides, the units that DNA is made of.

Researchers then hypothesized that supplementing pregnant women with folic acid, a form of folate, would reduce the risks of NTDs.

The results were strong. One study found that folic acid supplementation reduced the risk of NTDs by 70%. Similar studies found high rates as well.

Enough evidence indicating the positive effect of folic acid supplementation that in 1998 the Food and Drug Administration instituted dietary folic acid fortification of enriched grains.

This was a major shift in U.S. fortification policies. Previously the food supply had been fortified with supplements that would benefit the general health of the population. But in this case fortification was instituted to prevent a specific disorder in a small group of people.

The fortification policy has lead to as much as a 30% decrease in NTDs in the general US population. Not bad at all.

But the most important question has not yet been answered. We haven’t answered the question of how.

10 years after the fortification has been instituted, we still don’t know the mechanism by which folate prevents NTDs. Understanding the mechanism is critical for many reasons. Most importantly, understanding the mechanism is necessary to take a critical look at the fortification policy.

First, we need to know if fortification of the general population is necessary. If one or a few genes are isolated as risk factors for NTDs, then fortification programs can be targeted to those people. Also, if we know the mechanism of action we will have a better understanding of how much folic acid should be added to diets. We will also be able to find out if the current fortification policy is in any way harmful.

Leaving the question of how unanswered is a major problem in medicine today. There are many medical treatments that are prescribed without the underlying effect, the mechanism, being known. Sometimes prescribing physicians don’t know the specific effects of a drug. Sometimes, like in the case of folic acid, it isn’t known by anyone.

Understanding the mechanisms of drugs and applying the findings to better treatments is known as evidence based medicine. Evidence based medicine is relatively new. As far as we have come in biomedicine, there are still many questions left unanswered. The advancement of biomedicine relies on answering the question of how.


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