For decades, we’ve known that folic acid can help prevent serious birth defects of the brain and spinal cord, but we haven’t fully understood how it does it. This study reveals a surprising missing piece: folic acid appears to work with an enzyme called ALDH1L1, which helps the developing embryo make retinoic acid, a vitamin A–derived signal needed for the nervous system to form properly. When the researchers switched off ALDH1L1, folic acid could no longer protect the developing neural tube. This new understanding could help scientists build on the success of folic acid, while also exploring why it does not prevent every neural tube defect and whether prevention could one day be made more effective for more pregnancies.

For more than 30 years, one piece of pregnancy advice has been remarkably consistent: take folic acid.

The reason is clear. Folic acid, or vitamin B9, can lower the risk of neural tube defects, serious birth defects that happen when the early structure that becomes the brain and spinal cord does not close properly. What has been much less clear is how folic acid works.

Now, researchers may have found an important part of the answer.

In a new study published in PNAS, scientists discovered that folic acid appears to rely on an enzyme called ALDH1L1. That enzyme helps produce retinoic acid, a powerful developmental signal made from vitamin A.

The study was led by Prof. Abraham Fainsod and his MD/Ph.D. student Tamir Edri of the Hebrew University of Jerusalem Faculty of Medicine with Prof. José António Belo of NOVA Medical School in Portugal and an international team of researchers.

The story begins very early in development.

Before an embryo has a recognizable brain or spinal cord, a sheet of cells called the neural plate begins to fold upward. Its edges must meet and close, almost like a zipper, to make the neural tube. If that process goes wrong, neural tube defects can result.

Scientists have long known that folic acid can help prevent many of these defects. But the vitamin seems to be doing more than simply supplying nutrients.

The new research suggests that folic acid helps switch on ALDH1L1, a gene that makes the ALDH1L1 enzyme. That enzyme can then help turn a vitamin A–related molecule called retinaldehyde into retinoic acid. Retinoic acid acts like a set of instructions, telling developing cells when to grow, what to become, where to go, and when to stop dividing.

To test whether ALDH1L1 was truly important, the researchers used frog embryos, a common model for studying early development. They created embryos with neural tube closure problems and then treated them with folic acid.

Folic acid helped many of the embryos develop more normally.

Then the researchers disrupted the ALDH1L1 gene.

This time, folic acid lost its protective effect.

That result was a major clue: without ALDH1L1, folic acid could no longer rescue the developing neural tube.

The team pushed the idea further, demonstrating that the human ALDH1L1 can produce retinoic acid. They also found evidence that the same biological pathway is active in mammalian cells, strengthening the possibility that the mechanism could be relevant to humans.

The researchers also saw what happened when this signaling system broke down.

When retinoic acid levels were too low, the cells that would become part of the nervous system multiplied too quickly. The neural plate became abnormally expanded. Folic acid helped bring that cell growth back toward normal—but only when ALDH1L1 was working.

The findings also raised another possibility.

Because ALDH1L1 uses a vitamin A–derived molecule to make retinoic acid, the researchers tested whether vitamin A and folic acid might work together. In their embryo experiments, small amounts of retinol, a form of vitamin A, improved the effect of low-dose folic acid.

That does not mean pregnant people should start taking extra vitamin A. The study warns that too much vitamin A can itself cause serious birth defects, and healthy development depends on keeping retinoic acid levels within a narrow range.

Instead, the discovery gives scientists a new way to think about a decades-old question. Folic acid may not protect the developing nervous system by acting alone. It may work partly by helping the embryo produce the right amount of another crucial developmental signal at exactly the right time.

The finding could also help explain why folic acid works well in many pregnancies but does not prevent every neural tube defect. The authors say problems in the ALDH1L1–retinoic acid pathway could be one possible reason, although much more research is needed to determine whether the same mechanism operates in human pregnancy.