Meet Arc Core Investigator Isha Jain, who is decoding how oxygen and nutrients shape our physiology

On June 9, Arc welcomed Isha Jain as our eighth Core Investigator. Jain (X: @ishahjain) has spent more than a decade studying how the human body senses, and responds to, external molecules—especially oxygen and vitamins.

In 2016, Jain discovered that hypoxia (or low oxygen levels) could rescue mice with mitochondrial dysfunction, overturning a long-held assumption that more oxygen tends to be good for human health. In the last decade, Jain's group has also discovered pathways for oxygen sensing, adaptation and beyond.

At Arc Institute, Jain's group is using genome-wide CRISPR screens, mass spectrometry, and other tools to understand how the body senses and responds to oxygen and also, more recently, vitamins. Her laboratory then aims to develop therapies based on those results.

Below, Jain discusses her group's latest discoveries, the revival of mechanistic research into vitamins, and how Arc Institute enables her metabolite-centric approach.

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Your group showed that low oxygen levels could be used to rescue mice with Leigh syndrome, a somewhat common type of mitochondrial disease. How did that study shift the scientific community's ideas about oxygen and its role in disease?

The general public and scientific community tend to assume that more oxygen is a good thing. You need oxygen for life; the more, the better. But what we discovered in that story, and have refined further over the last few years, is what we call the Goldilocks oxygen principle. It's not that more oxygen necessarily equals better, but rather that every person has a 'sweet spot' oxygen level, depending on their age, disease, genetic background and so on.

How do you figure out that 'Goldilocks' level for each person?

That's a major mission in our lab. We're taking a couple approaches. The first is a genetic approach, where we use genetic screens to interrogate which genetic perturbations are amenable to hypoxia or hyperoxia-based therapies. The second approach is high altitude epidemiology. We're using existing data to look at which diseases—monogenic or more complex ones—are less prevalent at higher altitudes. And then we try to recapitulate those epidemiology findings on mice in the laboratory.

Historically, molecular biologists studying oxygen have focused on a protein called HIF, or "hypoxia-inducible factor." HIF is a transcription factor that switches on genes in response to low oxygen levels. But your recent work suggests that oxygen-sensing may be much more involved and include new molecular players. Can you tell us about that?

Yeah, definitely. For the last 20 or 30 years, the field almost exclusively focused on HIF. Historically, it makes sense—HIF is a major regulator. It's responsible for a broad transcriptional response under low-oxygen conditions and is active in every cell and tissue. The 2019 Nobel Prize in Physiology or Medicine was given for the discovery of HIF.

Humans live across a wide range of oxygen concentrations, though, and HIF itself is responsive only within a relatively narrow range. At extremely low oxygen levels, like during a heart attack or stroke, oxygen levels approach zero, and HIF isn't perfectly tuned to respond optimally in these extreme scenarios. Likewise, it doesn't respond well to hyperoxic conditions. So it was an open question as to whether there might also be sensors for excess oxygen, or hyperoxia.

Until recently, none had been clearly reported. Our lab recently proposed one, and I think we're among the first to suggest a dedicated hyperoxia-sensing pathway. This pathway might be optimized to detect higher-than-normal oxygen levels, although it's still unclear if it senses oxygen directly or detects downstream products of oxygen, like superoxide.

And we think there's still a lot to discover here. There are over 200 oxygen-dependent enzymes in the body, many of which directly or indirectly control transcription, including epigenetic regulators. We have promising leads, but it's still early days.

Why did your lab move to Arc Institute?

I moved to Arc because I like working on risky, high-impact questions. Arc enables a style of research where the main constraint is our own creativity, rather than external limitations. This allows us to pursue unconventional ideas—like developing therapies based on environmental or dietary factors, rather than traditional drugs.

For example, our recent papers have shown how hypoxia, or low oxygen, could be leveraged to treat both rare and common diseases. We've identified small molecules that chemically simulate low oxygen conditions in tissues, even while breathing normal air. We are working on expanding these into new therapeutic strategies for the patient population.

Your group recently started studying vitamin sensing, too. What are the big, unanswered questions in that field?

We really think it's time for a revival in vitamin research. While there's great science happening, it's usually focused narrowly on a specific vitamin or pathway. Very few labs, if any, study vitamins as a broader class of metabolites.

There are several unanswered questions here. The first is: How are vitamins sensed by the body? Vitamins have to come from the outside—your diet—and their availability can fluctuate depending on what you're eating or even your environment. If you're out in a remote region and don't have access to the same foods you'd have in San Francisco, your body must recognize this difference and adapt. It might respond by increasing vitamin uptake or suppressing their usage. But we don't fully understand how that happens.

Another surprisingly open question is: What are the precise functions of all these vitamins? Even though vitamins have been known for over a century, we still don't fully understand their exact biochemical roles. Many vitamins are simply labeled as "antioxidants," but that's not a specific biochemical function. We still need to figure out which reactions it's involved in, what proteins it binds to, and how exactly it operates in the cell.

Lastly, from a therapeutic angle, there's the question of which diseases would genuinely benefit from vitamin supplementation or deprivation—and why. There's a lot of pseudoscience out there suggesting that just eating more vitamins is universally beneficial, which isn't always true. In fact, some vitamins become toxic at high doses. So we'd like to figure out which genetic or common diseases would actually respond positively to precise adjustments in vitamin levels.

Why has it been so difficult to study vitamins, and their role in the body, in a rigorous and mechanistic way?

I think it's a combination of things. Vitamins were studied very mechanistically and rigorously in the early 1900s. Back when vitamins were first discovered, the best biochemists in the world were racing to find the next one. There was even a term—"vitamin hunters"—because if you discovered a new vitamin, you'd win a Nobel Prize.

But vitamins eventually fell out of fashion. There was a period when vitamins became associated with pseudoscience. Vitamins became linked more to the supplements industry and less to rigorous research, so people moved away from studying them seriously.

Today, though, things have changed. We now have powerful tools that make studying vitamins much easier. For example, vitamins tend to be present in very low amounts, which makes them really difficult to detect. But now we have precise mass spectrometry methods and advanced genetic tools, making it more tractable than ever before. It's a great time to revisit the field.

Why did you decide to study oxygen and vitamins?

Because they weren't getting much attention. We often do a kind of mental "deletion experiment"—imagining that if we didn't exist, would this discovery happen anyway? For many research topics, the answer feels like yes: if I didn't make a particular discovery, someone else would probably make it next week. But for oxygen and vitamins, I sensed there were gaps—these areas were high-impact, understudied (at least in the way that we approach them), and also tractable. That combination seemed worth pursuing. At least, that was my hunch; we'll see if it plays out.

Arc's mission is focused on complex diseases, and it seems your work could be relevant for all of them. How would you like the Arc community to collaborate or engage with your group?

Yeah, since we focus on fundamental metabolites like oxygen and vitamins, our work naturally intersects with many diseases and organ systems. Oxygen is the substrate involved in the most reactions in the human body, and vitamins as a class are similarly widespread. Vitamin-derived cofactors like FAD (vitamin B2), NAD+ (vitamin B3), for example, each interact with hundreds of enzymes. But because we're metabolite-centric—and not really experts on any individual diseases or methods—we're looking to work with many researchers across Arc.