Q&A: Low oxygen as potential therapy for chronic disease

Oxygen is the breath of life, right? Because it keeps our bodies and organs from functioning as they should, supplemental oxygen helps when chronic lung disease or respiratory illness hamper breathing. 

That’s why it’s counterintuitive to think low oxygen could be a therapy for chronic conditions ranging from mitochondrial diseases and autoimmune disorders to Parkinson’s and even aging. Vamsi Mootha, a systems biologist leading labs at Massachusetts General Hospital and the Broad Institute of Harvard and MIT, and Robert Rogers, a former fellow in his lab, wrote a review of the evolving research, published in Science Translational Medicine, that invoked high-altitude history as well as lab experiments in mice.

Mootha talked with STAT on Wednesday about what might be next for modestly modulating the air we breathe. This interview has been edited for length and clarity, but not his warning: “Hypoxia can be dangerous, and I can’t emphasize that enough. Hypoxia in the extreme can be very detrimental, even deadly.”

What sparked your interest in low oxygen, known as hypoxia?

Our lab has long been interested in rare mitochondrial diseases as well as common diseases that are associated with mitochondrial dysfunction. A dream of ours had always been to try to find a suppressor of mitochondrial dysfunction that could be useful potentially for many genetically distinct forms or rare diseases, or even common conditions that are associated with mitochondrial dysfunction.

How did you go about this?

About 10 years ago, we did a genetic screen that gave rise to what initially seemed to be a counterintuitive idea: that low oxygen might actually be beneficial in the setting of a broken mitochondrion. At the time many folks thought that if you had a state of mitochondrial dysfunction, you should infuse more oxygen to power the system. But the screen told us to do the exact opposite. It’s something that we ran with in the laboratory.

What did you test?

We used chemicals to induce mitochondrial toxicity, looking for suppressors. That’s what gave rise to the idea that hypoxia could somehow be beneficial. 

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What are some different illnesses where there’s mitochondrial dysfunction?

So there’s a very large number of rare diseases. Some of them are maternally transmitted. Some of them are Mendelian, where typically children are born with birth defects in the mitochondrion. Some of these disorders are things like Leigh syndrome, Friedrich’s ataxia, and some of them go by abbreviations such as MELAS. 

But then there are some common conditions, such as Parkinson’s disease and other neurodegenerative diseases where if you look at autopsy material, you’ll see evidence of impaired mitochondrial function. Even the common aging process: as all of us age, the number and activity of mitochondria decline. So there’s a number of different conditions that are associated with mitochondrial dysfunction and hence our desire to try to find generic ways of suppressing that dysfunction. 

Vamsi Mootha: “Maybe the air conditioners of tomorrow will also control our oxygen levels.”Courtesy Tslil Ast / Broad Institute

What happened in lab animals?

What’s been remarkable over the last decade or so is that in many but not all preclinical models of mitochondrial disease, if you place them in low ambient oxygen, the disease is significantly improved. And what’s particularly exciting, that appears to be an evolutionarily conserved phenomenon. So you could take mouse models, even yeast models, and there appears to be a very, very profound kind of relationship between mitochondrial dysfunction and low ambient oxygen.

What goes wrong in mitochondrial disease?

You’ll recall that the organelle is called the “powerhouse of the cell.” It’s the powerhouse of the cell because it houses this machinery called the electron transport chain. There’s literally hundreds of different genes that are required for the proper functioning of the electron transport chain. And unfortunately, some of those can be mutated at birth to give rise to some of these diseases. 

We’re finding that in some of those disorders in preclinical models, we can actually alleviate the pathology, especially the CNS [central nervous system] pathology, by placing those models in low continuous hypoxia.

Let’s go back in time to a natural experiment.

In the 1960s and 1970s, there were border disputes between India and China. And the Indian army actually deployed more than 100,000 troops at the Indo-China border, about 20% of those at a very high altitude, about 17,000-foot elevation. The remainder were at the plains, and they lived there for about 23 years. 

In a paper published in the early ’70s, the Indian Army made a really fascinating observation that the troops that were living at high altitude, corresponding to the types of oxygen levels that we’re talking about in this review article, after a three-year period, they had a much lower incidence of things like cardiovascular disease, stroke and diabetes. And so I find that to just be an absolutely fascinating data point.

Tell us more about genes and environment.

We all know as physicians, as patients, as lay public, we know that disease emerges from the cross-product of genes and environment and chance. Especially here in Boston and in Cambridge, most of the emphasis is on trying to repair the root genetic cause of disease, but we can’t forget the other half of the equation. We know how important smoking cessation is, we know how important diet is. We wanted to put ambient oxygen levels into focus.

I think there’s probably a very intimate relationship between the evolution of mitochondria, the electric transfer chain, and changes and fluctuations in our Earth’s oxygenation levels. And this is purely speculative.

You’re going really far back in history.

The endosymbiotic event — the theory of when another organism probably engulfed mitochondria — probably took place about 1.8 billion years ago, after the great oxygenation event on our planet.  Might it be the case that when this endosymbiont engulfed a functioning mitochondrion, it enjoyed greater fitness as oxygen levels were rising? And now, and when the endosymbiont is broken, high ambient oxygen is actually detrimental.

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How could this help people today?

There is a growing confluence of preclinical data that suggests that what we’re calling chronic continuous hypoxia can be beneficial to many conditions, but this is associated with some real challenges. Hypoxia can be dangerous, and I can’t emphasize that enough. Hypoxia in the extreme can be very detrimental, even deadly.

At the same time, some of the disorders that we’re talking about represent a great unmet medical need.

How do you envision practically delivering chronic, continuous hypoxia to patients?

One is actually moving to a high altitude. So that could be one possibility, but maybe not the most practical. The sporting industry has developed all sorts of interesting technology that allows athletes to train under “high altitude” conditions: Portable nitrogen generators can be used to dilute the air that you breathe, and some athletes also live in tents where the air has been diluted with nitrogen.

I like to say that for decades, our air conditioners have been controlling temperature and humidity, but maybe the air conditioners of tomorrow will also control our oxygen levels.

You mention “hypoxia in a pill.”

A third possibility would be to try to bottle this up in a pill somehow so we could somehow induce chronic, continuous hypoxia using more traditional small molecules. So that’s what we call the hypoxia in a pill approach.

Tell me about what such a pill might include.

There have been several small molecules that have entered into clinical trials, even ones that have been approved for sickle cell, called hemoglobin affinity enhancers. These are small molecules that will bind to hemoglobin and it’ll park it into a tight conformation. When the hemoglobin is parked in that tight conformation, it tends to release oxygen less, so that’s a way to induce hypoxia.  

We’ve been able to show in a proof of concept study that some of those types of drugs in preclinical mouse models can provide neuroprotection and even extend lifespan.

In response to hypoxia, the body will try to increase its oxygen-carrying capacity. And so in that paper, we used another drug to basically block that response. The two-drug regimen in our laboratory, we kind of playfully call it a hypoxia in a pill regimen. 

What’s next?

We’re interested in other rare diseases, but also other common conditions. 

We’re trying to see whether we can optimize some of those small molecule regimens because that might be something a bit more practical to try to do in the clinic one day.

Are you still surprised by what you are learning?

This has just been a really, really exciting 10-year journey in science. 

There’s elements of this that were initially counterintuitive, but the more and more we think about it, there’s some logical aspects to it as well. 

STAT’s coverage of chronic health issues is supported by a grant from Bloomberg Philanthropies. Our financial supporters are not involved in any decisions about our journalism.

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