All eyes on space

Astronauts on long duration missions in space often develop a condition called Spaceflight Associated Neuro-ocular Syndrome (SANS) that leads to blurry vision. Scientists are developing both space- and Earth-based systems to study the mechanisms underlying SANS and to develop treatments for it. These tools won’t just stay in space — they’ll aid in the diagnosis and treatment of related eye diseases for people here on Earth.

Host: Stephanie DeMarco

Guests:

Prem Subramanian at the University of Colorado Anschutz

         

Kjell Lindgren at NASA

Andrew Lee at the Houston Methodist Hospital

   

Tasneem Sharma at the Indiana University

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Transcript

Stephanie DeMarco: Hello everyone, and welcome back to a new episode of DDN Dialogues! I’m your host, Stephanie DeMarco. Today’s story is, what you might call, a little bit — out of this world.

NASA Audio of Mercury 7 Mission: Five, four, three, two, one, zero. [inaudible] Liftoff! The clock has started. Roger, loud and clear, Gus. Roger you look good down here. Periscope is out. And we have a go. Roger. Sweet words [inaudible].

DeMarco: Imagine: It’s the year 2050, and you’re hurtling through space on one of the first human missions to Mars. Over the course of months, you watch the Earth shrink into a pale blue dot, looking hardly different from the other stars across the inky blackness of space. 

But, as the months go by, you begin to notice that everything looks a little less sharp than it did before. There’s a blur in a particular spot in your vision, and now you find yourself squinting to read the numbers on the ship’s instruments. Millions of miles away from the nearest eye doctor, you’ve developed a condition completely unique to spaceflight called Spaceflight-Associated Neuro-ocular Syndrome or SANS.

Prem Subramanian: NASA has categorized SANS as the number two health hazard limiting our ability to do deep space exploration with number one being radiation exposure. So, it's clearly a really high priority problem to understand and to solve. The real concern is with a deep space exploration mission that could last for years that these changes could keep occurring, and get worse and worse, and eventually lead to vision loss in the midst of a mission.

DeMarco: That’s Prem Subramanian, a neuro-ophthalmologist at the University of Colorado Anschutz who studies SANS. With companies like SpaceX and Blue Origin launching people into orbit and NASA’s Artemis missions to send astronauts back to the Moon, we as humans are venturing deeper into space and for longer periods of time than ever before. This is putting space travelers at higher risk of potentially permanent changes to their vision.

But now, scientists are developing new space- and Earth-based tools to study SANS and to test potential treatments for it. And while SANS may be unique to spaceflight, these researchers are finding that many of these new methods may also lead to new treatments for common eye conditions here on Earth.

Human beings — and all life on Earth — evolved in the presence of gravity. So, when we’re released from its clutches, our bodies go a little haywire. Bones lose density, muscles waste away without exercise, and the immune system gets thrown completely out of whack. Kjell Lindgren, a NASA astronaut who has flown on two space missions and spent a little more than 311 days in space, has firsthand experience with many of these changes.

Kjell Lindgren: The typical changes that we see with eyesight in the average crew member is that if you didn't need to use reading glasses on the ground, you may have to use them on orbit. That meant, when I was working on a procedure, when I was reading email or when I'm doing maintenance or some activity that's precise or fine that I generally needed my glasses to be able to do that effectively. And, of course, it's easy to misplace glasses on the ground, it's even easier to misplace them on orbit. So, I provided no end of entertainment to my younger crew members, when I needed help finding my glasses, and so I got a good amount of ribbing for that as well.

DeMarco: I can’t even imagine! You can’t exactly put them down anywhere. They just sort of float away.

Lindgren: For awhile there, we were we were down to our our last pair, and they had to to resort to some drastic measures to make sure I’d be able to find those if I needed to.

DeMarco: So, while short-term vision changes are just another weird thing that happens to the body in space, researchers noticed that as more astronauts returned from longer missions, they came back with more severe changes to their vision.

Lindgren: The issues popped up when some of our crew members in the 2000s experienced more permanent or longer-term visual changes. That's really what kicked this investigation off to try and understand the etiology of the underlying issues that were contributing to these visual changes. What we thought were acute and temporary visual changes for a long time, now recognize to maybe be part of this larger continuum of SANS.

Subramanian: In the late 2000s, we started to notice that some long duration spaceflight astronauts were having swelling of their optic nerves, and then in 2011, a more comprehensive report about this was published. 

DeMarco: In that report, scientists noted that in addition to optic nerve swelling, one of the clearest changes in astronauts’ eyes took place in the choroid, the blood vessel filled layer of the eye that sits just behind the retina and in front of the back wall of the eye.

Subramanian: That choroid swells. It becomes thicker than it is in a terrestrial environment, and that choroidal swelling can be associated with some change in the refractive error of the eye. It makes people a little bit farsighted, makes it harder to focus at near.

DeMarco: Why the choroid and the optic nerve swells, though, is still unclear. But scientists’ prime suspect is the loss of gravity. Andrew Lee, a neuro-opthalmologist at Houston Methodist Hospital told me more.

Andrew Lee: The precise mechanism of SANS is unknown. However, it is believed to be microgravity. So fluid, which normally would be pulled down towards your feet, gets stuck upstairs — both in your head and in the orbit.

DeMarco: In fact, scientists have observed that when pressure in the head increases in certain conditions on Earth, people have similar changes to their vision.

Subramanian: When SANS was first recognized, it was called VIIP: Vision Impairment Intracranial Pressure syndrome because the optic nerve swelling that was seen was thought to be very similar to the elevated pressure disorder on Earth called Idiopathic Intracranial Hypertension. Now that we've learned more about SANS, we know it may not be quite the same, but there are some features that they share. Patients with IIH get swelling of their optic nerves. They have high pressure in their head. That swelling of their optic nerves can lead to visual disturbances, even vision loss.  

Lee: There are other proposed mechanisms, however, including metabolic things, and it's not clear whether the fluid is only in the orbit or in the head as well, causing increased intracranial pressure. So, there are multiple other fluid dynamic problems that could be at play. The best countermeasure that we have for SANS is just to return to Earth and return to our gravitational field.

DeMarco: But if astronauts are months away from Earth, simply coming back home won’t solve the problem. And sometimes, even returning to Earth’s gravity doesn’t fix things either.

Subramanian: There has been at least one astronaut who had persistent swelling of the optic nerve for at least 20 months after returning to the terrestrial environment, and we still don’t know exactly why it persisted that long. Also, that choroid layer can develop some irregularity within it that we can see when we look in the eye as a fold, and those folds can sometimes persist as well.

DeMarco: The best way to study a condition that’s unique to spaceflight seems like it would be in space. But, sending scientists up to space is not exactly cost-effective or feasible. But, that’s not to say that nothing can be done in space.

Lindgren: We've got a remarkably robust research program, including some of the ability to image the eye both on the ground and in space. We use ocular coherence tomography which provides just an absolutely amazing view of the layers of the back of the eye — really the layers that are most affected by some of the SANS changes, and so we're looking at the choroid and the retina even during the flight, we're able to monitor the crew's anatomic changes as well as visual acuity through the testing that we do.

DeMarco:  Lee, Subramanian, and other researchers are developing new tools to better understand the mechanisms of SANS directly in space. For Subramanian, that looks like a little like a contact lens.

Subramanian: We are working with SpaceX astronauts going on the Polaris Dawn mission, who are going to be wearing a special contact lens that measures the pressure in the eye, the intraocular pressure, and measures it constantly over the course of hours to give us a better understanding because there may be some kind of relationship between changes in eye pressure and what is happening with the optic nerve swelling. So, we're also going to measure the length of their eye because that tells us something about swelling in that choroid. 

DeMarco: Lee has also come up with a wearable way to monitor SANS in space.

Lee: Space is a commodity in space, so it takes a lot of money just to send something up there. And the amount of available real estate that we have on the International Space Station is very small, so we can't be sending giant machines. We really want to have something that's portable, ideally wearable head mounted, and so the devices that we've been working on are head mounted goggle-based displays where the types of tests that we're doing — the visual acuity, the visual field, testing the contrast — could be generated inside of a goggle. 

DeMarco: Lee has already started testing this device on healthy participants and found that it’s user-friendly, safe, and convenient for people to use. He and his team are now working on integrating it with an interactive, artificial intelligence component. AI will be important especially for testing and diagnosing SANS on long-term space missions.

Lee: The trip to Mars is so long — 15 months round trip. Ideally, we would have devices that would collect all the data very quickly, and then we could analyze it in real time. Of course, there's a delay in the signal the further and further you are away, so the interactive component could be potentially AI driven so that the doctor wouldn't actually have to be talking to the astronaut in real time, especially when that kind of conversation might be 20 minutes before you get the answer because it's just so far away. This technology has both terrestrial and extra-terrestrial applications. We hope to develop the device both for testing of SANS, but for testing of other conditions that would improve the lives of people here on earth as well.

DeMarco: While devices that monitor astronauts’ eyes during spaceflight will undoubtedly help researchers understand SANS better, cleverly-designed Earth-based strategies have potential too.

Subramanian: One way is by looking at astronauts when they come back from long duration spaceflight and studying what they look like when they return to Earth compared to what they looked like when they went, and what I mean by that is you can do things like MRI scans even of their brains to look for characteristic changes that might occur because of shifts in body fluids and exposure to that microgravity environment.

There is an analogue of microgravity that has been developed, where people are assigned to strict bedrest lying on their backs and tilted six degrees head down, so to mimic that pooling of fluid toward the head. And that six degree head down tilt model has been pretty successful in reproducing some, but not all, of the changes that happen when astronauts are in true spaceflight, and the differences actually between what happens in that experimental model and what happens in real spaceflight may actually teach us something about what is causing some of these problems.

DeMarco: These methods have improved researchers’ knowledge of what happens to astronauts during spaceflight, but scientists still want a way to investigate how specific pressures in both the head and the eye contribute to SANS. A new strategy came from Tasneem Sharma, an ophthalmology researcher at Indiana University, who was originally looking for a way to study and test treatments for glaucoma.

Tasneem Sharma: So, glaucoma is a disease that is prevalent. Almost 70 million people suffer due to the disease worldwide, and one of the most or major risk factors for glaucoma is elevated pressure within the eye.

DeMarco: In glaucoma, the optic nerve becomes damaged, which leads to progressive and incurable vision loss. Sharma got her start working in tissue engineering and stem cells. And during her postdoctoral research, she differentiated skin fibroblasts into stem cells, which she then differentiated into human retinal neurons. She and her colleagues could then test potential glaucoma treatments on these newly formed retinal neurons.

Sharma: We have stem cells. We have glaucoma, and we have all these mouse models. But there is not a human model system that we can study all of this in, and that's what kind of gave birth to the model, which is the Translaminar Autonomous System.

DeMarco: To study human eyes in the Translaminar Autonomous System — or TAS for short — Sharma and her team take a donor human eye and cut it down the equator, bisecting the eye with the lens and the iris on one side and the back of the eye and the optic nerve on the other. She and her team then place the back half of the eye face-down on top of a 3D-printed dome structure in the bottom part of the TAS chamber. This way the optic nerve points upward. They place a lid on top of the bottom chamber and use fluid flowing at different rates to set a specific pressure in each chamber.

Sharma: It constantly measures pressure within that top chamber where the nerve is, and the chamber which is internal to the eye. We can kind of mimic and modulate some of these pressure dynamics in the human eye, so we can test how this eye would react under high and low pressure conditions to mimic the pathophysiology of glaucoma. And then if we put in a drug, would that help the cells or the retinal neurons survive better?

DeMarco: She and her team started applying for funding to continue her research using this new system.

Sharma: I had kind of emailed a couple of different funding agencies here and there. One of the funding agencies that I had you know just sent a paragraph about my model to was Translational Research Institute for Space Health. Emmanuel Urquieta, he called and he's like, “this is a very novel model. Astronauts when they go into space flight, over long duration space missions of more than six months, almost 70% of them see some sort of visual defects, and this is termed now as Spaceflight-Associated Neuro-ocular Syndrome. So we see hyperopic shifts in eye, basically. Because there is conditions of microgravity, all the fluid in the body shifts to the brain, and that actually causes pressure on the eye. And could we use your system to characterize some of these effects? So, why don't you apply for this grant? And, if we like it, we will fund you.” And, that's what happened.

DeMarco: So, Sharma and her team set up their TAS to study donor human eyes under a range of different intraocular and intracranial pressures that astronauts are thought to experience under microgravity conditions.

Sharma: We were really excited. We wanted to do a 14-day study and a 30-day study, and then COVID hit, and when COVID hit, all the human eyes that started coming into the lab were COVID positive, and we couldn't accept them anymore. So, we had to really streamline our project and publish with the smaller sample cohort that we had. But even in that small sample cohort, we were really amazed by the kind of trajectory and the trends that we are seeing: that there is a possibility that pressure dynamics around the nerve and inside the eye could be making changes, and that the astronauts over long duration space missions could be having vision defects.

DeMarco: They saw that while the overall shape of the back of the eye remained the same under these spaceflight-like pressures, there were major changes at the molecular level. When they analyzed gene expression in peripheral retinal tissue, the researchers saw increased expression of genes involved in inflammation and apoptosis. They then isolated the optic nerves from these eyes. And, in all of the microgravity-modeled pressure conditions, they saw clear degeneration of the optic nerve axons.

Sharma: One of the things that happens due to this pressure dynamics in microgravity for these astronauts is the nerve that connects the eye to the brain also becomes torturous or kinks. And we saw that when this kinking happens, it increases the degeneration in the eye. That was a proof of concept for us, so that was really interesting also data-wise.

DeMarco: Now that she has a way to model SANS in an ex vivo system on Earth, Sharma wants to better characterize SANS and to use TAS to begin testing potential therapeutics.

Sharma: Right now, pressure is not the only hypothesis for Spaceflight-Associated Neuro-ocular Syndrome. Hypothetically, there could be elevated carbon dioxide levels, salt diet, different one carbon metabolism pathways, venous blood pressure mechanism, venous flow pressure mechanisms, all these other pathways that could be causing the SANS to be developing.

Maybe there is elevated intracranial pressure because of the fluid shifts, and that's what's causing this. So, our model allows us to kind of tease that out. It does not say that, okay, all the other pathways are not a part of it, but the big question is, is that elevated intracranial pressure, is that a pathogenic event? From the trends that we saw with our data, there is the possibility that is a pathogenic event we need to explore that further for astronauts.

Lindgren: We're really grateful that the human research community has stepped up to help us identify and characterize this process. As we go further away from the Earth, deeper into the solar system, for longer periods of time, it's something that we need to truly fully understand so that we can hopefully mitigate those changes and decrease the risk of permanent changes in eye health.

Lee: SANS is exciting and interesting to me as a neuro-ophthalmologist just for the neuro ocular structural findings that we see. However, in terms of a bigger picture, it's deeply ingrained in the human spirit to want to explore, and that exploration can be an inner exploration of our bodies and our minds or an outer exploration into the mysteries of space and the origins of our universe. And, and after all, that's what science is: exploration. So, for me to participate in the manned spaceflight program, even if the participation is just a small part of the eye, is very exciting.

DeMarco: That’s it for this episode of DDN Dialogues. Thank you to Prem Subramanian, Kjell Lindgren, Andrew Lee, and Tasneem Sharma for talking with me for this episode, and thank you so much for listening! Until next time, I’m your host Stephanie DeMarco. 

This episode of DDN Dialogues was reported, written, and edited by me, with additional audio editing by Jessica Smart. To never miss an episode, subscribe to DDN Dialogues wherever you get your podcasts.

And, the next time you look up at the night sky, think of just how many pairs of glasses are floating around the International Space Station, helping human beings see the secrets of the universe a little more clearly.