Main Engine Cut Off - T+49: Dr. Thomas Lang

Episode Date: June 5, 2017

Dr. Thomas Lang, Professor of Radiology and Biomedical Imaging at the UCSF School of Medicine, joins the show to discuss human health and physiology in space. This episode of Main Engine Cut Off is brought to you by 13 executive producers—Kris, Pat, Matt, Jorge, Brad, Ryan, Laszlo, Jamison, Guinevere, and four anonymous—and 51 other supporters on Patreon. Thomas Lang | UCSF Profiles NASA Honors Two UCSF Scientists for Top Discoveries in Microgravity | UC San Francisco Browse Articles | npj Microgravity Towards human exploration of space: the THESEUS review series on muscle and bone research priorities | npj Microgravity The Space Show - March 7, 2017 - Dr. Francis Cucinotta on space radiation Study Reveals Immune System is Dazed and Confused During Spaceflight | NASA For an Immune Cell, Microgravity Mimics Aging | NASA Spaceflight alters expression of microRNA during T-cell activation. - PubMed - NCBI Spaceflight and simulated microgravity cause a significant reduction of key gene expression in early T-cell activation. - PubMed - NCBI Skeletal health in long-duration astronauts: nature, assessment, and management recommendations from the NASA Bone Summit. - PubMed - NCBI Email your thoughts and comments to [e-mail] Follow @WeHaveMECO Subscribe on Apple Podcasts, Overcast, Google Play, Stitcher, or elsewhere Subscribe to the Main Engine Cut Off Newsletter Buy shirts and Rocket Socks from the Main Engine Cut Off Shop Support Main Engine Cut Off on Patreon

We've got another special guest with us this week, a little bit different than the past couple of guests have been. This is an entirely new area of focus for Main Engine Cutoff. This is about medicine in space and human physiology in space, where we're at now, where we're going into the future. And to help me do that, I've got Dr. Thomas Lang here, a professor of radiology and biomedical imaging at the UCSF School of Medicine out in San Francisco.

He's here to talk to us today about all sorts of things, an overview of human health in space, where we're at, where we're going, things that we can do to help out some of these problems that we're seeing in the humans that are flying in space today and the humans that might be flying to the moon or Mars in the near future. But before we jump into all of those topics with Dr. Lang, I want to say a quick thank you to all of you out there supporting Main Engine Cutoff on Patreon. There are 64 of you over there supporting the show, including 13 executive producers

who have produced this episode of Main Engine Cutoff, made this episode possible, and I'm hugely thankful for their support. They are Chris, Pat, Matt, George, Brad, Ryan, Laszlo, Jameson, Guinevere, and four anonymous

executive producers. Them, along with 51 others, are supporting Managing Cutoff, making this possible week in and week out over at patreon.com slash miko. I could not do it without your support. Thank you so much for it. One more quick thing before we dive in with Dr. Lang. Over at managingcutoff.com, I will post the show notes for this show. So as we talk about things that might be interesting for you to follow along with, or things that you might want to read up on later,

I will post a link there at MainEngineCutoff.com, including Dr. Lang's bio and some of the work that he's done in the past. So head over to MainEngineCutoff and check out some of those reading materials, either now and follow along, or later on, you'll have some reading material after listening to the conversation. So without further ado, let's get into it. Dr. Lang, thanks for joining us on the show here. It's exciting to have somebody with real expertise.

Oh, well, thank you. I enjoy your podcast so much. Yeah, so I guess for a little background for everyone else out there, I actually got an email a couple weeks back from Dr. Lang, and turns out he's quite an expert in his own right. So I said, hey, why don't you come on the show? Because the medicine side of spaceflight is something that I've not really gotten into too much, not because I don't want to or don't find it interesting. I also actually find it very interesting. I just have no expertise in that area at all. So this is kind of the first of a series of podcasts I'm going to do that focus on the

medicine side and the physiology side of spaceflight. So we've got a bunch of topics to dive into today as a good primer for this entire series of things that I've got in mind. But maybe to start, could you give us a little background on yourself, how you got started, how you got interested in the spaceflight side of medicine, and where you're at today? Yeah, so I'm a nuclear chemist by training, and was finishing up my PhD in the late 1990s at UC Berkeley, and actually got interested in medical imaging as an application of some of the work that the experimental techniques that we were using. And so I did a postdoc in the radiology department at UCSF and later joined as a faculty member and started a program in quantitative imaging of bone and muscle using

CT. And the director of the group in which I, you know, to which I belong when I started as a faculty member had a conference in Japan, which was basically a, you know, a meeting of all the medical research components of the different space agencies, you know, to agree on sort of a joint focus for the advent of the International Space Station. And so this was in maybe 1996. And I met a researcher there from Baylor College of Medicine named Adrian LeBlanc. And I had presented some of the work that had done on quantitative imaging of bone with CT. And Adrian suggested that we use this for a request for proposals to study changes in human physiology in the space station crews. And so we applied jointly with a collaborative proposal to use these techniques I had worked on to look at changes of bone in long duration spaceflight based on sort of pre-flight and post-flight measurements on these

initial space station crews. And the proposal was funded, and this would have been maybe 1999. And, you know, I've been working in the area ever since. So really the entire history of the space station itself, really from inception, you know, if you don't count the little 80s time period when the idea was coming about. Right. So there was a lot of, you know, there was work, particularly in the mid 90s, using sort of the earliest generation of bone dense optometry equipment on NASA Mir crews and on Mir cosmonauts, but really the space station was just this great new platform that was coming in. And I believe, I'm not totally sure, but I believe that our experiment was the first human subjects experiment to be approved for space station.

Wow. Because, you know, as we went through the, just the, the multiple layers of NASA approval procedures, I think that the various administrators were kind of telling us that we were guinea pigs for new processes, etc. So I think we were the first. sense on how things have changed in that regard since? Did you find that it was very hard to get through back in the day, or was it a lot easier because there wasn't so much history built up? You know, I think it was a little of both. You know, it's when you've got new capabilities and new equipment and new players, you know, you have to try out new procedures. For example, the R experiment involved Russian crews as crew members, as well as American crew members. And while some of that had been worked out in the Mir studies, you know, there were various, you know, obstacles that had to be overcome to include the Russian crews. You know, on the other hand, there wasn't a huge traffic of experiments going on at the space station at

that time. And, you know, it was a high priority to, to get things going. So we had a lot of, uh, support from NASA, you know, to help us work through all of these different issues. from NASA, you know, to help us work through all of these different issues. So, you know, I think that, you know, there were advantages and, you know, obstacles. So to bring us up to today, you've been working on a series of papers with a whole cast of people. As recently as this past February, you were the first author on a paper published in Nature. Could you tell us a bit about this thesis review series? Yeah, so Theseus is, yeah, Theseus, yeah. It stands for the European Research Priorities for Human Exploration of Space. And both NASA and the European Space Agency have had, you know, a similar approach, which is come up with sort of a rational evidence-based framework for prioritizing, you know, the kind of research we have to do to, you know, understand the health risks that astronauts will encounter in different regimes of space flight such as low Earth orbit, eventually missions to asteroid, missions to Mars, and deal with, set up the correct research priorities. And NASA has a process called the, you know, the bioastronautics roadmap, where through, you know, NASA experts and interaction with external experts, they define risks based on, you know, the existing medical evidence and then formalize these risks and develop priorities.

and then formalize these risks and develop priorities. And in this case, Theseus was a similar effort by the European community to come up with a similar approach for addressing risks associated with long-duration spaceflight in a way that could either develop or profit from the kind of technical strengths that have developed in Europe. And so essentially, you know, what they did is they sort of divided this gigantic task of preparing humans for long duration spaceflight or understanding what the health considerations and risks and mitigations were for long duration spaceflight into different areas. And those were, for example, integrated systems physiology, which was the group that I belonged

to. There's psychology and human machine systems, radiation, habitat management, and healthcare. human machine systems, radiation, habitat management, and healthcare. And so I was part of an overall group called Integrated Systems Physiology, which included the immune system, you know, nutritional problems, in my case, bone and muscle effects. And so there was a group of us from literally all over the world. And I've got to hand it to the organizers of this effort that they not only included Europeans, but reached out to Americans, Canadians, Japanese, across the board. together over a period of I would say starting maybe 2010 and we met several times at different places in France Germany I think once even in Tunisia and we sort of sorted out based on discussions of this large group what we felt the major priorities for kind of musculoskeletal medicine was in spaceflight. What are the major problems and, you know, what are the most important things

to look at in terms of defining problems and coming up with countermeasures and things like that? And the recommendations of this, of our group, as well as the other subgroups in this integrated systems physiology effort we wrote those up as manuscripts uh for um nature microgravity and so i believe all of the recommendations of this integrated systems physiology group have been published in in this nature journal I'm not sure there may be one that's still still out there, but everything has been peer-reviewed and And published in terms of our you know recommendations So these papers have been published pretty regularly for the past while like I said There's one just this past February that was published. So it's been a pretty frequent thing the last couple of years, or was it

a lot of work up front and kind of a slow trickle of papers throughout? Well, I think it was a lot of work up front, you know, with the meetings and then, you know, writing up the minutes of the meetings and collecting everybody's thoughts then, you know, writing up the minutes of the meetings and collecting everybody's thoughts and, you know, coming up with consensus documents after each meeting. And then, you know, there was sort of a period where it continued with a trickle. So, you know, there was a lot of effort sort of between 2010 up to perhaps 2013. And then really the rest of it was just figuring out how to get all this published. And, you know, this the organizers of the effort reached out to this nature microgravity journal, which had just been founded. And we were able to publish our

recommendations in that journal after a pretty exhausting peer review. I mean, I think the manuscript that we put in went back and forth at least three or four times. Wow. Let's dive into the details a little bit on human health in space in general. Let's start with an overview of really the main focus areas of things that change in space, things that go wrong that we have to work to prevent from happening during a long-duration spaceflight. So, you know, everything that we've done up so far up to this point, with the exception of, you know, the Apollo missions have been within low Earth orbit. And, you know, that has had sort of two advantages. One of them, you know, we're close to Earth. So if there's some sort of emergency, you know,

a crew can get into, you know, a Soyuz and maybe eventually a, you know, a Dragon and return back home. And, you know, there's the additional benefit of being within Earth's, you know, within the protection of Earth's magnetic field, which, you know, protects us against both, you know, solar and galactic radiation. So that's where we've been so far. But, you know, with the, you know, this, this gateway, deep space gateway that NASA is now proposing, and with the eventual missions to Mars, we're not only going to have very long missions, which we're starting to have, you know, on the space station with, you know, Scott Kelly's one year mission, but very long missions, as well as outside of, you know, outside of the protection of Earth's

magnetic field. So now, you know, for example, for a nominal Mars mission, you're looking at about, you know, let's say 180 days out, 180 days back in, potentially a 500-day stay on Mars. That's a number that's been batted about for a long time. That's a long period. You're looking at least at 360 days in transit. That's 360 days outside of Earth's magnetic field. So you're exposed not only to larger doses of solar radiation, and you've got the galactic background, but you've got this factor of the isolation. You are really, really far from Earth, and you're in microgravity for a very long period of time, you know, longer than anything we've done so far.

So what that does is, you know, essentially you're taking, you know, the main problem is you're taking the human system and exposing it to sort of these three main stressors and you know the first one being microgravity you know we're completely evolved to living in 1g then you've got this radiation background which is much higher than that of earth and you know higher than that of uh low earth orbit and then finally you know you've got the factor of the isolation you. You're essentially in this vehicle with a small number of people, and you're very far from Earth. And not only that, you've got this sort of delayed communication, the further that you get. I forget how long it takes for a radio signal from Mars to reach Earth, but it's a delay of a few minutes. Yeah, it could be up to like a half hour in some cases too, which is a round trip. It gets pretty extensive. So all of these effects just have tremendous impact on the human system. I think the isolation aspect, that's probably the easiest thing to picture for people, even though it's impossible to picture because we've never done it.

I think, you know, when you think about it as somebody who's not even interested in space flight, there's a certain thing that resonates with them that is like, oh, yeah, I wouldn't necessarily like sitting in my own car for three years at a time. So that's something that I feel like is easy to bring home to people. The other aspects are more difficult to really understand because I think when you tell people that there's a galactic cosmic radiation background at all times, that you start to get into an area that people necessarily haven't thought about a lot. So the radiation aspects and the microgravity aspects, those seem to be the things that are

harder to grasp for people, whether they are interested in space or not. Could you go a little bit more into what the changes are in microgravity specifically, and then some of the things that we're concerned about, about the radiation environment that it would take to get to Mars, for example? So let's start off with microgravity. So, you know, we're evolved to working in, you know, 1G on Earth. And so now we go into microgravity. So crews, for example, go on the space station and their skeletons are unloaded, their muscles are unloaded. their muscles are unloaded. And so, for example, let's say you put somebody has a spinal cord injury and ends up in a wheelchair. If you look at their bones in their legs over an extended period of time, for example, with CT scanning, you'll see atrophy of the bone. And that's because our skeletal system is really an organ which has a function which is evolved towards supporting the contractions of our muscles and supporting our weight in 1G. And when that input, that mechanical input goes away, the material of the bone goes away. The mineral is, the bone is

demineralized. And, you know, as vertebrates, we have this beautiful system that allows us to have these very tough and resilient skeletons, which are also very light. And the way we are able to accomplish that on earth is by, you know, the sort of exquisite, well-tuned action of these bone resorbing cells called osteoclasts and bone forming cells called osteoblasts. As our bone is damaged by use, we have cells called osteocytes, which sort of detect local micro damage. They signal the osteoclasts to come in and just like a paving crew, they, you know, they come in with their basically a dissolving agent and dissolve that damaged bone and the osteoblasts then repave it. And so you have this sort of, when everything is working well and we're under, you know, 1G, this process that maintains

our skeletal mass and our skeletal geometry just as we need it to fulfill our function of supporting muscle contractions and load bearing. So, for example, when we age, the biochemical signals that regulate these cells change because of loss of sex steroids, like, for example, estradiol. And so that causes and that results in a net bone loss because it activates, you know, these osteoclastic cells. In space, you have the same thing that happens, you know, if somebody is put in a wheelchair on Earth, you have disuse osteoporosis. So the loss of mechanical load results in activation of these cells that remove bone. So you have a net loss of bone in space.

And similarly, with the lack of need for muscle contraction, you have muscle atrophy. So unless you undertake countermeasures to try and kind of replace the loading forces that a person has on Earth, you're going to get an atrophy of these musculoskeletal tissues. And so that's, you know, one of the challenges with microgravity and this atrophy of muscle tissue, it also goes to, you know, the cardiovascular system, you have a loss of function there. Our ability to sort of know where our different limbs are, proprioception and all that, that depends on our neurovestibular system, you know, which is closely tied to this fluid in our ears. In microgravity, that signaling is sent awry. So there are adaptations, you know, to that as well. So we're, you know, we're kind of a different beast in microgravity than we are here on Earth. And, you know, the problem that we want to prevent is, for example, as our bones lose mass and they lose

structure, they weaken, they're less resistant to force. So you want, for example, if somebody goes on to the surface of Mars, you don't want them to have, for example, an osteoporotic fracture, which would be a devastating injury. Similarly, you don't want people who have been up in space to come back and have sort of chronic skeletal health problems that might lead them to have a really severe case of osteoporosis when they're much older. And similarly, you know, similarly with skeletal muscle, you know, as our skeletal muscle atrophies in space, you know, we want to have the muscle strength and endurance to accomplish, you know, whatever task we're going to accomplish in an EVA. Plus, you know,

we want people to be able to come back to Earth and, you know, be able to rehabilitate and recover their past function. Yeah, I don't think you, I don't think anything interesting you can do on the surface of Mars doesn't involve lifting something. That seems to be like, you know, baseline usefulness for a human on the surface of Mars involves lifting equipment around the surface, be it scientific equipment or construction equipment of some sort. So that'll obviously be incredibly important once we do get on the surface of Mars. So that'll obviously be incredibly important once we do get on the surface of Mars.

Right. And so there, when, you know, people design spacesuits and, you know, design kind of the protocols that, you know, astronauts will eventually use on their EVA, the biomechanics, you know, how somebody's bones and joints and muscles are going to move, you know, become, you know, really become part of the spacecraft, spacesuit design, as well as, you know, the protocols that they have to follow when, you know, they're on the surface of Mars. And, you know, how do they move things around? How do they lift, pick things up? You know, how do they prevent themselves from having falls and stuff like that? keep up with the way they are now in space. So if you try to think about how they would do to heal in space, that's a huge concern and something that we don't talk about a lot. We talk about how to maintain our current state, but not about how to repair from a broken state. So if you're

on an EVA and something happens that you break a bone, you could be down and out for the whole mission. I think we're trained to think, oh, you'll be out of commission for a little while, and then you'll be back on your feet. But realistically, in space, not that we know a lot about, you know, how things heal from a fracture in space yet, thankfully, but you might not be able to get back into a working order for the entire duration of the mission. Yeah, and it's not only a consideration of bone,

you know, it's a consideration for soft tissue injuries as well. So there is, you know, there's been a lot of effort, primarily using animal models to look at the process of fracture healing in space. And in this case, you know, most of that work has been done using simulated microgravity. So, you know, what before we had the show, we talked about analog studies where we can't always, you know, be able to we aren't always able to study things in the space environment. Sometimes we have to simulate the space environment. we have to simulate the space environment. So one thing that, you know, researchers in our field do if they want to really look at processes at kind of the cell and tissue level is use animal models. And for a lot of studies of bone loss and fracture healing and things like that, you know, where you want to look at what's going on down at the cellular level, at the microstructural level of bone, etc. Or, you know, in the case of healing of a fracture under controlled conditions, you use typically a rodent model. This could be a mouse or in some cases a rat. So in the late 1980s, there was a researcher at NASA Ames called Emily Maury Holton who worked out a protocol for what's called hind limb unloading.

process where you can sort of simulate microgravity in an earthbound rodent model, you know, without flying the animal. And so what they do is they actually suspend the hind limbs of these animals by attaching the tail to a kind of trapeze so that it's allowed to move sort of quasi-freely around its cage and, you know, engage in its rodent activities, but where its hind limbs are suspended off the ground. And so that allows you to kind of look at this disuse osteoporosis that's associated with spaceflight. And people have used that model to look at what happens when, you know, fractures heal in microgravity. So in this case, they induced a fracture and then, you know, let the animal move around while the fracture healed. And essentially, you know, what they were able to show for different types of fractures was that, you know, what they were able to show for different types of fractures was that, you know, the fracture union was delayed and that, you know, the quality of

that healed bone was not the same as the quality of the bone back on earth. So there were issues related to fracture healing that, you know, may, you know, that seem to be related as people have looked into this in more depth with impairment of angiogenesis, which is the ability of the body to form blood vessels around this wound site and impairment in the regenerative ability of a bone. So, you know, bone, like other tissues, has its pregenitor cells and, you know, fully functioning bone cells arise from those pregenitor cells in the case of bone injury, for example. And the ability of those cells to form, you know, active, you know, bone cells is reduced. So there are various reasons why it's thought that microgravity could have this impact. I believe the CRS-10 mission that SpaceX launched a couple of weeks back, they had mice on that mission that I remember reading something that

they had artificially induced fractures in their legs that they were sending up to observe their healing. Obviously, that's a pretty expensive proposition. So, you know, what you're talking about with the analog facility is something that you can do here on Earth to do the same kind of research, but at a much lower cost than it would be to actually book space on a flight up to the space station, and time on the space station, crew time, and all of that sort of stuff. So what other sort of analog facilities are out there? You told us about the suspended sort of situation, but what else is there that we can take advantage of?

So I just want to get back to this, you know, the CRS-10 mission you were referring to. So there have been, you know, SpaceX has really given us the ability to, you know, the advent of Dragon has given us the ability to fly animals to the space station, you know, fly them or specimens from them back down again. And while these, you know, the hind limb unloading analog allowed us to have, you know, a lot of insight we wouldn't be able to have otherwise, being able to fly the animal and see how these injuries heal kind of in a much more natural context, that's a huge payback. So, you know, the improved quality of the information that we get tends to compensate for the additional expense. But going back to your question about analogs, so you have different analogs for different, you know, different purposes. So, for example, if you really want to look at the effect of radiation

you know on for example bone or muscle tissue or on the immune system under very controlled conditions then it's natural to use you know an animal as an analog whether that and you know for example on earth subjected to radiation from an accelerator facility, etc., or, you know, for looking at fracture healing, things like that. One analog that we can use for studying the effect of disuse on bone and muscle is long-duration bedrests. is a long duration bed rest. So in particularly in Europe, they're, they're doing this very actively. Um, there's what's called 60 day bed rest. And so the, in this case, you have experimental subjects who are recruited and they're willing to spend, you know, two months in bed. And they lie in bed in a six degree head down tilt. And think of it as like a two month hospital stay.

They can't get up, they can't support their skeletons. And what it does is if you just put somebody to bed for two months, it essentially, to a surprisingly good extent, recapitulates some of the musculoskeletal effects of spaceflight. So that's an, that's one type of analog facility, a head down, uh, you know, six degree head down bed rest facility. And so there, you know, you can have people in these laboratories. You can very tightly control their diet. You can control other aspects of their environment. And then you can do quantitative measurements to see what happens to, you know, various elements of their

physiology, like their bone architecture or their, you know, their muscle mass or muscle strength. You can also use this approach to test countermeasures. So you put somebody to bed and maybe you already have data on what happens with that protocol when you don't intervene. You already have data on what happens with that protocol when you don't intervene. And now you can take that control group and compare it to different experimental groups. So there was a similar bedrest study going on in a NASA facility in Galveston. And what they could do was, for example, put people suspended on a vertical treadmill. So this treadmill is called the SLS or space locomotion system. And so I don't know if you could imagine it. You know, you have somebody who's suspended from these harnesses and this treadmill is vertical and

their feet are on the treadmill. And so they can do things like look at the effect of running protocols, of weightlifting protocols, squats and deadlifts, things like that. And they can look at all sorts of aspects of mixing different types of exercise with different types of nutrition and the timing thereof, and the ability to prevent some of the deterioration that you see in long duration spaceflight. And so that's another type of analog. With psychological, you know, with isolation, you know, because it's not that hard to achieve models for isolation. You know, there are, for example, there are polar research stations.

So, you know, in the Antarctic highlands, you know, they have U.S. and European research stations where people are in these stations for nine months. Or, you know, to some extent, you might be able to do studies on nuclear submarine crews who are on very, very long missions. You can look at there are different. There's, for example, the Nemo facility, which is an underwater lab off the coast of Florida where, you know, astronauts spend, you know, periods of time underwater, and then they use that environment, you know, to practice EVAs and things like that. And there are different isolation facilities. You know, in Houston, you have the HERO facility, which might be what, 18, 30 days, you have this facility in Hawaii, You have facilities in the Arctic. So those are other types of analogs.

And then you can consider the International Space Station as an analog, right? So there you have an analog that has to some extent isolation, although you can be in rapid communication with Earth as need be. You can return to Earth relatively quickly in the case of an emergency, but you definitely have full exposure to microgravity. You have exposure to higher radiation than we see on the surface of Earth, but not as high as we would get in deep space beyond Earth's magnetic field. And then finally, this deep space gateway that NASA is discussing is itself kind of an analog for a mission to Mars, right? That's definitely how they're envisioning it. I think you'll find varying opinions on the facility itself from Mars enthusiasts.

Notably, Robert Zubrin's not too pumped about the plan, but that's not uncommon for him and NASA to disagree a bit. of making use of these analog facilities and the ISS itself, that's really there so that we can develop countermeasures for the different issues. Can you walk us through a little bit about how some proposed countermeasure makes its way through the process and how it makes use of analog facilities, how it makes use of the ISS or other space vehicles that are flying actively? how it makes use of the ISS or other space vehicles that are flying actively. How does it make its way through that process to become something that we find a lot of hope in for future missions? So I've been involved in the problem of bone loss, you know, together with NASA for a long time. And when the, the, the issue of bone loss was suspected, you know, even before people went into space, you know, so it was known that people would be weightless and, uh, you know, some of the sort of severe bone loss. So for example,

you know, when the first cosmonaut cruise, so Adrian LeBlanc, some of the sort of severe bone loss. So for example, you know, when the first cosmonaut crews, so Adrian LeBlanc, who was the, the, the researcher I spoke to you about, uh, earlier on in the show, um, he did a study where they looked, I believe at 19, uh, mere crew pre and post flight. And so they were finding, for example, that these people lost, you know, a percent and a half per month of bone mineral density from their hip. So per month of space flight, and that corresponds to about the rate of loss per year in a postmenopausal woman. So it was known that, you know, you were getting these dramatic losses in, um, you know, in long duration space flight. So what we did is we studied the

first cruise of the international space station and there, you know, they flew a resistance device. So it was thought, okay, there weren't really, there wasn't really a, aside from, I believe, a treadmill and an exercise bicycle, there weren't really any resistance exercise countermeasures on the Mir spacecraft. Maybe Russians will argue with you, but I think that's generally the consensus. So knowing that this was the case, NASA flew a resistance device on the space station, and that was called IRED interim resistance exercise device and this was an exercise device that permitted squats and I believe deadlifts and it had a relatively limited range of motion and a relatively limited sort of total load and

limited sort of total load. And, you know, it was hoped that by using resistance exercise, where, for example, you know, when you're doing these squats and deadlifts, you're activating muscle forces that, you know, are based on the contractions of muscles that attach directly, for example, at your hip. And so the mechanical force levels that you get from these exercises are very, very high, you know, even compared to sort of forces that you get from walking around or supporting yourself in gravity. And so it was hoped that they would be able to exercise on the IRED, even with its limitations, and that would prevent, you know, the kind of bone loss that they were seeing on Mir. And so when we did our study, where we published data, I believe on the pre post flight data on the first 14 on 14 of the first International Space Station crew members, so this was Mission 2 up through Mission 8, we found that the rates of bone loss, you know, including using more advanced measures like looking at the hip strength as opposed merely to its density using an approach called finite element modeling, we found losses, very large losses of bone density and strength that were the same or perhaps exceeded what was seen on mirror. And that sort of let people know that that interim measure wasn't, you know, wasn't really working very well. In the meantime, you

know, that was seen as an, as an interim measure. So, you know, in the meantime, they were developing a much more high-powered resistance exercise device called Advanced Resistant Exercise Device, or ARED. And so this was a monster of a machine that, you know, as opposed to 250 pounds, you could squat 600 pounds and, you know, much larger range of motion properly instrumented so that people could check in with, you know, I guess like an RFID or barcode type device. And, you know, their exercise sessions would be logged and recorded. And that device was tested. I think it underwent safety testing and a training study showing ability to use this device to build muscle here on earth. I don't think it was tested in a bedrest study before it was flown.

At any rate, it was flown in 2004. And in parallel, they were also, you know, NASA was also looking at the ability of drugs called antiresorptives or bisphosphonates, which block these bone-resorbing cells called osteoclasts. And a study was done using alendronate, which was essentially Fosamax, which was really the first generation of osteoporosis drug. And we did a, you know, a study of seven crew members who exercised on the resistance, advanced resistance exercise device. drug compared to crews who, you know, crew members who exercised on ARED without taking the drug compared to those earlier crew members who exercised on that initial IRED. And what was found was that the ARED, you know, exercising with this particularly heavy exercise protocol that, you know, what you're trying to do is essentially replace some of the mechanical loading that you lose from not being on earth.

You replace it with these sessions of huge muscle contractions and muscle forces, etc. The people who did the ARED exercise lost significantly less bone than the people, you know, the control group from earlier on, you know, from those first missions. So it was partially effective. It did not stop bone loss, but it reduced it, you know, to about half or a third of what it was previously. about half or a third of what it was previously. And then by using the combination of this anti-resorptive drug and the resistance exercise protocol, we were able to show that, you know, bone loss, at least in our seven crew was completely halted. So theoretically, you know, we do have the ability to use a combination of resistance exercise and these sorts of drug treatments to prevent bone loss. But, you know, that sort of approach, I think, needs to be optimized later on to make

it more efficient and reduce risks, etc. You know, when you're doing heavy resistance exercise, like the astronauts do pretty much every day on the space station, there's always the, you know, the risk of sprains, strains, other soft tissue injuries, things like that. So if you can potentially combine that with a drug, you might be able to either, you know, reduce the intensity of the exercise or perhaps change the dose of the drug. But then, you know, a previous study to this combined exercise drug study looked at, Previous study to this combined exercise drug study looked at, you know, the first five astronauts studied who used the ARED. And the investigators there took a very careful look at nutrition and vitamin D supplementation in addition to mechanical loading with exercise. And they found that they were able to make substantial progress in reducing this bone loss.

The other thing I find curious about some of this is that there are other factors that go into how some sort of exercise equipment would be used on a spacecraft. The ISS is big enough that if somebody's exercising, you can make your way into another node or something like that because it might be kind of noisy. But if you start looking at different architectures for spacecraft, even something like the Deep Space Gateway, that's not a very big spacecraft.

So if you have some sort of very extensive exercise to do and it's a couple hours a day per crew member, that could quickly get close to around the clock exercise going on, which would be pretty disruptive. So do any of those sort of side effects of how a specific countermeasure would affect the other crew members, does that stuff sort of make its way into these studies as well? to make its way into these studies as well? So I think that that's a really important consideration. I mean, this exercise gym, so on the space station, they have the ARED, which is a fairly big machine, plus they have the SEVIS, which is, is it SEVIS or TEVIS? I forget what it's called, but it's the exercise bicycle, plus they have the treadmill, which is, is it SEVIS or TEVIS? I forget what it's called, but it's the exercise bicycle. Plus they have the treadmill, which is called Colbert. Um, so they have these three devices,

essentially a gym. You're not going to have that volume in something like the deep space gateway. And I think what that is prompting is the design of more compact exercise devices, you know, real considerations of looking at the impact of exercise on other physiologic systems, looking at, for example, combining exercise, different exercise modalities on one device with a relatively small form factor, as well as, you know, combining exercise with drugs to work in a way where perhaps you can reduce the burden of exercise, you know, the time burden and the space burden. So that's, to round out where we're at today with some of these effects. It sounds like we have the bone loss at least pretty well understood for where

we are at in our exploration roadmap overall. Where are we at with some of the other, specifically the physiological ones? Does the muscle aspects come along with that because they're worked out by some of the same methods, or is it something else entirely? So, you know, the muscle to some extent works along with that. So what we found, you know, when we looked at the early space station crews and, you know, the Mir cruise, for example, you would see like really significant losses of muscle power and muscle volume. So for example, you know, if you look at the peak power of the calf muscle, you know, and this is on the sort

of the early space station cruise, it would go down by, you know, a third, even with the sort of exercise that was being done on the sort of interim exercise equipment. And with the new exercise equipment like ARED, you still see, you know, depending on, you know, depending on the muscle group, losses of sort of up to 15% of muscle strength over a mission. And to some extent, you know, those are relatively quickly recovered when astronauts come back. But even with this sort of intense exercise, you know, it's not been possible to completely prevent losses of muscle strength. And, you know, there's a lot of work that's gone into sort of studying, you know, at this muscle atrophy at the cellular level, looking at the, you know, effects not only, you know, at this muscle atrophy at the cellular level, looking at the, you know, effects, not only,

you know, at these muscle volumes, but at the individual muscle fibers and what happens to them, et cetera. But, you know, it looks like that even with this sort of state of the art countermeasures that we have on ISS, there's, you know, muscle loss is still there to some extent. And there are also some immune issue, immune system issues that we found throughout time. Is that something that we're still working through? Are there countermeasures for that as well? It's something that we're still working through and you know there are thoughts for countermeasures but there's a lot of you know basic science that's still being done and we've known about immune issues for a long time so i think if you looked at all of the apollo crew crew, you know, about half of them came back with, you know, colds or infections or things

like that, particularly in relation to, you know, bacteria and other agents that, you know, where the infections are related to a compromised immune system. you know, where the infections are related to a compromised immune system. And the immune system in microgravity and space is really different in Earth. So people have been studying, you know, on Mir and then eventually on the space station, flying immune cells and seeing what's happening to them compared to earth you know earth controls and controls for example in a what's called a rotating wall vessel where you know on a spacecraft like the ISS you can take cells and expose them to microgravity and then you can expose them to varying degrees of gravity depending on

the rotation of this vessel. So I want to give a shout out to my colleague Millie Hughes-Fulford at UCSF. And what she did is she looked in particular at human T cells. And what she did is she had a group of, so these T cells are really, if you look at all the different types of immune cells, you know, T cells are very important for sort of playing a role in organizing the immune response. And, you know, what she found was that when you compared T cells on the space station that were, you know, under 1G in this rotating wall vessel to unloaded T cells, the sequence of events, molecular events, the gene expressions, the expression of micro RNAs were really different in the unloaded T cells compared to the loaded T cells. And, you know, being able to do studies like this and looking at specifically which molecular pathways are altered starts to

give you kind of an evidence base for starting to develop, you know, drugs to deal with, you know, compromise of the immune system that you get in spaceflight. And that just dealt with the, you know, the microgravity aspect. There's also, you know, you might expect if the radiation exposure is much higher in going beyond low Earth gravity, that there are going to be additional radiation effects on these immune cells. So the immune system is definitely compromised. that there are going to be additional radiation effects on these immune cells. So the immune system is definitely compromised.

What Millie found was that these T cells became activated, but there was a time delay compared to the loaded controls, etc. I have a feeling that I'm going to be sending Millie an email to get her on the show in the future. Oh, yeah, you definitely want to get Millie on the show. Yeah, I think we're going to circle back to that question. I just want to finish up with a few other countermeasures first, because that sounds like partial gravity stuff is something that I have a lot of questions about. And I also, you know, when I send out little notifications about interviews to some of the patrons, and they send in some questions,

and a lot of them were about partial gravity as well. So that's something that we should circle back to for sure. So one thing about Millie, she comes at this sort of space life sciences research from a dual perspective. So she was an astronaut on a shuttle astronaut, as well as, you know, having had a long career as a basic researcher at UCSF. So, you know, she can sort of give you the perspective of an astronaut and the perspective of a career life sciences researcher. I like that idea. That sounds exciting. This is what I'm talking about. We got to get this series of conversations going. And this is just a great way to start it out. You know, there's a lot of these tiny issues that kind of get glazed over because what we

hear about so often is the bone, the bone loss, the radiation, and things like that. But there's so many other issues that don't come up that much, but are equally as important. And another one that I hear about sometimes, but it still sounds like it's a little bit on the, maybe the cutting edge because we're just now getting enough experience to see it. We still don't know all the details of it, but there's some problems with vision as well in space. And it affects some people more than others, men more than women. But I'm not quite sure where that's at today. Is that something that you've encountered at all throughout this series of papers? So it's not an area of research that I can speak in any detail with.

area of research that I can speak in any detail with. But, you know, one thing we do see is that intracranial pressure goes up in, you know, in microgravity and space station astronauts. And that includes the, you know, the pressures on the structures in the eye, which deforms the visual field. And, you know, that's not something that I've been keeping track of particularly, but, you know, it's an important thing, you know, if people have distortions in vision that can compromise them during the vision or, you know, impair, potentially impair their long-term eye health. So, you know, that might be something that you want to bring, you know, some of the people who are working on the problem in NASA on. Yeah, it's hard to get a handle on where that's at, because it's, you know, it's another one of those issues where you kind of get some people that hand wave it away or some people that say it's a big showstopper because you don't want to end up at Mars and not be able to see anything through the center of your vision. So, you know, there's a lot of these questions as well that seem to vary a lot based on who you talk with. And probably the king of that is radiation itself. You either have people that say, this is not a showstopper by any means. We have the technology to get to Mars successfully and not die of cancer by the time we get back. You

have other people saying that it's something that we need to address right now or we can't go out and do anything beyond Earth. Where is that at? Obviously from the radiology department, you've got a perspective on this that I'm interested to hear. Where are we at on that? Is it a showstopper? Is it not?

Do we have proper countermeasures or do we need to be working on some? So I think whether it's a showstopper or not is a matter of opinion, but I think it would be useful just to kind of go over the different levels of radiation exposure that are associated with different activities on Earth or in space. So for example, if, you know, just by one year of background, just, you know, living somewhere in the United States, you know, we might get anywhere between sort of 2.4 to 3.6 millisieverts per year and just background radiation. Um, If we have an abdominal CT scan, that single abdominal CT scan might give us somewhere between sort of 6 and 10 millisieverts one year on the space station, right? So this would be, you know, a Scott Kelly-like mission on the space station, you know, it's about 150 millisieverts. A career astronaut exposure, you know, across multiple missions, right, is anywhere in low

orbit might be anywhere between one to four millisieverts. If we take like a nominal Mars mission, and we're looking at maybe 180 days out, 500 days on Mars, 180 days in, and I know people are discussing different trajectories to Mars to, you know, to get us there more quickly. But just taking into account those parameters, you know, one is looking about a 1000 millisievert dose.

So that's essentially in one of these trips, you're getting, you know, kind of in the ballpark of what a career astronaut is allowed, you know, over the, an astronaut is allowed over the course of their career. Um, the annual limit for radiation workers, nuclear power plants, et cetera, 20 millisieverts per year. And if you have radiation therapy for lymphoma, you're talking about 35,000 millisieverts which would you know be like 35 times 30 times what our you know Mars astronaut would get so there are different levels of radiation exposure at those at the kind of levels of radiation exposure that are associated with space or with

CT scanning, you know, things like that, it's sort of hard to estimate, you know, the risk of getting cancer as a result of that. You know, one of the problems that we have is, you know, we don't have enough cases of, you know, in the spaceflight community with virtually any endpoint. We don't have enough people, you know, who have flown in space to do this sort of a rough estimate that based on the radiation that, you know, we get per X number of people, maybe per million people or something like that, due to, you know, just earthbound sources of radiation. We might get 40 cases of cancer or. of radiation, we might get 40 cases of cancer or, let's see, but, you know, with one of these Mars missions, you know, perhaps there would be 60. So there would be, you know, it's thought that the risk of cancer would go up as a result of being exposed to that higher level of radiation, you know, but is it a showstopper? You know, that's really a matter of opinion. I think what is important is to work as hard as we possibly can on, you know, radiation protection. And so,

you know, to that extent, there's a lot of work going on in, you know, how do you design shielding for spacecraft? So, you know, if you, if you look primarily that the primary source of radiation exposure in a spacecraft is going to be probably solar protons. You know, you would have probably fairly effective shielding that might be water or plastic, perhaps putting the supplies or the spacecraft in a geometry where, you know, people could go there for protection. You know, the issue that those supplies get used up over the course of the mission. in using water or in the case of the substitute, plastic, as shielding against at least these solar protons. The thin aluminum skin of the spacecraft, what happens is these protons come in and they collide with the aluminum and cause secondary radiation. As you thicken up the aluminum, that secondary radiation tends to be absorbed.

But, you know, it's not something I'm an expert in, but there certainly has to be a lot of effort into design of shielding. With respect to cosmic rays, you know, you have protons just like you do from the sun, but there are also, you know, heavy ions. And the exposure to these heavy ions is very small. But when they do interact with the human tissue, they do deposit a lot of energy. interact with the human tissue, they do deposit a lot of energy. And, you know, I'm not sure anybody really knows how to shield against that. So there, in addition to questions of shielding, you know, people look at, okay, you know, what are the types of cancers that are going to be more sensitive to increased radiation exposure? And what are the countermeasures to those types

of cancers, you know, that where there seems to be, you know, some evidence in preventing them here on Earth? So, for example, it's thought that one of the cancers that might, you know, have a higher probability of happening, space flight is colon cancer. So are there, you know, have a higher probability of happening. Space flight is colon cancer. So are there, you know, things like antioxidants and dietary supplements that astronauts could take that would reduce the risk of colon cancer and sort of modulate the increase of risk that would occur as you're exposed to more radiation. So that sort of takes us into moving ahead in spaceflight and what's coming down the line for us in the next couple of years, next couple of decades, even if we look out

farther than that. As we move into things like the Deep Space Gateway or even some of the SpaceX plans for heading out to Mars, what do you think the key areas should be to focus on when it comes to human health in spaceflight and these endeavors? What do you think should be the primary focus or the things that we emphasize as we move into that? Oh, that's a huge question. Oh, that's a huge question. First of all, you know, I think one thing to take into account is that we've tended to approach, you know, approach human physiology in space as sort of part of the engineering system, right? So your astronaut is part of the engineering system. And so into your engineering calculations, you have to factor the risk that a bone will fail.

And then how do you reduce the risk by treating the bone? And how do you treat the muscle? And how do you treat the heart? And how do you treat the muscle and how do you treat the heart? And, you know, how do you treat the psychological effects of isolation and how do you treat effects on the immune system? And I think that all of these different effects are interrelated. So, for example, if you're doing exercise to prevent bone loss, you know, that is also, you know, having its effect on muscle. And it also, you know, we have to understand what effect the exercise has, you know, on, you know, on brain function and on psychology and things like that, you know, how is,

you know, how is nutrition related to, you know, how is nutrition related to all of these different physiological systems? So to me, you know, one of the challenges that we have to really look at in the future is tying all these systems together and, you know, in studying the impact of an intervention on one system, look at the effects on others. And because in reality, what we're doing is we're protecting the whole human being. As opposed, you know, in relation to what we're doing is we're protecting the whole human being. As opposed, you know, in relation to what do you make your overall priority? I think that that's always best addressed when you put everybody together, you know, all of the different, you know, spaceflight and physiology experts, I would love to see them come together with spacecraft designers. You know, are there ways of developing a spacecraft around the human,

as opposed to, you know, working out the risk of travel in each spacecraft for discrete components of this human system. So my interest in all this would be to a much broader perspective. How you implement a broader perspective scientifically, that's always very challenging. But that would always be my interest. So you brought up the deep space gateway a few times. Is that something that you've thought about a lot or is it really just, you know, NASA hasn't really put out that much about it to be honest. So I just was wondering if you had any thoughts on how that relates to both what you were just talking about, about designing a spacecraft around a human and also how it applies to where we're

at with medical research today and things that we don't know yet. You know, it's going to be in a different environment than the ISS. It's going to be a little bit more isolated, more exposed to that radiation environment, a different environment entirely than the research we've done so far. So in both of those regards, the design of such a destination and the actual location choice of it, do you have any thoughts on how that might shake out for the medical concerns? So I guess I like the idea of something like the deep space gateway. I can't speak to whether it should be positioned around Mars or whether it should be positioned, you know, at an inflection point. But I like the idea of a long duration facility outside of Earth's orbit.

And, you know, you think our ultimate goal, you know, we want to someday go to Mars. You know, we want to go and systematically live in space. You know, maybe we'll go back to the moon. At any rate, you know, if you look at all of the factors that go into managing the risk, for example, of going to Mars, you have a ton of factors that are just related to being in space. And then you have another set of factors that are just related to being in space. And then you have another set of factors that are related to the planetary surface. And when you have to take a facility and put it into a gravitational potential well like Mars, it implies, you know, a tremendous amount of extra infrastructure and cost. And so if you're taking the approach of, you know, looking at the risk piece by piece, then it makes, to me, it makes

a lot of sense to have something like a deep space gateway where you can, you know, reprise a lot of the effects of a Mars mission, but not have the extra expenditure and extra investment and risk associated with actually putting somebody on the planet. And there, I think it's, as you point out, that you're going to have the ability to look at as you point out, right, that you're going to have the ability to look at, um, prolonged exposure to microgravity, you know, increased level of isolation, um, to really look more in depth at the radiation exposure, things like that. Um, the issue with doing this, you know, in humans is it'll be very valuable data, but relatively few people will be there. And, you know, when you have humans in space, they all have slightly different protocols for eating, sleeping, exercising, et cetera.

So it's not really from the point of view of studying physiology, a super controlled experiment. Um, so that's why I'm hoping that when they launch this thing, if they end up launching it, that this sort of facility, you know, we'll have animal experimental facilities and cell experimental facilities. So we can do these sorts of studies, you know, really in the environment of deep space. So that's sort of my perspective. Just as sort of a, you know, a natural progression of things, I kind of like the approach of sort of in a slow linear process, increasing the risk and looking at as many of the risks as possible, you know,

without, you know, having to go on to a planetary surface and, you know, take that final big risk of getting people on and off and spend that, you know, enormous amount of effort in figuring that out. If you can resolve, you can resolve a bunch of these issues without doing that, to me, that seems very logical. The last big question mark that goes along with that is, we've spent a lot of time in microgravity with the ISS, with Mir, everything else that we've done in low-Earth orbit. We may spend a lot of time in microgravity at Deep Space Gateway, but we haven't really spent any time in partial gravity, either at lunar gravity, which is about one-sixth of what Earth's is,

or at Martian gravity, which is about one-third. And you brought up how your friend Millie did some experiments with T-cells and in-space artificial gravity. But we haven't done anything for a full human yet. So that's curious to me in that when we start going down to the lunar surface or to Mars' surface, that's going to be kind of an entirely new territory for research in how humans respond to that partial gravity environment. Do you have any thoughts on how that sort of research might come about or might progress? Again, it's going to be one of those cases where there's not a lot of people in your sample size. It's going to be a very small amount of people at

first that are down there on the lunar surface, if that's where NASA and Blue Origin and the like seem to be heading. So how do you think that would go? And do you think it would look similar to the early days in low Earth orbit? Or do you think it would look vastly different because of the different environment we're in today? So just to make an initial stab at that question, there's some research in partial gravity that's occurring now. So the Japanese, in their Kibo module have flown a small animal centrifuge. So, you know, we can actually start to look at the effects of partial gravity in mitigating some of the effects of spaceflight in animal models. So that's now available on the space station. And with respect to effects of partial gravity on human physiology, you know, I think that's just

fundamentally new territory. And, you know, at least from what I know of some of the very early experiments on bone that were done using, for example, partial hind limb unloading, you know, simulations of partial gravity using modified hind limb unloading approaches, it isn't clear that, you know, at least one 6G or even a third G makes that much of a difference with respect to bone and muscle. I mean, I don't have the final publications of that research, but certainly the initial indications were that it may very well be that these partial gravity environments aren't sufficient to mitigate the effects of unloading. It's exciting to know that we're on the verge of an entirely new area. Yeah, and I think that we'll be learning a lot, you know, with these, uh, these Mars missions. Um, and, you know, I can only hope that as we progress and move on to something like the deep space gateway,

if we end up building that, um, you know, that there will be basic science that goes along with it so that we can really, you know, understand some of these effects of, you know, going into deep space on a more fundamental level. Awesome. Dr. Lange, thank you so much for joining us on the show. I hope that you'll be our source of all things medicine as we venture into this whole new realm of territory for the podcast. Yeah, I hope you get, you know, there are a lot of sources out there. And, you know, in reality, this sort of the field of medicine in space is just as large as medicine on Earth, right? Because every single human system is affected by space flight. So, you know, my own experience in detail is a relatively small part of this overall picture. But, you know, I think that there will be, I think it's great that you're, you know, making this effort to bring, you know, the human biology, the physiology, the medical side into this, because it's just

such an important part of spaceflight. And there are a lot of people out there who have done a lot of really interesting work in psychology, in immunology, in space radiation, and I hope that you'll be able to bring them on and bring their perspectives in. Well, you know, I hope that you'll be able to bring them on and bring their perspectives in. Well, thank you very much. I don't think I can start this out any better than this show. So thank you again so much for joining me. Oh, thank you. I, you know, as I said, I love your podcast and I'm so happy to be able to be part of it. That's it for us today. Thank you so much for listening. Thank you so much again, Dr. Lang,

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