Drugs in Space
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Pushkin. Sometimes getting better is harder than getting sick. Waiting on hold for an appointment, standing in line at the pharmacy, the whole healthcare system can feel like a headache. Amazon One Medical and Amazon Pharmacy are changing that.

Get convenient virtual care 24-7 with Amazon One Medical and have your prescriptions delivered right to your door with Amazon Pharmacy. No more lines, no more hassles. Just affordable, fast care. Thanks to Amazon Pharmacy and Amazon One Medical, health care just got less painful. Learn more at health.amazon.com.

One subject we've discussed from time to time on this show is space, outer space, for obvious reasons, you know, final frontier, etc. Another subject we've done a bunch of episodes about, drug research, figuring out new and better ways to make new medicines. Also for obvious reasons, it's high stakes life or death innovation. Today, we're combining those two subjects. It's a show about drug research in space.

I'm Jacob Goldstein, and this is What's Your Problem, the show where I talk to people who are trying to make technological progress. My guest today is Paul Reichert. He's a research scientist at the drug company Merck. Paul's problem is this. How can you run experiments in space to make better drugs on Earth? To be clear, Paul has not gone to space himself.

But over the past 30 or so years, he has sent tubes full of proteins and drugs up to space. First on the space shuttle, and more recently on rockets to the International Space Station. And he's instructed astronauts on how to carry out dozens of experiments in space. One of Paul's more recent experiments looked at a common type of drug called monoclonal antibodies.

Monoclonal antibodies are used to treat cancer, among other diseases, and they're currently very time-consuming and very expensive to deliver. And what Paul was trying to figure out was a cheaper, faster way to deliver those drugs. We'll talk about that experiment later in the show.

Paul specializes in crystallization, basically getting molecules to form crystal structures. And crystallization is important in the drug business in a few ways. For one thing, it's really important for studying the molecules that drugs target. And for another, crystallization plays an important role in the process of manufacturing drugs. So to start, I asked Paul, what are the reasons for going to space to do crystallization experiments? Okay. Okay.

One is the obvious one is sedimentation. We all see astronauts floating in space. So when you go grow crystals in space, they too remain suspended in space as they grow. And this suspended particle then has an opportunity then to grow more perfect than it would if it was sedimenting, dropping in the solution as it was being formed.

So on Earth, when you're trying to do this, you have this problem, which is the particles sink to the bottom, like whatever. Correct. Coffee grounds in a cup or something. But when you're in space, you don't have that problem because there is no sinking and there is no ground. Right. And the second property we'd like to take advantage of is that molecules move more slowly in space. Right.

So processes that involve adding molecules to say like a crystal, the molecules have a chance then to be discriminate to get the best molecule fit within the crystal lattice.

Okay, so now we know why space is a good place to—really, you're trying to form crystals, fundamentally, right? It's a good place to cause molecules to crystallize, for the reasons you articulated. I don't want to do all 30 years of your working on crystals in space, but I wonder if there's a moment from the early space shuttle era—what was one

kind of important early finding you had from your work on the space shuttle. I have a interesting but very sad story to say about that. One of the last flights, space shuttle flights that we did was STS-107, that's Space Transportation System 107, and that was Columbia.

went up in January 2003. And we were trying to grow large crystals suitable for structural studies. And I uniquely had the opportunity, since one of the people in our team was retiring, so we got to go to the launch site

of Columbia the night before launch. We went 130 feet up in the air onto a scaffolding up until the top of where the nose of the shuttle was, and it was cold, freezing cold. Little did we know, but the next day upon launch, a frozen chunk of that solid rocket booster would fall and hit the wing

of space shuttle Columbia, and that upon reentry two weeks later would cause the breakup of Columbia over Texas. There was a debris field over 63 miles for that. And the death of the astronauts, right? Yes. So NASA at that point decided that they would focus on building the International Space Station

and no longer spend time with secondary projects like this. About three, four months after this disaster, I got a call from NASA and said, we found some of your bottles. I had flew 100 small 1ml bottles, and they said, we found a few of them. Would you like to come down and take a look at them?

So I said, yes. So I go down to the shuttle reconstruction site. They had a dedicated site there. And I found three vials. And within those three bottles, there were crystals. And those crystals, when we did the X-ray diffraction study, diffracted better than any crystals we had ever seen before.

So one of my great honors in my life was about three months after that, NASA asked me, would you be willing to talk to the families of the astronauts and tell them about the results of your experiment? So it was a great honor for me to have this opportunity again.

to hopefully give some consolation to the families about, you know, we did get some science from this, and give them some relief in their suffering. And what are the practical implications of having crystals that diffract really well? Why is that meaningful?

It allows you to see the intimate contacts that are made within the protein to design the better small molecule drugs that are in complex with those proteins. So one of the interesting things was is that the crystals that grew from that experiment was from an impure sample. We're actually looking at it for purification.

And one of the impurities in there was zinc. And we basically found that the reason why the crystals diffracted so much better than what we had previously seen before is because there was a zinc in between two molecules of interferon, stabilizing it, allowing it to have a really stable form. So that was something that was... I have to say that a lot of microgravity research...

You're really at the basic level, and it gives you an opportunity to really change the way you think because you're so focused on very simple steps in a process. You could see the protein more clearly than anyone had ever seen it before. Absolutely. So that was the key finding. So we get now into...

Well into the 21st century here, and there's this new class of drugs, monoclonal antibodies, that are very powerful drugs, but they're very hard to deliver, right? And this is a problem you're working on solving. So tell me about the problem with delivering monoclonal antibodies. Okay. The issue is that still to this day, most monoclonal antibody therapeutics are

which are given for a range of different modalities from cancer to cardiovascular disease to infective diseases. They've really revolutionized the way pharmaceutical research has been going on. So they're very good drugs. However, in the case of oncology patients especially,

They have to get an infusion every three weeks, and this is usually in a hospital setting. So this is an all-day affair, not only for the patient, but usually a caregiver that's accompanying their patient who's taking time off from work to go for these infusions every three weeks.

And usually therapy could go as long as six months to a year. So this is a tremendous impact on both the patient and the caregiver. And it adds to the expense, right? Non-trivially, it's more expensive just because it takes more labor on the side of the hospital or the infusion center. It's a complicated, expensive, time-consuming process. It's about half the cost of the delivery of the drug

is this infusion, all right? Yeah. So we are looking at opportunities to make crystalline suspensions. So one of the, let me take a step back and say, one of the issues with making, well, why don't you just make a high concentrated liquid formulation that you can inject?

So the issue is... To be clear, just make it be a shot, like getting a flu shot or something, fast and easy. Right. So the problem is that in the liquid form, okay, as you increase the concentration, it becomes thick and more difficult to...

to uh in inject so i don't think most people would enjoy getting an injection that may take five ten minutes of time in order to get the same dose as you would an infusion it would be extremely painful patients would not accept that kind of of of a delivery system of pain yeah

Pain over a long period of time, let me put it this way. So we decided to look at, there was some evidence that high concentrated crystalline suspensions are lower in viscosity than the comparable liquid formulations. So we went about looking to see if we could crystallize monoclonal antibodies.

And we had success with one monoclonal antibody. And ultimately, we discovered conditions for crystallizing pembrolizumab, which is an active pharmaceutical ingredient for one of our oncology drugs. And so you're studying it on Earth, right? Trying to understand if you can get it into a crystal structure so that...

so that it could be given as a quick injection rather than as a long infusion. You're going to go to space. I'll spoil the story. You're going to go to space. You're going to send something up to space to study. But why? Did you try and do it on Earth first, and did it work? Absolutely, it works. The question is, can you make it better? We always like to come up with the best solutions.

therapeutic that we can deliver that has the stability and properties that we're looking for in a final product. And then second to that, we're always looking at opportunities to improve the manufacture of our drugs, possibly reduce cost

and then have a more stable formulation. For example, one of our goals would be to show that a crystalline suspension, since it's inherently more stable, does that allow you to take a monoclonal antibody drug that is stored in a refrigerator?

to now be allowed to be stable, say, for six months at room temperature. And therefore, that has a big impact on the number of patients globally that can treat. So then if it could be a shot that is stable at room temperature, then that opens up a lot of the developing world that right now is, frankly, just doesn't have the infrastructure to deliver refrigerated infusion drugs. Correct.

Do you just call up NASA and say, hey, NASA, it's me. I want to send something to the space station? No, that's not how it works. So let me take a step back and say that after the space shuttle Columbia broke apart over Texas, there was no microgravity research, actively research going on to about 2010, 2011,

And the US Congress said, "We built this station, we have this beautiful laboratory in space and it's being underutilized." So they set up a nonprofit called the Center for the Advancement of Science in Space and allowed them to manage science on the International Space Station. So about 2011, 2012, somebody from CASIS,

reached out to me and said, "Would you be interested in doing some microgravity research? Come up with a proposal?" That's a nice call to get. Yes. And so you propose this crystallization research on a monoclonal antibody. Right. And they say yes. And what happens?

All right. So we were at this time was the early stages of where SpaceX, the Falcon 9 rockets were starting to deliver their Dragon module to resupply missions to the International Space Station. And we got manifested in 2014 to crystallize a monoclonal antibody.

Manifested in this context, it's not some new age term. It means you got put on the list of stuff that gets to go up there. Yes, that's what it means. You know, it was basically... You're on the manifest. You're on the manifest. These are all the, you know, NASA terms, you know, you're manifested, you know. So we always do...

The same experiment on ground that we do in space. Basically as a control. As a control. You do a control. And not only that, we usually do it in triplicate to ensure that it's not a one-off or something that's not, you know what I mean? I mean, if you're sending one of them all the way to space, you might as well do three on Earth. Well, we do three in space, too.

Oh, interesting. Uh-huh. So that it's not N of one. It's not N of one. At least you can show reproducibility that this is a real finding that you have. And so it goes up on a Falcon 9 rocket. It gets to the space station. Are you involved as it's happening? Are you like talking to the astronauts on the phone? That's a good question. Usually there's a NASA person.

that's talking directly to the astronauts while they're activating our experiment. And I can actually watch by video and I can send messages through cases through NASA that

If I see anything that's unusual. So you're like texting the astronaut, being like, wait, wait, no, turn it the other way or what? Like what is going on? That's a very good point. They have iPads that they use. And there's very detailed instructions of the process that they're doing while doing these experiments. You've got to keep in mind that they're doing hundreds of experiments every

You know, so astronauts on the space station, presumably they're busy, right? They're very busy. And, you know, one of the things that's always impressed me is the is the fact that they're they're very focused people.

calm individuals. I feel like that's what you'd really want to optimize for in selecting an astronaut, right? Calm and focused is what I would hire for if I was hiring an astronaut. And they're curious, too. Oh, nice. They see their unique opportunity to impact science. And you can tell that they're enjoying what they're doing. I always found it to be extremely interesting

interesting people, you know, inquisitive people. In a minute, Paul's tubes come back from space and he gets to look at his space crystals. Hey, it's Jacob. I'm here with Rachel Botsman. Rachel lectures on trust at Oxford University, and she is the author of a new Pushkin audiobook called How to Trust and Be Trusted.

Hi, Rachel. Hi, Jacob. Rachel Botsman, tell me three things I need to know about trust. Number one, do not mistake confidence for competence. Big trust mistake. So when people are making trust decisions, they often look for confidence versus competence. Number two, transparency doesn't equal more trust.

Big myth and misconception and a real problem actually in the tech world. The reason why is because trust is a confident relationship with the unknown. So what are you doing? If you make things more transparent, you're reducing the need for trust. And number three, become a stellar expectation setter. Inconsistency with expectations really damages trust.

I love it. Say the name of the book again and why everybody should listen to it. So it's called How to Trust and Be Trusted. Intentionally, it's a two-way title because we have to give trust and we have to earn trust.

And the reason why I wrote it is because we often hear about how trust is in a state of crisis or how it's in a state of decline. But there's lots of things that you can do to improve trust in your own lives, to improve trust in your teams, trusting yourself to take more risks, or even making smarter trust decisions. Rachel Botsman, the new audiobook is called How to Trust and Be Trusted. Great to talk with you.

It's so good to talk with you, and I really hope listeners listen to it because it can change people's lives. I asked Paul how he gets the results of his experiments from space. Like, what happens after his crystals come back? In the early days, the Dragon module would parachute down in the Pacific Ocean off of California, and there would be a tugboat

that would go and would pluck that Dragon module out of the ocean. It would be two days back to the harbor in Long Beach. And I would go there, and I always thought it was hysterical because if you were in Kennedy Space Center, there's so much security. You can't get near anything. When this boat gets to the dock in Long Beach,

They plucked this thing out of the water, put it up on the dock. They set up some folding tables and said, here's your experiment. Here's your stuff? It's just like a yard sale or something, but stuff from space? Yeah, it's like picking up fish at the dock. Yeah.

And they hand it over. And I would always be laughing hysterical as they would do this. You know what I mean? So you go, you walk up to the table, you say, those are my tubes. They give you the tubes. And then what do you go look at them under a microscope? Like, what do you actually do? We, we, we take, we take the experiments then. And believe it or not, in the early days, we would just, I was, this was before the

There was so many regulations about flying. I would have a cooler that I would keep and carry the cooler back on the flight back to New Jersey then to do analyze the experiment. Like they just think it's a cooler full of beer or something, not your perfect crystals. You can't do that now. By 2016, how are you doing it? On this particular one, it was 2016, right? What do you actually do? 2016,

We flew 100 1ml bottles. So these are all different connections, conditions, looking at... 1ml is tiny, 100 tiny little... They're little bottles. And we get our experiment back. And then we, at that point, the Dragon was parachuting down in the Gulf of Mexico.

And there is a helicopter that then picks up the Dragon module, brings it to Kennedy Space Center. And then within two hours, I have the experiment. And so what do you see? That first look, this thing's been up to space. It's been back. You look at it. What do you see when you look at it? Well, these crystals are extremely small.

Sure. So it requires looking at the microscope. But since it's concentrated, we can immediately tell that what we sent up was clear, a clear liquid, is now a paste, you know what I mean, a white paste, and that looking at it closely on the microscope, we could see that there were crystals that were there. So what was unique about the SpaceX experiment

10 experiment that we did with pembrolizumab is remember the goal was to get large big single crystals and

Well, we had one group of experiments where we got really, really small crystals and a lot of them. And I said, what's going on? So the ground experiment, comparable ground experiment, had larger particles that were less homogeneous. So the overall population was more broad.

Whereas... It's more heterogeneous. It wasn't as orderly. More heterogeneous, correct. Yeah, okay. So we thought this would be an excellent opportunity to look at these two types of results and see whether it makes a difference. Are they less viscous? And do they show better injectability properties? And what we found was is that the smaller particles that were uniformed

gave lower viscosity, better injectability properties. So that's what you want. That's what we want. And it was not where we were looking. We were up in the range of particles that were like 10 to 30 microns

And then all of a sudden we had particles that were really small and they showed this result. So it's a surprise. You didn't expect to get small particles. Correct. Right. So what we did then, once we got that result, was we came up with processes on Earth that would mimic those results that we got in microgravity.

And then we were able to get a high-density, high-yielding process from that. Huh. So is the hope, then, that this can lead to injectable versions, not just of this particular monoclonal antibody, but of monoclonal antibodies more generally? Absolutely. So I want to talk about what you're working on next. And I'm curious in particular about how you've been inspired by an astronaut named Kate Robbins. She was a...

molecular biologist from Stanford slash astronaut. And I watched a video of her when she was in a mission 2016 where she said she can take one personal item up to space. So she takes a pipette or up to space and she just starts moving liquids around the same way you do on earth. And this just blew me away.

because all of my experiments that I had done before that were always in locked down hardware, you know what I mean? With minimal contact. Like the idea that somebody could be pipetting in space to you as a sort of working scientist is amazing. Oh my God, if we could pipette up there, we can do anything. Absolutely. Because up until that point,

We always felt as though we had to take processes that we did on Earth and then get them to, you know, jerry-rig them to get to work in microgravity hardware. So that was always the issue, okay? So when I saw, you know, Dr. Kate Rubins start pipetting in space…

It opened, it like blew me away. I was sitting in the audience and I was looking around. I said, did you just see that? Did you just see what she was doing? Because what does it mean to you when you see that? What do you think? What does it mean to you? I mean, what it says to me, and it may sound strange, is that you can do the same thing that Edison did.

100 years ago. So you can have a laboratory or a base, okay? And you can move liquids and you can play around with different things. And it just opens up a whole other world of opportunities for discovery and innovation in real time. One pipette of revolution in one pipette. In one pipette. So what do you want to do with this new

world of possibilities. So what we did internally here is we came up with our own 3D printed hardware, okay, so that we could mix liquids and then all the astronaut has to do is flip the switch and you can mix back and forth with the syringes back and forth to get a homogeneous solution. So this gives you an opportunity to manipulate

your experiments in space, you know, and do a wide range of different experiments. A lab in space. The dream is a lab in space. Absolutely. You really have an opportunity to play with things and to discover. To me, that, you know, I'm a tinkerer. So that's someone I love to play with different things and get surprises. And I think that's what attracted me to doing this type of research.

We'll be back in a minute with The Lightning Round. Hey, it's Jacob. I'm here with Rachel Botsman. Rachel lectures on trust at Oxford University, and she is the author of a new Pushkin audiobook called How to Trust and Be Trusted. Hi, Rachel. Hi, Jacob. Rachel Botsman, tell me three things I need to know about trust. Number one, do not mistake trust.

Confidence for competence. Big trust mistake. So when people are making trust decisions, they often look for confidence versus competence. Number two, transparency doesn't equal more trust. Big myth and misconception. And a real problem actually in the tech world. The reason why is because trust is a confident relationship with the unknown. So what are you doing if you make things more transparent?

You're reducing the need for trust. And number three, become a stellar expectation setter. Inconsistency with expectations really damages trust. I love it. Say the name of the book again and why everybody should listen to it. So it's called How to Trust and Be Trusted. Intentionally, it's a two-way title because we have to give trust and we have to earn trust.

And the reason why I wrote it is because we often hear about how trust is in a state of crisis or how it's in a state of decline. But there's lots of things that you can do to improve trust in your own lives, to improve trust in your teams, trusting yourself to take more risks, or even making smarter trust decisions. Rachel Botsman, the new audiobook is called How to Trust and Be Trusted. Great to talk with you.

It's so good to talk with you, and I really hope listeners listen to it because it can change people's lives. Let's finish with the lightning round. Do you think you'll go to space before you die? No, I don't think so. You want to go to space? I think if I was younger, I would want to go to space, but I think my time has passed. Okay.

If I understand correctly, you've lived in New Jersey for all of your life or most of your life. What's the most underrated Bruce Springsteen album? I'm not really into Bruce Springsteen. Is there another New Jersey artist of some sort who you want to praise at this moment?

Well, I just listened to an interview by Bon Jovi. Okay. Are you more of a Bon Jovi guy? Yeah, I would say I'm more of a Bon Jovi. And what impressed me is his interaction with trying to solve the homeless situation. And he does a number of charity concerts as well. And that's really impressed me. I didn't know...

That there was this side of Bon Jovi. What's one thing you wish more people understood about space? That there's tremendous opportunity to discover new things, taking advantage of what low Earth orbit laboratories could offer to improving human health. Is there some like dream thing

study you would love to do in space? Like if you weren't constrained by logistics or cost or something, is there some intellectual question you have or a practical question you have that you would love to answer with an experiment in microgravity? That's an interesting question because I think

That would require – I would love to be an astronaut, even though I just told you I didn't want to be one. I would love to be an astronaut and have the opportunity to tinker, I mean to have an opportunity to do a wide range of different experiments.

And, you know, experience them firsthand, you know, and being allowed to do the second generation. Oh, I found this. Wow. Why don't I try this? Why don't I try that? Why don't I try this? You know, I just love that process. And right now you don't have that opportunity to do iterative experiments.

Yeah. So tinkering. I'd love to be able to tinker in space. Maybe you need like a remote control robot, right? You need a lab up on the space station with a robot that you can drive from like a joystick on Earth. I feel like that might do it. Yeah. That would be a step forward. Yes. Seems not impossible. No, it's not. Paul Reichert is a scientist. He works in the Department of Protein and Structural Chemistry at Merck.

Today's show was produced by Gabriel Hunter Chang. It was edited by Lydia Jean Cott and engineered by Sarah Bouguere. You can email us at problem at pushkin.fm. I'm Jacob Goldstein, and we'll be back next week with another episode of What's Your Problem? Sometimes getting better is harder than getting sick. Waiting on hold for an appointment, standing in line at the pharmacy, the whole health care system can feel like a headache. Amazon One Medical and Amazon Pharmacy are changing that.

Get convenient virtual care 24-7 with Amazon One Medical and have your prescriptions delivered right to your door with Amazon Pharmacy. No more lines, no more hassles. Just affordable, fast care. Thanks to Amazon Pharmacy and Amazon One Medical, healthcare just got less painful. Learn more at health.amazon.com.

Hey, it's Jacob. I'm here with Rachel Botsman. Rachel lectures on trust at Oxford University, and she is the author of a new Pushkin audiobook called How to Trust and Be Trusted. Hi, Rachel. Hi, Jacob. Rachel Botsman, tell me three things I need to know about trust. Number one, do not mistake trust.

Confidence for competence. Big trust mistake. So when people are making trust decisions, they often look for confidence versus competence. Number two, transparency doesn't equal more trust. Big myth and misconception. And a real problem actually in the tech world. The reason why is because trust is a confident relationship with the unknown. So what are you doing if you make things more transparent?

You're reducing the need for trust. And number three, become a stellar expectation setter. Inconsistency with expectations really damages trust. I love it. Say the name of the book again and why everybody should listen to it. So it's called How to Trust and Be Trusted. Intentionally, it's a two-way title because we have to give trust and we have to earn trust.

And the reason why I wrote it is because we often hear about how trust is in a state of crisis or how it's in a state of decline. But there's lots of things that you can do to improve trust in your own lives, to improve trust in your teams, trusting yourself to take more risks, or even making smarter trust decisions. Rachel Botsman, the new audiobook is called How to Trust and Be Trusted. Great to talk with you.

It's so good to talk with you and I really hope listeners listen to it because it can change people's lives.