Credit: NASA/Roscosmos | The International Space Station suspended over planet Earth, as photographed by the Expedition 56 crew after undocking.
The lack of gravity in space opens up unique opportunities for drug design and development. With the influx of commercial entities providing access to low-Earth orbit, both the discovery and manufacture of drugs in space may one day become practical, affordable—and, perhaps, commonplace.
Researchers usually take gravity for granted, but its impact on scientific experiments is profound. Without gravity, convection—the rise of warmer, less-dense fluid above colder, denser fluid—shuts down. Sedimentation is no longer possible. Buoyancy becomes irrelevant. Diffusion is the only way that molecular heat and matter can get around. In living things, the lack of an up or down can upend biochemistry. This is because life on Earth has only ever adapted to the planet’s gravitational pull since the first organisms appeared 4 billion years ago.
Gravity’s influences on experiments might not seem worth pondering given that it is omnipresent on Earth. But with space as an experimental setting, gravity can be another variable that scientists can toggle on and off.
Researchers from academic institutions and the pharmaceutical industry have been conducting biomedical research in the inhospitable environment of space, ironically, to create therapies that can improve health back on Earth. Even drugs for COVID-19 have taken a spin in orbit. In late 2020 and early 2022, the company InnoStudio flew its experiments to the International Space Station (ISS) to see whether microgravity could help improve the stability of Gilead Sciences’ antiviral remdesivir to increase the efficiency and reduce the risk profile of the drug formulation.
“That was one of the very first experiments with anti-COVID drugs in space,” InnoStudio founder and executive chairman Ferenc Darvas says. He calls science’s spaceward trend “necessary.”
Despite space’s far-flung location and all the logistic hurdles that come with accessing it, research groups line up to do experiments there. Studies done in microgravity often yield surprises that can advance scientific understanding of natural phenomena back on Earth. But for those in the pharmaceutical industry, space could offer more than fundamental findings.
The drug industry is experiencing a surge in biologic medicines, a class of bulky, biobased pharmaceuticals that includes enzymes, nucleic acids, and antibodies. These drugs usually have intricate structures and involved processing steps. A low-gravity environment has several advantages that can accelerate the discovery and preclinical testing of these complex molecules.
At the same time, the rising demand for the unique environment of microgravity is encouraging commercial entities to provide relevant services for accessing low-Earth orbit. The ISS is scheduled to retire in less than a decade, but a boom of private space providers is emerging to mark a new era for science in space, one in which companies are betting that even drug manufacturing in space can be scalable and cost effective.
Astronauts have been conducting scientific research in space since the early days of spaceflight. In the 1970s, experiments aboard Russia’s Salyut stations and the US’s Skylab included many studies in biomedicine, which focused on the physiological impacts of human spaceflight, the biological mechanisms of those effects, and lifestyle interventions to counter them. When those space labs retired, research continued aboard shuttles that afforded days of microgravity exposure at a time. In the 1990s, the launch of the Shuttle-Mir space station program facilitated longer-duration research in orbit for experiments that included the chemistry and pharmacodynamics of drugs under weightlessness. This program paved the way for the construction of the ISS. The ISS—a research facility that’s as large as a US football field and assembled from US, European, Russian, Canadian, and Japanese modules—has continuously housed humans in orbit since it first opened its hatches in 2000.
All the shuttles and stations occupy low-Earth orbit, so they are close enough to Earth that they are still subject to approximately 90% of the planet’s tug. But they experience near weightlessness because objects in orbit are in a constant state of free fall. For example, zipping 28,000 km/h, the ISS plummets toward Earth at the same speed that Earth’s round surface curves away from beneath it.
Companies and academic institutions submit proposals through space agencies such as NASA and the European Space Agency to get spots for experiments on the ISS. Those who are accepted are then paired up with experienced companies called implementation partners to adapt their experiments for space.
The competition to use experiment facilities on the ISS is fierce. As booked up as the facilities and resources are, though, research for drug discovery and development has always found a home on the ISS.
“Part of our mission managing the International Space Station National Lab is to enable access to space for research and technology development that benefit those here on Earth," says Michael Roberts, chief scientist of the ISS National Laboratory.
Behind many diseases are proteins gone awry. Proteins are complex macromolecules with precise and intricate structures that dictate what other molecules they bind to. Identifying a protein’s structure is usually the first step toward designing drugs that can interact with it. To obtain this information, scientists typically crystallize the protein into an ordered array in the same way that atoms order themselves in a crystal lattice. The crystal can then be analyzed with X-ray diffraction to determine the individual protein’s structure.
Protein crystallization is a finicky process that requires tightly controlled conditions. The process involves slowly coaxing a supersaturated solution of dissolved proteins to form solid crystals. The quality and size of these crystals are dictated by the experimental conditions, and many proteins don’t crystallize well in a typical lab.
Thanks to microgravity, space-grown protein crystals are often larger and have fewer defects than those prepared on the ground.
“You’re removing convective and sedimentation forces that are acting upon the molecules on Earth,” says Robert Garmise, a principal investigator at Bristol Myers Squibb (BMS) who is leading his company’s research efforts in space. “Those forces could influence the way that the protein is moving in solution. So by removing those forces, you can actually get better, more-uniform crystals that can grow to larger sizes.”
Protein crystallization was one of the earliest experiments conducted in space. According to the ISS publication International Space Station Benefits for Humanity 2022, over 500 experiments on protein crystal growth have been conducted on the station, making them by far the largest category of experiments run on the ISS. Companies are part of this niche domain of research. Merck & Co. has crystallized proteins in space since the early 2000s, and Garmise says that BMS added crystallization experiments to its list of experiments on the ISS by 2017..
“I think now [the field has] matured to the point where we understand where there are some real advantages to protein crystal growth that will generate large health benefits here on Earth,” the ISS’s Roberts says.
Space has allowed research groups to narrow the conditions for crystallizing particularly persnickety proteins. Proteins such as insulin and interferon-signaling proteins were crystallized in space in the early days of space experimentation, which led to a better understanding of their structures. The Japan Aerospace Exploration Agency (JAXA) has conducted protein crystallization experiments since the ISS set up shop. A JAXA-led study parsed the structure of key proteins associated with Duchenne muscular dystrophy, allowing researchers to design treatments for the genetic disorder. One of the drug candidates, Taiho Pharmaceutical’s TAS-205, is now in Phase 3 clinical trials.
For one company, the Cambridge, Massachusetts–based biotech MicroQuin, a single crystallization experiment run in space kick-started an entire drug pipeline centered on one versatile class of targets. The company develops therapeutics targeting transmembrane BAX inhibitor motif–containing proteins. This family of proteins called TMBIMs helps regulate a cell’s internal environment and its eventual death.
Transmembrane proteins like TMBIMs are notoriously difficult to crystallize. They’re commonly insoluble because they’re made up of a patchwork of hydrophilic and hydrophobic domains. They tend to precipitate out of buffer solutions, so they need lots of cajoling to stay put. It’s challenging to grow TMBIM proteins into crystals, let alone into solids large enough for protein structure identification. “Transmembrane proteins are a nightmare,” says Scott Robinson, MicroQuin’s president and chief scientific officer. “But if you send them to space, you can circumvent a lot of those problems.”
In 2018, the company won a spot on the ISS National Lab and Boeing–funded MassChallenge accelerator program to crystallize the TMBIM6 protein on the ISS the following year.
Microgravity was vital for the crystallization process because it reduced the formation of concentration gradients in the supersaturated protein solutions. For example, under normal gravitational conditions, the protein concentration in a typical 1 M solution may vary from 0.95 M at the top of an Eppendorf Tube to 1.05 M at the bottom, Robinson says. “Whereas in microgravity, this might be 0.999 and 1.001. It’s subtle.” The pockets of slightly higher concentrations in solutions on Earth can tip proteins toward aggregating haphazardly instead of forming tidy crystals.
MicroQuin’s experiment on the ISS paved the way for its researchers to obtain the structures of the TMBIM6 protein in multiple conformations. Armed with this structural data, the scientists designed molecules that could slot onto active TMBIM6 present in cancer cells but leave the inactive proteins in healthy cells alone.
“As far as we know, we’re the only group in the world that has that structural information” for TMBIM proteins, Robinson says. “The work on the ISS has probably saved us another 5–8 years.” Since the experiment in 2019, the company has developed drug leads that target TMBIM proteins to treat ovarian and breast cancers as well as traumatic brain injury, and it’s eyeing other TMBIM-associated disorders for future targets.
Plenty of companies are using space for protein crystallization, although they may need several experimental rounds to land on the right conditions. In late 2020, BMS experimented with 12 protein crystallization conditions on the ISS for an undisclosed monoclonal antibody, but all of them failed to produce useful crystals. Such failure is common in research, including that done on the ISS. But given the long queue for spots on the station’s roster of experiments, it won’t be easy to do follow-up studies. Still, Garmise says the company hasn’t ruled out trying again in the future.
The pharma giant has had better success with other crystallization experiments in space. One of its drug candidates, another undisclosed monoclonal antibody, crystallizes into fine needles on Earth. This shape tends to clog filters during processing. When Garmise’s team cultivated the same crystals on the ISS, the researchers obtained pom-pom-shaped structures—a promising start toward the goal of growing more spherical shapes, which would reduce the clogging problem.
The team hasn’t been able to re-create those shapes on Earth, but space gave the researchers “a good understanding of what types of forces are acting on our molecules,” Garmise says, which may affect the crystallization of those compounds.
Gravity may also influence the overall distribution of the sizes and shapes of crystals that pop out from their supersaturated solution This distribution dictates the suspension’s fluid properties, which may in turn make or break the drug delivery process—how easily a drug can be injected, for instance. BMS is among several companies trying to better understand and control this crystal formation to improve drug delivery.
Producing protein crystals in space to formulate them into a drug suspension may give them more desireable properties than those of their Earth-made counterparts. The poster child for drugs that have benefited from an extraterrestrial rendezvous is Merck & Co.’s cancer drug pembrolizumab, or Keytruda. The monoclonal antibody is one of the world’s best-selling drugs for its effectiveness in treating various cancers. But, like many biologics, Keytruda has to be administered intravenously as a solution in the clinic. Merck has been exploring whether the drug can be reformulated into a subcutaneous injection for self-administration at home.
In such a formulation, the drug must be much more concentrated while maintaining a low enough viscosity to pass through the syringe needle. Dissolved protein solutions may take on a syrupy consistency at high concentrations. Fine crystal suspensions might be more suitable for injections, as they can carry high levels of the proteins yet stay sufficiently runny.
Merck’s scientists realized that space might be a good place to narrow down the crystallization conditions for making Keytruda into an injectable formulation.
In 2017, Keytruda boarded its first flight to the ISS. The preliminary results were promising: the crystals in suspension that were made in microgravity were smaller on average and had more homogeneous sizes than those on Earth.
“We looked at the viscosity and the injectability properties, and we found that the smaller, more-uniform-population crystals that we got in microgravity were clearly better,” Merck principal investigator Paul Reichert says.
He and his team are completing their analysis on their latest protein crystallization experiment, which returned from space earlier this year. Should Merck choose to reformulate Keytruda into a crystalline suspension, Reichert says that the company will probably look to replicate on Earth the ideal crystallization conditions his team found in space.
It’s fairly simple to understand what happens in a flask in a microgravity environment. But the picture is much less clear when it comes to how microgravity wreaks havoc in cells, tissues, and entire organisms. “In crystallization, you’ve only got, like, five chemicals going on,” MicroQuin’s Robinson says. “In the cell—whew! It’s complex. It’s got millions of things going on.”
Experiment facilities on board:
Research investigations to date:
Experiment-carrying expeditions to the ISS to date:
Scientists have known that spaceflight is hard on the body since the early days of space exploration. Astronauts have exhibited signs of accelerated bone and muscle loss, a weakened immune system, and altered gene expression after a sojourn in space. Researchers are still investigating the mechanisms for these sweeping changes. In the meantime, drug developers are already exploiting the biological shifts triggered by space for pharmaceutical testing.
Since many of the symptoms of space travel resemble the effects of aging, drug developers have used space to test their aging-related treatments in cell cultures, tissues, and animals. Scientists can save time, as they don’t have to wait for these specimens to age naturally back on Earth before testing.
Amgen ran preclinical trials of two osteoporosis drugs, Evenity in 2011 and Prolia in the early 2000s, on mice in microgravity. The data helped the company strengthen its new drug applications and cases for approval by the US Food and Drug Administration for both therapies. In 2016, Eli Lilly and Company dosed mice with a muscle-boosting antibody before their trip to the ISS, and the researchers found that the treatment preempted space’s atrophying effect on muscles.
In other tests of cell growth, researchers have found that stem cells can grow more rapidly in space. Biologist Chunhui Xu of Emory University is in the midst of conducting a series of spaceflight experiments to study how space triggers this boost. She hopes to replicate the effects back on Earth one day. Such capabilities would be valuable for treating heart failure as the blood-pumping organ has poor regenerative capabilities. Xu estimates that up to 1 billion cells are needed to replace scar tissues in a damaged heart. Space might help make stem cell therapy more practical if scientists like Xu can unlock microgravity’s secrets and re-create its proliferative effects on stem cells on terra firma.
Space poses logistic hurdles to researchers who want to access it. For one, there’s not a lot of experiment space in space—today, there’s only the ISS, which is staffed with only seven or so astronauts running all the experiments on board at any given time.
Access is an issue. Launching experiments using SpaceX’s shuttles costs $1,500–$300,000 per kilogram of payload, depending on the fraction of the cargo weight each experiment takes up per mission, although government agencies are often the ones footing the bill.
Researchers prepare for several years for each experiment, revising procedures, doing test runs, miniaturizing hardware, and mercilessly pruning their experiments to reduce the payload weight.
After every experiment in space, “you always end up with more questions,” says Abba Zubair, a clinical pathologist at the Mayo Clinic in Florida. But, he adds, it takes at least several years to return to space for another go. He led a research effort on mesenchymal stem cells on the ISS in the late 2010s.
There are ways to accelerate follow-up research, or bypass the need to go to space altogether in the first place. Researchers can turn to more accessible albeit imperfect alternatives that mimic microgravity, such as short-term parabolic flights to provide their experiment payloads minutes of weightlessness. Another option for solution-based experiments is random positioning machines that tilt vials in all directions and scramble gravity’s relative direction.
For those who have the privilege of sending their experiments to space, research in microgravity has traditionally been regarded as only a means to an end. Because of the ISS’s limited space, most studies are aimed at finding new insights that can be put to use in labs on Earth.
But with the rise of space commercialization, pharmaceutical manufacturing in microgravity is looking more feasible. Although the ISS is set to retire by 2031 (Russia alluded to an early withdrawal once it finishes building its own station), private companies are already taking steps to fill this service vacuum.
NASA, which works with four other space agencies to manage the ISS, has signed agreements with Blue Origin, Northrop Grumman, and Nanoracks to build commercial stations that will launch straight from Earth into orbit. Another company, Axiom Space, is building a station off an ISS docking port that will detach when construction is complete. Private companies and NASA argue that the entry of commercial players will democratize space access for research. Commercialization may also lower costs, as corporations such as SpaceX have reduced the prices of orbital transportation.
NASA hopes to transition from the role of space station operator to customer. “It will relieve NASA of some of the expense of owning and operating one of the only laboratories in space,” Roberts says.
Several companies plan to offer in-space manufacturing services, and at least one has a pharma focus. Redwire, a space infrastructure company, has parked research equipment on the ISS and reserved berths on new commercial stations. Among the services it will offer is growing batches of protein seed crystals in space that companies can use to cultivate large, high-quality crystals back on the ground. Redwire is partnering with Lilly to validate its manufacturing technologies.
“The ultimate hope is that we can do large-scale manufacturing in microgravity,” says John Vellinger, Redwire’s executive vice president for in-space manufacturing and operations. He calls the coming commercialization era “the second golden age of space.”
One group has toyed with the idea of a stem cell factory in space to make cell therapies more practical. Given experiments suggesting that stem cells proliferate more quickly in microgravity than on Earth, researchers at Cedars-Sinai Medical Center hypothesize that space would allow for a more efficient and scalable pipeline for supplying stem cells for the clinic. Earlier this year, the researchers announced that they would partner with Axiom to establish methods for the mass production of stem cells in space.
For at least one company, space manufacturing may be a necessity. LambdaVision, which fabricates artificial retinas intended to restore vision in people who are blind, is taking advantage of microgravity to deposit atoms-thick protein films on a polymer membrane. The manufacturing process can take up to a week. On Earth, tiny convection vortices, minute concentration gradients, and sedimentation effects may interfere with the films’ homogeneity. And since the protein films are so thin, traditional manufacturing processes under normal gravity conditions just won’t cut it.
“There’s unfortunately no way to replicate the microgravity environment, at least for the long-term needs that we have,” says Jordan Greco, the chief scientific officer of LambdaVision.
The biotech has sent six experiments to the ISS to date and has a seventh one slated for the end of this month. The first several were for refining the hardware for an automated deposition process. The company is still analyzing microgravity’s full impact on the films produced on the most recent spaceflight. But given the success of protein crystallization in space, LambdaVision is optimistic that microgravity will similarly boost its film quality.
Economic considerations aside, perhaps there’s a simpler reason for the rising popularity of space experiments: space is cool. Researchers who have the opportunity to fly their experiments to space often describe a sense of wonderment from knowing that their research is in orbit. While most scientists won’t get to visit the inky void themselves, their experiments will, and that knowledge, they say, is satisfying.
For their first ISS experiment, Greco and his colleagues at LambdaVision headed to the Kennedy Space Center in Florida to watch the launch of the SpaceX rocket ferrying their protein film project. It was an experience Greco says he will never forget: “To see that rocket go up and know your research is on there was just an incredible experience—an incredible feeling.”
This story was updated on Nov. 18, 2022, to note that Bristol Myers Squibb’s protein crystallization research on the International Space Station began by 2017. The company did not begin these experiments on space shuttles in the 1990s. The story was also updated to remove the NASA affiliation from Michael Roberts’s title of chief scientist of the International Space Station National Laboratory.
This story was updated on Nov. 18, 2022, to add that Merck & Co. had protein crystallization experiments in space by the early 2000s.