On a cool December afternoon in 2018, on a viewing platform at the Kennedy Space Center at Cape Canaveral in Florida, Jordan Greco watched his research project leave planet Earth. As chief scientific officer of the Connecticut-based biotech LambdaVision, he had spent years developing a protein-based artificial retina to treat patients blinded or severely visually impaired by retinal degenerative diseases. At 1:15 PM that day, a Falcon 9 launch rocket lit up the sky as it blasted the SpaceX Dragon cargo spacecraft toward the International Space Station (ISS), carrying onboard the proteins that make up Greco’s artificial retina.
“It didn’t really hit me until we were sitting on the balcony at the NASA complex and seeing that rocket off in the distance,” Greco recalls. “Our protein, our experiment that we’ve been working on for years, is on that thing.”
Once the SpaceX capsule docked at the ISS, an astronaut in the station’s near-weightless environment was to initiate an experiment that Greco hoped would help him understand how to improve the artificial retina’s function. Back on Earth, he and his colleagues had been making progress with the retina—essentially a small film covered in hundreds of layers of the microbial light-activated protein bacteriorhodopsin—but were struggling to produce consistently high-quality retinas.
The team suspected that the bacteriorhodopsin proteins should be oriented the same way with respect to one another for the artificial retina to create robust electrical signals and communicate effectively with patients’ neurons. But the team’s process of dipping the film into protein solutions seemed to generate somewhat disordered protein arrangements. Greco suspected that gravity was negatively affecting the layering process—for instance, by causing the proteins in the solution to undergo sedimentation, he explains. To test that hypothesis, he and his colleagues sent materials to the ISS to repeat part of the experiment in microgravity.
Microgravity influences scientific experiments in many ways that appeal to drug developers.
Scientific research in space has thrived over the past decade, but it’s only recently that the pharmaceutical and biotech sector has started getting in on the action, pursuing new ways to study drugs and other medical treatments. Pharma giants including Merck, AstraZeneca, Eli Lilly, and Sanofi, along with dozens of smaller companies, have all sent experiments to the ISS to reap the unique benefits of microgravity. Of the 150 or so life science research projects supported in the 2019-2020 fiscal year by the Center for the Advancement of Science in Space (CASIS)—a nonprofit that collaborates with NASA to manage the US National Laboratory on the ISS—more than a third have been led by pharmaceutical and biotechnology companies, says CASIS’s interim chief scientist, Mike Roberts.
Such endeavors could one day help improve astronaut health and equip humanity for longer ventures into space, but their primary aim is to develop or improve drugs for people on Earth. That’s certainly the hope of Greco and his colleagues, who found out a few months after that December afternoon that, as they’d hypothesized, the proteins layered in space appeared to have more-orderly arrangements—an improvement that could benefit the artificial retina’s function.
Studies such as these have yet to yield new blockbuster drugs or even significant improvements to existing ones. Research in space is slow, and the costs are sky-high. All projects are subsidized through NASA, and many rely on additional financial support through federal grants, spurring a new kind of space race—one aiming to prove that such projects are profitable enough for the private sector to fund on their own. “Overcoming that 1G gravitational pull to get rockets up to low Earth orbit or beyond is expensive still,” says Roberts. But even so, “we’ve seen a significant uptick in interest” in conducting experiments in space.
The benefits of microgravity
While microgravity can be achieved for a few moments on an aircraft rounding the top of a parabolic flight, or simulated imperfectly in bioreactors on Earth, the best way to conduct experiments under sustained microgravity is to go to the ISS. The station orbits approximately 400 km from the planet’s surface and is close enough to Earth to experience about 90 percent of its gravitational pull, but astronauts aboard the station feel nearly weightless because it’s in constant free fall around the planet.
The resulting microgravity conditions in this setting influence scientific experiments in many ways that appeal to drug developers. There are minimal convection currents in fluids, for instance, and hardly any sedimentation—conditions advantageous not only for LambdaVision’s layering procedure but also for processes such as protein crystallization, whereby proteins form a regular array. Under near weightlessness, “you get a [higher-quality] crystal than [what you’d get through] the crystallization process on Earth,” making certain proteins easier to study and more attractive as drugs, explains Marlise dos Santos, an aerospace pharmacy specialist at InnovaSpace, a UK-based think tank that promotes life science in space, among other activities related to extreme environments.
Paul Reichert, a research scientist at Schering-Plough and at Merck after their merger, was one of the first in the pharmaceutical industry to recognize the value of near weightlessness for protein crystallization. In the 1990s, before the ISS was operational, he collaborated with NASA to send interferon alfa-2b, the active ingredient in the company’s antiviral and cancer drug intron A, into low Earth orbit on the Space Shuttle to see if it would crystallize in space. Upon studying the product that was returned to Earth, Reichert noticed that the protein had turned into small crystals with perfectly uniform size—the kind that would be ideal for drug delivery.
Although the crystallized interferon alfa-2b was never commercialized, Reichert has conducted similar experiments on the ISS with the monoclonal antibody pembrolizumab, the key ingredient in Merck’s popular oncology drug Keytruda. Because antibodies aren’t very soluble under standard conditions, treatments such as Keytruda tend to form viscous solutions at high concentrations and need to be delivered in burdensome, lengthy, and regular intravenous infusions. If pembrolizumab took the form of a compact crystalline suspension, however, it could be deliverable as an injection, Reichert explains. In his most recent experiment, published in npj Microgravity, he and his colleagues found that cooling pembrolizumab on the ISS yielded “a uniform population of particles [that] actually gave a better injectability profile than the heterogeneous population of crystals that we got on Earth,” Reichert says.
Eli Lilly has also sent its products to the ISS to be crystallized, in this case to make them easier to study structurally using analytical techniques such as X-ray diffraction. The company has also flown mice to the ISS to test an experimental drug that boosts muscle growth. Under microgravity, the loss of physical
strain on bone and muscle accelerates the natural onset of common musculo-skeletal diseases in rodents, making them ideal models of such human conditions, explains Jeremy Hinds, a senior research scientist at Lilly. In addition, Hinds is studying whether near weightlessness affects the process of freeze-drying materials, a common step in drug distribution and storage. Microgravity “could have positive outcomes on the physical properties and resulting drug product performance,” he explains in an email to The Scientist.
CASIS, which selects the research projects that go to the US national lab on the ISS and provides companies with logistical support, is also working with a number of smaller companies studying everything from treatments for rare diseases to medical devices. One such company is MIT spinout MakerHealth, which has spent nearly a decade creating a device that can produce a number of personalized pharmaceuticals on demand. A mission is slated for 2021 to carry the device’s mechanical reactors to the ISS, where they’ll produce some simple compounds in space. Engineer Jose Gomez-Marquez of MIT’s Little Devices Lab who helped develop the device says the experiment could not only show that it’s possible to make drugs in space—a prerequisite for humanity’s future ventures into outer space—but also help his team understand the typical gravitational constraints on the device’s function and how they can improve it further: “It’s a fundamental physics question.”
Challenges in space research
While research and development in space is well underway, progress has been slow, says Reichert. “We’re still in the infancy of doing this kind of work.”
Many of the challenges are logistical. Only six astronauts are stationed on the ISS; their time for experimental work is limited, and basic laboratory tasks such as pipetting and moving reagents around are challenging in microgravity. That’s in part why pharma entities and biotechs typically contract companies that specialize in automating scientific experiments and packing them into flight-ready “cube labs,” which astronauts simply need to activate to have the experiments conduct themselves. LambdaVision, for instance, worked with the microgravity research company Space Tango to turn their 2018 layering experiment and a more recent study of how bacteriorhodopsin functions under microgravity into miniature labs.
The downside of such arrangements is that researchers are often limited to one experiment at a time, and results can be a long time coming, Reichert says. “The astronaut just activates the experiment that sits there for two to three weeks, and then it comes back on a Dragon SpaceX module a month later, and then we first see what the results are.”
Doing research in space comes with a host of other challenges as well, such as organizing simultaneous control experiments on the ground, and adapting research methods to the nonstandard laboratory equipment on the ISS. For Paul Jaminet, founder and president of the Massachusetts-based oncology startup Angiex, which undertook an experiment on the ISS in 2018, the endeavor “turned out to be significantly more work than we thought it would be.” The company’s experiment showed that endothelial cells’ response to one of the company’s cancer drugs changed over the course of their time on the ISS, and that the cells generally grew and behaved differently in space than on Earth. In particular, the cells displayed unique characteristics that Angiex founder and head of research Shou-Ching Jaminet tells The Scientist could mimic certain features of cardiovascular conditions afflicting humans on Earth. The husband-and-wife team is interested in continuing that line of research, but due to the amount of labor, time, and money involved, it’s taken a backseat to the company’s work on drug candidates and other projects that are further along.
Researchers are often limited to one experiment at a time, and results can be a long time coming.
The biggest challenge is indeed the sheer cost of space experiments. Getting a single experiment to and back from the ISS can cost some $7.5 million, according to CASIS. Currently, flights to and from the ISS and astronaut time are covered by NASA, and the hardware and research costs of such experiments are sometimes partially funded through federal grants. Some smaller companies, including MakerHealth, Lambda-Vision, and Angiex, financed their endeavors with six-figure microgravity research grants awarded by a partnership between CASIS and Boeing through the Boston-based business accelerator program MassChallenge.
These generous subsidies and incentives are part of a long-term effort by NASA to coax private companies to recognize the value of R&D in space. In addition to bringing benefits to people on Earth, companies ideally would ultimately pay for their own research and help the US National Laboratory on the ISS become self-supporting. However, a 2018 report by NASA’s Office of the Inspector General criticized CASIS for failing to recruit enough commercial users to the space station, and “question[ed] whether a sufficient business case exists under which private companies will be able to develop a self-sustaining and profit-making business [on the ISS].”
That’s broadly in line with an analysis by Nicholas Vonortas, a microeconomist at George Washington University who received a NASA grant in 2015 to conduct a cost-benefit analysis of using protein crystallization on the ISS to get better structural information about peptides. Through economic models that considered the risk of experiments failing, among other factors, Vonortas found that the potential financial benefits of crystallizing proteins on the ISS will likely not be enough to outweigh the costs if they’re shouldered by the private sector alone. “All of this together, when you do the calculations, brings a result that is not as attractive as the scientists think,” he tells The Scientist.
Space pharmacy ahead?
Costs may decrease over time as travel to and from the ISS becomes more frequent, Vonortas says. Entrepreneur Elon Musk, for instance, has said he wants to establish a more regular service to the station than there is currently—an idea not without its skeptics. But a significant source of uncertainty is that the ISS, after more than 110,000 laps around the planet, may be nearing the end of its life. NASA and other participating space agencies plan to continue operations through 2024, but what happens after that is unclear.
Instead, pharma research of the future may take advantage of independent initiatives developed by a growing community of companies working to make conducting experiments in sustained microgravity cheaper, faster, and more accessible for life scientists. For instance, the Israeli-Swiss company SpacePharma, founded in 2011, develops autonomous research stations that can be operated from the ground. “Until now, unless you were part of NASA or some space agency, it was very difficult to initiate and perform such experiments” in space, says Guy Samburski, SpacePharma’s director of chemical and pharmaceutical applications.
The company recently launched the satellite DIDO 3, carrying four experiments by Italian and Israeli researchers on board, all packed into a milk carton–size box. The satellite won’t return to Earth, but is currently recording and transmitting research data back to scientists on the ground. SpacePharma’s next launch will involve a larger system that will eventually return home so researchers can physically collect materials and results. British spaceflight company Virgin Galactic and Jeff Bezos’s space company Blue Origin have also begun to offer such opportunities to scientists.
The emergence of an entire ecosystem devoted to bringing pharmaceutical research into space has opened up new possibilities to those in the industry. “Could we have space labs in the sky that can operate autonomously and discover new lifesaving medications for us?” Gomez-Marquez asks. And while the return on investment currently isn’t ideal, many believe such research will become profitable over time. Eventually, “[it] might be financially beneficial for a company to have things produced or manufactured in space,” in the same way we outsource drug production to different countries on Earth, suggests Thais Russomano, a space medicine expert and cofounder and CEO of InnovaSpace. In fact, LambdaVision is already considering launching production of its artificial retina in space, encouraged by the potential superiority of space-made products.
Whether such visions become reality, only time will tell. “If you’re asking me whether this is possible—absolutely, this is technically possible,” Vonortas says. But “the economics is a problem.”