Drug discovery and development
Drugs in space: the pharmacy orbiting the Earth
Researchers are busy developing pharmaceutical solutions for astronauts, but that extraterrestrial research could also have implications for how medicines are delivered on Earth.
For 20 years, the International Space Station (ISS) has hurtled around the Earth roughly 16 times per day at speeds of 8 kilometres per second. In that time, 241 astronauts from 19 countries have boarded — the most recent being those who arrived in SpaceX’s Dragon Endeavour in May 2020. Having the right medicines onboard for these long stints in space, which can last months at a time while complex tests and experiments are carried out in the microgravity environment, is crucial.
Medical kits taken onboard the ISS now contain more than 190 different, frequently used pharmaceuticals. A 2017 study of drug consumption on the ISS showed that each crew member took four medicines per week on average: most commonly analgesics, decongestants and sleep aids.
Resupply missions are a highly choreographed international operation that must be executed with near perfection every time
Replenishing these medical kits is a complex task. A procession of smaller shuttles and spacecraft carrying supplies — including food, water, equipment and medicines — attach to the ISS in a tightly controlled sequence. These resupply missions are described by the National Aeronautics and Space Administration (NASA) as a “highly choreographed international operation that must be executed with near perfection every time”. The delicacy of this procedure was highlighted by the failure of three different resupply rockets during an eight-month period in 2014–2015.
Despite the complexities, the fact that the ISS sits only 400 kilometres from Earth (a distance known as low-Earth orbit [LEO]) makes these regular resupply missions — around eight or nine times a year — possible and keeps the limited pharmacies onboard stocked up. However, NASA’s plans to take manned spacecraft to the moon and Mars in the coming years has forced a rethink; these distances are simply too far for regular resupply missions to work.
“The paradigm of resupplying medicines has shifted drastically,” says Emmanuel Urquieta, a scientist at the Translational Research Institute for Space Health (TRISH), at Baylor College of Medicine in Houston, Texas.
With spacecraft and crew at an average of 225 million kilometres from Earth, resupply missions would be out of the question, requiring onboard pharmacies to hold up to three years’ worth of supplies. At the same time, travel beyond LEO would expose crews and medicines to increased levels of radiation, which could lead to a shift in the types of medical conditions that arise and the ways in which the medicines perform.
Extending shelf life
With no possibility of resupply, the first challenge researchers are grappling with is the shelf life of existing pharmaceuticals. Expiration dates on over-the-counter medicines can be as short as 12 months from the date of manufacture, and they can be even shorter in space, says Urquieta.
Owing to storage limitations onboard, medicines will likely be stripped of all of their bulky outer packaging, including blister packs, reducing shelf life and potential stability, which will be compounded further by increased radiation beyond LEO.
Although how long it takes medicines to degrade after removal of the original packaging is part of ongoing research, it is thought that longer-term exposure to gamma radiation in space could affect the stability of medicines, alter ingredients or potentially lead to the production of toxic byproducts.
You have an environment onboard a spacecraft that is dry with low humidity, which will reduce the shelf life of pharmaceuticals
“On top of that, you have an environment onboard a spacecraft that is dry with low humidity, which will reduce the shelf life of pharmaceuticals too,” adds Urquieta.
One area researchers are looking at that could help combat this degradation is the viability of bio-based coatings. A team at Tufts University in Massachusetts is investigating whether a thin layer of silk proteins applied to medicines could act as a protective shield from exposure to environmental extremes, such as increased radiation. Trials are ongoing as to how this could perform in space, with further results expected by the end of 2020.
Elsewhere, researchers are looking at manufacturing medicines onboard the spacecraft to help reduce the reliance on existing supplies. One possible scenario is 3D printing of medicines, whereby ingredients are sprayed and layered to create the right compounds as and when astronauts need them; an option already being explored by the military.
However, in space, this approach still comes with its challenges. “These machines are really big,” Urquieta explains, “and the spacecraft taking astronauts to Mars will be really small.”
In addition, “the ingredients would also be exposed to the same environmental factors, such as radiation, and could also degrade. That takes you back to square one.”
A synthetic approach
Another strand of pharmaceutical manufacturing — synthetic biology — is the focus of research at TRISH. An emerging discipline, it explores how to modify natural products to create medicines. In other words, it transforms a biological cell into an industrial biofactory.
In theory, Urquieta explains, it would enable astronauts to grow natural organisms that have been gene-edited to produce pharmaceuticals, and all they would need to fit on the spacecraft is a library of modified DNA ready to be inserted.
“It would mean you don’t need to worry about bringing a huge machine onboard, or ingredients that would expire,” he says.
In January 2020, TRISH awarded a two-year, USD 800,000 grant to a project led by chemical engineering professor Karen McDonald, from the University of California, exploring how to genetically modify lettuce so that it can produce medicines in this way.
One trial, led by McDonald, involves genetically altering the plant to produce parathyroid hormone — an approved drug for treating osteoporosis — that would allow crews to respond to the negative impact on bone density resulting from long periods in zero gravity.
The team is also aiming to make this process achievable in a 24-hour period. By creating plants that can be modified to quickly manufacture medicines, the technology could be used to respond to the outbreak of an infectious disease in space.
The hope is that this could be achieved using either a ‘gene gun’, which ‘shoots’ DNA into the plant host, or by infecting plants with genetically modified viruses that are not transmissible to humans, but would replicate quickly in the plant to produce the desired ingredient.
How much lettuce would equate to a 500mg dose of [paracetamol] for a headache?
However, research such as this is only at the proof of concept stage, Urquieta is quick to point out, with many questions yet to be answered: in particular, how the drugs produced would be administered and how the dosages would be calculated.
“For example, how much lettuce would equate to a 500mg dose of [paracetamol] for a headache?” he asks.
“Is it better to purify the lettuce and then extract the medicine? Answering these questions is the next phase of the research.”
At the Langer Lab, at the Massachusetts Institute of Technology, the challenges around dosage and delivery of pharmaceuticals are already being worked on.
The lab has typically focused on finding innovative ways to administer medicines in low-resource settings, such as developing countries in sub-Saharan Africa, explains postdoctoral fellow Miguel Jimenez.
More recently, however, it has begun to investigate how some of its terrestrial solutions for medicine delivery could be adapted for deep space travel.
“There are clear links between low-resource settings on Earth and those you find on long-term exploration missions in space,” says Jimenez.
“Because of their duties to the mission and other pressures on them, astronauts simply can’t be taking multiple pills per day all the time.”
Astronauts simply can’t be taking multiple pills per day all the time
One solution is a drug depot that can be implanted into an astronaut’s gastric system to deliver multiple doses of medicine over a prolonged period of time.
Originally created to deliver antibiotics to patients with tuberculosis, the team is now looking at whether a similar system, which can be adapted for any drug, could be used onboard spacecraft as a way to minimise storage space and treat diseases efficiently.
Again, plenty of questions remain, cautions Jimenez. One that the team has been investigating is whether, given that devices would be self-administered by the astronaut and sit internally, there would be issues with the forces involved in launch and landing. For example, could these forces cause movement of the device that could lead to the rupture of internal organs?
And, of course, there is the overarching question — what medicines might astronauts actually need in long-term space travel and will they work as effectively?
The side effects of space travel
“When humans are exposed to the microgravity of space, all body systems are affected,” says Thais Russomano, co-founder and chief executive of InnovaSpace, a global space life science and telehealth consultancy firm. The sudden shift to a microgravity environment leads to space motion sickness in 70% of astronauts in the first 72 hours of a mission, for example.
“Bones and skeletal muscles that are no longer required to support the weight of our bodies lose their mass,” she adds. “The immune system seems to become less active in microgravity with changes in stress hormonal levels, and the cardiovascular and respiratory systems adapt by redistributing blood and fluids from the lower to the upper body and decreasing its plasma volume and heart size.”
These are just a few of the physiological side effects she lists, and all could be exacerbated in deep space (see Figure).
Figure: The side effects of space
Source: NASA; BBC
One solution being explored by researchers at Michigan State University is an algorithmic tool that monitors each astronaut’s physiological changes using digital inputs and biometrics, to track their health and, in doing so, make precise predictions on what medicines they might need in advance.
However, research into how these medicines will then perform is less common, says Marlise Santos, space pharmacy and telepharmacy lead at InnovaSpace. The last study to explore the relationship between pharmacokinetics and space travel was in 2009, she points out, and it only looked at the absorption of paracetamol under space flight conditions.
Little is known as to whether or not these drugs are metabolised, absorbed and secreted in the same way in microgravity
“No other pharmacokinetic study has been carried out since then. Therefore, we really need a greater number of experiments to be performed so a better understanding and knowledge can be gained of the effect of drugs in space,” she says.
“The dose and dose intervals of medications given to astronauts during spaceflight currently follow the same regimens as prescribed on Earth,” Russomano adds. “However, little is known as to whether or not these drugs are metabolised, absorbed and secreted in the same way in microgravity.”
“Research on medicines in space has been ongoing for more than 40 years; however, many questions remain unanswered and there are still many challenges to overcome,” Santos notes.
And these questions have become distinctly more urgent with the prospect of astronauts travelling to Mars within our lifetime. But it is not only astronauts that will benefit from space medicine.
What could all this mean on Earth?
Experimentation in space is costly and difficult to secure investment for, Santos explains. “It is often difficult for investors to understand just how much space science can contribute to life on Earth.” However, there are many ways in which space and pharmaceuticals on Earth intersect.
For example, several tools have been developed to treat cancer by making use of the microgravity environment onboard the ISS, in which people or objects appear to be weightless. One advancement has been the discovery of a process called ‘microencapsulation’, by which drugs are held within liquid-filled biodegradable micro-balloons, enabling them to be delivered to specific treatment sites in a patient with cancer.
The microgravity environment on the ISS allows liquids that would not usually mix on Earth to combine and spontaneously form tiny spherical liquid-filled bubbles surrounded by a semipermeable outer membrane. Studying the samples upon return to Earth can help scientists to understand how to create the same microcapsules on Earth.
The microgravity environment has also helped to speed up the development of several therapies now used on Earth, including vaccinations against Salmonella and methicillin-resistance Staphylococcus aureus (MRSA).
The microgravity environment has helped to speed up the development of several therapies now used on Earth
In 2018, US company Angiex began developing a drug onboard ISS that could destroy blood vessels in tumours. In a microgravity environment, blood vessels do not grow as well as they do on Earth, making the results more potent and speeding up development.
Finally, the crystallisation of proteins is a key element in terrestrial drug development. Researchers have found that crystals grown in space have fewer imperfections than those on Earth – and experiments are ongoing to study this process and potentially use it for faster drug development on Earth.
Urquieta also believes that manufacturing and delivery mechanisms for pharmaceuticals that could operate in space travel could be used in combat scenarios or under-served communities.
He gives the example of synthetic biology: “We know how expensive it is to have a factory that produces pharmaceuticals … [but] manufacturing via synthetic biology doesn’t require a huge facility.”
It could simply be used anywhere; it is possible to grow gene-edited fruits and vegetables “producing pharmaceuticals at a comparable cost”.
“I absolutely think this work has terrestrial applications,” he says.
Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2020.20208033
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