Orthopedic surgeon Chia Soo and her husband, orthodontist Eric Kang Ting, were both working at the University of California, Los Angeles (UCLA) when they realized their research on bone development might find a home in space.

National Aeronautics and Space Administration (NASA) Deputy Director Julie Robinson visited UCLA during her tenure as NASA Chief Scientist to speak about research on the International Space Station (ISS). “It was like a revelation,” said Soo. “She talked about how it's possible for normal people to work with NASA [and] have the astronauts carry out their studies. There's a lot of hoops you have to jump through, but it's possible.” 

Soo and Ting quickly applied for and won a grant with the Center for the Advancement of Science and Space (CASIS) to test a molecule that they had developed to treat loss of bone density, a common aftereffect of long-duration human spaceflight (1). Their findings published in npj Microgravity offer a new potential treatment for bone loss, both in space and here on Earth (2). “We hope that one day [our treatment] could be used to keep humans in space healthier in that when they do go to an environment with gravity, they don't experience the significant effects [like] bone fragility,” said Soo.

Soo and Ting have spent the majority of their decades-long careers researching and treating craniofacial anomalies in children. In the 1980s, Ting studied unilateral coronal craniosynostosis, where half the skull develops normally while the other half develops bone prematurely (3). In examining the differences in gene expression between the two halves of skull samples with this condition, Ting found the healthy half expressed more Nell-1, which codes for a protein that regulates cell differentiation. “[Ting] was the first one in the world, actually, to figure out that Nell-1  was involved in bone growth,” said Soo. 

Ting’s discovery led to years of studying rodent models to evaluate Nell-1's effects on bone growth. They eventually found that injecting the human recombinant NELL-1 protein lessened osteoporosis and restored bone loss in several animal models (4). 

With the CASIS grant in hand, Soo and Ting decided to test whether the addition of NELL-1 also affected bone loss in mice in space. However, this treatment with “NELL-1 alone” required an injection every two days. According to Soo, this was their first challenge in getting their experiments to space. “We got project specifications from NASA or the International Space Station that, ‘Well, no, the astronauts only have time every two weeks, and they can't be trying to cannulate a little tail vein when things are floating around in space,’” said Soo. 

To make the recombinant NELL-1 last longer in the bloodstream and reduce the frequency of injections, the pair reached out to then UCLA bioengineer Benjamin Wu, a coauthor of the study. Wu added a polyethylene glycol (PEG) modification that tripled NELL-1’s half-life and an inactivated bisphosphonate moiety (BP) that specifically targeted the bone. They first confirmed in a mouse model on Earth that the newly modified NELL-1 (BP-NELL-PEG) improved binding to the bone mineral hydroxyapatite, increased markers for bone cell differentiation and development, and decreased markers for osteoclast activity — bone degradation. They were then ready to send BP-NELL-PEG and rodent models to space.

“We remember launch day vividly,” said Soo. Their initial launch day was canceled due to overcast weather, which their labs had prepared for by raising multiple cohorts of mice so that they wouldn’t age out. A couple days later, the sky cleared, and they watched their animals go up in a SpaceX rocket ship. “It was the coolest thing in the world,” said Soo. “We’re still pinching ourselves that it really happened.” 

Astronauts Peggy Whitson and Jack Fisher injected BP-NELL-PEG into the space cohort of mice every two weeks for nine weeks and scanned the mice while another team performed parallel experiments on the ground at the Kennedy Space Center. Soo recalled an elaborate setup that NASA Ames had built, both to keep the mice in place in microgravity and to keep them safe throughout the spaceflight and during landing.

The animal cohort of the study was the first live return of this size, and the team had veterinarians on hand for when the mice returned. “We had no clue what [the status of the mice] would be,” said Soo. “When we [opened the box], you could see the cute little mice. They're alive, and they're happy. They look well groomed. They didn't look disheveled, and so it showed that the research hardware system designed by NASA Ames worked perfectly.”

While the untreated mice in the space cohort experienced significant bone loss in the femur, tibia, and lumbar, mice injected with BP-NELL-PEG maintained the same bone mineral density and bone volume as untreated mice on the ground. Treated ground mice had increased bone density, suggesting that BP-NELL-PEG could be a viable treatment on Earth as well.

“Soo and her team have really demonstrated the utility of the spaceflight induced bone loss model,” said Michael Roberts, a microbiologist and Chief Scientific Officer at the ISS National Lab who was not involved in the study. Roberts was eager to see them take their BP-NELL-PEG molecule through to clinical trials, potentially with follow-up experiments on the ISS.

Ting, who is now at the Forsyth Institute, and Soo are working on another paper with a more detailed analysis of the live return cohort data. Given that Nell-1  had previously been associated with the brain, they’re also currently exploring the potential connection between bone and brain development. However, their ultimate priority remains treating children with craniofacial problems, which Ting explained, the pharmaceutical industry have long overlooked. Ting hopes that he can leverage these applications in osteoporosis and spaceflight-induced bone loss to garner interest in finally bringing their treatment to clinical trials for craniofacial conditions. “I have patients who I've seen for 20 years, and we see them almost every month,” said Ting. “We watched them grow up and develop not just physically [but] also mentally and all aspects. ... We have a very strong feeling for those kids.” 

Whichever direction they take, the pair will continue collaborations within and outside of the laboratory. “Our basic research [is] intertwined with how we met and our marriage,” said Ting. “That’s how she has [come to] like me, so it's quite fruitful for myself too, to be her husband.”

References

1. Svanichuk, M. et al. A systematic review and meta-analysis of bone loss in space travelers. npj Microgravity  6, 13 (2020). 
2. Ha, P. et al. Bisphosphonate conjugation enhances the bone-specificity of NELL-1-based systemic therapy for spaceflight-induced bone loss in mice. npj Microgravity  9, 75 (2023).
3. Ting, K. et al. Human NELL-1 expressed in unilateral coronal synostosis. J Bone Miner Res  14, 80-89 (1999).
4. James, A.W. et al. NELL-1 in the treatment of osteoporotic bone loss. Nat Commun  6, 7362 (2015).