One Small Step for Man, One Giant Leap For Science

The Medicine Maker has previously published a number of articles about making biopharmaceuticals in space. Imagine the possibilities… if we can make medicines in space, we can make them anywhere. Here, we speak with Daniel Hornburg, Vice President of Proteomics at Seer, a biotech company analyzing the proteomes of astronauts in hopes that the findings will teach scientists more about how proteins work and how we can tackle disease.

How did you – and Seer – become interested in space?
 

I’ve always been driven by my desire to understand how the world works. When I was little, I wanted to become an astronaut or a scientist. While I am still fascinated by space travel and astronomy as a scientist, I’ve been studying biomolecules, the smallest constituents of life – ranging from peptides to proteins to lipids to metabolites – for over 15 years.  At Seer, my team drives interdisciplinary research by developing and using new technologies for faster, deeper, and more precise interrogation of thousands of biomolecules. With our technology, I am excited to explore the dynamic molecular choreography that constitutes life and how it is affected by space travel – ultimately uniting the two ideas that have excited me for as long as I can remember.

Seer is building platform technologies for quantitative exploration of the proteome, which we believe is the next frontier in biology. In contrast to the genome, proteins are dynamically regulated, biochemically complex, and closer to the phenotype; hence, analyzing the proteome offers an opportunity to understand human health and disease in a much more detailed and direct way. The challenge with proteins in samples such as blood plasma is that their abundance is distributed across many orders of magnitude. In fact, just 22 proteins make up 99 percent of the plasma protein mass. A challenging dynamic range of protein abundance has made it impossible to scale both throughput of the assay and depth of coverage for the low-abundance part of the proteome. We believe that deep quantitative sampling of the plasma proteome at scale will enable the scientific community to discover new protein signatures that provide information about the state of a subject’s health and, together with genomics information, expand our mechanistic understanding of diseases.

How does space affect our proteins?
 

Approximately 600 humans have spent time in space and these astronaut-scientists themselves usually become part of experiments with every new mission. Astronaut datasets are unique, containing detailed physiologic information. Our experimental methods and technologies evolve every year – and so do our insights.

Proteins are the functional building blocks of all cells and mediate nearly every biological process. As with every physiological response, diseases involve proteins at work. For example, if an astronaut experiences muscle atrophy due to microgravity, protein complexes that degrade other protein complexes are most likely involved. When stress leads to increased levels of inflammation, the process is modulated by signaling proteins such as cytokines circulating in blood. Even a disrupted circadian rhythm will be associated with alterations in the proteome. We are just beginning to understand how environments such as space are reprogramming our proteome.

The Translational Research Institute for Space Health (TRISH) is an academic consortium of the Baylor College of Medicine, California Institute of Technology, and Massachusetts Institute of Technology. TRISH works closely with NASA to develop and fund innovative health research and technology development with two goals: i) to help astronauts stay healthy; and ii) to apply the knowledge and investment in space health research to benefit all people on Earth.

To date, only a limited number of documented studies have investigated the effects of spaceflight on the human proteome. The small documented number of human studies has relied on analytical tools that did not provide adequate depth of insight due to technical limitations. Studies looking at subsets of the proteome provide valuable information, but a gap exists in our understanding of how extreme environments impact human physiology on a systems level. There is a real opportunity to further characterize the human proteome using some of the newer quantitative tools that are available.

What can you tell us about Seer’s work with NASA, Cornell Medicine, and SpaceX?
 

Seer started collaborating with SpaceX and TRISH in 2021 to understand what happens to humans during space travel. For our part, Seer is contributing deep plasma proteomics exploration using a novel nanoparticle-based workflow we developed in conjunction with unbiased mass spectrometry as a readout. Additional partners are exploring different molecular facets of human health; for example, Weill Cornell Medicine is studying the astronaut microbiome. Ultimately, researchers will combine molecular layers to yield a more complete picture of how the forces of space affect humans.

In September 2021, SpaceX launched its Inspiration4 mission, which spent three days in low-Earth orbit. Our partners took samples from the four-person crew – two men and two women – before take-off and after return. Seer is currently analyzing the samples and determining how the flight changed the molecular composition of the blood.

Our nanoparticles compress and capture the extremely large (and commonly inaccessible) amount of molecular information in blood plasma in so-called protein coronas, rendering it significantly more accessible to downstream detectors such as mass spectrometers. We then use machine learning to interpret the signals, which tell us about the molecular composition of each sample and reveal the astronaut’s biomolecular state. We can then compare post-flight molecular profiles between the four astronauts, as well as to their pre-flight profiles. This tells us how low gravity, higher levels of radiation, and other aspects of space affect the human body at the molecular level, which in turn can help us prepare for future space missions.

How can understanding how our biology reacts to extreme environments benefit biomedical research?
 

Life is complex and studying how the human body reacts to the stresses of space not only helps us prepare for future missions, but may also lead to a better understanding of some biomolecules’ physiological and pathological roles. Because proteins are closer to the phenotype than RNA molecules or the genome, for example, we expect that proteins will dynamically respond to perturbations, providing a snapshot of the body’s state and how it adapts to a changing environment. Importantly, contributing data in a standardized and unified way to an open-access database sets a good precedent in making these important datasets available to all medical researchers, whether studying space adaptations or normal human physiology.

What insight from the project so far are you allowed to share?
 

Although data analysis and integration are still ongoing, we have already seen multiple proteins and functional families of proteins altered in association with spaceflight. Seer  presented an abstract at the American Society for Mass Spectrometry meeting in June that details some preliminary proteomic findings.

What are the biggest challenges in your work and how are you approaching them?
 

We have the ability to quantify thousands of proteins with our technology. One of the key challenges is that, so far, we have only looked at a few subjects with very narrow demographics at a few timepoints pre- and post-flight. Limited diversity and sample numbers present challenges from a statistical point of view. Some of the changes will be subtle and require more frequent sampling during missions and from many more biological replicates (astronauts) to become evident. Though I personally see this as a great justification to make it to space, the current study will generate hypotheses that we can test in follow-up experiments here on Earth. Eventually, we will grow the number of data points and “diversity” in multi-omic research conducted in space to accurately generalize from individuals to populations, but we must start somewhere to learn and progress.

What are the timelines for the project?
 

We conducted the initial analysis and are integrating the proteomics data with other omics data in collaboration with our partners. Though we gained interesting insights from these pilot studies, future missions with more frequent sampling and larger cohorts will be key to unlocking the full potential of deep molecular profiling. In the long term, we are excited that this first proof-of-concept plasma proteome study will contribute to TRISH’s open-access health database and their broader mission of consolidating knowledge around the impact of commercial spaceflight on human physiology.

What types of medicines could eventually be developed on the back of this work?
 

The biggest opportunity for proteomics-driven medicine is in the preventative space. Seer’s nanoparticle technology allows us to see small differences in proteins, particularly those that are low-abundance, and doing that at a scale that enables detection of novel and more complex biomarker signatures. This is opening the door to detecting diseases much earlier than we could in the past. Because these tools are highly sensitive, we can see small changes within a person’s body long before they start to experience symptoms. Historically, people often visit the doctor when they have visible signs of illness but, by that point, the damage is already done. Our goal is to map negative health trajectories before the disease occurs, which can inform preventative treatments.

Anything else to add?
 

Multi-omics research and technology development is never a one-man show. All this work is made possible because smart people from around the globe get together and work together. I have a fantastic team at Seer and we have brilliant collaborators in both academia and industry. What connects us is the universal language of science, our drive to step into new territories, and curiosity about what we will learn.