Cheryl Nickerson
Lynn Harper
NASA has a long history of producing sound, hypothesis-driven science that advances our fundamental understanding of important human health problems and has been well-received by the scientific community. Our goal for this workshop is to demonstrate a bulletproof credible case that this fundamental understanding can be translated into the commercial investment in space biotech. We could have built the biotech case solely on the NASA work accomplished at the Ames research center and Johnson Space Center. While NASA's collective work on microgravity analogues such as the rotating wall vessel (RWV) bioreactor and other models has been meaningful,we elected to hold this workshop to include the scientific community from outside of NASA to solicit their opinion regarding the validity of the case for biotech investment in spaceflight.
Now I want to introduce Dr. Cheryl Nickerson, an Associate Professor in
the Department of Microbiology and Immunology at the Tulane University Health
Sciences Center. In recognition of her contributions and outstanding research
efforts that support the United States Space Program, Cheryl received the
Presidential Early Career Award for Scientists and Engineers from NASA in
2002, which was presented by President Bush at the White House, was Woman
of the Year in New Orleans in 2003, and was an Astronaut Candidate Finalist
for the Astronaut Class of 2004. During the early years of the space program,
the physical forces associated with microgravity were not expected to alter
the biology of cells. Today, we have found that not only do these forces
affect cells, but they can be used as a tool to enhance our understanding
of cell function and lead to vaccines and therapeutics to treat human disease.
Dr. Nickerson will now present her research that documents the potential
that the biotech commercialization of spaceflight holds for the development
of products that will enhance the quality of life on Earth.
Cheryl Nickerson
Title of Dr. Nickerson's presentation:
"A Vision to Commercialization - Spaceflight Platforms Toward Innovations in Infectious Disease Control"
Highlights of this talk:
There is tremendous potential that the ISS holds for infectious disease,
especially with regard to the development of novel therapeutics, vaccines
and diagnostics to treat, prevent, and control infectious diseases.
Infectious disease is the leading cause of death worldwide, especially in children. As such, it has a major impact on national and global social, economic, political, and security issues. In the US alone, total cost of infectious disease exceeds $120 billion annually due to direct medical and lost productivity costs. Globally the costs are staggering. There are new diseases and reemerging infectious diseases for which we lack effective treatments. In addition, increasing antibiotic resistance in many bacteria and the possibility of the intentional misuse of microbial pathogens as weapons of bioterrorism add to our need to have a better fundamental understanding of how pathogens cause disease. Collectively, this means that we need new ways of treating, preventing, and diagnosing infectious disease.
Current estimates of bringing a new drug to market are close to 1 billion dollars and require extended development times of over 10 years before it reaches patients. Even incremental decreases in this cost and time are of tremendous importance.
So what advantage can space flight offer to expedite the commercial product development of novel treatments for infectious disease - both in terms of reducing time to market and cost to produce? Spaceflight has been shown to induce key changes in both human and microbial cells that are directly relevant to infectious disease, including changes in immune system function, microbial growth rates, antibiotic resistance, and cell surface properties. However, we don't know the mechanism by which these changes are occurring. We must know the mechanism to get to the product. The goal is to establish more ideal models of pathogenesis with which to study infectious disease. The more realistic the model, the more closely it resembles what happens during the natural course of infection, and the more likely that it will lead to the development of novel therapeutics, vaccines, and other countermeasures to treat and prevent infectious disease. We have been able to model some of the changes in cellular responses observed during spaceflight using ground-based analogues of spaceflight. These ground-based analogues have been used in my lab as well as in those of other investigators. Novel insight has emerged from these studies that is contributing in meaningful ways to our understanding of how microbial pathogens cause infectious disease and potential new targets for drug development. As good as these ground-based models are, they are only mimicking aspects of cellular changes observed in-flight. It is exciting to think of the potential of identifying the target mechanisms in space, investigating those target mechanisms on Earth in terms of their role in infectious disease, and their potential to lead to the discovery of previously unknown molecular targets and mechanisms which would lend themselves to commercial product development of therapeutics and vaccines.
Novel Enabling Technology
There is precedent for NASA biotechnology that has been derived from its manned spaceflight program and translated here on Earth into novel enabling products that enhance our health on a daily basis. Indeed, each dollar invested in space programs has yielded many new products, technologies, and processes on Earth, including ultrasound scanners, laser surgery, CAT scans, programmable pacemakers, automatic insulin pumps, robot-guided wheelchairs, and research to develop cures for osteoporosis. Indeed, many space-related studies that were originally designed for crew health to mitigate disease during flight have led to novel enabling technologies which could (and have) significantly enhanced human health on Earth.
The NASA novel enabling technology that we use in our lab to provide highly predictive models for infectious disease studies with Earth-based applications is the Rotating Wall Vessel bioreactor (RWV). Originally designed to culture cells in the lab under conditions that mimic aspects of spaceflight, culture of cells in the RWV provides growth cues similar to those encountered in vivo, especially in terms of mechanical fluid shear forces which are relevant to those encountered in the body and which have a profound impact on both eukaryotic and prokaryotic physiology. This takes on additional relevance to infectious disease when one considers that the levels of fluid shear in the bioreactor are relevant to those encountered in vivo by both the host and pathogen. Indeed, the culture of both mammalian and microbial cells in the RWV has led to major advances in tissue engineering and microbial pathogenesis research, especially in terms of providing physiologically relevant infection models.
For example, research in our lab has shown that cultivation of a leading
food-borne bacterial pathogen, Salmonella typhimurium, in the RWV
profoundly alters the gene expression, physiology, and disease causing potential
of this organism. Specifically, Salmonella grown in the RWV exhibits
an enhanced disease-causing potential and increased ability to resist being
killed by environmental stresses relevant to those found in the human body.
We also showed that when grown in the RWV, Salmonella globally changes
its gene expression pattern, and we identified 163 genes whose expression
changed in response to culture in the RWV. From this work, we have identified
previously uncharacterized molecular targets that may have potential for
the development of novel therapeutics against human disease caused by Salmonella.
Of course, these studies were conducted in a ground-based analogue of spaceflight (i.e. the RWV) that was designed to simulate aspects of spaceflight. But there will be important differences between culture in the RWV and during spaceflight. So we are very interested to determine the direct effect of spaceflight on gene expression and virulence in this pathogen, as well as other model microbes. In fact, we know how to do in-flight work and we currently have an experiment on-board the International Space Station (ISS) and another one that is manifested to fly when Shuttle returns to flight to address this very question. Salmonella typhimurium is one of the target microbial pathogens that is included in this study. This study will provide a better understanding of the genetic response to microgravity and how this environment may affect microbial virulence. Molecular targets identified through these types of spaceflight studies have potential to offer important direction into development of therapeutics against infectious disease.
In another use of the RWV, we have also used this bioreactor to culture biologically meaningful models of 3-D human cells and tissues for the study of infectious disease. In this regard, the RWV provides an alternative approach to enhance the differentiated features of cell culture models. In particular, it recognizes that organs and tissues function in a 3-D environment in the body, and that the 3-D structure of a tissue is essential for its differentiated form and function. When cultured in the RWV, mammalian cells are able to grow in three-dimensions, aggregate based on natural cellular affinities, and differentiate into organotypic cell-based models that mimic many of the features of the parental tissue in vivo, and thus are relevant to the complex environment encountered by pathogens during the natural course of infection. The availability of reliable, reproducible 3-D tissue assemblies that model important aspects of the structure and function of human tissues holds tremendous promise in infectious disease research. Such models will lead to the development of novel therapeutic and diagnostic strategies for the prevention and treatment of human infectious disease, including protection against biological warfare agents.
Our laboratory has established a variety of different 3-D cell culture models from different human cells and tissues that are currently being used by us in infection studies. These models include small intestine, colon, placenta, lung, bladder, periodontal ligament, and a neuronal model. Each of these 3-D cell cultures have been proven to be biologically meaningful models of their respective in vivo parental tissues. Importantly, we have been able to demonstrate that pathogens establish infection of our 3-D cell cultures in ways that model important aspects of an in vivo infection. These 3-D cell cultures a) complement existing in vitro models used to study host-pathogen interactions; b) facilitate meaningful dissection of the molecular mechanisms of infectious disease; and c) hold real potential to lead to the development of novel therapeutic strategies for prevention and treatment.
I am also delighted that Tulane University has made an internal investment to create the "Tulane Center of Excellence in Bioengineering" which is based on the use of 3-D cell culture to lead to commercialization of products for human health issues, including infectious disease, cancer, reproductive disorders, testing of therapeutic drugs, and growing tissues for transplantation. I serve as Director of this Center, and Dr. Tim Hammond is the Co-Director. Initiated by Tulane and supported by Tulane and private sponsorship, we ultimately envision a federally and corporate funded Center of Excellence at Tulane for 3-D cell culture.
Again, the RWV is a ground-based analogue of spaceflight, and there will be important changes in the 3-D cultures in-flight as compared to when grown in the RWV. Spaceflight will build upon our knowledge gained from ground-based analogue studies, and will provide a novel environment that holds real potential to offer insight into fundamental biological responses that are directly relevant to infectious disease. In particular, spaceflight offers real potential to promote better or more ideal pathogenesis models. It is anticipated that such improved models will lead to reduction, replacement, & refinement of animal models, improved time to market for product, and lower costs for product development.
In this regard, the 3-D cell cultures are ideal flight models for infection analysis to study the host-pathogen interaction in flight, as they maintain their differentiated form and function during spaceflight, and provide a high throughput platform that is highly controlled and reproducible. In addition, use of our 3-D tissue models has been peer-reviewed and approved as an appropriate model system for study of host-pathogen interaction in flight.
Where do we go from here?
The vision for commercialization is that we go from flight experiment, to intellectual property, to innovative solutions toward the treatment and control of infectious disease, and ultimately patented vaccines, therapeutics and diagnostics.
There are many people on our collaborative research team across the country in academia, private industry, and of course, at the NASA Johnson Space Center and at Ames Research Center, who are instrumental to the success of our on-going research efforts. I am grateful to each and every one of them for their committed support to these collaborative studies, and I look forward immensely to future developments.