Repurposing Metformin as an anti-cancer agent: microgravity studies in Saccharomyces cerevisiae (Drug Metabolism) - 07.14.16

Overview | Description | Applications | Operations | Results | Publications | Imagery

ISS Science for Everyone

Science Objectives for Everyone
Metformin is a drug commonly used to treat type 2 diabetes, which is often associated with obesity. Along with lowering blood sugar and cholesterol, metformin has been shown to protect diabetic patients against several forms of cancer. Repurposing Metformin as an anti-cancer agent: microgravity studies in Saccharomyces cerevisiae (Drug Metabolism) studies yeast cells to understand how drugs act on tumors, and whether metformin can serve as an anti-cancer drug.
Science Results for Everyone
Information Pending

The following content was provided by Timothy G. Hammond, M.B.B.S., and is maintained in a database by the ISS Program Science Office.
Experiment Details

OpNom: Drug Metabolism

Principal Investigator(s)
Timothy G. Hammond, M.B.B.S., Durham Veterans' Affairs Medical Center, Durham, NC, United States

Co-Investigator(s)/Collaborator(s)
Holly H. Birdsall, M.D., Ph.D., Department of Veterans Affairs Office of Research and Development, Washington, DC, United States
Patricia Allen, M.S., US Department of Veterans Affairs, Durham, NC, United States
Corey Nislow, seqWell Inc., Beverly, MA, United States

Developer(s)
BioServe Space Technologies, University of Colorado, Boulder, CO, United States

Sponsoring Space Agency
National Aeronautics and Space Administration (NASA)

Sponsoring Organization
National Laboratory (NL)

Research Benefits
Earth Benefits, Scientific Discovery

ISS Expedition Duration
September 2014 - March 2015

Expeditions Assigned
41/42

Previous Missions
STS-135

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Experiment Description

Research Overview

  • Repurposing Metformin as an anti-cancer agent: microgravity studies in Saccharomyces cerevisiae (Drug Metabolism) evaluates the molecular interaction of the anti-diabetic drug Metformin and yeast under microgravity conditions. Metformin has unexpectedly been found to protect diabetics against diverse forms of cancer.
  • Drug Metabolism studies the pathways by which Metformin affects yeast cells at the level of the genome.
  • Drug Metabolism seeks to understand how Metformin mediates its anti-cancer effects at the molecular level.
  • Repurposing drugs with the view of minimizing drug interactions and unwanted side effects is a goal of Drug Metabolism.
  • The Drug Metabolism research may lead to new drugs or new targets for cancer.
     

Description
Yeast (Saccharomyces cerevisiae) is a model eukaryotic cell with well characterized genome containing many genes relevant to human disease.  Repurposing Metformin as an anti-cancer agent: microgravity studies in Saccharomyces cerevisiae (Drug Metabolism) represents collaboration between the Center for the Advancement of Science in Space (CASIS) and the Department of Veterans Affairs to evaluate the molecular mechanism of action of various chemotherapeutic and other drugs in yeast under microgravity conditions.  Microgravity alters mass transport of drugs and other molecules in unique ways that are thought to simulate what occurs in the body.  By studying how drugs affect yeast cells at the level of the genome, it should be possible to better understand how drugs exert their effects on specific tissues, which would be valuable both from the perspective of understanding and improving drug effectiveness but also with the view to minimizing drug interactions and unwanted side effects.   Drug Metabolism utilizes a yeast deletion series (a large array of yeast with various genes knocked out that are grown together) to determine which genes impart improved survival to yeast strains grown in the presence of a test drug.  Results are compared to yeast strains grown without drug and strains grown on the ground with and without the drug. This research could lead to new drugs or drug targets for cancer.

Metformin is a widely used, potent, first-line oral therapy for Type 2 diabetes. More recently, metformin has been found to also protect against certain types of cancer, reduce cancer-related mortality, and even have direct tumoricidal (tumor destroying) effects. The mechanism(s) of metformin’s activity against cancer and the downstream pathways are still incompletely defined, largely due to lack of a model system with low oxygen and high carbon dioxide levels characteristic of tumors. Genetically engineered yeast, retain many of the complexities of mammalian cells and are highly effective tools for the analysis of drug pathways. Microgravity, with very low convection is ideally placed to solve this problem by allowing reproduction of clinically and biologically relevant redox states and gas levels in yeast cells at microscopic levels. Thus yeast in space flight provide a mechanism to analyze drug pathways in ways that are not currently achievable by any other means in ground-based studies. To analyze drug targets in the HaploInsufficiency (HIP) assay, a series of yeast are molecularly engineered to delete one copy of each gene in the genome and replace it with a unique DNA bar code. Clones that are haploinsufficient for the drug target gene(s) are more vulnerable and grow less well in the presence of the drug. The yeast library can be grown as a mixture and DNA sequencing or chip hybridization quantifies the relative abundance of each member. Yeast DNA is stable and is stored on the International Space Station (ISS) as needed until return to ground for final analysis.

On space shuttle flight STS-135 the unique ISS profile of the HIP assay was baselined. STS-135 experimental data demonstrated a unique footprint to the oxidation status of yeast cells in microgravity for drug pathway analysis, characterized by specific changes in mitochondrial and ribosomal respiratory function with minimal stress response. In Drug Metabolisim it is hypothesized that the unique footprint to the oxidation status of yeast cells in microgravity for drug pathway analysis identifies unique anti-cancer drug targets for the antifungal drug metformin. This directly addresses microbial growth and physiological responses encountered in the multiple stimuli of the space flight environment.

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Applications

Space Applications
Research suggests that drugs behave differently when administered in space than they do on Earth. To understand why, researchers must determine the pathways in which drugs work inside cells while in microgravity. This provides insight into how drugs exert their influence on specific tissues. A difference in drug activity in space-based patients as compared to Earth-based patients has important implications for crew health on long-duration space missions.

Earth Applications
Yeast is a model organism for a wide variety of health disorders, enabling scientists to study genetics and disease on a cellular level. This investigation studies how a common drug affects yeast cells at the genetic level, providing new insight into how the drug works in the body. Results improve drug effectiveness, minimize unwanted interactions and side effects, and illuminate the specific ways in which a drug works. Research building upon this investigation could lead to new drugs or new genetic targets for treating cancer.

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Operations

Operational Requirements and Protocols

The experiment must be initiated within three weeks of reaching orbit. The samples must be returned within one year. Cold Stowage assets are required during all mission phases.


As the yeast arrives at the station frozen, the timing of this experiment has a degree of flexibility.  When the time to initiate the experiment arrives, frozen yeast inoculum are retrieved from its coldstowage (CS) asset and thawed.  The BioCell Habitats are opened, the inoculum syringe is attached to the first in the set of three BioCells and the yeast is injected and mixed into this media filled BioCell.  The BioCell is replaced into its habitat, which is then placed into a 30C CGBA for incubation.  At a later time point, after accessing CGBA and the habitat, an empty syringe is connected to the first BioCell and a small portion of the yeast/media mixture is withdrawn and subsequently injected into the second (middle) BioCell.  At that same time, a portion of the first BioCell’s culture is sampled and frozen in a CS asset.  Again the experiment is returned to CGBA for incubation.  A second transfer operation moves a portion of the experiment culture from the second to the third BioCell for growth and, again, a sample of the second BioCell’s contents is frozen.  After appropriate growth, a final round of samples is taken from the third BioCell and frozen for return.  

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Decadal Survey Recommendations

Information Pending

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Results/More Information

Information Pending

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Related Websites
BioServe

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Imagery

image BioServe Space Technologies’ BioCell space flight hardware in flight configuration for the Repurposing Metformin as an anti-cancer agent: microgravity studies in Saccharomyces cerevisiae (Drug Metabolism) investigation. Image courtesy of BioServe Space Technologies.
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image Repurposing Metformin as an anti-cancer agent: microgravity studies in Saccharomyces cerevisiae (Drug Metabolism) utilizes BioServe Space Technologies’ BioCell space flight hardware. Image courtesy of BioServe Space Technologies.
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image NASA Image: ISS041E055406 - ESA astronaut Alex Gerst working with Drug Metabolism experiment.
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image NASA Image: ISS041E055412 - ESA astronaut Alex Gerst working with Drug Metabolism experiment.
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image NASA Image: ISS041E055416 - ESA astronaut Alex Gerst working with Drug Metabolism experiment.
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