Benoit Smagghe

Benoit Smagghe

Visiting Researcher

Dr. Smagghe received his Ph.D. (2007) in Biochemistry, Biophysics, and Molecular Biology from Iowa State University. His graduate research in Dr. Mark S. Hargrove laboratory, focused on the study of plant and human hexacoordinate hemoglobins. His studies concentrated in understanding how hexacoordinate hemoglobins are able to bind ligands like oxygen, nitric oxide, and carbon monoxide and correlate their biophysical and biochemical behaviors to physiological functions.
After graduating from Iowa State University Dr. Smagghe interest in science was more focused on understanding the molecular mechanisms that are involved in cancer or other diseases in order to contribute with his research, in a more direct way, to develop new or better therapeutics. In 2007, Dr. Smagghe joined Dr. Timothy A. Springer's laboratory at the Immune Disease Institute, Children’s hospital of Boston at Harvard Medical School. During his postdoctoral training, Dr. Smagghe lead several projects focused on the understanding and characterization of the activation mechanism of integrins and on the development of engineered proteins to determine their structural features to facilitate structure-assisted design of new drugs.
In 2011, Dr. Smagghe joined the research team at Minerva Biotechnologies in Waltham, Massachusetts. He is leading projects in two research areas. One is focused on the development of anti-cancer therapeutics and the other is focused on the development of novel stem cell reagents. The second research interest in the area of regenerative medicine concerns the development of methods for the culture of human stem cells, in particular, new growth factors that maintain stem cells in a “ground state” that is required for the use of stem cells in human therapies and other medical applications.
Dr. Smagghe joined the Microbiology department in August 2014 as a visiting Researcher.
Snyder 319

Research Interests

• Protein engineering
• Cancer therapeutics
• Stem cell reagents

Current Research

I am presently a Research Scientist (since January 2011) and part of the research team at Minerva Biotechnologies in Waltham, Massachusetts. I am leading projects in two research areas. One is focused on the development of anti-cancer therapeutics and the other is focused on the development of novel stem cell reagents. My research on cancer, concerns the study of a membrane receptor (MUC1*) that stimulates cancer development. My research also involves the study of ligands that can block the receptor stimulation, the discovery of the signal transduction pathways that are affected by those ligands and the mechanisms that inhibit cancer growth. The receptor in question is present on most cancer cells and constitutes an ideal target for novel cancer therapeutics development. This includes the development of antibodies that block the signal stimulating cancer growth and the use of nanoparticle assays to test small molecule inhibitors developed by chemist at Minerva Biotechnologies. My second research interest in the area of regenerative medicine concerns the development of methods for the culture of human stem cells, in particular, new growth factors that maintain stem cells in a “ground state” that is required for the use of stem cells in human therapies and other medical applications.

Since I began work at Minerva, I have been the lead scientist on projects to develop antibody-based therapeutics that block the cancer-promoting MUC1* activated pathway. I have led multiple aspects of this work including testing of candidate antibodies and small molecules in cell based assays to determine their effects on a large array of cancer cells known to be expressing the MUC1* receptor, including breast cancer cells. Bivalent ligands, including IgGs favor cancer progression by dimerizing and activating MUC1*. Binding of a monovalent ligand, including Fab fragment deactivate the MUC1* receptor and, therefore, inhibit cancer growth. I am the lead scientist responsible for the generation of Fab and had to optimize each step of this complex process for a large scale production and purification of a Fab that is suitable for our assays and for the efficacy and toxicity studies in animal. I have personally tested several Fabs in a cell based assay and isolated candidates having an anti-tumor effect. Both embryonic stem (ES) and induced pluripotent stem (iPS) cells hold great promise for the treatment of a wide variety of acquired or hereditary diseases. The major obstacles to clinical applications are: 1) developing cell culture methods that will comply with expected FDA requirements; 2) culturing enough high quality pluripotent stem cells. In an attempt to create a growth system that enables self-renewal of stem cells, we discovered that NME1 (NM23) can be used as the only growth factor or cytokine required for the culture of human pluripotent stem cells. I am the scientist that discovered how to engineer, express and purify the unique growth factor (NME1) that maintains its oligomerization state as a dimer which is the only active form able to dimerize and activate the membrane receptor MUC1*. NME1 dimers make human stem cells grow in the true pluripotent state called the “naïve” or “ground”state. With my colleagues Andrew Stewart and Mark Carter, who led Minerva’s stem cell team, we showed that human stem cells were converted to, and maintained in, the “naïve” state by culturing the cells in the dimeric form of a NME1. Interestingly, subsequent exposure of the naïve cells to bFGF, the standard growth factor used in all human stem cell culture reversed the process and caused the cells to enter the “primed” state. As predicted by comparison to mouse naive cells, the NME1 cultured stem cells had a much higher cloning efficiency than the same cells cultured in FGF-containing media and differentiated in a coordinated way with as high as 90% of the cells in a local environment differentiating down the same germline. Our growth system, including the NME1 growth factor that I perfected, is free of feeder cells, conditioned media, exogenously added cytokines or growth factors. After initial acclimation to the new media, the stem cells remain essentially 100% pluripotent, requiring no manual dissection or other manipulations that would interfere with large scale production and automated stem cell culture. This important work is the subject of a patent on which I am a co-inventor along with Minerva’s CEO Cynthia Bamdad (Media For Stem Cell Proliferation and Induction, PCT/US12/60684).

The NME1 growth factor described in the 2013 PLoS ONE article and important extensions thereof, constitute an important breakthrough in the human stem cell field as the cells in the naïve state will allow the production of better quality cells for the treatment of incurable diseases, including Alzheimer’s disease, Parkinson’s disease, Spinal cord injury, Heart disease, Stroke, Diabetes, Brain injury, Rheumatoid arthritis, Leukemia and other cancers.

Selected Publications

  1. Carter M.G.*, Stewart A.K.*, Smagghe B.J.*, Rapley J.A., Lynch E., Bernier K.J., Keating K.W., Hatziioannou V.M., Hartman E.J. and Bamdad C.C. (2015) A primitive Growth Factor, NME7AB, is Sufficient to Induce Stable Naïve State Human Pluripotency; Reprogramming in this Novel Growth Factor Confers Superior Differentiation. Submitted to Stem cells. * co-first author
  2. Smagghe B.J. Stewart A.K., Carter M.G., Shelton L.S., Bernier K.J., Hartman E.J., Calhoun A.K., Hatziioannou V.M., Lillacci G., Kirk B.A., DiNardo B.A., Kosik K.S., Bamdad C. (2013) MUC1* Ligand, NM23-H1, Is a Novel Growth Factor That Maintains Human Stem Cells in a More Naïve State. PLoS ONE 8(3): e58601.
  3. Eng E.T., Smagghe B.J., Walz T. and Springer T.A. (2011) Intact αIIbβ3 extends after activation measured by solution x-ray scattering and electron microscopy. Journal of biological chemistry. 286:35218-35226.
  4. Thompson A.B., Calhoun A.K., Smagghe B.J., Stevens M.D., Wotkowicz M.T., Hatziioannou V.M., Bamdad C. (2011) A Gold Nanoparticle Platform for Protein–Protein Interactions and Drug Discovery. ACS Applied Materials & Interfaces,3: 2979-2987.
  5. Smagghe B.J., Huang P., Ban Y.A., Baker D. and Springer T.A. (2010) Modulation of integrin activation by an entropic spring in the β-knee. Journal of biological chemistry, 285:32954-32956.
  6. Smagghe B.J., Hoy J.A., Percifield R., Kundu S., Hargrove M.S., Sarath G., Hilbert JL., Watts R.A., Dennis E.S., Peacock W.J., Dewilde S., Moens L., Blouin G.C., Olson J.S., Appleby C.A. (2009) Correlations between oxygen affinity and sequence classifications of plant hemoglobins. Biopolymers, 91:1083-1096.
  7. Smagghe, B. J., Trent J.T., III and Hargrove M. S. (2008) NO dioxygenase activity in hemoglobins is ubiquitous in vitro, but limited by reduction in vivo. PloS ONE 3(4): e2039.
  8. Galland R., Blervacq A-S., Blassiau C., Smagghe B. J., Decottignies J-P. and Hilbert J-L. (2007) Glutathione-S-transferase is Detected During Somatic Embryogenesis in Chicory, Plant signaling & behavior 2, 343-348.
  9. Hoy J. A., Robinson H., Trent J. T. III, Kakar S., Smagghe B. J., and Hargrove M. S. (2007) Plant Hemoglobins: A Molecular Fossil Record for the Evolution of Oxygen Transport, Journal of Molecular Biology 371, 168-179.
  10. Smagghe B. J., Blervacq A-S., Blassiau C., Decottignies J-P., Jacquot J-P., Hargrove M. S., and Hilbert J-L. (2007) Immunolocalization of non-symbiotic hemoglobins during somatic embryogenesis in chicory, Plant signaling & behavior 2, 43-49.
  11. 1. Hoy J. A., Smagghe B. J., Halder P. and Hargrove M. S. (2007) Covalent heme attachment in Synechocystis hemoglobin is required to prevent ferrous heme dissociation, Protein Science 16, 250-260.
  12. Smagghe B. J., Kundu S., Hoy J. A., Halder P., Weiland T. R., Savage A., Venugopal A., Goodman M., Premer S. and Hargrove M. S. (2006) Role of phenylalanine B10 in plant nonsymbiotic hemoglobins, Biochemistry 45, 9735-9745.
  13. Smagghe B. J., Sarath G., Ross E., Hilbert J-l., and Hargrove M. S. (2006) Slow Ligand Binding Kinetics Dominate Ferrous Hexacoordinate Hemoglobin Reactivities and Reveal Differences between Plants and Other Species, Biochemistry 45, 561-570.