ASSOCIATIONS 

• Dr. Michael S. Diamond (born 1964)   ...

  • • Interview : [Dr. Michael S. Diamond (born 1964) said]:   "The person that most profoundly shaped the way I approach science, I think, was my PhD advisor [Dr. Timothy "Tim" Alan Springer (born 1948)] at Harvard Medical School. I spent the most time with him, in terms of years that I was actually training"    ( Source :  [HP00DF][GDrive] )

COMPANIES

• • • Moderna, Inc.      -  

      • • " When [Moderna, Inc.] launched its IPO in December 2018, [Dr. Timothy "Tim" Alan Springer (born 1948)] became the company's fourth-largest shareholder and made $400 million, after investing $5 million in the startup early on  "      (  [HK00B2][GDrive]    ) 

        • "[Dr. Derrick James Rossi (born 1966)] had developed a method of modifying mRNA first via transfection into human cells, then dedifferentiating it into bone marrow stem cells which could then be further differentiated into desired target cell types. Rossi approached fellow Harvard University faculty member [Dr. Timothy "Tim" Alan Springer (born 1948) ], who solicited co-investment from Kenneth R. Chien, Bob Langer, and Venture Studio Flagship Ventures, run by [Dr. Noubar Afeyan (born 1962)].  Together they founded a company named from the combined terms "modified" and "RNA" that just happens to contain "modern".     (  [HK007R][GDrive]  ) 

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....

Saved Wikipedia (March 26 2023) for "Timothy A. Springer"

Saved source :  [HK00B2][GDrive]   

Born

February 23, 1948

Fort Benning, Georgia

Alma mater

Harvard University (PhD)

University of California, Berkeley (BS)

Scientific career

Fields

Biology, immunology, structural biology

Institutions

Harvard Medical School

Boston Children's Hospital

Doctoral advisor

Jack Strominger

Website

Springer Lab

Timothy "Tim" A. Springer, Ph.D. is an immunologist and Latham Family Professor at Harvard Medical School.[1] Springer is best known for his pioneering work in discovering the first integrins[2][3] and intercellular adhesion molecules (ICAMs)[4] and elucidating how these cell adhesion molecules function in the immune system. His innovative use of monoclonal antibodies in his research[3][5][6] paved the way for the development of therapeutic antibodies, known as selective adhesion molecule inhibitors, to treat autoimmune diseases. In recent years, Springer's research interest has expanded to include malaria, transforming growth factor beta (TGF-β) signaling molecules, and von Willebrand factor.[7][8]

Education and training[edit]

Springer attended the University of California, Berkeley, where he majored in biochemistry. After graduating Phi Beta Kappa with Distinction and the Departmental Citation, he went on to do his Ph.D. in the lab of Jack Strominger at Harvard University. Following his graduate work, Springer received his postdoctoral training under the guidance of César Milstein at the University of Cambridge.[citation needed]

Research focus[edit]

His lab elucidated different steps in the homing process of lymphocytes with a special focus on the integrin LFA-1.[5] His research encompasses the cell adhesion molecules and chemotactic signals involved in lymphocyte migration in health and disease.

Business career[edit]

When [Moderna, Inc.] launched its IPO in December 2018, Springer became the company's fourth-largest shareholder and made $400 million, after investing $5 million in the startup early on. Earlier, he had made around $100 million on his first venture LeukoSite, which in 1999 had been bought by Millennium Pharmaceuticals.[9] Springer is also a founder of biotechnology companies Morphic Therapeutic[10] and Scholar Rock.[11] He is also a main investor in Selecta Biosciences.[12] During the coronavirus pandemic crisis, Springer became a billionaire boosting his net worth to more than $1 billion after shares of biotech surge.[13] He has a stake in Moderna Inc, the U.S biotech firm which developed a vaccine for the SARS-CoV-2 virus.[14]

Philanthropy[edit]

In 2017, Springer co-founded the Institute for Protein Innovation (IPI), a 501(c)(3) nonprofit organization, with Springer providing a $10 million foundational grant.[15][16] Springer has also endowed chairs at Boston Children's Hospital, at Berkeley in honor of Professor Jack Kirsch, and at Harvard in honor of his parents, Asa and Patricia Springer. [17][18]

Awards[edit]

• 1993 - American Heart Association Basic Research Prize

• 1995 - Cancer Research Institute William B. Coley Award

• 1996 - Member, National Academy of Sciences

• 2001 - Fellow, American Academy of Arts and Sciences[19]

• 2004 - Crafoord Prize[20]

• 2004 - Guggenheim Fellowship[21]

• 2013 - AAAS Fellow[22]

• 2014 - AAI-Life Technologies Meritorious Career Award, American Association of Immunologists[23]

• 2014 - Henry M. Stratton Medal American Society of Hematology[24]

  1. 1. 2019 - Canada Gairdner International Award[25]

• 2022 - Albert Lasker Award for Basic Medical Research.[26]

Selected publications

• Doud, M.B.; Koksal, A.C.; Mi, L-Z.; Song, G. Lu; Springer, T.A. (2012). "An unexpected fold in the circumsporozoite protein target of malaria vaccines". Proc Natl Acad Sci USA. 109 (20): 7817–22. Bibcode:2012PNAS..109.7817D. doi:10.1073/pnas.1205737109. PMC 3356675. PMID 22547819.
• Springer, T.A.; Dustin, M.L. (2012). "Integrin Inside-Out Signaling and the Immunological Synapse". Curr Opin Cell Biol. 24 (1): 107–115. doi:10.1016/j.ceb.2011.10.004. PMC 3294052. PMID 22129583.
• Shi, M.; Zhu, J.; Wang, R.; Chen, X.; Mi, L.; Walz, T.; Springer, T.A. (2011). "Latent TGF-β structure and activation". Nature. 474 (7351): 343–349. doi:10.1038/nature10152. PMC 4717672. PMID 21677751.

References

• ^ Springer CV
• ^ Kürzinger K, Reynolds T, Germain RN, Davignon D, Martz E, Springer TA (1981). "A novel lymphocyte function-associated antigen (LFA-1): cellular distribution, quantitative expression, and structure". J. Immunol. 127 (2): 596–602. PMID 6788846.
• a b Sanchez-Madrid F, Krensky AM, Ware CF, Robbins E, Strominger JL, Burakoff SJ, Springer TA (1982). "Three distinct antigens associated with human T-lymphocyte-mediated cytolysis: LFA-1, LFA-2, and LFA-3". Proc Natl Acad Sci U S A. 79 (23): 7489–93. Bibcode:1982PNAS...79.7489S. doi:10.1073/pnas.79.23.7489. PMC 347365. PMID 6984191.
• ^ Rothlein R, Dustin ML, Marlin SD, Springer TA (1986). "A human intercellular adhesion molecule (ICAM-1) distinct from LFA-1". J Immunol. 137 (4): 1270–4. PMID 3525675.
• a b Davignon, D; Martz, E; Reynolds, T; Kürzinger, K; Springer, TA (1981). "Lymphocyte function-associated antigen 1 (LFA-1) a surface antigen distinct from Lyt-2,3 that participates in T lymphocyte-mediated killing". Proc. Natl. Acad. Sci. U.S.A. 78 (7): 4535–9. Bibcode:1981PNAS...78.4535D. doi:10.1073/pnas.78.7.4535. PMC 319826. PMID 7027264.
• ^ Springer TA (1990). "Adhesion receptors of the immune system". Nature. 346 (6283): 425–34. Bibcode:1990Natur.346..425S. doi:10.1038/346425a0. PMID 1974032. S2CID 2154164.
• ^ "Timothy A. Springer - Faculty Profile".
• ^ "Springer Lab - Research Projects".
• ^ Term Sheet: The 2018 State of Startups, Fortune
• ^ GSK, Pfizer, AbbVie back next-gen integrin drugs in $52M Series A, FierceBiotech
• ^ Cambridge biotech Scholar Rock gets $80m in deal with Gilead, Boston Globe
• ^ Gormley, Brian (2017-07-19). "Biotech Entrepreneur Timothy Springer Has Another Act". Wall Street Journal. ISSN 0099-9660. Retrieved 2020-05-19.
• ^ Tognini, Giacomo. "Exclusive: Meet The Harvard Professor Who Became A Billionaire Thanks To Coronavirus". Forbes. Retrieved 2020-05-19.
• ^ "Harvard Professor Reaps 17,000% Return on Early Moderna Bet". Bloomberg.com. 22 April 2020.
• ^ Gormley, Brian (19 July 2017), "Biotech Entrepreneur Timothy Springer Has Another Act", The Wall Street Journal
• ^ Institute for Protein Innovation Launched at Harvard with $15M in Grants, Genetic Engineering & Biotechnology News, 11 May 2017
• ^ "James Hurley, Kirsch Springer Chair in Biological Sciences".
• ^ Wu Honored with Springer Professorship, Harvard Medical School, 20 June 2013
• ^ "American Academy of Arts and Sciences List of Active Members by Class" (PDF). Retrieved 4 March 2014.
• ^ Förare, Jonas (2004-01-29). "White-blood-cell migration explained" (Press release). Sweden: Royal Swedish Academy of Sciences. Retrieved 2014-01-03.
• ^ Brooks, Andrew. "Guggenheim selects seven faculty, affiliates". Harvard Gazette.
• ^ Zambon, Kat. "AAAS Council Elects 388 New AAAS Fellows".
• ^ "2014 AAI Award Recipients".
• ^ "The American Society of Hematology Honors Geraldine P. Schechter, MD, and Timothy Springer, PhD, with 2014 Henry M. Stratton Medal".
• ^ 2019 Canada Gairdner International Award
• ^ Albert Lasker Award for Basic Medical Research.

Middle name "Alan"

Harvard staff profile ... 

https://bcmp.hms.harvard.edu/faculty-staff/timothy-alan-springer

2023-03-27-bcmp-hms-harvard-edu-faculty-staff-timothy-alan-springer.pdf

2023-03-27-bcmp-hms-harvard-edu-faculty-staff-timothy-alan-springer-img-1.jpg

Timothy Alan Springer, Ph.D.

Timothy Alan Springer, Ph.D.

Latham Family Professor of Biological Chemistry and Molecular Pharmacology

We work on receptor-ligand interactions and signal transmission across membranes. We use a wide range of structural, cell biological, and single molecule techniques to answer important questions relevant to immunology, hemostasis, mammalian biology, and human disease.

Timothy A. Springer received his B.A. in Biochemistry from University of California in 1971, his Ph.D. in Molecular Biology and Biochemistry from Harvard in 1976, and did a fellowship with Cesar Milstein in Cambridge, England. He began as Assistant Professor on the Quad at HMS in 1977 and has been here ever since, although his institution has changed several times.  Since 1989 Springer has been Latham Family Professor. He currently is Professor of Biological Chemistry and Molecular Pharmacology and of Medicine at HMS and in the Program of Cellular and Molecular Medicine, and in the Division of Hematology, Department of Medicine at Children’s Hospital.

Springer discovered with monoclonal antibodies, then cloned and functionally and structurally characterized, many of the adhesion receptors in the immune system. He was the first to demonstrate that lymphocytes and leukocytes had adhesion molecules. His work on these receptors has advanced to characterizing their interactions and allosteric transitions by x-ray crystallography, electron microscopy, and laser tweezers force spectroscopy.

He discovered the lymphocyte function-associated (LFA) molecules, the intercellular adhesion molecules (ICAMs), and the first subfamily of integrins. He discovered that LFA-1 bound to ICAM-1, that LFA-2 (CD2) bound to LFA-3, and that blocking either of these adhesion pathways could block antigen recognition by T lymphocytes.  These two pathways were the first examples of like-unlike cell adhesive recognition in biology.  These discoveries directly led to the development and FDA approval of efalizumab (Raptiva, Genentech) - an antibody to LFA-1, and Alefacept (Amevive, Biogen) - the LFA-3 ectodomain fused to Fc, both for plaque psoriasis.

Springer later discovered the three step paradigm for leukocyte diapedesis: 1) rolling adhesion of leukocytes on the vessel wall through a translating zone of selectin-carbohydrate adhesion; 2) activation of G protein-coupled receptors on the leukocyte by chemoattractants presented by vascular endothelium; and 3) activation of integrin adhesiveness for CAMs on endothelium, which mediates firm adhesion and leukocyte migration through the vessel wall.  The use of different molecular digits in each step creates area codes that govern which particular subset of leukocytes or lymphocytes will emigrate from the bloodstream to a particular subset of inflammatory signals.  This together with the realization that blocking any of these steps could completely block emigration led Springer to found LeukoSite in 1993.  In 1996 LeukoSite published that an antibody to integrin a4b7, a lymphocyte homing receptor for mucosal tissues, rapidly resolved colitis in non-human primates.  This antibody, vedolizumab (Entyvio, Takeda) was approved for moderate to severe ulcerative colitis and Crohns disease in 2014.  Springer recruited to the SAB Herman Waldmann, the creator of the antibody CAMPATH-1 (Alemtuzumab). Waldmann arranged to license CAMPATH-1 to LeukoSite in 1997, which was approved by the FDA for B cell chronic lymphocytic leukemia in 2001. CAMPATH was later acquired by Genzyme, and reintroduced as Lemtrada, which was approved for multiple sclerosis in 2013.  LeukoSite went public in 1998 and acquired ProScript and with it the proteasome inhibitor bortezimib in 1999, which was approved for multiple myeloma in 2003 (Velcade, Millenium Pharmaceuticals).  LeukoSite was acquired by Millenium in December 1999 and as 35% of Millenium was valued at $3 billion by 2001.

Springer’s academic interests now focus on how protein conformational change together with tensile force activates integrins, von Willebrand factor, the transforming growth factor-b family, and adhesins on malaria sporozoites, and discovering new binding partners.  Springer has over 500 publications, a Hirsch index of 147, and over 30 patents.  He is a member of the National Academy of Sciences and his honors include the Crafoord Prize, the American Association of Immunologists Meritorious Career Award, and the Stratton Medal from the American Society of Hematology.

Springer is an investor in Selecta Bioscience since its B round and a founding investor in Moderna Therapeutics.  He is a Resident Professor at Pfizer.  He is founder and investor in Scholar Rock and in Morphic Rock Therapeutics, and board member and lead angel of Ab Initio Biotherapeutics.  As a philanthropist, Springer has endowed Chairs at Harvard Medical School and Children’s Hospital, and is on the Children’s Hospital Boston Board of Trust.

Current projects include a non-profit to advance entrepeneurship and innovation in protein therapeutics and open-source antibodies and small molecules. Next is a dual-acting malaria vaccine, to both protect humans from being infected, and to prevent mosquitos from transmitting infection.

Research:

We work on receptor-ligand interactions and signal transmission across membranes. We use a wide range of structural, cell biological, and single molecule techniques to answer important questions relevant to immunology, hemostasis, mammalian biology, and human disease. A common theme throughout our research is how force interacts with protein conformational change to activate integrins, von Willebrand factor, proteins of the transforming growth factor-beta family, and adhesins on malaria sporozoites. Some areas that currently fascinate us follow.

How are conformational signals transmitted across membranes in integrins, over long distances between the distal ligand-binding domains and cytoplasmic domains, and how is integrin activation coordinated with the actin cytoskeleton to mediate cell migration? How do G proteins and kinases activate integrins (inside-out signaling) so they can bind to extracellular ligands and cytoskeletal proteins, to coordinate adhesion and directional cell migration and mediate inside-out and outside-in signaling? How is integrin activation confined to lamellipodia? We have proposed that a mechanism for coordinating binding to ligands outside the cell and the cytoskeleton inside the cell is inherent in integrin structure and the allosteric pathways that relate the bent - closed headpiece; extended- closed headpiece; and extended – open headpiece conformations. Cell biological experiments are required to test this hypothesis.

How do representative members of the integrin family work? This family is quite diverse, and we study representative integrins including LFA-1, Mac-1, αXβ2, α4β1, and α4β7on leukocytes, αIIbb3 on platelets, and the αV integrins that bind and activate TGF-β. To gain a broad overview, we may extend to other subfamilies including those that recognize collagen and laminin.

How can integrins, depending on their activation state, mediate transient adhesion that supports rolling, or alternatively, firm adhesion, in postcapillary venules? This question is being addressed with integrins α4β1, α4β7, and their ligands MAdCAM-1, and VCAM-1, which mediate both lymphocyte homing in the vasculature and cell adhesion and immune responses in tissues. Furthermore, we are examining how small drug-candidate molecules and antibodies in the clinic for asthma, multiple sclerosis, and inflammatory bowel disease bind to these integrins.

We have initiated single molecule laser tweezer and atomic force microscopy measurements for understanding the mechanobiology of cell adhesion and diverse physiologic processes including hemostasis and thrombosis. How can adhesion molecules such as integrins and selectins resist substantial forces that should break receptor-ligand noncovalent bonds? Does the fact that many adhesion receptors have high affinity conformations that are more extended than the low affinity conformation along the cell attachment site - ligand binding site axis give them a mechanical advantage in resisting force? Can we measure this using novel receptor-ligand constructs with laser tweezers or the atomic force microscope? Does von Willebrand factor sense shear in the bloodstream and activate hemostasis because extension reveals otherwise hidden receptor binding sites?

One new area of research in the lab is von Willebrand factor and mutations that cause the important bleeding diathesis, von Willebrand disease. We are pursuing single molecule experiments, functional assays, electron microscopy, and crystallography to understand the complex mechanobiology of VWF, which is the largest soluble protein in the body and functions as a shear sensor in the vasculature to arrest arteriolar bleeding. The conformation of VWF, its binding to ligands on the vessel wall and on platelets, and its cleavage by ADAMTS13 are regulated by shear.

A second new area is malaria. We posit that the structures of important vaccine targets will reveal both interesting biology, and enable rational development of vaccines. These vaccines will focus the immune response on conserved epitopes, and avoid masking by polymorphic epitopes that pathogens often use to evade immune responses. Proteins on sporozoites are candidates for vaccines that prevent infection. We are interested in determining the structure of the sheath that surrounds sporozoites, its main component the circumsporozoite protein, and the motility protein TRAP. Proteins on gametocytes are targets for vaccines that prevent Plasmodium fertilization and infection in mosquitoes, and prevent transmission to other humans. These proteins include a family unique to Apicomplexans with 6-Cys domains, and HAP2, a putative gamete fusogen conserved in many eukaryotic phyla.

A third new area is TGF-β signaling, which regulates development, wound healing, immune responses, and tumour-cell growth and inhibition. Latent TGF-β and receptors for active TGF-β are ubiquitous; it is activation of TGF-β in the extracellular space that limits activity. We have determined a structure of the latent TGF-β1 procomplex (pro-TGF-β1), which reveals how the latency associated peptide (LAP), a 250 residue prodomain, forms a ring that shields the 110-residue growth factor from receptor-binding and participates in its activation through interactions with αV integrins and latent TGF-β binding proteins (LTBPs). We also have studied how a different cell surface protein called GARP becomes disulfide linked to latent TGF-β, and presents it for activation by integrins αVβ6 and αVβ8 that are expressed on immune cells, and bind to an RGD motif in LAP. We believe that yet another cell surface molecule that presents latent TGF-β remains to be discovered.

We are now interested in understanding how other proteins of the 33-member TGF-β family are activated, particularly TGF-β2, which lacks the RGD integrin-binding motif in its LAP sequence.  More recently, we have solved the structure of the closely related bone morphogenetic protein 9 (BMP9) procomplex, which adopts a markedly different conformation than pro-TGF-β1 that is consistent with its non-latency. These studies are further uncovering the tremendous functional and structural diversity within the TGF-β family, and a wide range of projects, all the way from knockout mice to structure determination, are in the offing.

Finally, we always strive to make connections between basic research and disease. In the past, we have found inherited defects of integrins in leukocyte adhesion deficiency, ICAM-1 as the cellular receptor for rhinovirus, and SDF-1 as the natural ligand for the HIV coreceptor CXCR4. Our discoveries of LFA-1 and LFA-3 resulted in the drugs efalizumab (Raptiva, LFA-1 antibody, Genentech) and alefacept (Amevive, LFA-3-Fc fusion protein, Biogen). We are currently developing and characterizing antibodies specific for the activated conformation of integrin I domains as therapeutics for autoimmune disease. Our work has important implications for development and improvement of therapeutics directed to many receptors.