History

History

Origins of the Center

The origins of the Center for Cell Signaling can be traced to the 1980’s from a faculty-organized initiative called the Molecular Biology Institute and a strategic plan for the University called “Plan for the Year 2000.” This plan targeted molecular biology and cellular signaling as areas for growth and development. Provost Paul Gross appointed Robert Kadner, Professor of Microbiology, as Acting Director of the Molecular Biology Institute on May 13, 1987. A Research Service Foundation award in the amount of $10,000 was given to the Institute for the purpose of initial administrative support. In the fall of 1988, the Board of Visitors of the University of Virginia funded the Institute from the Academic Enhancement Program through the Office of the Provost. Over a period of five years (1989-1993) $1.2 million from University unrestricted endowment income was committed to the newly established Molecular Biology Institute.

The Molecular Biology Institute was to operate across administrative and geographic boundaries in order to bring together related research and scholarly activities that were distributed among several departments and schools. The Institute was composed of more than fifty faculty members with research programs in several critical areas of molecular and cell biology. Investigators were housed in eight departments in the School of Medicine and the College of Arts and Sciences. Some specific aims of the Institute were to: recruit faculty to fill in gaps in the spectrum of molecular biology research already represented at the University, especially signal transduction; to increase collaborative, interdisciplinary research and education; and to actively pursue private-sector funding.

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The Markey Center

Coincident with creation of the Molecular Biology Institute, in July of 1987 Robert M. Carey, Dean of the School of Medicine, requested $20 million in support from the Lucille P. Markey Charitable Trust (see below) to establish a new research center that would focus on “the molecular mechanisms of intracellular signaling processes.” Dean Carey proposed that the Trust support recruitment of new faculty and associated personnel, laboratory startup costs, core equipment purchase (total of $13M) plus renovation of research facilities (cost $7 M). Following evaluation of the proposal the Trust agreed in summer of 1989 to grant $6.1 million to the University of Virginia to establish what came to be known as the Markey Center for Cell Signaling. Funding began in February of 1990 with the first of five payments.

In the spring of 1990, Paul R. Gross, then University Professor of Life Sciences and Director of the Center for Advanced Studies, became the Director of both the Molecular Biology Institute and Markey Center for Cell Signaling. He accepted the appointment with the understanding it would only be until a new Director could be hired. From that time forward the Institute and Center effectively merged, in terms of mission, activities and finances. As Director, Paul Gross guided the recruitment of the first group of new faculty. A Steering Committee was established to provide oversight and guidance. Members of this Committee were Gene Block, Joyce Hamlin, Robert Kadner, J. Thomas Parsons, David Castle, Jay Hirsh, Robert Kretsinger, Avril Somlyo, Paul Gross, Donald Hunt, Kevin Lynch, and Michael Thorner. Between July 1990 and July 1992, using funds from the Markey Center for Cell Signaling six new faculty were recruited to the University in departments of Chemistry, Neuroscience, Pharmacology, Biology, and Microbiology. These faculty were assigned office and laboratory space in the individual departments. Their initial salary support, as well as substantial start-up funding for research programs were derived from funds provided by the Lucille P. Markey Charitable Trust.

The new University Hospital opened in 1990 relieving the old hospital, called the “MultiStory Building,” from duty and this structure went through a floor-by-floor renovation, with demolition of patient rooms and nursing stations and reconstruction of the entire infrastructure. The top floor was built out as faculty offices and research laboratories. The architectural firm RTKL of Baltimore, MD designed the new laboratories and OMNI Construction carried out demolition of the hospital interior, followed by construction of new facilities, during 1992-1994. The space was divided into a total of nine laboratories, six for the Center for Cell Signaling and three for faculty in the Center for Biological Timing, supported at that time by a grant from the National Science Foundation. In addition there was a conference room and autoclave/glassware washing facility to be shared by the two Centers.

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Center for Cell Signaling (1994-1999)

In parallel with renovation of the MultiStory Building the School of Medicine conducted a national search for a new Director who was to assume a leadership role in organizing the Center and recruiting faculty into the new facilities. The residual Markey Trust funds were designated for faculty and staff salaries and start-up expenses for newly recruited faculty. The selection committee was headed by John Marshall, Chair of the Department of Internal Medicine, and included Gene Block, Joyce Hamlin, Bert Litman, Kevin Lynch and J. Thomas Parsons. From the applicants, six finalists were invited for seminars, and select candidates returned for meetings with the Dean and department chairs. The Dean then had additional face-to-face negotiations and in the spring of 1994 David L. Brautigan was recruited from Brown University to become the Director of the renamed Center for Cell Signaling with appointment as Professor of Microbiology and Internal Medicine.

In November 1994 laboratories in the renovated space on the 7th floor of the MultiStory Building were first occupied. Recruitment of new faculty investigators during 1995-1996 focused on building a group that would study how cell signals regulate the process of nucleo-cytoplasmic transport and how phosphorylation pathways regulate gene expression. Transport is the process that segregates eucaroytic cells into two major compartments, nucleus and cytoplasm, and the distribution of various transcription factors that activate gene expression between compartments is regulated by signaling. Recruiting efforts were successful when three new faculty joined the Center: Ian Macara, a leader in research on small GTP binding proteins and nuclear transport, and Deborah Lannigan, investigating the role of phosphorylation in regulation of the estrogen receptor, were recruited from the University of Vermont. Bryce Paschal, a postdoctoral fellow studying nuclear import of proteins with Larry Gerace at the Scripps Institute joined the Center and accepted appointment as Assistant Professor in the Department of Biochemistry and Molecular Genetics.

Renovations to the Center were done during 1997, to bring facilities into compliance with federal safety regulations, and at the same time make more space available. The Center is in a building that has out-patient clinical services and is open to the general public, with tens of thousands of patient visits each year. All floors are serviced by a central set of four elevators and all the laboratories open onto main corridors connected to the elevator lobby. Because of concerns about security, and biological and radioactive materials, remodeling was done to close off the elevator lobby with all-glass entry doors that are controlled by electronic locks operated with an entry code from a touchpad. The stairwells on the ends of the building were equipped with one-way exits and electronic releases connected to the fire safety system. The renovations made the entire floor one secure work area, giving a completely open-door environment, enhancing the sense of openness and giving freedom of movement between different rooms and laboratories. Glass-front cabinets were built into recesses along the walls of side corridors, providing much needed storage space for laboratory supplies, in compliance with safety ordinances. Rooms built for storage were converted to working microscope rooms, and closet space was built along the corridor.

Completing the growth of the Center involved a continuous search and interview process during 1997-1999. This effort identified two additional junior faculty members whose research interests and expertise complemented the rest of the Center. Lucy Pemberton, fellow at Rockefeller University with Gunther Blobel, uses yeast genetics to study nuclear import and David Wotton, at Memorial Sloan-Kettering with Joan Massague, studies signaling via TGF-beta with special emphasis on factors that repress transcription. These new faculty joined the Center in November, 1999. This completed the growth phase of the Center and committed all the remainder of funds from the L. P. Markey Trust.

During this period the Center was home base for two significant educational outreach activities. A two year grant from the Dwight D. Eisenhower program of the US Department of Education provided support for a “Teachers Teaching Teachers” program. This engaged over 20 high school science teachers from Fairfax County VA with two master teachers to train and demonstrate a hands-on investigative approach to teaching high school science. The program was administered from the Center for Cell Signaling, with primary instruction at the Thomas Jefferson High School for Science and Technology in Fairfax, VA, and multiple visits and some program activities in Charlottesville. Faculty and graduate student specialists from the UVA Curry School of Education participated and provided program assessment with specific quantitative instruments, interviews and a summary evaluation. A handbook for teachers “Experiments with Enzymes” based on program activities was printed and distributed by the State Board of Education to every high school in the Commonwealth. A second outreach program involved a collaboration with the City of Charlottesville and Piedmont Virginia Community College (PVCC). David Brautigan proposed a biotechnology training program to prepare laboratory specialists as part of its workforce development initiative. This program was adopted by PVCC, approved by the State Board, and implemented as part of the curriculum. PVCC faculty were trained in molecular biology and biochemistry in the Center for Cell Signaling and the Center provided administrative and staff support for the program. UVA faculty and staff continue to the present time to participate in the biotech program courses and the biotech curriculum advisory committee. This has made significant and on-going links between UVA and PVCC. Further, a partnership of University, City, PVCC and private organizations created a biotechnology training facility that was first housed in a converted beauty parlor on West Main St. and used for PVCC classes. This facility was later moved along with other PVCC classrooms and non-profit organizations into the Connected Community Technology Center on Grove St. just two blocks from the Medical Center. These are examples of where the Center for Cell Signaling has effectively represented the School of Medicine and the University in relations with a local community college, City government, and state-wide education programs.

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Center for Cell Signaling (1999-2004)

The past five years of the Center have been a period of internal development and maturation, coupled with leadership and participation in SOM and University initiatives. Each of the new Assistant Professors attracted graduate students and research assistants and commenced independent research programs. Multiple grant applications were prepared and submitted and extramural funding from private foundations (American Cancer Society, March of Dimes) and from National Institutes of Health has been secured. Scientific discoveries by our new faculty groups produced results that were published in top-tier peer-reviewed journals. All junior faculty have developed robust research programs, participated fully in department-based teaching, advising and committee assignments and have been promoted on or ahead of schedule.

Center for Cell Signaling members also have played an important role over the past five years in the development and application of cell imaging technology in the School of Medicine and University-wide. This involved obtaining two major extramural grants, a $1M grant from the W. M. Keck Foundation (1999-2003) and a $400K shared instrumentation grant from the National Center for Research Resources (NCRR). David Brautigan was Principal Investigator for the Keck Program that established the Keck Center for Cellular Imaging, housed in Gilmer Hall with the Department of Biology in the College and Arts & Sciences. This new Center has provided sophisticated microscopy facilities, developed algorithms for FRET imaging, and built and operated multiphoton microscopy systems. Investigators from across grounds, including Chemistry, Neurology, Engineering and other departments have benefited from the facilities, expertise and hands-on assistance. Seminars and courses for the University community and two international workshops have been organized by the Keck Center and these benefited from involvement and participation of faculty, students and staff from the Center for Cell Signaling. Professor Ian Macara secured the NCRR grant for a Zeiss 510 confocal microscope, and as Principal Investigator he also became the faculty director of the School of Medicine Advanced Microscopy Facility (AMF), which as the primary confocal laboratory has three separate microscope imaging systems, and is now located within Center for Cell Signaling space. Macara’s research program depends heavily on sophisticated cellular imaging, and he has a key role in keeping the AMF at the cutting edge of new developments, which benefits the entire University research community.

The Center for Cell Signaling pioneered an in-house academic drug discovery and training program named PharmaBiologicals. The concept was to combine the expertise of Center and School of Medicine investigators on cancer cell biology and biochemical assays, in particular for protein kinases, with the expertise of Chemistry Department on natural products isolation and synthesis. This program was to train students and fellows in the process of drug discovery starting from high-throughput screening. Chemistry Professor Sid Hecht possessed a unique resource - a library of extracts from diverse plant species. These extracts were arrayed into 96 well microplates for robotic screening and employed assays for protein kinases from cell signaling pathways related to human cancer to identify bioactive chemicals. The Center for Cell Signaling dedicated laboratory space, and with support from the UVA Cancer Center purchased a state-of-the-art robotic liquid handling workstation manufactured by Tecan®, like that used in the pharmaceutical industry. Industry support allowed two Center faculty Deb Lannigan and Assistant Professor of Pathology (research) Jeffrey A. Smith to find an extract with high specific inhibitory activity and the Chemistry team isolated the active chemical species and determined its structure. A patent has been filed on this compound called SLO101 for possible therapeutic applications and the Center research team of Lannigan and Smith is pursuing translational development of this as a drug for cancer therapy. Overall, this has been a successful experiment in combining University resources in cell signaling and chemistry, and has spurred new program activities in the Cancer Center that involve future directions for the Center for Cell Signaling.

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Paul R. Gross, Founding Director

 

Paul

Paul R. Gross

Paul Gross earned his BA and PhD degrees at the University of Pennsylvania and was a National Science Foundation postdoctoral fellow at the University of Edinburgh. He joined the faculty of the University of Virginia in the fall of 1986, after serving nine years as President and Director of the Marine Biological Laboratory in Woods Hole, Massachusetts. Earlier faculty positions were held at New York University, Brown University, Massachusetts Institute of Technology, and the University of Rochester, where he chaired the Biology Department and served as the University Dean of Graduate Studies.

A developmental and molecular biologist, Dr. Gross was one of the first to fuse these two disciplines. In the process, he helped to establish training programs in this interdisciplinary field of inquiry at Brown, MIT and the University of Rochester. Among his discoveries is "maternal messenger RNA," a of macromolecules in the egg which control early embryonic development.

Dr. Gross was elected to the American Academy of Arts and Sciences of 1982. From 1986 through 1989 he served as Vice President and Provost of the University of Virginia, occupying the Robert C. Taylor Chair in the Department of Biology. During his tenure as Provost, Dr. Gross had a key role in securing institutional support for the Molecular Biology Institute which evolved into the Center for Cell Signaling. He served as Director of the Center for Advanced Studies from 1989 to 1995, and Director of the Molecular Biology Institute and the Markey Center between 1990 and 1994. Dr. Gross retired from the University of Virginia and returned to Cape Cod in 1996 to write and lecture on science, society and culture.

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The Kentucky Lady: Lucille P. Markey

Lucille Parker was born to a hardscrabble life in Lewis County Kentucky in the small town of Tollesboro on December 11, 1888, to a father who was a livery stable operator and a mother who, though wheel-chair-bound, reared seven children. Lucille would later change this information. Years later, as the heiress of Calumet Thoroughbred Farm, she would tell wealthy friends in Kentucky Bluegrass Country that her ancestors were the Parkers of Maysville, a very prominent family that had large tobacco holdings and a successful warehouse business.

GeneMarkey

Gene Markey and Lucille P. Markey, holding her Yorkshire terrier Timmy Tammy, pose for a photograph used on a Christmas greeting card.

Calumet Farm was famous, and eventually infamous, in Kentucky's renown bluegrass region. The thoroughbred horse stable, with its striking devil's-red-and-blue silks on the backs of the jockeys, produced eight Kentucky Derby winners--two of which, Whirlaway and Citation, went on to win the American racing Triple Crown in 1941 and 1948, respectively. For more than 60 years, Calumet was a byword for consistency and winning quality both on the track and in the breeding shed.

Calumet was founded in 1924 by William Monroe Wright (1851-1931), a miller's son and Chicago-based ace salesman who amassed one of the greatest fortunes in America after developing an improved baking powder, which he called Calumet. For Wright, who enjoyed a good horse and the thrill of a sporting wager, buying a 407-acre farm in Kentucky where he could breed and raise trotting horses seemed natural.

William Wright's son Warren Wright (1875-1950) was an accomplished business man in his own right. He engineered one of the biggest mergers of the 1920s, the $32 million buyout of the Calumet baking powder company by Postum, one of the major deals on the way to the birth of General Foods Corp. William Wright then retired to Lexington to enjoy his horses, taking son and astute businessman Warren along to handle the business aspects of thoroughbred horse breeding.

Warren Wright met Lucille Parker in Chicago and plucked her from her working-class existence there, then deposited her into the fairy-tale life of multimillionaires and Kentucky socialites. But as Lucille P. Wright, she was never invited into the winner's circle with her husband when Calumet's horses won. She stayed strictly in the background. Her only publicized role at Calumet was in naming the horses. She also remained in his shadow socially, and they rarely entertained in Lexington during the 1930s, although they were invited to the best of the legendary bluegrass bashes.

Warren Wright's death in 1950 at age 75 had little real impact on the thoroughbred racing team he had assembled after his father's death. His estate was valued at approximately $20 million in stocks, bonds, cash, oil and gas properties in 7 states, a mansion in Miami and, of course, Calumet Farm. Under the terms of his will, his widow, Lucille, then 62 years old, could have sold the farm. Instead she accepted the challenge of being "Mrs. Calumet." Her opportunity to stand in the winner's circle had finally come. Shortly after his funeral, she told her staff, "I want you all to continue to run the farm exactly like Mr. Wright taught you to do." The Farm continued to thrive, and Lucille Wright became the imperious dowager queen of Calumet.

After Warren Wright's death, Lucille Wright blossomed, creating a new life barely resembling the old. She kept Calumet but sold her Miami estate and purchased a mansion in the Bel-Air district of Los Angeles. It was in Hollywood during 1950-51 that she met the man who really turned her life into a fairy tale: Gene Markey, a man known for his flair for the dramatic.

LucilleMarkey

Lucille P. Markey (left) and cosmetics magnate Elizabeth Arden enjoy high society with the Prince Aly Khan, at a party in the Calumet log cabin.

In 1952, Lucille Wright married Rear Admiral Gene Markey (1895-1980), the thrice-divorced (from Joan Bennett, then Hedy Lamarr, then Myrna Loy) Hollywood writer and raconteur. During the 30s he had written and produced movies in Hollywood, probably best known for producing "Wee Willie Winkie," starring Shirley Temple in 1937. His movie "Glory," filmed at and around Calumet, was a spin-off of a racing movie classic "Pride of the Bluegrass." Gene Markey was also a decorated WWII war hero, earning the Bronze Star, the Legion of Merit, the French Legion of Honor and other commendations. He served on the staff of Admiral William F. "Bull" Halsey in the Third Fleet at Guadalcanal. When Gene Markey arrived at Calumet, it was like a cabaret moving into a mausoleum. Movie stars came to visit, parties lasted all night, and Gene and Lucille Markey and their beloved Calumet Farm became an important focus of social activity in Bluegrass Country.

 

Despite the distractions,Calumet continued to flourish. Lucille Markey's contributions toward Calumet's dominance in the field of racing and breeding were considerable. She traveled the world but returned to Calumet for spring and fall racing at Keeneland and Churchill Downs as her schedule and health permitted. She supervised many of the thoroughbred matings which produced champion after champion at Calumet.She was also the final arbiter inmajor decisions affecting both the farms and racing stock. Between 1951 and her death in 1982, Calumet homebreds went to the post in the Kentucky Derby eight times, winning with Hill Gail (1952), Iron Liege (1957), Tim Tam (1958) and Forward Pass (1968). There were many winners and plenty of glory, peaking in 1978 with the legendary Alydar who won the prestigious pre-Derby race, the Blue Grass Stakes, then ran second to Affirmed in all three races of the Triple Crown in 1978.

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The Lucille P. Markey Charitable Trust

At the time of Lucille P. Markey's death in 1982, Calumet Farm was worth $37 million and her personal assets totaled $300 million. She left not a cent to her family, expressing in her will that her son Warren Wright, Jr and his family were amply provided for by the multimillion dollar estate left in trust to them by her first husband, Warren Wright Sr.

Lucille P. Markey, probably sensitized to the importance of medical research during Gene Markey's decline and eventual death from colon cancer in 1980, decided to leave her entire estate to biomedical research. The Lucille P. Markey Charitable Trust was created under the Last Will and Testament of Mrs. Markey at the date of her death on July 24, 1982, in Miami Beach. The bulk of her estate came to the Trust, $300 million. The Trust commenced operation in October 1983, when it received the initial distribution from Mrs. Markey's estate. During the 1980s and early 1990s, earnings on the assets in the stock market and from gas and oil properties ballooned the value of the Trust to approximately $500 million. Mrs. Markey's will stipulated that the Trust cease operation by 1997 and that all assets and earnings be dispersed by that time. The Trust closed June 30, 1997.

Mrs. Markey had directed that the Trust's assets be used exclusively for "supporting and encouraging basic medical research." Awards were made under the direction of the Board of Trustees including its Director for Medical Sciences, Dr. Robert J. Glaser, formerly Dean of Schools of Medicine at Stanford University and the University of Colorado and faculty member of the Schools of Medicine at Harvard University and Washington University. During the life of the Trust, awards totaling approximately $500 million were made to medical schools and research institutes throughout the United States. The most significant awards were made for establishment and continuing support of research centers and programs. Smallerawards were made in support of permanent endowments, graduate studies and postdoctoral fellowships.

 


Source Material

Auerbach, Ann Hagedorn. 1994. Wild Ride: the rise and fall of Calumet Farm, Inc., America's premier racing dynasty. Henry Holt and Company.

Desens, Carl. 1994. Death of a Thoroughbred. A review of Wild Ride, in Business Week, May 30, 1994.

Private communication from Kentucky Derby Museum, Louisville, Kentucky.

Photo Credits

Lucille and Gene Markey: Melinda Markey Bena.

Lucille Markey, with Prince Aly Khan and Elizabeth Arden: Bertha Cochran Wright and Henryk de Kwiatkowski: Lexington Herald-Leader.