By George Barany^a and Svetlana Mojsov^b
a University of Minnesota, Twin Cities
^b The Rockefeller University

The American Peptide Society is proud to share with its membership an 88-minute video entitled “Peptide and Protein Synthesis: Origin and Development“, created in 2001 under the leadership of Professor Bruce Merrifield of The Rockefeller University. We do so on the auspicious occasion of the 60th anniversary of Merrifield’s transformative sole-authored paper “Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide” in the July 20, 1963 issue of volume 85 of the Journal of the American Chemical Society (JACS) on pages 2149–2154.

With the ushering in of a new millennium and Bruce Merrifield’s 80th birthday on the horizon, an ad hoc group of peptide scientists, consisting of, in alphabetical order, Art Felix, Elizabeth “Libby” Merrifield, Alexander R. Mitchell, Svetlana Mojsov, James P. Tam, and Cecille Unson, along with Bruce Merrifield himself, conceived of the idea to create a video that would teach the principles and highlight notable successes of the peptide field. Further, the video aimed to provide historical perspective, going all the way back to Emil Fischer and Theodor Curtius at the beginning of the 20th century, and touching on the contributions of giants such as Max Bergmann, Miklos Bodanszky, Louis Carpino, Vincent du Vigneaud, Joseph Fruton, Ralph Hirschmann, Klaus Hofmann, Josef Rudinger, Frederick Sanger, Bob Sheppard, Robert Schwyzer, Theodor Wieland, Erich Wünsch, and Leonidas Zervas, among many others. The story was to be told, as much as possible, through the words and images of those field-shaping practitioners who were still active as of the time the video was created.

Although the project started on a decidedly amateur basis (see below), Jim Pfeiffer was soon brought on board to produce the work, and David Kampman was recruited to narrate the film. Financial support was provided through generous donations from the American Peptide Society, Aventis Pharma/Selectide, Lilly Research Laboratories, Mixture Sciences Inc., and the Pels Family Center, along with individual contributions from George and Barbara Barany, Robert and Betsy Feinberg, David Live, Garland and Suzanne Marshall, and Thomas P. Sakmar.

The first video interviews took place in July 2000, in dimly lit hotel rooms during the Sixth Chinese Peptide Symposium at Huangshan, China. There, with James P. Tam serving as interlocutor and Cecille Unson handling a Sony H18 MP camcorder, the reminiscences and perspectives from Yu-Cang Du, Victor J. Hruby, Garland R. Marshall, and Yun-Hua Ye were memorialized. The project picked up momentum in mid-September of the same year, at the 26th European Peptide Symposium in Montpellier, France, where Tam and Unson conducted filmed interviews with, in alphabetical order, David Andreu, Sándor Bajusz, Leo Benoiton, Christian Birr, Dieter Brandenburg, Charles M. Deber, Alex N. Eberle, Mati Fridkin, Murray Goodman, Vadim Ivanov, John Jones, Günther Jung, Horst Kessler, Yoshiaki Kiso, Teresa Kubiak, Gotfryd Kupryszewski, Rao Makineni, Maurice Manning, Jean Martinez, Luis Moroder, Abraham Patchornik, Robert Ramage, Raniero Rocchi, Shumpei Sakakibara, Peter Schiller, Ian Smith, John M. Stewart, Claudio Toniolo, Dan Veber, and John D. Wade. About a week later, David Andreu, on one of his frequent trips to Budapest, filmed a conversation he had with Kálmán Medzihradsky of the Hungarian Academy of Sciences in the latter’s office at the Eötvös Loránd University.

Continuing, David Andreu and Martin Engelhard made a pilgrimage to Aachen, Germany, in March 2001, where they interviewed Helmut Zahn and Bernd Gutte. Towards the end of April 2001, Art Felix and James P. Tam, along with videographer Jim Pfeiffer, visited The Rockefeller University campus, where they filmed Bruce Merrifield speaking from his Flexner Hall office and explaining an early model automated peptide synthesizer in his laboratory. Then, Art Felix offered his own commentaries on multiple important issues in peptide synthesis from the Flexner seminar room, and, coincidentally, Richard D. DiMarchi, who happened to be in town that same week, was interviewed in the Cohn library. During May 2001, Cecille Unson interviewed Arnold Marglin when the latter was visiting New York City from Boston and Richard A. Houghten contributed some videotaped remarks from La Jolla, California.

Bruce Merrifield had a major hand in deciding who should be interviewed and what they should be asked, and made a point of including an international roster representing academia and various branches of the chemical and biotechnology industries. Furthermore, he took charge of the narrative and layout of the evolving video.

From some 25 hours of raw footage, Merrifield and the team went through nearly a dozen script iterations, sharing an hour-long rough cut of the still-unfinished film on June 15, 2001 at a Satellite Symposium to the 17th American Peptide Symposium in San Diego, California. The final version, which incorporated important new material recorded by Kit Lam in Davis, California and James P. Tam at Vanderbilt University in Tennessee, was completed in December 2001.

The movie opens with some dramatic animations playing to Wagner’s overture to “The Flying Dutchman” and then features, in order, sections on: “Founding Fathers,” “Protecting Groups,” “Deprotection Reagents,” “Activating Reagents,” “Landmark Syntheses,” “Peptide Symposia,” “Solid Phase Peptide Synthesis,” “Automation,” “Commercial Instruments,” “Synthesis of Proteins,” “Multiple Syntheses,” “Peptide Ligation,” and “Prospects for Peptides in the Pharmaceutical Industry.”

For its closing section, “The Future,” the video relied on tape recording supplied by Arno F. Spatola from a roundtable session entitled “Perspectives for the New Peptide Millennium,” organized by George Barany and Gregg B. Fields for the 16th American Peptide Symposium in Minneapolis in June 1999. This offers insights, in order, from Arno F. Spatola, Murray Goodman, Dan Veber, Charles M. Deber, Robert S. Hodges, Robin Offord, Tom W. Muir, and Victor J. Hruby, with an optimistic final word from Bruce Merrifield. The full written complement to the aforementioned session appears on pages 797–804 in the Symposium proceedings. The video ends with a scroll of credits, while playing “Peptide Dreams,” composed and performed by Charles M. Deber. The revised version was shown in January 2003 on The Rockefeller University campus, and quite a few peptide scientists around the world received a VHS or PAL tape accompanied by a handwritten note from Merrifield.

As a bonus, the American Peptide Society is sharing The Rockefeller University’s recording of the Merrifield Memorial Symposium, held in Caspary Hall on November 13, 2006. We are grateful to The Rockefeller University Development Office for their kind permission to do so. This public event was attended by approximately three hundred people, including many former colleagues and supervisees, as well as Libby Merrifield, Libby and Bruce’s six children, Nancy Waugh, James Merrifield, Betsy Grindstaff, Cathy Edwards, Laurie Nelson, and Sally Giannandrea, with their spouses, and ten grandchildren.

The program, entitled “A Tribute to Bruce Merrifield: Celebrating his Scientific Life and Achievements,” opened with remarks from Paul Nurse, President of the University, and David Rockefeller, Honorary Chairman of the Board of Trustees. This was followed by a biographical overview of R. Bruce Merrifield, presented by Arthur M. Felix. Next, Jeffrey I. Seeman, founding editor of the American Chemical Society, ACS, “Profiles, Pathways and Dreams” series in which Bruce’s 1993 scientific autobiography, “Life During a Golden Age of Peptide Chemistry” appeared, presented a plaque commemorating Merrifield’s groundbreaking 1963 JACS paper as an inaugural recipient of the ACS Division of History “Citation for Chemical Breakthroughs.” Then, American Peptide Society (APS) President Jane V. Aldrich presented a plaque commemorating Merrifield’s life and career contributions. Both the ACS and APS plaques are now displayed at the entrance to renovated laboratories on the fourth floor of Flexner Hall, where Merrifield worked. A 12-minute video, “Invention and Development of Solid Phase Peptide Synthesis,” presented Merrifield’s description, excerpted from the larger video project, of how he came up with the idea of peptide synthesis on a solid support, SPPS.

Two scientific sessions, chaired respectively by Arthur M. Felix, morning, and Alexander R. Mitchell, afternoon, featured findings and reflections from associates and alumni of the Merrifield laboratory from their own independent careers and from their interactions over the years with Bruce. In order, the speakers were John M. Stewart, “Remembering Bruce: The Early Years,” Maurice Manning, “Personal Reflections of Bruce Merrifield,” Arnold Marglin, “Reminiscences of Bruce Merrifield,” Robert S. Hodges, “Merrifield, Ribonuclease, and Antimicrobial Peptides,” Cecille Unson, “Merrifield Laboratory: Last Member Standing,” Garland R. Marshall, “Across the Bench from Bruce – the Early Years,” Bernd Gutte, “Solid Phase Synthesis for a Lifetime,” George Barany, “Chemistry of Carbamoyl Disulfides,” Richard D. DiMarchi, “Think Different,” James P. Tam, “To Protect or not Protect: A Journey to Synthetic Protein,” and David Andreu, “The Merrifield Contribution to the Field of Antibiotic Peptides.” The Memorial closed with perspectives from Alex Mitchell and a short video clip of Bruce’s heartfelt thanks and thoughts on the occasion of the 80th birthday celebration in San Diego.

A final bonus centers on Wednesday, October 17, 1984, the day that word came from Stockholm that Merrifield had been selected as the 1984 Nobel laureate in Chemistry. The Rockefeller University hastily arranged a press conference, where Merrifield was introduced by President Joshua Lederberg to thunderous applause. Thanks to David Live, who was among those present, the American Peptide Society is delighted to share a 24-minute audio recording of the press conference, missing only Lederberg’s short introduction. Our presentation is decorated by photos provided by David Andreu, David Live, the Merrifield family, and The Rockefeller University, among others.

For more about Merrifield and his legacy, please see the 2008 memorial issue of Biopolymers: Peptide Science, volume 90, issue 3, that the two of us jointly edited–it includes a number of articles that complement invited lectures from the November 2006 event. Also, for a special treat, please click here and here to access a pair of crossword puzzles that one of us co-constructed with members of the Merrifield family to honor their parents.

Many materials relevant to the topics covered in this essay are now permanently archived at the Science History Institute (SHI), formerly the Chemical Heritage Foundation (CHF) in Philadelphia, PA, as well as the Rockefeller Archive Center in Sleepy Hollow, New York. The SHI includes a public museum, which exhibits an original solid phase peptide synthesizer with its “player piano” programming drum and all relevant glassware and hardware, especially the key rotary valves, along with the notebook in which Merrifield, on May 26, 1959, first penned his succinct and prescient vision for his new approach to peptide synthesis.

The authors are indebted to Fernando Albericio, David Andreu, Michael J. Barany, Nagarajan “Mouli” Chandramouli, Charles M. Deber, Richard D. DiMarchi, Cathy Merrifield Edwards, Art Felix, Jed F. Fisher, Gregg B. Fields, Dee Graefe, Betsy Merrifield Grindstaff, Robert P. Hammer, Noreen J. Hickok, David Live, Maurice Manning, Alexander R. Mitchell, Laurie Merrifield Nelson, Cecille Unson O’Brien, Jim Pfeiffer, Jeffrey I. Seeman, James P. Tam, Dan Veber, John D. Wade, and Nancy Merrifield Waugh for their help and encouragement at the time that this essay was prepared, and that the associated materials for the web were compiled and annotated. We also appreciate the efforts of Noah and Arthur Robinson to reconstruct the original synthesizer and organize “the notebook” for the CHF/SHI science museum, and furthermore to reproduce “the notebook” in a hard-bound volume that was distributed in March 2013 at the inaugural Bruce Merrifield Distinguished Lecture at The Rockefeller University. Finally, we are grateful to Patrick Shea and Roger Turner of CHF/SHI, Bethany J. Antos, Bob Clark, Susan E. McDade, and Margaret “Meg” Hogan Snyder from the Rockefeller Archive Center, James Carrozza, Jeff Hennefeld, Frank Hoke, Marnie Imhoff, Sandra Levy, and Teresa L. Solomon from The Rockefeller University, Justin R. Kellin, Christie L. Martin, Eric Shulz, and Chuck Tomlinson from the University of Minnesota; and Lauren Cline, Lars Sahl, and Joel P. Schneider from the American Peptide Society, all for their continued help in preserving the legacy of Bruce Merrifield.