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Remembering Bruce Merrifield

2008; Wiley; Volume: 90; Issue: 3 Linguagem: Inglês

10.1002/bip.20943

1097-0282

Various Chemistry Research Topics

Bruce Merrifield considered his coworkers in the laboratory as members of his other family (Figure 1). In his autobiography “Life during a Golden Age of Peptide Chemistry” he writes (page 220), “We operate quite a close-knit group, willing to help and share.” Bruce and Libby Merrifield with their children, Bruce's mother and members of the laboratory at a lab party at their home in Cresskill, New Jersey in 1969. Standing from left to right: Bruce Merrifield, Libby Merrifield, Josephine Lewis, Mrs. Lorene Merrifield with Sally in front, Nancy Merrifield, Betsy Merrifield, Arun Dhundale, Adelaide Glasson Acquaviva, Dorothy Cohen, Barbara Mitchell holding Nicole Mitchell (partially hidden from view), Alexander Mitchell, Balz Gisin, Phyllis Marglin with Stephanie and Amy Marglin in front, Arnold Marglin, Jim Merrifield, Bernd Gutte, Su Sun Wang. Sitting on the grass: Laurie and Cathy Merrifield with the family dog Friskie. (Photo courtesy of Alexander Mitchell) These feelings were best reflected in the relationships he established with his research assistants. Most of them joined Merrifield's research group immediately after graduating from college and worked closely with Bruce Merrifield on research projects that were separate from those of the graduate students and post-doctoral fellows. Merrifield's research assistants met with him every day to review the progress of the previous day's experiments and discuss the next step. Their recollections are arranged in a chronological order and reflect different stages in the life of the laboratory which were changing through the 70's, 80's, and 90's as the solid phase method became more widely accepted and Bruce Merrifield received an increasing number of academic recognitions and prizes. The first in this section is from Anita Bach Riemen who worked with Bruce Merrifield from 1968 till 1980. Chronologically, it follows the recollections of Sibilla Dale Hershey and Angela Corigliano Murphy which are published in the Personal Reflections section of this issue. Recollections of the Research Assistants Anita E. Bach Riemen Artist/Owner CCA Gallery, Zionsville, Indiana Retired from Midwest Biotech, Fishers, Indiana A LETTER TO BRUCE Dear Bruce, I worked in your lab for 12 years, eight of which I was your technician. Young, and this job being my first out of college, I had no idea what a wonderful experience this would be for me. I met people from all around the world including my future husband. Looking back I realize what a phenomenal job you did in running such a large lab. You knew what everyone was doing, and you were always on top of the situation. More importantly, you ran your lab with integrity and with openness for sharing ideas. You were always there to help when problems arose. Your door was open. Yes, there were differences and disappointments, but you never raised your voice in anger, and continued with determination and perseverance. You were not only a dedicated scientist but also a wonderful family man. I worked in your lab at a time when my own parents had moved away and I always considered you my second dad. I am grateful for the personal advice you gave me. Bruce, you are a special man and I admire you so very much. I will always keep you and your family in my heart. Love, Anita. Bonnie Guernsey Trotta Mount Kisco, New York I have the greatest admiration for Dr. Merrifield. I worked with the Merrifield team in 1973–1976 and have many vivid memories of those wonderful years. We, assistants, were always treated with extreme courtesy and were honored with being included in very sophisticated seminars and studies. My primary task was to perform amino acid analyses of synthetic peptides generated by the scientists in the lab. The lab seemed to bathe in the smell of methylene chloride, our primary solvent, and I still remember the gentle understanding Dr. Merrifield had with me the night I melted an entire linoleum floor by forgetting to detach the still from a 50 gallon drum of the methylene chloride. I find myself back at Rockefeller these days in conjunction with the NY Stem Cell Research Foundation. I have a baby granddaughter with Type I diabetes and have a prejudiced faith that this research will result in future cures of many disabilities. Lucy Naayem Eskeland Science Writer and Publisher Science2Discover, Inc., Del Mar, California Despite his successes and remarkable accomplishments, Dr. Merrifield remained a gentle and a humble human being. That is what made him a great man. I had a shaky beginning in his lab—a week after hiring me as his research assistant, I got stuck in a snow storm in Buffalo, NY, and missed a couple of work days. Then when I got back to the lab, 3 days later, I had a DMF spill, which caused me to skid and fall. Libby quickly took me to the shower—my toes shriveled like prunes, and my clothes felt like cardboard. Two days later, I became ill and was forced to miss another three work days. Dr. Merrifield was very kind to call me at home and make sure that I was all right. With all that time off, I was sure that he would fire me. I ended up working in his lab for another 3 1/2 years. Most of my work was synthesizing and purifying potential peptide vaccines, which was done in collaboration with other laboratories. Dr. Merrifield took time from his very busy schedule, to teach me the biochemistry behind each experiment. Instead of just following a written protocol, he encouraged me to develop a critical thinking approach at every step. This made my lab experience enjoyable. Dr. Merrifield loved working in the lab. Whenever time permitted, he was hard at work, synthesizing a peptide at his workbench across from mine. As time went on, he accumulated a large collection of laboratory glassware. When we ran out of a beaker, a flask, or a funnel, we knew where to find one! He and Libby were very punctual, always appearing in the lab at 9:00 am and leaving at 5:00 pm. That schedule never changed during my time in his lab. I remember many mornings when I would come in a little late and Dee, his secretary, or Libby, would let me know that he was displeased. But he was very patient, and never gave up on me. I also remember the lunches—Dr. Merrifield always made a point to invite everyone in the lab to join him at the cafeteria. His famous yearly barbecue parties at his home were also delightfully memorable. I feel privileged that while working as his research assistant, he received the 1984 Nobel Prize in chemistry—it was an exciting time! (Figure 2). He was a big influence in my decision to continue graduate studies in biomedical sciences. I will always cherish the memories during those days and feel very blessed to have known him and Libby. Bruce Merrifield with members of his group in the library of the fourth floor of Flexner Hall on October 17, 1984 after receiving the announcement of the Nobel Prize award in chemistry. From left to right: front row: Lupe Gautier-Anaya, Nagarajan Chandramouli, Emil Kaiser, Bruce Merrifield, Maqsood Sheik, Lucy Naayem Eskeland, Linda Tsai Huang, Atif Nakhla; middle row: David Andreu, Teresa Kubiak, Ellen Matheis Gurzenda, Bogumil Hetnarski, James Tam, Zong-Qu Li, Nick Pileggi, Libby Merrifield, Scott Daniels, Anantha Reddy, Susanne Leal; back row: John McDermed, Stephen Altschul, William Heath, Sam Steel, Memo Issac, Bruce Erickson, Dick Hampton, David Wang, Shabbir Kahn (Photo Courtesy of the Rockefeller University Archives). William B. Macaulay Anne Youle Stein Professor of Clinical Orthopaedic Surgery, Advisory Dean College of Physicians and Surgeons, and Director Center for Hip and Knee Replacement, Columbia University Medical Center, New York, New York As the greatest role model anyone could have, Bruce touched many lives throughout his years in an extremely positive way, but perhaps none more so than mine. Bruce was a wholesome man with the most integrity, honesty, and well developed sense of righteousness that I will ever meet, I am sure. I had the good fortune to work as a researcher in the Merrifield Lab on the fourth floor of Flexner from June of 1986 till July of 1988. I am most grateful to have the opportunity to relay some fond memories. Of course this is about Bruce, but I must tell you about myself (despite the fact that this goes against what R.B. has taught us) along the way to give you an appreciation of how much impact he has had on my life and that of my entire family. As a senior at Trinity College (Hartford, CT) in the spring of 1986, I decided that I would take a job as a research assistant at a major scientific institution in Manhattan. This would allow me to examine my options of either entering graduate school in Chemistry (which I seemed to display some facility in during College) versus entering medical school or chasing my childhood dream of becoming a physician (perhaps mastering the biological sciences which I found a struggle during the preceding 4 years). I began pounding the pavement looking for research technician jobs in New York City during a 1 week vacation in March of 1986. Dressed in a jacket and tie, I visited the Human Resource (HR) Offices at Columbia, Cornell, Mount Sinai, NYU, and Sloan-Kettering. I was getting a sinking feeling that my applications would sit in drawers, never to be read by someone who might be able to employ me. Adjacent to Cornell and Sloan-Kettering, of course, was The Rockefeller University. I had read about the Rockefeller Institute, and knew it to be a place of high repute, but always with an eye towards medical school, I had not really considered the option of seeking work on this beautiful tree-studded campus. From across the street, it seemed inviting and since I had not yet even sat down for a real interview after nearly a week's worth of meandering, I decided to visit HR at Rockefeller. I was greeted there graciously by Virginia (Ginny) Huffman who asked me to thumb through a book listing the research interests of all the labs on campus and a description of the Laboratory Heads… seven of which had previously been awarded Nobel Prizes; most recently Bruce Merrifield, Ph.D. in Chemistry. I read with great interest this listing for the Merrifield Lab because I had been a Biochemistry major at Trinity when the 1984 Nobel had been announced and was struck with the simplicity and ingenuity of the revolutionary technique, Solid Phase Peptide Synthesis (SPPS). I told Ginny that I would be happy to speak with anyone from this list of labs, but because of my background in organic and analytical chemistry, that meeting someone from the Merrifield Lab would be ideal. She stepped away to the phone and came back in a few minutes stating that I could either interview with Dr. Merrifield at that time, or in about 90 min after he had come back from lunch (a steadfast daily tradition eating with everyone from the Lab that could break away). Heart pounding, I chose the latter. I was certain I would be grilled during this interview with the Master Chemist and unless I was familiar with his last 5 publications and all the nuances of SPPS, I would be sent home having failed in my mission with no real hope that the other HR Offices would call me. Off to the Rockefeller Library I went and for 75 min I devoured as much detail about polystyrene resins, protection schemes, and bioactive peptides as I could get my hands on. Nervous as an elementary school boy being called to the Principal's Office, on the 4th Floor of Flexner I shook Bruce Merrifield's warm gentle palm with my sweaty hand. For the next 40 min we discussed the Knicks, family, and hobbies. Each time I tried to turn the discussion toward t-BOC and FMOC, Bruce really just wanted to know more about me as a person. I had been given my first life lesson by my mentor. Advancement of the Lab and the blinded pursuit of scientific accolades and success were clearly less important to him than if I would fit into the harmony of his lab and his life. I promised him 2 years after being offered the job on the spot and I returned to Trinity College knowing that I had had excellent opportunity ahead of me. For the next 2 years, along with my co-workers Jim Singer, Cecille Unson, Chandramouli, Barry Cunningham, Nick Pileggi, and Paul Harris to name a few, I continued to learn life lessons from the Mentor. I observed a devoted family man whose true joy in life was derived from being with his wife every day. Bruce and Libby raised many children who were scattered throughout the country, all successful in raising their own families and providing them with many grandchildren and merry holidays. Somehow, after just being in the lab for a few months, I knew that I had become part of his extended family and that was a nice feeling. I witnessed a most humble man who despite having climbed to the pinnacle of his field, shunned the spotlight and any additional attention that might be given him. It was rare to get him to talk about being honored in Stockholm… it made him feel uneasy. He would never complain about how he had developed skin cancer through a misguided attempt to clear his adolescent facial skin with X-rays. I once worked up the nerve to ask him why he had to purchase an expensive automated peptide synthesizer, when he had been the innovator. I half-expected that I might uncover some pent-up frustration about his failure to patent the invention. On the other hand, it was calmly explained to me that SPPS was his one gift to the World and Science and he had no regret for not trying to profit from it. At the time, I am sure I did not understand, but since the years have passed, it makes perfect sense to me now. During my time in the Lab, I met my “Libby” who happened to be working in the Cerami Lab at the time. In July of 1988, Araxi Pasagian (my wife of 20 years) and I married at the Cathedral of the Holy Trinity in the 70s on the Upper East Side. Bruce was witness to this event (with Libby, of course). My association with R.B. Merrifield and resultant maturation allowed me to matriculate at Columbia's College of Physicians and Surgeons, an institution where I currently serve as an Advisory Dean, devoting much of my time to the mentoring of impressionable young medical students. I serve as Director (Founder) Center for Hip and Knee Replacement, and was recently promoted to Full Professor and named the Anne Youle Stein Professor of Clinical Orthopaedic Surgery. I persist at CUMC in clinical research endeavors and in the treatment of large numbers of patients each year with hip fractures and arthritis of the hip and knee. This position allowed me in some small way to repay my debt to my mentor by treating his right hip fracture in September of 2003. The fracture healed and this allowed him to walk for the final three years of his life—an incredible life of an amazing man which will be inadequately honored through this collection of reminiscences. Kevin Fitzpatrick IMS Health Consulting, New York, New York I knew Dr. Merrifield from my experiences as a research assistant in his lab in the early nineties. When I started working with him, I had just finished my undergraduate studies and I was quite undirected professionally and in need of role models. One of the first things I learned about him, other than his being a Nobel Prize winner, was that he was down to earth. He had achieved a pinnacle accomplishment in the world of science and yet he would invite me and the other assistants to lunch with the lab on a daily basis. Dr. Merrifield was also a people person. He and Libby would have the lab out to their house every year for a backyard barbecue with volleyball, horseshoes and, of course, the competitive leaf raking event (Figure 3). Bruce and Libby Merrifield with current and past members of the laboratory and their guests at a lab party in their home in Cresskill, New Jersey around 1989. From left to right: sitting on the grass: Dick Hampton (with the back to the camera), spouse of Xiao Hong Ke, son of Thomas Gentry, Thomas Gentry with daughters in front, Donna Gentry, Mauro Galantino, Jonathan Tam in front Xiao Hong Ke, Greta Tam in front of James Tam, Linda Huang holding Alina Huang, Pedro Clavijo, S.A. Acharya'a and B.N. Manjula's son standing, Sardana's daughter standing, Cecille Unson, Lupe Gautier-Anaya holding Luis Anaya, David Wade, Li Gen; first row standing: Wen Liu, Arthur Felix, Tracy Durrah, guest, Meena Vaidyanathan, Emil Kaiser, Bhavani Chandranmouli holding Meera Chandarnmouli, Nira Makov, Lenore Martin, Ellen Gurzenda holding Valerie Gurzenda, Bonnie Kaiser, Janet Woolley, Cui-Rong Wu, B. N. Manjula, guests of Pedro Clavijo in front of Mohinder Sardana and Vinod Sardana, Libby Merrifield, Lene Berg, Pat Murphy, Joe Murphy, Bruce Merrifield, Shen Zhi Yi; rear row: Yian Lu, Sylvaine Tam, Ling Chang-Ying, guest, Rolf Berg (with the camera), Wo Lin Huang, Yao-Zong Lin, Jan Jezek, Don Whitney, Cathy Volin, Jim O Brien, David Andreu, Douglas Macdonald (Photo courtesy of Arthur Felix). Dr. Merrifield enjoyed mentoring. He would always take time to talk through questions or concerns one of us was facing about a reaction or experiment. Though I am sure many of our inquiries were simplistic from his perspective, he never made us feel that way. And when I asked for his recommendation to graduate school, he expressed a genuine interest in supporting me despite the fact that I was not pursuing the sciences, but an MBA instead (I think he probably saw before I did that I was not destined to be a star scientist). Dr. Merrifield personified qualities that I still aspire to: commitment to achievement, modesty, patience, and an understanding of people. I only had the chance to work with him for a few years, but these are the memories that stay with me. Douglas Macdonald Director, Drug Discovery, CHDI Foundation, Inc., Los Angeles, California Kindness, honesty, and mentor, these are three words that I would use to describe Dr. Bruce Merrifield. From the first time I met Bruce at my interview for a position in his group, he put me at ease and was genuinely interested in the work that I had conducted, even as an undergraduate. Once I began working in his group he provided advice, guidance, and encouragement to me on my assigned projects. This interest continued even after I had left his group to attend graduate school at the Boston University School of Medicine. He was even so kind to allow me to return to Rockefeller to synthesize peptides for my doctoral thesis. And while I only spent a little over two years in his laboratory, I think a commonality for us Merrifield alumni is that the time spent in his laboratory was an extremely formative period in our lives. I know that I will always treasure the advice and friendship that he showed towards me. In retrospect, he had considerable influence on the direction of my professional career. It was the experience of working in his laboratory, together with his encouragement that stimulated my interest and inspired me to pursue my doctorate degree that put me on the path to my current profession and position as Director of Drug Discovery at CHDI Foundation, Inc., a biotech company solely focused on Huntington disease. Lastly, I will especially treasure the memories of our daily lunchtime conversations. The far ranging discussions we had, together with the overall atmosphere at Rockefeller, stimulated my desire to pursue a career in the biomedical sciences. I owe Dr. Merrifield a great debt of gratitude and I will remember him often as the individual who encouraged me to strive for excellence, always leading by example. Ken Rotondi Department of Chemistry, Department of Biochemistry and Molecular Biology, University of Massachusetts-Amherst, Amherst, Massachusetts I was fortunate to work as a technician in the Merrifield lab from 1991 until 1995. I had just received my masters in organic chemistry from Penn State and was excited at the prospect of working in New York and especially at the Rockefeller, which I had been notified was looking for research assistants. As I outlined my experience to the Rockefeller personnel liaison, I recall her looking through papers, frowning and finally saying, “It looks like you would be a good match for Dr. Merrifield's laboratory.” My shock must have been obvious as she looked at me and said, “You have heard of him?” I said that indeed I had. She said she had not yet met him but had heard that he was quite nice; this was the understatement of a lifetime. She called ahead and took me to see Bruce in his office, walking around that old chest freezer with the floor fan pointed at its radiator, just to keep it limping along. Bruce and I talked about chemistry, what I had studied, and my research project. It seems that this only lasted maybe 15 or 20 min. Somehow we began talking about New York. Much of my family is in the New York City area and I know the city well. Bruce proudly showed me a photograph of the Chrysler Building he had taken from his office window years before. I found that he and Libby had been married 13 days before my parents had in 1949. Our conversation moved over many topics and he made me feel that I had known him forever. When Bruce finally said, “well, there are other things I need to get done today,” I realized that we had been talking for over an hour and a half. I apologized for taking so much of his time. He just laughed, said that he would get done what he needed to get done and said that I had the job. He then got a curious expression on his face and said; “Well, I guess I should check your references” smiled and asked me when I would like to start. When I decided to move to New York, I had thought that a year there would be a reasonable amount of time to spend. I ended up spending four and a half years in Bruce's lab. The Rockefeller felt like Oz to a young researcher, the incredible science being conducted, the parade of distinguished speakers we had the privilege of hearing each week, and, of course, the close familial feel to the Merrifield Laboratory. In my time at the Rockefeller I ate lunch with Bruce roughly a thousand times. He was very fond of the group getting together for lunch and virtually insisted upon it. I recall trying to finish a reaction and Bruce coming to the door of my lab with Emil Kaiser at his side. He announced that it was lunchtime. I told them I would be down in a bit and Bruce simply said, “ya gotta eat!” so I noted where I was in the reaction and duly went off to lunch. It was not uncommon to find 16–20 people or more around one of the large tables in the Tower dining hall. Typically the whole lab was there along with other PIs, scientists, and employees who were friends of Bruce and Libby. Even if the table was “full” the arrival of another was inevitably greeted by Bruce having us all move our chairs outward a little; there was always room for one or two more. The conversations were about any and all topics, from research problems to politics to social issues, with Bruce listening in rapt attention before jumping in with a comment or insight. I remember Bruce saying that when he first arrived at Rockefeller the lunchroom was in Founders Hall and it was scientific staff only. He said that the topic of conversation was exclusively science and that no one would be caught talking about such low matters as sports. Bruce seemed to enjoy the freedom to discuss whatever topic was on the table, so to speak, and yes, we even talked about sports occasionally. In my life I have never met another person who was as humble in the face of their celebrity and immense accomplishments as was Bruce Merrifield. Bruce had time for everyone and anyone. In walking with him through the Rockefeller tunnels, it was immediately apparent to anyone that he knew just about everybody, and everybody knew him. From the service staff to the professional staff there was no one that Bruce did not stop and greet. Additionally, there was no work in the lab that was beneath him. I was working one day, running a Lo-Hi HF cleavage in one lab, a preparative HPLC purification in another lab and analytical HPLC checks in a third. One of our support staff came in and asked me if I could take all the sliding glass doors off our equipment cabinets so she could clean them. I told her that I was busy at the moment and to ask me again later. About 5 min later, who should walk in and start removing the glass doors but Bruce, I was completely shamed and managed to find some time to take over the task. With respect to the development of solid phase peptide synthesis, my memories of Bruce serve to highlight his personality. He could be mischievous, was always humble and had the ability to see and present lessons from life. When I asked him about the, “Ah Ha” moment of conceiving SPPS he got a little grin on his face and said with a laugh that after the Nobel was awarded, “You would be amazed how many people called me up and told me they had the same idea.” He immediately became quite serious and said that in fact SPPS was an idea whose time had come and that someone was going to realize its potential. He was sure that if he had not developed it some contemporaneous scientist would have. He went on to say that he feared that it would be hard if not impossible for a piece of work such as his to be done today. He pointed out that he conceived of the idea in 1959 and worked for 4 years before publishing “Solid Phase Peptide Synthesis I. The Synthesis of a Tetrapeptide” in 1963. He stressed this, 4 years, no publications from the work. He wondered if the current pace in science would allow a Principle Investigator to tolerate a post-doc in their laboratory that long without a publication. As he often did, he credited D.W. Woolley as an excellent and patient mentor. I have tried to underscore the feeling of family that pervaded the Merrifield Laboratory. I could write enough to fill this volume and still not tell all the stories and share all the feelings. I would be willing to bet that most people who were fortunate enough to work with Bruce saw him as more than a mentor, who he certainly was, but also as a father. Indeed I felt, and feel to this day, that Bruce and Libby are surrogate parents of mine. Their interest in the individuals in the lab went far beyond the merely scientific and career level, their advice on matters of the heart and soul was as good as any best friend. Libby, he was lucky to have you and you him. Bruce, I will always love and miss you. Recollections of the Graduate Students Michael W. Draper Medical Fellow, Lilly Research Laboratories, Indianapolis, Indiana There are many great scientists, and Bruce Merrifield is certainly among the greatest. However, not all great scientists rank high in their human qualities, but Bruce stands alone in this regard. He is certainly one of the kindest, most compassionate, and most considerate individuals I have ever met. When I first approached him in 1970, with the proposal that I work on my doctoral thesis in his laboratory, he received me with open arms. During my entire association with him, he was a constant and supportive teacher and mentor. He always had time for me, and we had numerous discussions about my ideas, my research plans, and my results, and he always gave me the kind of support and encouragement so vital to the success of a graduate student. I was among the many colleagues in Bruce's lab who knew that his priorities were always ordered with our success ahead of even his own personal scientific goals. Bruce was a delight at scientific meetings, where his presentations were always well-organized and cogent, and presented with great dignity and even appropriate humor. Many less gifted scientists were critical of some of his work, but I always saw Bruce behave with grace and compassion, even when occasionally presented with situations that would have elicited angry reactions from some of us. I have other wonderful memories of Bruce, Libby, and their family. We were invited to an annual autumn event at their place in New Jersey. The food and fellowship was always wonderful, and my kids still remember jumping into the leaf piles in their yard, even though they were very young at the time. Bruce's life was a model of the finest work of a scientist. His scientific contributions were appropriately recognized by the Nobel and other important prizes. His contributions as a husband, a father, a friend, a mentor—the finest of human beings—are perhaps even a greater legacy. Norman Kagan Director, The Albert Faille Wilderness League, Minneapolis, Minnesota Dr. Merrifield was a steadfast supporter. Though I was working on synthetic porphyrin chemistry and not peptide synthesis, I was given the same warm regard as others in the laboratory. One recollection from my time with the group was of a summer's afternoon that had gone wrong. It was a warm sunny day in August of 1974 with only a few of us at work. Rather than convene our usual end of week luncheon review, someone suggested we take in a movie at an air conditioned theater. I had noticed that a musical version of “Flash Gordon” was playing at the art theater by the south side of the Plaza Hotel on Fifth Avenue, and we headed out. I think there were five of us: Dr. Merrifield, Balz Gisin, Bob Hodges, Alex Mitchell, me and maybe Bob Feinberg. It turned out that the film was “Flesh Gordon,” an erotic spoof of the 1930s classic, but we went in anyway. I cannot recall if the movie was amusing or not as I was mortified, being a grad student with his mentor. Mercifully, it was not long and it was only us guys there. Afterwards, we walked back to the Rockefeller in silence and resumed our work. Dr. Merrifield never said an unkind word, about this or any other errors that I had made. Arthur Pomerantz Surgical Oncology Associates of South Florida, West Palm Beach, Florida My best remembrance of Bruce Merrifield was how kind he was to all of us in a