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Supplement: Looking Ahead in Honoring the Past |
1 From the International Nutrition Foundation, Boston, MA (NSS); Global Foods and Amino Acids of Ajinomoto, Kanagawa, Japan (TK); Xanthus Life Sciences, Cambridge, MA (AAA); and the University of Vermont, College of Medicine, Burlington, VT (NKF)
2 Presented at a memorial symposium held in honor of Vernon R Young in Cambridge, MA, 12 November 2004.
3 Reprints not available. Address correspondence to NK Fukagawa, University of Vermont, College of Medicine, 89 Beaumont Avenue, Given C-207, Burlington, Vermont 05405. E-mail: naomi.fukagawa{at}uvm.edu.
INTRODUCTION
It was just 1 y ago in our favorite Italian restaurant on Cambridge Street that Vernon Young and I began to discuss the festschrift that his many friends wanted to organize for him at the Massachusetts Institute of Technology (MIT). In agreeing to this, he indicated that he wanted us to look to the future of nutrition and to highlight the new disciplinary opportunities for nutrition scientists. We wanted to schedule it early in 2004, but space was not available at MIT. With characteristic optimism, although undergoing treatment for renal cancer, Vernon insisted on November 12, the first date an auditorium would be available at MIT and near what would have been his 67th birthday on November 15.
Ultimately Vernon chose the topics, proposed the speakers, and planned today's meeting as a festschrift and we both envisioned a large and enthusiastic gathering. In his final hours in the hospital when Vernon could no longer speak, I assured him in the presence of his family, all of whom are here today, that we would hold the symposium as we planned it and he smiled. Today we honor that promise.
It is appropriate that before the scientific sessions, we begin with 3 brief presentations describing Vernon as a person, a scientist, and a visionary. The first topic is presented by Dr Takuzo Kitamura, who provided the financial support from the Ajinomoto Company of Japan that allowed Vernon to begin his pioneering research on lysine and who came to know Vernon as charismatic, sympathetic, and dedicated. Dr Kitamura has committed his company to not only the full support of this symposium but also major additional recognition.
VERNON R YOUNG, THE MAN
Presented by Takuzo Kitamura
It is a great honor to be able to co-chair this memorial symposium for Vernon Young today. Furthermore, I feel especially honored to be side by side with Dr Nevin Scrimshaw, whom Dr Young very much respected and sincerely cared for. In representing the Ajinomoto Company, I would like to explain to you the relation between the company and Vernon Young.
The company's first contact with Dr Young was in 1980 when the Food and Drug Administration held public board inquiries on the safety of aspartame. Dr Young was one of the board members, and he gave us many helpful suggestions. In the spring of 1982, we built our pharmaceutical-grade amino acid plant in Raleigh, NC, which is still the one and only pharmaceutical-grade amino acid plant in the United States. To commemorate that occasion, we asked Dr Young and 2 other prominent professors to organize the first symposium on amino acids by inviting as many leading amino acid researchers as possible of that time. The proceedings of that symposium were published the next year.
From 1995 through 1998, we pursued a project together with Dr Scrimshaw to determine the requirement level of L-lysine for human adults. The result was epoch-making. We found that what Dr Young had predicted was correct. The age-old theory concerning amino acid requirements for human adults had to be thoroughly revised. We sponsored an international symposium on glutamine in 2000 and one on arginine in 2004, both of which were organized under the leadership of Dr Young.
From 2001 through 2003, Dr Young played an important role as the head of the organizing committee for symposia sponsored by the International Council of Amino Acid Science (ICAAS). In April 2003, the Ajinomoto Company announced a new Ajinomoto Research Program to support amino acid researchers worldwide. Dr Young's contribution to this program was of course very significant, and we received the last consultation from him in January of this year.
As I mentioned earlier, we held an arginine symposium in April 2004 in Bermuda, which was to be presided over by Dr Young. But the dreadful disease captured him about this time last year and, to our surprise, he informed us by e-mail of the nature of his disease and its treatment plans elaborately. By the end of last year (2003), we began to know from his e-mails that his choice of treatment had become very limited. To unload his burden, we asked him to step down from various responsibilities he had with us. However, he turned down our proposals. It was only on February 27th that he decided not to go to Bermuda, where the arginine symposium was to be held on April 5th.
When looking back over the almost 25 y of our relationship, I find that the past 10 y deepened it very much. Dr Young's contribution to the progress of amino acids research increased every year, especially in the past 5 y. This was because Dr Young's interests in amino acids very often overlapped those of our company. He was a person who really loved research; but if he was only a studious researcher, our relation would not have been so long-lasting and versatile. In addition to his wonderful ability as a research scientist, he had the talent to attract us with his special charm as a person. Furthermore, he was a person with a strong will and responsibility toward science.
In March of this year, I proposed a visit with him on my way to Bermuda. I was surprised by his response that he wanted to have lunch with me at his favorite seafood restaurant in Boston, very near this hall. However, my appointment with him was not realized because I was informed of his death on my arrival in the United States. On the date of the luncheon appointment, I visited Mrs Young and she told me about the last words of Dr Young; what he lamented was that he could not continue his research. She told me, pointing to his room, that many papers were still scattered waiting to be completed.
Professor Young was a person who fell in love with research and continued his research until the end of his life. It was not only his pleasing personality but also his hidden strong will and sense of responsibility toward science that attracted us so much.
Furthermore, he was a person with an international heart that made us feel at home, relaxed, and comfortable. We will miss his international nature forever. To show our gratitude for Dr Young's contribution to the progress in amino acids and nutrition research, Ajinomoto company has donated $100,000 to the American Society for Nutritional Sciences.
VERNON R YOUNG, THE SCIENTIST
Presented by Nevin S Scrimshaw
As Institute Professor Emeritus, MIT, and President of the International Nutrition Foundation, I have accepted the role of describing Vernon the scientist because we worked so closely and productively together for so many years in the Department of Nutrition and Food Science at MIT, beginning with his arrival from the University of California, Davis, as a new PhD in 1966.
Vernon R Young was recognized as the world's leading expert on protein and amino acid requirements. His innovative use of stable isotopes showed that the estimated essential amino acid requirement levels universally accepted since the 1940s were much too low. These erroneous values had been endorsed by a series of FAO/WHO committees including one that met in 1981 and published in 1985. With confirmation from collaboration with Anura Kurpad in Bangalore, he proposed a new "MIT" pattern that was adopted, with minor changes, by the 2003 FAO/WHO/UNU Expert Consultation. It recognized that adult essential amino acid requirements per gram of protein needed to be increased by a factor of 2 to 3. He has reported this work and a great deal of other groundbreaking research in >600 scientific publications.
Brilliance and exceptional scientific intuition characterized his research career. Young was the first to show in humans that urinary 3-methyl histidine is a direct indicator of muscle mass. A long series of papers with me and many graduate students described the nature and variations in obligatory nitrogen losses and nitrogen utilization that established the basis for accurately determining protein requirements.
The PhD research of Cutberto Garza that we confirmed through long-term nitrogen balance studies showed that MIT students consuming the recommended protein allowance proposed by an ad hoc FAO/WHO Expert Committee in 1973 lost lean body mass and had negative nitrogen balance and other adverse metabolic changes. Young designed the multilevel, short-term and single-level, long-term nitrogen balance approaches that were adopted for the United Nations University–sponsored uniform field trials in 15 countries. The results indicated that the existing international recommended allowance for dietary protein needed to be increased by one-third. These higher values were adopted in the 1985 report of the FAO/WHO/UNU Joint Expert Consultation on Protein-Energy requirements and had a profound effect on estimates of protein deficiency in developing countries and on agricultural and health policy.
Another extended series of studies that explored protein absorption and protein quality yielded improved procedures for the assessment of the quality of proteins of both vegetable and animal origin. In this period, Young's research group completed more studies of soy protein quality than did all other laboratories in the world combined. This was also true for the evaluation of the quality for humans of single-cell proteins from yeast, bacteria, and filamentous micro-fungi.
The qualitative importance of both protein synthesis and breakdown in premature infants was first shown in his studies using 15N as a tracer. With this approach, he showed a redistribution in the pattern of whole protein metabolism with advancing age. He extended these studies to show enhanced rates of protein synthesis and breakdown in children suffering from burns. This provided a metabolic explanation for the greatly increased protein requirements of burn patients.
In a very productive collaboration with Dennis Bier, Young showed that whole-body amino acid flux, protein synthesis, breakdown, and amino acid oxidation in humans respond to the content of meals and that these responses are modulated by the protein, amino acid, and energy components of the diet. These studies led to new approaches, which were based on amino acid kinetics with the use of stable-isotope probes, for determining the quantitative need for specific indispensable amino acids.
Using stable isotopes, Young also explored the metabolism of dispensable amino acids and developed an approach for quantifying the whole-body synthesis rate of dispensable amino acids, particularly alanine, glycine, proline, and arginine. The novel method involved a simultaneous administration of 2 amino acid tracers labeled with stable isotopes. This was the first time this approach had been used and it enabled him to demonstrate the sensitivity of whole-body alanine synthesis to changes in carbon, hydrogen, and nitrogen moieties.
More recently in a series of elegant multitracer studies with arginine, ornithine, and citrulline as probes, he concluded that arginine homeostasis is achieved by a balance between intake and breakdown, with synthesis playing only a minor role. Using a novel approach, Young also developed a stable-isotope method using 15N glycine tracers to explore changes in albumin synthesis with advancing age. His findings indicated that albumin synthesis is regulated by amino acid intake at a lower set-point in the elderly than in young adults. He also played a major role in developing and applying new stable-isotope techniques for studying, in humans, the metabolism of trace minerals, such as zinc, copper, iron, selenium, and calcium.
His membership in the National Academy of Sciences, 1990, and the Institute of Medicine, 1993, of the National Academy of Sciences attest to the quality and originality of his science. He has received almost every national and international honor in the field of nutrition. With Vernon's untimely death on March 30 of 2004, nutrition science suffered a severe blow. Time and again in the months since his death I have found myself wanting to consult with him on some nutrition issue, to enthusiastically share a scientific insight with him, and most of all to be stimulated and renewed by the warmth of his friendship.
After I moved to New Hampshire in 1990, Dr Ajami became Vernon's closest scientific confidant and friend, and together they spent many happy hours planning and speculating on the future of nutrition science. Dr Ajami is the Chief Scientific Officer of the biotech firm Xanthus Life Sciences Inc with offices in Technology Square.
VERNON R YOUNG, THE VISIONARY
Presented by Alfred M Ajami
Vernon Young's friends and colleagues knew him as a major figure in the nutritional science field, a shaker and a mover, but always warm, jovial, and considerate, a man of vast intellectual capability and at the same time exceptional modesty. Having spent the better part of two and a half decades joining him for lunch across the street from his office, I can attest to also knowing him as a visionary of eclectic tastes and scientific opinions. I have files full of notes, drawn on napkins, placemats, and menus, covering the range of our discussions on chemistry and biology, peppered with forays into physics, metaphysics, and philosophy, always with the expectation that we should chart new, integrative approaches within our respective disciplines.
We lent each other books. One of mine was of particular interest to him, Volume IV in the Loeb Classical Library covering Hippocrates and Heracleitus. Although lost within the quagmire of his study for some time, he returned it while we were preparing a manuscript that he expected would set a new paradigm for the study of metabolism. The corner of a napkin marked Chapter XII of the Regimen, Book I:
"But I will show that arts are visibly like to the affections of man, both visible and invisible. Seercraft is after this fashion. By the visible it gets knowledge of the invisible, by the invisible knowledge of the visible, by the present knowledge of the future...It took more than French fries and fried clams, his staple luncheon menu, to bring out the seercraft as we grappled with ways to bridge traditional nutritional science over the wave of the future, one posited on the emerging fields of genomics and metabolomics within the larger framework of systems biology. The time had come for Heraclitean change. We decided to have lunch at the Faculty Club of that other University in Cambridge. It was there, under the watchful portrait of the Reverend Dr Hedge, founder of the Examiner Club, that Vernon and I began a collaboration that transformed my career and set the stage for his new avocation.
We were joined at that meeting in the early 1990s by the late Peter Klein on the occasion of preparing a piece to commemorate Rudolph Schoenheimer, the undisputed innovator in using isotopic tracers as tools in nutritional science. The 3 of us noted that Schoenheimer did the work, but it was Heracleitus who had coined the term metabolism and described the concept of flux. As a consequence, my book was reborrowed and then disappeared for nearly another decade. But on the positive side, from that first of many conversations with Peter Klein and others, Vernon began to recast his global thinking more in terms of chemical biology than within the narrower confines of amino acid biochemistry, in which he had already become an undisputed grandmaster but one restless to forge further ahead.
Vernon reexamined the visible as a means to uncovering the invisible. I worked with him on the integrative biology of homeostasis, and we emerged with a fresh view on how to interrogate key enzyme pathways, at the crossroads between health and disease. "Gateway" enzymes led us to examine the comparative phenomenology of "metabolic hijacking," "underground metabolism," and "moonlighting proteins." These in turn provided insights into the definition of phenotypes and biomarker processes, together with yet-to-be implemented enabling technologies for diagnosis and prognosis. He posited, and I experimented with, ways to introduce "metabolic imaging" as a therapy metric, a quantitative tool for grading responders and nonresponders to interventions. His interest with these approaches was to explore what he called the "metabolic phenotype" in a manner that would provide a more contemporary nexus to the underlying molecular and chemical biology. At the same time, his enthusiasm and encouragement guided me into a new career focus using these formalisms, still shared with him in the nutritional science context, but, in my case, applied anew as tools in cancer drug discovery and development.
We shared many new beginnings, mine of necessity, and his by the stimulus of intellectual appetite. Vernon and I attended the same seminars and workshops where we learned to clone genes. We practiced the art of sequencing and the magic of RT-PCR. Vernon even ran an experiment on one of the first CodeLink microarrays to examine the effect of graded leucine dosing on the regulation of mTOR and related genes in the hypoxia and fuel-sensing pathways. Here again the connection became evident between his pioneering work on the leucine requirement at the organismic level and the leucine requirement at the molecular level. But we never did come to a conclusion as to whether differential gene expression microarrays, when executed with all the normalizations and calculations, would be any less work than 24-h leucine infusions!
Ever the optimist over the practicability, when properly guided, of intensively computational biology, Vernon also delved into proteomics and metabolomics. He embraced all the initiatives in this arena that his colleagues at the Shriners' Burns Institute and at the Massachusetts General Hospital had put into play and planned to move his own experimental focus in a similar direction. In preparation, Vernon would visit my laboratory and observe the MALDI profiles of proteins as they emerged from the machine's workstation. We were looking at proline and leucine repeats as biomarkers in receptor regulation experiments. He and I would then ask each other, as we had so often in previous collaborations with tracer experiments, what is it about leucine and proline? Vernon watched and took note as we dissected glutamate and arginine signaling pathways by multiplexed LC/MS/MS from microdissected tumor material. He urged us to persevere in this uncharted domain, whose utility was still suspect, just as he had when years earlier we both worked on a controversial tracer method for determining arginine flux into the nitric oxide–generating cycle.
Surely if Vernon had stayed with us longer, these techniques, and more like them, would have found application in his new brand of nutritional science. Machines produce data, and data are ultimately mechanistic. One needs the vision of a true seer to make sense of it. Vernon served on corporate boards, advisory committees, and countless scientific panels. They all regarded him as a "seer." but Vernon also wanted to be a "doer." He was convinced that the translational science that had captivated his imagination in recent years needed to be embraced and shared within his field. It is now our duty in his memory to make it so.
A few weeks after discharge from the fateful surgery that brought the disappointing news, Vernon and I returned to another familiar place, again under the gaze of the Reverend Dr Hedge. We dined at the Examiner Club and sat with the late Peter Davison, discussing his collection of poems, Breathing Room, which told of both the sense of loss and the confounding hope that accompanies a visit with death during a serious illness. I had lent the book to Vernon, and he had expressed an interest in meeting the author, perhaps to converse on shared experiences. Always attuned to finding a new epigraph or metaphor as an introduction to his latest review article, and in that inimitable Welsh way of his, Vernon asked Davison to suggest a clever phrase. Davison, who always showed a keen interest in science, then pointed to the last stanza of Eliot's "Four Quartets":
We shall not cease from explorationVernon had seen this all along. We will miss him.And the end of all our exploring
Will be to arrive where we started
And know the place for the first time.
ACKNOWLEDGMENTS
The assistance of Betty Griffin, Maureen Duffy, and others at Cambridge Isotope Laboratories Inc is sincerely appreciated. None of the authors had any conflicts of interest.
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