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Biographical Article

Peter J. Reeds (February 22, 1945–August 13, 2002)¹

U.S. Department of Agriculture/Agricultural Research Service, Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030

²To whom correspondence should be addressed. E-mail: tdavis{at}bcm.tmc.edu.

Peter Reeds was a brilliant scientist, valued colleague, caring mentor, treasured friend and, all in all, a truly exceptional human being. During his almost 30 years of highly productive research, he made a number of seminal contributions to our understanding of the interactions of protein and energy metabolism, particularly as they pertain to the nutritional regulation of the growth process and to nutrient partitioning in intermediary metabolism. Of Peter’s many talents, his ability to see beyond the immediate problem and to appreciate the broader implications of specific experimental results was fundamental to his success as a scientist. He regarded apparently disparate pieces of information as clues with which to unravel the inherently complex interrelationships among biological processes. A particularly distinguishing quality, which took on an increasingly significant role for Peter in his later years, was his ability to nurture and inspire young scientists. He was able to guide without being critical, and he always demonstrated humility regardless of his numerous achievements.

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	Beginnings

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Peter graduated in 1968 from the University of Southampton in England with a First Class (with Honors) degree in physiology and biochemistry. He obtained a Ph.D. in nutritional biochemistry, also from the University of Southampton, in 1971. His doctoral research focused on the interactions between insulin and growth hormone in the regulation of muscle protein synthesis and demonstrated the synergy between their separate mechanisms of action.

	Tropical Metabolism Research Unit

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To develop his expertise in the field of nutrition, Peter Reeds carried out his postdoctoral studies from 1971 to 1974 at the Tropical Metabolism Research Unit in Jamaica under the mentorship of Professors John Waterlow and David Picou. The topic of his research, the nutritional regulation of branched-chain amino acid catabolism in skeletal muscle, was the first example of Peter’s interests in using multiple-isotope tracers to probe metabolic interactions. The research that he carried out at the Tropical Metabolism Research Unit also marked his first use of stable isotope techniques. Early on in his research, he recognized that to determine the rates of nutrient utilization, measurements of the masses of the organs responsible for these metabolic processes were necessary. Accordingly, he developed a novel ¹⁵N creatine dilution technique to measure skeletal muscle mass in malnourished infants. He used this technique to demonstrate that, under conditions of careful nutritional management, the newly laid down tissue in this population of infants was composed of proportionately more muscle mass than fat mass. This work, performed in collaboration with Alan Jackson, led to publications that remain unique in their field (1 ).

During a brief period in 1975 at the University of Ibadan in Nigeria, Peter continued his research on the genesis of severe protein-energy malnutrition, focusing this time on the role of infection. His work there contributed to the growing recognition that the etiologies of kwashiorkor and marasmus were multifactorial in nature. He also demonstrated the value of specific serum proteins in the prognosis of severe undernutrition. Thus within 4 years of his graduation, Peter established the themes of his research career: the nutritional regulation of protein and energy metabolism, the metabolic basis of nutrient requirements and the absolute necessity of in vivo studies in the investigation of these processes.

	The Rowett Research Institute

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In 1976 Peter Reeds moved from Nigeria to the Rowett Research Institute in Aberdeen, Scotland, to work under the guidance of the director, Sir Kenneth Lyon Blaxter, for whom Peter always expressed profound respect. During the ensuing decade, the practical focus of his research was on growth regulation and the nutrient requirements of farm livestock, with particular emphasis on swine. In 1980 he published the first paper in which he documented the interactions among food intake, energy expenditure and whole-body protein turnover (2 ). The following year, he showed the equivalent effects, but the separate mechanisms, whereby dietary protein, carbohydrate and triglyceride alter the rates of protein deposition in young animals. Using data obtained from both human and animal studies, he developed quantitatively based lines of argument to define the contribution of protein turnover to energy expenditure. His collaborative studies with Malcolm Fuller and Gerald Lobley on the role of macronutrient intake in the regulation of protein metabolism in farm animals yielded a series of papers that have been used extensively in models of nutrient utilization for the determination of nutrient requirements.

While at the Rowett Research Institute, Peter Reeds also carried out a series of investigations at a more fundamental level on the regulation of skeletal muscle protein turnover. In collaboration with Bob Palmer and Ronald Smith, Peter identified the role of eicosanoids as regulatory molecules in the cascade linking mechanical activity, insulin and glucocorticoids to the regulation of muscle protein turnover (3 ). He showed that the stimulation of muscle protein synthesis by both exercise and insulin requires enhanced prostaglandin synthesis and that the reduction in muscle protein synthesis by glucocorticoids is associated with a reduction in prostaglandin production. The mutual interest of Peter Reeds and Peter Garlick in the hormonal and nutritional regulation of protein synthesis forged a friendship that began at London School of Hygiene and Tropical Medicine, flourished at the Rowett Research Institute, and endured throughout a lifetime.

Peter Reeds also performed the first systematic investigations on the mechanism of action of the growth-promoting ß₂-adrenergic agonists, at the level of protein synthesis and degradation. The research was continued by Charlotte Maltin at the Rowett Research Institute and led to clinically relevant observations on the interactions between muscle innervation and adrenergic regulatory mechanisms. Thus Peter used his natural facility for integrative thinking to link diet, endocrinology and cellular metabolism into coherent models with which to describe growth regulation and energetic efficiency.

	Children’s Nutrition Research Center

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In 1987 Peter Reeds was recruited by Buford Nichols to join the Children’s Nutrition Research Center in the Department of Pediatrics at Baylor College of Medicine, thereby enabling the revitalization of his longstanding interests in human pediatric nutrition. As he began to consider human protein requirements, Peter was especially intent on understanding two aspects of growth: the relationship between appropriate growth in physical size and optimal functional development, and the contribution of individual tissues and organs to the overall nutrient requirements of the rapidly growing neonate. He pursued these interests through the combined efforts of Marta Fiorotto, who was investigating the effects of nutrient intake on the composition of early postnatal growth, and Teresa Davis, who was concerned with the hormonal regulation of muscle protein metabolism. Their research demonstrated that the amino acid needs of skeletal muscle are a primary determinant of growth in the early postnatal period and that when intake is suboptimal, the adaptations in muscle protein kinetics mitigate disruption of the functional maturation of the tissue despite a significant curtailment in net muscle protein accretion (4 ). Furthermore a combination of numerous studies showed that the high efficiency with which dietary amino acids are used for growth in the neonate is due in large part to the exquisite sensitivity of muscle protein synthesis to feeding in the neonate and that this response is mediated by the associated changes in circulating insulin and amino acids (5 ).

Another major factor that contributed to Peter’s accepting a position at the Children’s Nutrition Research Center was his realization that the use of stable isotope tracers would open the door to a more complete understanding of nutrient utilization and intermediary metabolism in the intact organism. The initial issue that he set out to examine was the metabolic fate of the nonessential amino acids. Much of the mainstream nutritional research in the twentieth century had been devoted to the identification of essential dietary nutrients and their metabolism. Peter always emphasized, however, that just because many organic nutrients were termed "nonessential" did not imply that their nutritional physiology and metabolism were unimportant. At the time that Peter was beginning to focus his attention on this issue, a number of nutritional scientists were reassessing the nature of nonessentiality within the field of amino acid nutrition, with the aim of defining more precisely the criteria for "conditionally essential." Peter was of the opinion that nonessential amino acids are of critical importance to the organism, first, because nonessential amino acids appeared to be of specific importance close to body nitrogen equilibrium and, second, because they provide the substrates for the synthesis of a wide array of intermediary metabolites that are of critical functional importance to the organism. Peter regarded the fact that through evolution, organisms had retained the ability to synthesize these molecules, as evidence of their extreme physiological importance. The problem was to measure, in an accurate and informative way, the rates and regulation of the metabolic pathways that were responsible for the synthesis of key nutrients such as the amino acids glutamate and glutamine.

In developing his research, Peter Reeds recognized and exploited the ability of selected ion monitoring mass spectrometry to follow the metabolism of labeled molecules. As applied to nutritional essentiality, the concept of the approach that he developed was simple, but its implications proved to be very important. He reasoned that if a molecule that an organism was unable to synthesize was introduced in a form in which all the carbons were ¹³C, the demonstration of the presence of only two isotopic forms (i.e., the naturally occurring, fully unlabeled form and the fully labeled tracer form) provided unequivocal evidence of nutritional essentiality without recourse to indirect end points, such as weight gain. The key conceptual development, however, was the realization that the reverse was also true, that is, when the uniformly labeled ¹³C form of a molecule that the organism could synthesize was introduced, the return of specific labeled fragments to the metabolic pool could be readily measured by selected ion mass spectrometry. Thus by measuring the relative levels of labeling in the uniformly labeled tracer and comparing those with the levels of labeling in the molecules bearing less than a full complement of ¹³C atoms, the relationship between the intake and the biosynthesis of the nonessential nutrient in question could be calculated. In the earliest study, which focused on the laying hen and was carried out in collaboration with Peter Klein and Heiner Berthold, the approach immediately revealed a number of important aspects of the intermediary metabolism of nonessential amino acids (6 ). The results demonstrated the existence of a hierarchy of biosynthetic activity among amino acids, with key molecules, such as glutamic acid, being derived almost entirely from endogenous synthesis, whereas other supposedly "nonessential amino acids," such as serine, were synthesized to a much lesser extent. Indeed, this research identified the potentially conditional essential nature of proline. Then Peter went on to demonstrate that exactly the same hierarchy existed in adult humans; he showed, moreover, the in vivo existence of two separate pathways of plasma arginine biosynthesis.

While developing the conceptual and experimental basis of an extremely powerful tool for the understanding of organic nutrient metabolism, by means of numerous collaborations, Peter Reeds continued to pursue his interest in the regulation of protein turnover. A central problem in the determination of in vivo rates of tissue protein synthesis, of which Peter wrote extensively, is the ability to accurately determine the isotopic labeling of the amino acids used as precursors for the synthesis of protein. It had been known for at least 30 years that the amino acid pools in cells were highly compartmentalized and that simple measurements of isotopic labeling in blood or tissue free amino acid pools could provide a substantially misleading estimate of the degree of labeling of the true precursor pools. Peter recognized that one approach to determine the labeling of the appropriate intracellular amino acid precursor pools was to measure the degree of labeling of rapidly turning over proteins. He carried out significant research in exploiting the labeling of the rapidly turning over protein VLDL apolipoprotein B-100 as a measure of the degree of labeling of the hepatic amino acid precursor pool. In a 1992 paper on the nutritional regulation of amino acid utilization for apoB-100 synthesis, Peter showed that one of the tracers that he was using, the nonessential amino acid alanine, equilibrated isotopically with its transamination partner, pyruvate (7 ). Furthermore he observed that there was a preferential utilization of newly synthesized alanine for hepatic protein synthesis. Moreover, he argued that if a U-¹³C form of a precursor for nonessential amino acid synthesis, such as glucose, was used, the steady-state labeling of amino acids in apoB-100 could be used to measure the overall and positional labeling of the ketoacids from which these amino acids were derived. Thus it was possible to noninvasively probe the labeling of the complex intermediary metabolite pools of the liver. This line of reasoning opened up a completely new approach to the in vivo investigation of the intersections among carbohydrate, lipid and amino acid metabolism.

This innovative combination of techniques was then applied to in vivo investigations in which pathways that previously had resisted accurate estimation were dissected. In collaboration with Farook Jahoor and Tom Jaksic, Peter confirmed the hierarchy of biosynthetic activity among nonessential amino acids in infants and demonstrated the influence of stage of development on gluconeogenic capacity in extremely low-birth-weight infants. He also identified the key role of de novo synthesis of nucleotides in the elaboration of ribonucleic acids.

Peter extended his understanding of protein kinetics to the cellular level, in particular, to the mechanisms whereby diet and disease alter the expression of molecules that are crucial for optimal function. It was generally recognized that when proteins are synthesized in a precursor form and must be posttranslationally modified, accurate estimates of their synthesis rates are precluded by the use of inaccurate precursor pool measurements and that the true labeling time of the final product is not the same as the infusion time. To overcome these problems, Peter, in collaboration with Mary Dudley, developed the "nested-infusion" approach to measure the synthesis rate of intestinal brush-border hydrolase, a posttranslationally modified protein. Instead of infusing one tracer and taking multiple samples at different times, they infused multiple, but metabolically equivalent, stable amino acid isotopomers for different lengths of time and collected a single tissue sample at the end of the infusion (8 ). In conjunction with compartmental modeling, the synthesis rates of the primary translation product, the intermediate products and the final mature product were determined. When all of these parameters were evaluated together, they provided a clear picture of how diet can influence discrete intracellular processes. Moreover the minimally invasive nature of this approach enables fairly complex intracellular events to be investigated in vivo.

Peter Reeds also expanded the use of stable isotope-labeled amino acids to the diagnosis of inherited urea cycle disorders and the evaluation of the efficacy of different treatment therapies. In collaboration with Brendan Lee, he demonstrated that the ratio of labeled urea and labeled glutamine is a sensitive index of urea cycle activity in disorders of the urea cycle and can be used to measure in vivo disease severity and the efficacy of the patient’s therapeutic management (9 ).

In a series of studies performed in collaboration with Douglas Burrin and Barbara Stoll, Peter returned to his longest-standing interest, the metabolism and utilization of dietary amino acids. This time, however, his focus was the gastrointestinal tract, which he considered to be of central importance to the overall health and nutrient economy of the organism. He recognized that maintenance of the functional and structural integrity of the organ was crucial for the survival of the organism. Within a short period, and with the use of a unique combination of multiple tracers, isotopomer distribution analysis, and trans-organ balance measurements, he characterized the high degree of metabolic compartmentation within the intestinal mucosa. Furthermore he established the key role of enteral amino acids for the maintenance of glutathione and arginine biosynthesis. This research also generated new information on the relationships between arterial and enteral amino acids and the energy and protein metabolism of the intestinal mucosa. It was demonstrated that amino acids are the primary fuel for energy generation by the gut and that dietary amino acids, not systemic amino acids, are preferably used for the synthesis of gut mucosal proteins as well as the synthesis of hepatic-derived plasma proteins (10 ). These investigations reopened the debate on the relationship between nutritional essentiality and physiological importance and led to a reappraisal of our assessment of the amino acid adequacies of common diets. Thus Peter not only generated research that is of direct practical importance to our understanding of the formulation of dietary recommendations but also did so from investigations of the underlying biology of nutrient requirements. It was in large part for his work on amino acid metabolism in the gut that Peter Reeds received the Osborne and Mendel Award in 1998 for outstanding research in nutrition from the American Society for Nutritional Sciences.

	Contributions to the National and International Nutrition Communities

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Peter Reeds made many contributions to the nutritional science community and was extensively involved in the affairs of the American Society for Nutritional Sciences. He was an associate editor of the Journal of Nutrition for many years, a councilor to the American Society for Nutritional Sciences and a member of various committees of the Society. He was a member of the editorial boards of the British Journal of Nutrition, the Biochemical Journal and the American Journal of Physiology. Peter chaired the review panel on the Human Nutrient Requirements for Optimal Function for the U.S. Department of Agriculture/National Research Institute competitive grants program and was a member of the National Institutes of Health Nutrition Study Section, as well as of the review panels of the British and Canadian Medical Research Councils. He was a world-renowned expert on protein and amino acid metabolism and served on the Dietary Reference Intake Committee of the Food and Nutrition Board of the National Academy of Sciences. He also provided the expert consultation positions on amino acid/protein requirements to national and international policy groups, such as the FAO/World Health Organization/UNU. He was a much sought-after lecturer and writer of review articles, and it was in these forums that his brilliant ability to integrate numerous scientific observations, and thereby reveal their broader implications, was readily apparent.

Peter Reeds made many seminal contributions to understanding of nutritional physiology and biochemistry as they pertain to the biology of growth. Moreover he was committed fully to elucidating the ramifications of these findings for the nutritional health of society as a whole. Peter was always concerned that the currently overwhelming preoccupation with characterizing the human genome was draining the new generation of bright minds from the enormous challenge that we still confront in fully understanding the contribution of nutrient intake to human and animal health. Thus in 2001 Peter Reeds left the Children’s Nutrition Research Center to assume a position as Professor of Animal Sciences in the Faculty Excellence Program at the University of Illinois at Urbana-Champaign, where he could teach and mentor graduate students. Peter’s sudden death on August 13, 2002, from complications of Legionnaire’s disease, was mourned by his countless friends, colleagues and members of the nutrition science community. He is buried in Champaign, Illinois.

	FOOTNOTES

 
¹ The authors were closely mentored by Peter Reeds and went on to become his scientific collaborators during his 14-year sojourn at the Children’s Nutrition Research Center.

Manuscript received 13 September 2002. Initial review completed 3 October 2002. Revision accepted 9 October 2002.

	LITERATURE CITED

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1. Reeds, P. J., Jackson, A. A., Picou, D. & Poulter, N. (1978) Muscle mass and composition in malnourished infants and children and changes seen after recovery. Pediatr. Res. 12:613-618.[Medline]

2. Reeds, P. J., Cadenhead, A., Fuller, M. F., Lobley, G. E. & McDonald, J. D. (1980) Protein turnover in growing pigs: effects of age and food intake. Br. J. Nutr. 43:445-455.[Medline]

3. Palmer, R. M., Bain, P. A. & Reeds, P. J. (1985) The effect of insulin and intermittent mechanical stretching on rates of protein synthesis and degradation in isolated rabbit muscle. Biochem. J. 230:117-123.[Medline]

4. Fiorotto, M. L., Burrin, D. G., Perez, M. & Reeds, P. J. (1991) Intake and use of milk nutrients by rat pups suckled in small, medium, or large litters. Am. J. Physiol. Regulat. Integrat. Comp. Physiol. 260:R1104-R1113.[Abstract/Free Full Text]

5. Davis, T. A., Fiorotto, M. L., Nguyen, H. V. & Reeds, P. J. (1993) Enhanced response of muscle protein synthesis and plasma insulin to food intake in suckled rats. Am. J. Physiol. Regulat. Integrat. Comp. Physiol. 265:R334-R340.[Abstract/Free Full Text]

6. Berthold, H. K., Hachey, D. L., Reeds, P. J., Thomas, O. P., Hoeksema, S. & Klein, P. D. (1991) Uniformly ¹³C-labeled algal protein used to determine amino acid essentiality in vivo. Proc. Natl. Acad. Sci. U. S. A. 88:8091-8095.[Abstract/Free Full Text]

7. Reeds, P. J., Hachey, D. L., Patterson, B. W., Motil, K. J. & Klein, P. D. (1992) VLDL apolipoprotein B-100, a potential indicator of the isotopic labeling of the hepatic protein synthetic precursor pool in humans: studies with multiple stable isotopically labeled amino acids. J. Nutr. 122:457-466.

8. Dudley, M. A., Burrin, D. G., Wykes, L. J., Toffolo, G., Cobelli, C., Nichols, B. L., Rosenberger, J., Jahoor, F. & Reeds, P. J. (1998) Protein kinetics determined in vivo with a multiple-tracer, single-sample protocol: application to lactase synthesis. Am. J. Physiol. Gastrointest. Liver Physiol. 274:G591-G598.[Abstract/Free Full Text]

9. Lee, B., Yu, H., Jahoor, F., O’Brian, W., Beaudet, A. L. & Reeds, P. (2000) In vivo urea cycle flux distinguishes and correlates with phenotypic severity in disorders of the urea cycle. Proc. Natl. Acad. Sci. U. S. A. 97:8021-8026.[Abstract/Free Full Text]

10. Stoll, B., Burrin, D. G., Henry, J., Jahoor, F. & Reeds, P. J. (1997) Phenylalanine utilization by the gut and liver measured with intravenous and intragastric tracers in pigs. Am. J. Physiol. Gastrointest. Liver Physiol. 273:G1208-G1217.[Abstract/Free Full Text]

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