sexta-feira, 15 de janeiro de 2010

Victor Herbert (1927–2002)

Biographical Article

Victor Herbert (1927–2002)

John M. Scott1
Biochemistry Department, Trinity College, Dublin 2, Ireland

1To whom correspondence should be addressed. E-mail:
In his favorite place, New York City, Victor Herbert (MD, JD, MACP, FRSM London) passed away on 19 November 2002. He lived for 75 years, most of them studded with events and controversies even to the end. In his field of research and teaching, it was clear to all that Victor had left an outstanding and lastingcontribution. However, he made this contribution over his long career with a passion and conviction that not infrequently bruised and bemused some of his colleagues. Most of his colleagues recognized Victor’s brilliance and accommodated his, at times, overzealous behavior. However, Victor did not suffer fools gladly and in Victor’s book, this was by no means a rare condition. He could be outspoken, often at quite public venues, and in the quiet conventions of academia, this was often a surprise.In his later years, when Victor took on the food quacks and those promulgating nutrition misinformation for their own commercial profit, his combative skills came into their own. Victor was a fearless opponent of exploitation of the public by nutrition misinformation, and he relentlessly pursued and confronted both verbally and in many articles and books those who pedaled such views. Having armed himself with a law degree along the way, Victor was not subject to the usual tactics of such people,namely, the threat of litigation. There is no doubt that Victor made a valuable contribution in research and in his latter years in espousing the cause of the consumer.

Ancestry, childhood, and military service

Victor Herbert was born in New York in 1927. His father was Irish-American and Victor was proud that his namesake, the composer Victor Herbert, was in his lineage. His father fought and died in the Spanish Civil War as a volunteer in the fight against Franco. This left Victor to be cared for by his mother, a Russian émigré of Jewish extraction when Victor was only 10. Worse was to come with the death of his mother 3 years later, leaving Victor at the age of 13 spending a number of years in orphanages until he enlisted in the U.S. Army in 1944 at the age of 17. Victor recalled his time in the 82nd Airborne division during World War II with fondness and humor. He had some great reminiscences about his various army experiences in WW II, Korea, and more recently, in Iraq. One was never quite sure if some of these were apocryphal. For example, at a recent symposium in Arnheim, Victor recounted how he had dropped in there several decades earlier (by parachute). It is clear, though, that Victor loved the U.S. Army and was rightfully proud of the fact that he was a retired Lt. Colonel in the Green Berets.


After doing his bit fighting Hitler, as Victor would have recounted, he did a B.S. in Chemistry in Columbia, enrolling in 1946 and graduating in 1948. This was followed by a medical degree completed in 1952. He began an internship in the Walter Reed Army Center, which was interrupted by a further tour of duty during the Korean War with Victor eventually finishing his residency training at the Albert Einstein College of Medicine in New York.

Early scientific career

It was his intention to continue in Hematology in New York when one of those career events happened to him that was to have a profound effect on his future. He was offered a research post by one of the outstanding medical scientists of the day, namely, Robert Castle, at the prestigious Thorndike Laboratory, an outpost of the Harvard Medical School situated at the Boston City Hospital. Here Victor spent 5 years that were to form the basis of a research insight and training that were to sustain him for several decades. He also became interested in the absorption and metabolism of vitamin B-12 to which he made several important contributions, even at that early stage (1). As discussed later, it also set the scene for Victor’s most important and lasting contribution, namely, the Methyl Trap Hypothesis (2).
Another career fundamental developed at the Thorndike was his interest in folate and how its deficiency led through the various stages of megaloblastic anemia. He identified the stages of the development of folate deficiency, events that Victor demonstrated on himself by going on his famous folate deficiency diet (3). He showed that evidence of biochemical deficiency was progressively followed by the development of the classical anemia characterized by the appearance of abnormal red cell precursors called megaloblasts in the bone marrow. This latter observation required repeated bone marrow aspirations. When Victor nearly died of heart failure from the potassium depletion induced as a side effect of his thrice-boiled diet, many others would have abandoned the experiment as a close call with fatality. In contrast, he saw the recognition of this potassium deficiency as a triumph of his diagnostic skills and continued with the diet but now in the presence of potassium supplements. Another product of these early days was Victor’s interest in the laboratory assays for the early detection of folate and B-12 deficiency (4). He was at the forefront of the radiometric binding assay using intrinsic factor or ßlactoglobin to measure vitamin B-12 and folate, respectively (5,6). After he left the Thorndike in 1964, Victor was appointed Associate Director of Hematology at Mount Sinai Hospital. In 1970, he moved to his final research home at the Bronx Veterans Administration Hospital where he held various senior positions until his death.

My time in Victor Herbert’s laboratory

My first personal contact with Victor Herbert was when he visited my laboratory in Dublin in 1971. I had returned 3 years earlier from 2 years as an NIH postdoctoral fellow with Jesse Rabinowitz at the University of California-Berkeley where I had established an interest in folate. I was thus very pleased and flattered that somebody of Victor’s reputation would visit my laboratory, which was just then taking its early steps. I was even more flattered when Victor asked me to go and work with him in his laboratory in New York on an extended sabbatical. While I had reservations about leaving my newly founded laboratory, Victor was very persuasive and, in the event, my wife, Bella, our two children (aged 1 and 3 y), and I took ourselves off to New York for almost 2 years. Victor and his wife, Marilyn, could nothave been kinder to us. He set us up in an apartment near their home and our two families became close friends.
On the laboratory side, in retrospect, Victor did not need somebody like me getting in his way. Victor was essentially an ideas man, a practice at which he excelled more than anybody else that I have ever met. He was highly intelligent, doing a Columbia law degree and still running his laboratory during my time there. He had a vast knowledge of the literature. He also had great clinical intuition. He would work out from the literature and his clinical knowledge what was probably going on in some interesting area. He then gathered enough data to put this together in a form that he could submit for publication. My going on about intra- and interassay variations, replicating experiments that had already worked, only served to slow Victor down. He took all of this with good humor and fortunately did not let it get in the way of his flow of ideas or his use of the literature and clinical knowledge to produce publications, many of which have withstood the test of time. This was the way Victor had always worked best and I will cite later a few examples by way of illustration. During my time with Victor, a bit of him brushed off on me. I learned the value of taking a broader approach, of looking at the literature in a more general way, looking to see if the explanations that were being offered made clinical sense.
Perhaps Victor’s most celebrated contribution to the field was the Methyl Trap Hypothesis. This hypothesis is usually accredited in the literature to Herbert and Zalusky, 1962 (2) but also to Noronha and Silverman, 1962 (7). Victor was always very insistent that he first expressed this concept in 1961. He did this based on his observation of the literature and his own experience, namely, that there was an accumulation of plasma folate in subjects who were known to have vitamin B-12 deficiency. In his eventual paper in 1962 (2), he quotes four references of his own from 1961 to this effect. Victor’s laboratory experience was that people with vitamin B-12 deficiency had at least normal, and frequently, high levels of folate, which he suggested was "probably 5-methyltetrahydrofolate." Victor reasoned that this was due to the backing up of 5-methyltetrahydrofolate in the cells with consequent deprivation of the folate cofactors needed for synthesis. All Victor knew was that there was an accumulation of 5-methyltetrahydrofolate in the plasma of vitamin B-12 deficient patients. Did this mean that it was also accumulating in cells? Victor figured it had to be; in fact, in that paper, he and Zalusky said that "piled up" folate would tend to reduce the amount of folic acid available for other one-carbon unit transfers. Did he set up elaborate experiments to show that? No, Victor was quite happy that others would fill in these details, as indeed they did over the following decades.
Another high point in Victor’s career was Victor’s self-inflicted folate deficiency and the resultant biochemical and clinical consequences of such deficiency (3). If one asked at a graduate seminar of today did they think that a study with an n = 1 would be published and frequently cited, they would probably find that hard to imagine. As we all know, that is exactly what happened. No need for statistics if your data are convincing enough, as Victor would have seen it.
Killman et al. (8) developed the Deoxyuridine Suppression Test but it was Victor who saw the real potential of taking replicating bone marrow aspirates from subjects with vitamin B-12 and folate deficiency and challenging these cells with added folic acid or other folates, antifolates, vitamin B-12, alcohol, or drugs (9). His many papers using the Deoxyuridine Suppression Test gave a plethora of information and insight into the role of folate and vitamin B-12 in bone marrow cell replication.
Victor’s ideas kept coming. He was founding member of the idea that serum holotranscobalamin (Holo TC) was going to be a better measure of vitamin B-12 status than total vitamin B-12 (10). Did Victor show this? He would leave that detail for others. Victor had the ideas and he was getting on with life and other ideas.
Among Victor’s many awards were the McCollum Award (1972) by the American Society of Clinical Nutrition; the Middleton Award (1978) by the Veterans’ Administration; the Robert H. Hermon Award (1986) by the American Society of Clinical Nutrition; and an Honorary Membership Award (1993) by the American Dietetic Association. Dr. Victor Herbert was the author of more than 850 scientific papers, numerous book chapters, and several books, particularly in later years, on the subject of nutritional fraud.

Lasting memories

He will be missed at the National Meetings, the Homocysteine Conferences, FASEB Summer Conferences in Saxon’s River, and in Copper Mountain and Snowmass. We all have lasting memories at such meetings of Victor being first to the microphone. His interjections were frequently to remind some young investigator who had just had some scientific "breakthrough" that Victor had thought of and published it already. Inevitably, for many, when they went back and looked, it was there. Perhaps not with great numbers or great experimental detail, perhaps even in an abstract. Nevertheless, it was there. I was privileged that Victor counted me among his friends and, while over the years I am sure I gave him cause to be removed from that list, it never happened. For this, I am grateful.

Victor Herbert (1927–2002)

2. Herbert, V. & Zalusky, R. (1962) Interrelations of vitamin B-12 and folic acid metabolism: folic acid clearance studies. J. Clin. Investig. 41:1263-1276.
1. Herbert, V. (1959) Mechanism of intrinsic factor action in everted sacs of rat small intestine. J. Clin. Investig. 38:102-109.
3. Herbert, V. (1962) Experimental nutritional folate deficiency in man. Trans. Assoc. Am. Physicians 75:307-320.[Medline]
4. Herbert, V., Baker, H., Frank, O., Pasher, I., Sobotka, H. & Wasserman, L. R. (1960) The measurement of folic acid activity in serum: a diagnostic aid in the differentiation of the megaloblastic anaemias. Blood 15:228-235.[Abstract/Free Full Text]
5. Waxman, S., Schreiber, C. & Herbert, V. (1971) Radioisotopic assay for measurement of serum folate levels. Blood 38:219-228.[Abstract/Free Full Text]
6. Herbert, V. & Gottlieb, C. W. (1966) Haemoglobin-coated charcoal assay for serum vitamin in B-12. Blood 28:130-132.[Free Full Text]
7. Noronha, J. M. & Silverman, M. (1962) On folic acid, vitamin B-12, methionine and formiminoglutamic acid metabolism. Heinrich, H. C. eds. Vitamin B-12 and Intrinsic Factor 1962:728-736 Enke Stuttgart, Germany .
8. Killman, S. A. (1964) Erythropoietic response to thymidine in pernicious anaemia. Acta Med. Scand. 175:489-497.[Medline]
9. Das, K. C. & Herbert, V. (1978) The lymphocyte as a marker of past nutritional status: persistence of abnormal lymphocyte deoxyuridine (dU) suppression test and chromosomes in patients with past deficiency of folate and vitamin B-12. Br. J. Haematol. 38:219-233.[Medline]
10. Herzlich, B. & Herbert, V. (1988) Depletion of serum holotranscobalamin II. An early sign of negative vitamin B-12 balance. Lab. Investig. 58:332-337.[Medline]

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