# Reinhold Benesch
**Reinhold Benesch** (13 August 1919 – 30 December 1986) was a Polish-born American biochemist who spent his career working out how hemoglobin carries and releases oxygen, first at the [Marine Biological Laboratory](https://www.edgepedia.org/marine-biological-laboratory) and then as professor of biochemistry at Columbia University's College of Physicians and Surgeons.[1](https://www.nature.com/articles/325576a0) • [2](https://www.sciencehistory.org/education/scientific-biographies/reinhold-benesch-and-ruth-erica-benesch/) • [3](https://www.nytimes.com/1987/01/01/obituaries/dr-reinhold-benesch-biochemist-dies-at-67.html) According to a biographical notice, he is best known for identifying 2,3-diphosphoglycerate (DPG) as the molecule that regulates hemoglobin's oxygen affinity, a discovery made with his wife and lifelong collaborator, Ruth Erica Benesch. A Nobel chemistry laureate wrote that the discovery "opened a new era" in knowledge of the respiratory system.[1](https://www.nature.com/articles/325576a0) • [4](https://www.nytimes.com/2000/04/04/nyregion/ruth-benesch-75-biochemist.html)
| Fact | Detail |
|---|---|
| Born – died | 13 August 1919 (Poland) – 30 December 1986 (New York)[1](https://www.nature.com/articles/325576a0) • [2](https://www.sciencehistory.org/education/scientific-biographies/reinhold-benesch-and-ruth-erica-benesch/) |
| Field | Biochemistry of hemoglobin: oxygen transport, the Bohr effect, allostery[2](https://www.sciencehistory.org/education/scientific-biographies/reinhold-benesch-and-ruth-erica-benesch/) |
| Signature work | "How Do Small Molecules Do Great Things?", *New England Journal of Medicine*, 1969[5](https://www.nejm.org/doi/abs/10.1056/NEJM196905222802112) |
| Key discovery | 2,3-diphosphoglycerate as the regulator of hemoglobin's oxygen affinity (1966–1967)[1](https://www.nature.com/articles/325576a0) • [6](https://doi.org/10.1016/0006-291x(67)90228-8) |
| Training | BSc, University of Leeds, 1941; PhD, Northwestern University, 1950[2](https://www.sciencehistory.org/education/scientific-biographies/reinhold-benesch-and-ruth-erica-benesch/) |
| Collaboration | 125 joint papers with his wife, all but 13 on hemoglobin[1](https://www.nature.com/articles/325576a0) |
| Institutions | Marine Biological Laboratory, Woods Hole; Columbia University College of Physicians and Surgeons[7](https://www.pnas.org/doi/abs/10.1073/pnas.44.9.848) • [3](https://www.nytimes.com/1987/01/01/obituaries/dr-reinhold-benesch-biochemist-dies-at-67.html) |
## Early life and training
Benesch was born in Poland in 1919 and fled the country to escape anti-Semitism, earning his undergraduate degree at the [University of Leeds](https://www.edgepedia.org/university-of-leeds) in 1941.[2](https://www.sciencehistory.org/education/scientific-biographies/reinhold-benesch-and-ruth-erica-benesch/) His first research served the British war effort: by feeding hens sulfanilamide, which inhibits the carbonic anhydrase needed for eggshell calcification, he produced shell-less "floppy" eggs.[1](https://www.nature.com/articles/325576a0)
In England he met his future wife, Ruth Erica Leroi; according to the [Science History Institute](https://www.edgepedia.org/science-history-institute)'s biography, she had fled [Nazi Germany](https://www.edgepedia.org/nazi-germany) in 1939 and graduated from London University in 1946, and the two married the same year and emigrated to the United States in 1947.[1](https://www.nature.com/articles/325576a0) • [2](https://www.sciencehistory.org/education/scientific-biographies/reinhold-benesch-and-ruth-erica-benesch/) He entered graduate school at [Northwestern University](https://www.edgepedia.org/northwestern-university), taking his PhD in 1950.[2](https://www.sciencehistory.org/education/scientific-biographies/reinhold-benesch-and-ruth-erica-benesch/)
## Career at Columbia and earlier laboratories
His joint research with his wife dates at least to 1958, when they published "Thiolation of Proteins" in *PNAS* with affiliation to the Marine Biological Laboratory at Woods Hole, Massachusetts.[7](https://www.pnas.org/doi/abs/10.1073/pnas.44.9.848) At Columbia he was a professor of biochemistry sharing a research laboratory with his wife at the College of Physicians and Surgeons, where they worked together for the last 20 or so years of his life.[1](https://www.nature.com/articles/325576a0) • [3](https://www.nytimes.com/1987/01/01/obituaries/dr-reinhold-benesch-biochemist-dies-at-67.html) The couple signed some joint work with the initials "R 2 B 2".[2](https://www.sciencehistory.org/education/scientific-biographies/reinhold-benesch-and-ruth-erica-benesch/)
## Representative work
**Haemoglobin H.** His 1961 *Journal of Biological Chemistry* paper "The Chemistry of the Bohr Effect", co-authored with his wife, showed that hemoglobin H, an abnormal hemoglobin consisting of four beta polypeptide chains, has no [Bohr effect](https://www.edgepedia.org/bohr-effect), an oxygen affinity roughly ten times that of normal hemoglobin A, and no heme-heme interaction, from which they concluded that interactions between alpha and beta chains are essential for normal oxygen affinity.[8](https://doi.org/10.1016/s0021-9258(19)76403-5) Two *Nature* papers followed: "Isomeric forms of Hæmoglobin H" (1 June 1962)[9](https://pubmed.ncbi.nlm.nih.gov/13867177/) and "Properties of Hæmoglobin H and their Significance in Relation to Function of Hæmoglobin" (*Nature* 202:773–775, 1964).[10](https://doi.org/10.1038/202773a0) Their first hemoglobin work also disproved reports that the protein's sulfhydryl groups contribute to the Bohr effect, though they found the sulfhydryl reagent N-ethylmaleimide halves the alkaline Bohr effect.[1](https://www.nature.com/articles/325576a0)
**DPG and oxygen delivery.** In 1925 an earlier researcher had found considerable quantities of 2,3-diphosphoglycerate in mammalian red cells, but its function remained a mystery for over 40 years.[5](https://www.nejm.org/doi/abs/10.1056/NEJM196905222802112) A 1966 *PNAS* paper on subunit exchange and ligand binding set out the mechanism of the allosteric effect in hemoglobin,[11](https://www.pnas.org/doi/abs/10.1073/pnas.56.4.1268) and a 1967 paper in *Biochemical and Biophysical Research Communications* examined the effect of organic phosphates from the human erythrocyte on hemoglobin's allosteric properties.[6](https://doi.org/10.1016/0006-291x(67)90228-8) One obituary dates the DPG discovery to 1967; the *New York Times* obituary dates it to 1966.[1](https://www.nature.com/articles/325576a0) • [3](https://www.nytimes.com/1987/01/01/obituaries/dr-reinhold-benesch-biochemist-dies-at-67.html) Benesch and his wife showed that one mole of DPG combines with one mole of deoxy- but not oxyhaemoglobin, lowering oxygen affinity in a physiologically advantageous way, and they determined the thermodynamics of DPG binding and its influence on the Bohr effect.[1](https://www.nature.com/articles/325576a0) In practical terms, hemoglobin releases oxygen wherever carbon dioxide builds up in the body, delivering oxygen to the tissues that need it most.[2](https://www.sciencehistory.org/education/scientific-biographies/reinhold-benesch-and-ruth-erica-benesch/)
**The 1969 essay.** In "How Do Small Molecules Do Great Things?" (*New England Journal of Medicine*, 22 May 1969, vol. 280, pp. 1179–1180), Benesch argued that DPG acts by complexing hemoglobin in the deoxygenated state, a reaction that inhibits oxygen binding but facilitates oxygen unloading at physiologic oxygen tensions, making the small phosphate molecule an essential cofactor of the oxygen carrier.[5](https://www.nejm.org/doi/abs/10.1056/NEJM196905222802112)
**Methods.** The work depended on techniques they developed themselves: methods for stripping DPG from hemoglobin and the introduction of bis-Tris buffer (pK 6.5), which made oxygen equilibrium measurements reproducible.[1](https://www.nature.com/articles/325576a0) Their last joint paper used an invented method for measuring dissociation constants of weakly bound ligands to show that DPG and ATP bind to alpha-beta dimers rather than to oxyhaemoglobin tetramers.[1](https://www.nature.com/articles/325576a0)
## Standing in the history of biochemistry
A retrospective review of hemoglobin allostery names Reinhold Benesch among the major discoverers of the heterotropic interactions that influence oxygen binding, specifically the binding of organic phosphate anions such as diphosphoglycerate.[12](https://pubmed.ncbi.nlm.nih.gov/6986293/) The same review notes that this effect, although fully as important as proton binding and carbon dioxide binding, was not discovered for about half a century after the cooperative and carbon dioxide effects of hemoglobin were first described in 1904.[12](https://pubmed.ncbi.nlm.nih.gov/6986293/) Reinhold died on 30 December 1986, from complications of lymphatic cancer at Columbia-Presbyterian Medical Center.[1](https://www.nature.com/articles/325576a0) • [3](https://www.nytimes.com/1987/01/01/obituaries/dr-reinhold-benesch-biochemist-dies-at-67.html) • [2](https://www.sciencehistory.org/education/scientific-biographies/reinhold-benesch-and-ruth-erica-benesch/)
## References
1. Perutz, M. F., "Reinhold Benesch (1919–1986)", *Nature* 325, 576 (1987). https://www.nature.com/articles/325576a0
2. Science History Institute, "Reinhold Benesch and Ruth Erica Benesch". https://www.sciencehistory.org/education/scientific-biographies/reinhold-benesch-and-ruth-erica-benesch/
3. "Dr. Reinhold Benesch, Biochemist, Dies at 67", *The New York Times*, 1 January 1987. https://www.nytimes.com/1987/01/01/obituaries/dr-reinhold-benesch-biochemist-dies-at-67.html
4. "Ruth Benesch, 75, Biochemist", *The New York Times*, 4 April 2000. https://www.nytimes.com/2000/04/04/nyregion/ruth-benesch-75-biochemist.html
5. Benesch, R., "How Do Small Molecules Do Great Things?", *N Engl J Med* 280:1179–1180 (1969). https://www.nejm.org/doi/abs/10.1056/NEJM196905222802112
6. https://doi.org/10.1016/0006-291x(67)90228-8
7. Benesch, R. and Benesch, R. E., "Thiolation of Proteins", *PNAS* 44(9):848–853 (1958). https://www.pnas.org/doi/abs/10.1073/pnas.44.9.848
8. https://doi.org/10.1016/s0021-9258(19)76403-5
9. "Isomeric forms of Hæmoglobin H", *Nature*, published 1 June 1962. https://pubmed.ncbi.nlm.nih.gov/13867177/
10. Benesch, R. and Benesch, R. E., "Properties of Hæmoglobin H and their Significance in Relation to Function of Hæmoglobin", *Nature* 202:773–775 (1964). https://doi.org/10.1038/202773a0
11. "Subunit exchange and ligand binding. II. The mechanism of the allosteric effect in hemoglobin", *PNAS* 56(4):1268–1274 (1966). https://www.pnas.org/doi/abs/10.1073/pnas.56.4.1268
12. "Hemoglobin and the origins of the concept of allosterism", PubMed record. https://pubmed.ncbi.nlm.nih.gov/6986293/
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