A Comment on Historical Analysis in Biochemistry Jack S. Cohen, Franklin H. Portugal Perspectives in Biology and Medicine, Volume 18, Number 2, Winter 1975, pp. 204-207 (Article) Published by Johns Hopkins University Press DOI: https://doi.org/10.1353/pbm.1975.0011
For additional information about this article https://muse.jhu.edu/article/405495/summary
Access provided at 19 Nov 2019 17:19 GMT from University of Cambridge
A COMMENT ON HISTORICAL ANALYSIS IN BIOCHEMISTRY JACK S. COHEN* and FRANKLIN H. PORTUGAL^
Two authors have recently propounded what amount to historical formulae in analyzing the history of biochemistry. H. V. Wyatt's analysis of citations to the important paper by Avery, MacLeod, and McCarty [1] on transformation of pneumococci by DNA led him to conclude that "information ... is unrecognized until it is transformed into knowledge" [2]. However, citations are clearly inadequate as a means to determine the true impact of a given scientific contribution, not only because of subjectivity in the choice of citations. In the specific case of Avery et al.'s work on transformation, the results were known to most of the individu-
als most capable of assimilating them. These included Salvador Luria [3] of the "phage group"; Rollin Hotchkiss, who remembered "serious discussions on the subject with Delbrück, Cohen and especially Hershey in the period 1949-51" [4]; Joseph Fruton, who remembered "discussions at the lunch room of the Rockefeller Institute after Dr. Avery gave his
paper" [3]; and individuals present at discussions of this work at the Cold Spring Harbor Symposium in 1946 and elsewhere [5, 6]. Very little of these extensive personal contacts would be reflected in literature citations. Others have criticized Wyatt's analysis on similar grounds [7, 8]. Günther Stent, in analyzing the response to Avery et al.'s discovery, and several other discoveries which were seemingly ignored, has defined the concept of "prematurity" [9, 10, H]; that is, "a discovery is premature if its implications cannot be connected by a series of simple logical steps to canonical, or generally accepted knowledge" [9].1 This provocative concept, while it may be a tautology [3], appears to be very similar to the position taken by Arthur Koestler that discovery is "the perceiving of a situation or idea in two self-consistent, but habitually incompatible, frames of reference," a process which he termed "bisociation" [14]. *Reproduction Research Branch, National Institute of Child Health and Human De-
velopment, National Institutes of Health, Bethesda, Maryland 20014.
tViral Carcinogenesis Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20014. 'Similar views have been expressed by George W. Beadle [12, p. 31] and A. D. Hershey [13, p. 106],
204 I Jack S. Cohen and Franklin H. Portugal · History of Biochemistry
Whatever the respective merits of these historiographical formulae, they do tend to ignore the unique aspects of situations to which they are meant to apply in favor of their supposed similarities. In doing so they
do not tell us why a particular discovery might be judged "premature." For example, it is commonly believed that Gregor Mendel's discovery of genetic inheritence was completely forgotten from its publication in 1866 until its "rediscovery" in 1900, independently by de Vries, Correns, and Tschermak. Stent cites this as a prime example of "prematurity" [9]. It is interesting to note that Mendel had an extensive correspondence with Karl Nageli, a leading physiologist of his day [15, p. 56], and that Carl Correns was one of Nageli's students at that time [15, p. 137]. There were also several citations to Mendel's work in the period
1866-1900—for example, in the systematic listing by the botanist W. O. Focke published in 1881 [15, pp. 103, 137].
In the case of Avery et al.'s work on transformation by DNA, it is useful to know that World War II, which was still in progress, diverted attention; that Avery was an old man (67 years) at the time this work was published; and that he had a reserved temperament [16]. Several people questioned Avery's conclusions in the light of the prevalent belief in the genetic primacy of proteins.2 Also, unfortunately, experimental followups by Avery's associates [19, 20] to answer objections to the work were largely ignored. For example, the paper by Maclyn McCarty and O. T. Avery, entitled "Studies on the Chemical Nature of the Substance Inducing Transformation of Pneumococcal Types. II. Effect of Deoxyribonuclease on the Biological Activity of the Transforming Substance" [19], was (and is) rarely cited. In the summary of this paper it is stated: 2Alfred Mirsky, working at the Rockefeller Institute, has been mentioned as one of the chief questioners of DNA as the transforming substance by Hotchkiss [5] and Stent [17, p. 180], Mirsky's views at the time are most clearly expressed as: "Avery and his colleagues have shown decisively by inactivation experiments that desoxyribose nucleic acid is an essential part of the transforming agent, and if there actually is no protein in their prep-
aration, it would be obvious that the agent consists of nothing but nucleic acid. This is a
conclusion of the greatest interest in the study of the chemical basis of biological specificity, and it should therefore be scrutinized carefully. There can be little doubt in the mind of anyone who has prepared nucleic acid that traces of protein probably remain in even the best preparations. With the tests now available for detecting how much protein is present
in a nucleic acid preparation, it is probable that as much as 1 or 2 percent of protein could
be present in a preparation of 'pure, protein-free' nucleic acid. One of the most sensitive direct tests for protein is the Millón reaction, but in our experience a nucleic acid preparation containing as much as 5 percent of protein would give a negative Millón test. At
present the best criterion for the purity of a nucleic acid preparation is its elementary
composition and especially the nitrogen:phosphorus ratio. Presence of 2 percent of protein would increase this ratio, but only by an amount that is well within the range of variation found for the purest nucleic acid preparations. No experiment has yet been done which permits one to decide whether this much protein actually is present in the purified transforming agent, and if so, whether it is essential for its activity; in other words, it is not yet known which the transforming agent is—a nucleic acid or a nucleoprotein. To claim more, would be going beyond the experimental evidence" [18, pp. 134-135].
Perspectives in Biology and Medicine · Winter 1975 | 205
"It has been shown that extremely minute amounts of purified preparations of desoxyribonuclease are capable of bringing about the complete and irreversible inactivation of the transforming substance of Pneumococcus Type III."
These and other factors presumably contributed to the delay of 8 years, until the publication of confirmatory results by Hershey and Chase in 1952 [21], before the supposed general acceptance of the fact that DNA was the transforming principle [9, H]. Nevertheless, apart from Avery's co-workers, several others were active in this field in the
intervening period, including R. Austrian, A. Boivin, S. Cohen, H. Ephrussi-Taylor, and S. Zamenhof, and many did in fact accept the
implications of the results of Avery et al. [2]. Forexample, RenéJ. Dubos wrote in 1945: "Assuming that the substance which induces transforma-
tion is really a desoxyribonucleic acid, as the evidence strongly suggests, then nucleic acids of this type must be regarded not merely as structurally important, but as functionally active in determining the biochemical activities and specific characteristics of pneumococcal cells; they possess a biological specificity, the chemical basis of which is as yet undetermined" [22, p. 187]. This was not included in the citations quoted by Wyatt [2]. For people who accepted the implications of this work, it could hardly be described as "premature." The nucleic acid component of nuclein was considered to have a possibly important role in heredity long before Avery's work. Thus, E. B. Wilson, in the second edition of his influential book The Cell, published in 1900, stated:
During the mitotic or reproductive processes this combination (protein with
nucleic acid) appears to be dissolved, the albuminous elements being in large part split off, leaving the substance of the chromosome with a high percentage of
nucleinic acid, as shown by direct analysis of the sperm nucleus and as indicated
by the staining reactions of the chromosomes. There is, therefore, considerable grounds for the hypothesis that in a chemical sense this substance is the most essential element handed on from cell to cell whether by cell division or by
fertilization; and that it may be a primary feature of the constructive processes of the nucleus and through these be indirectly concerned with those of the cytoplasm. [23, p. 358]
This statement was deleted from the third edition, published in 1925, presumably reflecting the prevalent preoccupation with proteins and the effect of the tetranucleotide hypothesis for the structure of DNA on the opinions of the author.
It should also be noted that Griffith's original description of pneumococcal transformation was published in 1928 [24], but the identity of the transforming substance was not described by Avery et al. until 1944 [2]. In view of these facts, one should, perhaps, consider Avery et al.'s discovery "belated," as were so many other aspects of the 206 I Jack S. Cohen and Franklin H. Portugal · History of Biochemistry
understanding of the true nature of DNA. Since a discovery can hardly be "premature" and "belated" simultaneously, it is preferable to discard such labels as being unnecessarily deterministic. Our work on the history of DNA [25] gives us no reason to presume that the history of science is more of a science than history. REFERENCES
1.O. T. Avery, C. M. MacLeod, and M. McCarty. J. Exp. Med., 79:137, 1944.
2.H. V. Wyatt. Nature, 235:86, 1972.
3.Proc. Conf. Hist. Biochem. MoI. Biol., Am. Acad. Arts Sci., Boston, May 1970. Reviewed by J. Edsall. Science, 170:349, 1970.
4.R. D. Hotchkiss. Science, 169:664, 1970.
5. ---------. In: J. Cairns, G. Stent, and J. D. Watson (eds.). Phage and the origins of molecular biology, p. 180. Cold Spring Harbor, N.Y., 1966.
6.C. Lamanna. Science, 160:1397, 1968.
7.J. Lederberg. Nature, 239:234, 1972. 8.R. Olby. Nature, 239:295, 1972. 9.G. Stent. Sci. Am., 227(6): 84, 1972. 10. ---------. Science, 160:664, 1398, 1968.
11. --------- . The coming of the golden age: a view of the end of progress. New York: Natural History Press, 1969.
12.G. W. Beadle. In: J. Cairns, G. Stent, and J. D. Watson (eds.). Phage and the origins of molecular biology. Cold Spring Harbor, N.Y., 1966. 13.A. D. Hershey. In: J. Cairns, G. Stent, and J. D. Watson (eds.). Phage and the origins of molecular biology. Cold Spring Harbor, N.Y., 1966.
14.A. Koestler. The act of creation: a study of the conscious and unconscious in science and art. New York: Macmillan, 1967.
15.C. Stern and E. R. Sherwood. Origins of genetics: a Mendel source-book. San Francisco: Freeman, 1966. 16.R. D. Hotchkiss. Genetics, 51:1, 1965.
17.G. Stent. Molecular genetics. San Francisco: Freeman, 1971.
18.A. E. Mirsky and A. W. Pollister. J. Gen. Physiol., 30:117, 1946. 19.M. McCarty and O. T. Avery. J. Exp. Med., 83:89, 1946.
20.R. D. Hotchkiss. Colloques Int. Centre Natl. Rech. Sci. (Paris), 8:57, 1949. 21.A. D. Hershey and M. Chase. J. Gen. Physiol., 36:39, 1952. 22.R. Dubos. The bacterial cell. Cambridge, Mass.: Harvard Univ. Press, 1945.
23.E. Wilson. The cell in development and inheritance. 2d ed. New York: Macmillan, 1900.
24.F. Griffith. J. Hyg. (Camb.), 27:113, 1928. 25.F. H. Portugal and J. S. Cohen. DNA: a critical history of the first century. Cambridge, Mass.: M. I. T. Press (in press).
Perspectives in Biology and Medicine · Winter 1975 ¡ 207
For additional information about this article https://muse.jhu.edu/article/405495/summary
Access provided at 19 Nov 2019 17:19 GMT from University of Cambridge
A COMMENT ON HISTORICAL ANALYSIS IN BIOCHEMISTRY JACK S. COHEN* and FRANKLIN H. PORTUGAL^
Two authors have recently propounded what amount to historical formulae in analyzing the history of biochemistry. H. V. Wyatt's analysis of citations to the important paper by Avery, MacLeod, and McCarty [1] on transformation of pneumococci by DNA led him to conclude that "information ... is unrecognized until it is transformed into knowledge" [2]. However, citations are clearly inadequate as a means to determine the true impact of a given scientific contribution, not only because of subjectivity in the choice of citations. In the specific case of Avery et al.'s work on transformation, the results were known to most of the individu-
als most capable of assimilating them. These included Salvador Luria [3] of the "phage group"; Rollin Hotchkiss, who remembered "serious discussions on the subject with Delbrück, Cohen and especially Hershey in the period 1949-51" [4]; Joseph Fruton, who remembered "discussions at the lunch room of the Rockefeller Institute after Dr. Avery gave his
paper" [3]; and individuals present at discussions of this work at the Cold Spring Harbor Symposium in 1946 and elsewhere [5, 6]. Very little of these extensive personal contacts would be reflected in literature citations. Others have criticized Wyatt's analysis on similar grounds [7, 8]. Günther Stent, in analyzing the response to Avery et al.'s discovery, and several other discoveries which were seemingly ignored, has defined the concept of "prematurity" [9, 10, H]; that is, "a discovery is premature if its implications cannot be connected by a series of simple logical steps to canonical, or generally accepted knowledge" [9].1 This provocative concept, while it may be a tautology [3], appears to be very similar to the position taken by Arthur Koestler that discovery is "the perceiving of a situation or idea in two self-consistent, but habitually incompatible, frames of reference," a process which he termed "bisociation" [14]. *Reproduction Research Branch, National Institute of Child Health and Human De-
velopment, National Institutes of Health, Bethesda, Maryland 20014.
tViral Carcinogenesis Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20014. 'Similar views have been expressed by George W. Beadle [12, p. 31] and A. D. Hershey [13, p. 106],
204 I Jack S. Cohen and Franklin H. Portugal · History of Biochemistry
Whatever the respective merits of these historiographical formulae, they do tend to ignore the unique aspects of situations to which they are meant to apply in favor of their supposed similarities. In doing so they
do not tell us why a particular discovery might be judged "premature." For example, it is commonly believed that Gregor Mendel's discovery of genetic inheritence was completely forgotten from its publication in 1866 until its "rediscovery" in 1900, independently by de Vries, Correns, and Tschermak. Stent cites this as a prime example of "prematurity" [9]. It is interesting to note that Mendel had an extensive correspondence with Karl Nageli, a leading physiologist of his day [15, p. 56], and that Carl Correns was one of Nageli's students at that time [15, p. 137]. There were also several citations to Mendel's work in the period
1866-1900—for example, in the systematic listing by the botanist W. O. Focke published in 1881 [15, pp. 103, 137].
In the case of Avery et al.'s work on transformation by DNA, it is useful to know that World War II, which was still in progress, diverted attention; that Avery was an old man (67 years) at the time this work was published; and that he had a reserved temperament [16]. Several people questioned Avery's conclusions in the light of the prevalent belief in the genetic primacy of proteins.2 Also, unfortunately, experimental followups by Avery's associates [19, 20] to answer objections to the work were largely ignored. For example, the paper by Maclyn McCarty and O. T. Avery, entitled "Studies on the Chemical Nature of the Substance Inducing Transformation of Pneumococcal Types. II. Effect of Deoxyribonuclease on the Biological Activity of the Transforming Substance" [19], was (and is) rarely cited. In the summary of this paper it is stated: 2Alfred Mirsky, working at the Rockefeller Institute, has been mentioned as one of the chief questioners of DNA as the transforming substance by Hotchkiss [5] and Stent [17, p. 180], Mirsky's views at the time are most clearly expressed as: "Avery and his colleagues have shown decisively by inactivation experiments that desoxyribose nucleic acid is an essential part of the transforming agent, and if there actually is no protein in their prep-
aration, it would be obvious that the agent consists of nothing but nucleic acid. This is a
conclusion of the greatest interest in the study of the chemical basis of biological specificity, and it should therefore be scrutinized carefully. There can be little doubt in the mind of anyone who has prepared nucleic acid that traces of protein probably remain in even the best preparations. With the tests now available for detecting how much protein is present
in a nucleic acid preparation, it is probable that as much as 1 or 2 percent of protein could
be present in a preparation of 'pure, protein-free' nucleic acid. One of the most sensitive direct tests for protein is the Millón reaction, but in our experience a nucleic acid preparation containing as much as 5 percent of protein would give a negative Millón test. At
present the best criterion for the purity of a nucleic acid preparation is its elementary
composition and especially the nitrogen:phosphorus ratio. Presence of 2 percent of protein would increase this ratio, but only by an amount that is well within the range of variation found for the purest nucleic acid preparations. No experiment has yet been done which permits one to decide whether this much protein actually is present in the purified transforming agent, and if so, whether it is essential for its activity; in other words, it is not yet known which the transforming agent is—a nucleic acid or a nucleoprotein. To claim more, would be going beyond the experimental evidence" [18, pp. 134-135].
Perspectives in Biology and Medicine · Winter 1975 | 205
"It has been shown that extremely minute amounts of purified preparations of desoxyribonuclease are capable of bringing about the complete and irreversible inactivation of the transforming substance of Pneumococcus Type III."
These and other factors presumably contributed to the delay of 8 years, until the publication of confirmatory results by Hershey and Chase in 1952 [21], before the supposed general acceptance of the fact that DNA was the transforming principle [9, H]. Nevertheless, apart from Avery's co-workers, several others were active in this field in the
intervening period, including R. Austrian, A. Boivin, S. Cohen, H. Ephrussi-Taylor, and S. Zamenhof, and many did in fact accept the
implications of the results of Avery et al. [2]. Forexample, RenéJ. Dubos wrote in 1945: "Assuming that the substance which induces transforma-
tion is really a desoxyribonucleic acid, as the evidence strongly suggests, then nucleic acids of this type must be regarded not merely as structurally important, but as functionally active in determining the biochemical activities and specific characteristics of pneumococcal cells; they possess a biological specificity, the chemical basis of which is as yet undetermined" [22, p. 187]. This was not included in the citations quoted by Wyatt [2]. For people who accepted the implications of this work, it could hardly be described as "premature." The nucleic acid component of nuclein was considered to have a possibly important role in heredity long before Avery's work. Thus, E. B. Wilson, in the second edition of his influential book The Cell, published in 1900, stated:
During the mitotic or reproductive processes this combination (protein with
nucleic acid) appears to be dissolved, the albuminous elements being in large part split off, leaving the substance of the chromosome with a high percentage of
nucleinic acid, as shown by direct analysis of the sperm nucleus and as indicated
by the staining reactions of the chromosomes. There is, therefore, considerable grounds for the hypothesis that in a chemical sense this substance is the most essential element handed on from cell to cell whether by cell division or by
fertilization; and that it may be a primary feature of the constructive processes of the nucleus and through these be indirectly concerned with those of the cytoplasm. [23, p. 358]
This statement was deleted from the third edition, published in 1925, presumably reflecting the prevalent preoccupation with proteins and the effect of the tetranucleotide hypothesis for the structure of DNA on the opinions of the author.
It should also be noted that Griffith's original description of pneumococcal transformation was published in 1928 [24], but the identity of the transforming substance was not described by Avery et al. until 1944 [2]. In view of these facts, one should, perhaps, consider Avery et al.'s discovery "belated," as were so many other aspects of the 206 I Jack S. Cohen and Franklin H. Portugal · History of Biochemistry
understanding of the true nature of DNA. Since a discovery can hardly be "premature" and "belated" simultaneously, it is preferable to discard such labels as being unnecessarily deterministic. Our work on the history of DNA [25] gives us no reason to presume that the history of science is more of a science than history. REFERENCES
1.O. T. Avery, C. M. MacLeod, and M. McCarty. J. Exp. Med., 79:137, 1944.
2.H. V. Wyatt. Nature, 235:86, 1972.
3.Proc. Conf. Hist. Biochem. MoI. Biol., Am. Acad. Arts Sci., Boston, May 1970. Reviewed by J. Edsall. Science, 170:349, 1970.
4.R. D. Hotchkiss. Science, 169:664, 1970.
5. ---------. In: J. Cairns, G. Stent, and J. D. Watson (eds.). Phage and the origins of molecular biology, p. 180. Cold Spring Harbor, N.Y., 1966.
6.C. Lamanna. Science, 160:1397, 1968.
7.J. Lederberg. Nature, 239:234, 1972. 8.R. Olby. Nature, 239:295, 1972. 9.G. Stent. Sci. Am., 227(6): 84, 1972. 10. ---------. Science, 160:664, 1398, 1968.
11. --------- . The coming of the golden age: a view of the end of progress. New York: Natural History Press, 1969.
12.G. W. Beadle. In: J. Cairns, G. Stent, and J. D. Watson (eds.). Phage and the origins of molecular biology. Cold Spring Harbor, N.Y., 1966. 13.A. D. Hershey. In: J. Cairns, G. Stent, and J. D. Watson (eds.). Phage and the origins of molecular biology. Cold Spring Harbor, N.Y., 1966.
14.A. Koestler. The act of creation: a study of the conscious and unconscious in science and art. New York: Macmillan, 1967.
15.C. Stern and E. R. Sherwood. Origins of genetics: a Mendel source-book. San Francisco: Freeman, 1966. 16.R. D. Hotchkiss. Genetics, 51:1, 1965.
17.G. Stent. Molecular genetics. San Francisco: Freeman, 1971.
18.A. E. Mirsky and A. W. Pollister. J. Gen. Physiol., 30:117, 1946. 19.M. McCarty and O. T. Avery. J. Exp. Med., 83:89, 1946.
20.R. D. Hotchkiss. Colloques Int. Centre Natl. Rech. Sci. (Paris), 8:57, 1949. 21.A. D. Hershey and M. Chase. J. Gen. Physiol., 36:39, 1952. 22.R. Dubos. The bacterial cell. Cambridge, Mass.: Harvard Univ. Press, 1945.
23.E. Wilson. The cell in development and inheritance. 2d ed. New York: Macmillan, 1900.
24.F. Griffith. J. Hyg. (Camb.), 27:113, 1928. 25.F. H. Portugal and J. S. Cohen. DNA: a critical history of the first century. Cambridge, Mass.: M. I. T. Press (in press).
Perspectives in Biology and Medicine · Winter 1975 ¡ 207
