- Email: [email protected]
Protein thermodynamics and the cognitive ecology of biomedicine
Blood Cells, Molecules and Diseases 54 (2015) 231–233
Contents lists available at ScienceDirect
Blood Cells, Molecules and Diseases journal homepage: www.elsevier.com/locate/bcmd
Review
Protein thermodynamics and the cognitive ecology of biomedicine Neil S. Greenspan ⁎,1 Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106-7728, USA
a r t i c l e
i n f o
a b s t r a c t
Article history: Submitted 16 January 2015 Accepted 21 January 2015 Available online 30 January 2015
Assessments of scientific contributions critically influence decisions about grant funding and academic promotion. Unfortunately, there is a tendency for more junior and less assertive individuals to receive less credit than deserved. Acknowledgement of the complexity of relationships among researchers and the different modes of contributing to scientific progress could improve this situation. The thermodynamics of ligand binding is arguably among the most quantitative and empirically validated theoretical frameworks that permit precise apportionment of “credit” to multiple interacting entities that collectively account for a biologically relevant outcome, in this case, receptor–ligand complex formation. The process for assigning credit for research advances to individual researchers might benefit from emulating this thermodynamic thought process by recognizing that contributions of equal quantitative significance can be of different types and can originate through indirect effects. If the hypothesis that some categories of research contribution are frequently under-valued is correct, then calling attention to this state of affairs and providing an alternative way to conceptualize the task of credit attribution has the potential to begin altering the status quo. A beginning step to improving our credit attribution process would be the empirical investigation of accounts of contributions to particular scientific advances from all research team members. © 2015 Elsevier Inc. All rights reserved.
(Communicated by M. Narla, DSc, 21 January 2015) Keywords: Scientific advance Credit attribution Cooperation Cause Protein thermodynamics
Contents Background . . . . . . . . . . . . . Presentation of hypothesis . . . . . . Testing and implications of hypothesis Competing interests . . . . . . . . . Author’s contributions . . . . . . . . Author’s information . . . . . . . . Acknowledgments . . . . . . . . . References . . . . . . . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
Background In attending research seminars over the past twenty-five years, I have on multiple occasions listened to an eminent biomedical scientist describe how a postdoc or graduate student ignored his or her advice and thereby obtained a remarkable result. While some of these scientistsin-training may have reaped the benefits appropriately associated with
⁎ Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106-7288, USA. Fax: +1 216 368 1357. E-mail address: [email protected]. 1 Courier Service: Room 5130, Wolstein Research Building, 2103 Cornell Road, Cleveland, OH 44106-7288, USA.
http://dx.doi.org/10.1016/j.bcmd.2015.01.013 1079-9796/© 2015 Elsevier Inc. All rights reserved.
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
231 232 233 233 233 233 233 233
their significant contributions, there are sometimes unfortunate disparities in the ratio of reward to achievement for such junior researchers and even for more senior investigators working as members of research teams or as members of collaborations encompassing two or more laboratories. The pressure to work in teams has increased with the rise of expensive, highly sophisticated, high-throughput technologies that demand diverse skills and substantial expertise for optimal implementation and quality control as well as data acquisition, processing, presentation, and interpretation. Recent publications have called attention to significant limitations in traditional practices in the biomedical research community pertaining to the numbers of trainees, grant reviews, and manuscript reviews [1–6]. My purpose below is to call attention to and stimulate discussion
232
N.S. Greenspan / Blood Cells, Molecules and Diseases 54 (2015) 231–233
about limitations in standard practices for the attribution of credit for scientific advances. An interesting historical instance of the scenario alluded to above came to public attention with new information about the discovery of streptomycin, the first antibiotic effective against infection by Mycobacterium tuberculosis [7]. The standard account gave virtually all of the credit to Selman Waksman, who won a Nobel Prize for the discovery in 1952. Relevant documents uncovered relatively recently suggest, however, that Albert Schatz, a graduate student with Waksman at the time that streptomycin was identified, was actually the individual most directly responsible for the isolation of the antibiotic. Waksman may deserve a portion of the credit for developing the overall research framework within which Schatz operated or for arranging for testing of the compound after the initial isolation, but it can be argued that Schatz deserved a substantially greater share of the credit than he actually received. A more recent example of what is alleged to be a somewhat similar episode came to light in the aftermath of the announcement of the 2011 Nobel Prizes. A biomedical researcher in France, Bruno Lemaitre, alleged an injustice in connection with the awarding of the 2011 prize for Physiology or Medicine to his former research colleague and one-time administrative superior, Jules Hoffmann [8]. Dr. Lemaitre was the first author of the study that dramatically demonstrated the critical role of the drosophila protein, Toll, in host defense against fungal infections [9]. This highly consequential paper helped to initiate a major new sub-field of research focused on innate immune receptors. The preceding does not consider even more disturbing instances in which an idea is shared freely in the context of anticipated collaboration and the party receiving the information pursues the same investigational goals surreptitiously. An alleged case of this sort of ethically substandard behavior is described by Southwick [10]. Or consider the case, based loosely on a real situation about which I was informed, of a junior tenure-track faculty member whose grant proposal is effectively hijacked by a more senior colleague to whom the junior investigator reports. The justification offered for the transfer of PI status to the more senior individual, who did not conceive or initiate the line of inquiry in question, was “strategic grantsmanship.” Of course, the junior faculty member in this situation would undoubtedly ask, “Strategic from whose perspective?”. As the above vignettes suggest, there is reason to question the adequacy of the standard, often reflexive, thinking used in assigning responsibility for important scientific results. Another aspect of the problem relates to investigators, often but not exclusively women, who work in a highly collaborative manner with a primary focus on answering scientific questions and less focus on career advancement within an institution or on the sort of self-promotion often required for building an independent reputation [11]. My point is not that principal investigators, the typical recipients of the bulk of the credit for new findings, are always or necessarily excessively rewarded. I fully acknowledge the extensive physical and intellectual effort required to establish a research program and initiate a particular line of investigation. However, the distribution of credit for biomedical research progress should be more fully informed by an awareness of the potential complexities of interactions among researchers. I suggest that assessments of how researchers contribute to scientific advances can be usefully informed, in a metaphorical sense, by the patterns of thinking established for assessing the interactions among the subunits that constitute biological macromolecules. Presentation of hypothesis In studying the process of ligand binding from a biophysical perspective, it is sometimes of interest to apportion the “credit” for the interaction to the various participating subunits of the receptor, the ligand, or both. In more technical language, assuming for ease of discussion that we are dealing with protein–protein interactions, the goal is to
quantitatively determine the contributions to the free energy of complex formation (i.e., the net free energy driving the noncovalent association of receptor and ligand) attributable to individual amino acids of either molecular participant. While this cognitive exercise is not generally of direct use to most biomedical scientists, and is therefore likely to be of rather modest interest to many of them, what might be called “the logic of attribution” employed in this biophysical context applies much more broadly. The central issue is how to partition causal responsibility for an event or process that is the outcome of numerous participating elements that potentially influence one another. Similar issues arise at many levels of biological organization from the atomic and molecular scales of receptor–ligand interactions all the way “up” to the interactions among the sometimes functionally diverse members of research teams and well beyond to much larger collections of interacting agents. In the current era, there are extremely few individuals who truly function as solo investigators. Yet, both institutional and individual career trajectories can be substantially affected by the particulars of how credit for research team achievements is attributed. A key point that should be more widely appreciated is that causal attributions can involve different precise meanings for “caused,” an issue that can be addressed with less emotion in the setting of the biophysics of ligand binding. Before describing relevant aspects of the thought process for partitioning energetic contributions of individual amino acids of receptors and ligands, it is useful to explicitly consider that there can be multiple senses for the word “cause.” Over two millennia ago, Aristotle recognized four types of causes: material, efficient, formal, and final [12]. Applying this perspective to asking how a physical object, such as a table, has come to exist, causes can include: 1) the raw materials used to build the table, 2) the labor required for assembling the materials into the form of the table, 3) the blueprint or plan delineating the design of the table, and 4) the purpose motivating the builder or assembler to acquire the necessary materials and then prepare and implement the plans. We needn’t stick precisely to the Aristotelian scheme to benefit from appreciating the different ways in which individuals can advance a research project. What becomes clear in analyzing the energetic roles of individual amino acids is that different sorts of contributions can be identified and measured and the same amino acid can take on varied roles in different, but closely related, receptor–ligand complexes [13–15]. So, for example, an amino acid of the receptor, let us say an antibody to a viral protein, that is positioned in the center of the interface with viral antigen, would be likely to make multiple direct contacts with one or more amino acids of that antigen. Due to these multiple contacts, which could include any combination of one or more van der Waals contacts, hydrogen bonds, charge–charge interactions, and hydrophobic interactions, this receptor subunit may contribute substantially to the enthalpic component of the free energy of complex formation. Another receptor residue that does not make contact with the viral protein could contribute to the free energy of complex formation by virtue of a somewhat indirect molecular mechanism, such as being relatively fixed in position in the unbound state but highly mobile in the bound state, thereby adding to the entropic component of binding. Another possibility is that a non-contact receptor residue serves to crucially position a contact residue so that it makes maximally favorable contacts with the antigen. Evidence consistent with the preceding hypothetical scenarios comes from studies, for example, of two different antibodies that were subjected to systematic mutation in the hopes of increasing the affinities for their respective cognate antigens. Different research groups discovered that, unexpectedly, all of the mutations associated with improved affinity affected non-contact residues [16,17]. Therefore, the magnitude of an energetic increment is not necessarily reflective of whether the effect is direct or indirect or of whether its mechanism of contribution is readily apparent.
N.S. Greenspan / Blood Cells, Molecules and Diseases 54 (2015) 231–233
Furthermore, a single substitution at a precise position in a polypeptide chain can alter the manner by which an unmodified amino acid contributes to the energetics of receptor–ligand interaction, even “flipping” its net effect from positive to negative or vice versa [13]. The preceding can be true even if the relevant unchanged residue is distant from the mutated one in the primary and tertiary structures of the protein [14]. Testing and implications of hypothesis Applying these insights to the current-day teams that perform biomedical research, it is not always clear that individuals other than nominal team leaders receive credit and rewards quantitatively commensurate with their intellectual or physical contributions to ultimate success. At many levels within and beyond institutions, there are often forces, such as those relating to the demands of institutional or organizational public relations that dictate a preference for a highly visible and readily recognized recipient of multiple accolades and rewards. Preference for such readily recognized “heroes” is now widespread. Thus, academic medical institutions have evolved along with the rest of American culture towards what economists Robert Frank and Philip Cook have called a “winner-take-all” model [18,19]. The first step to rectifying this deficiency in the standard practices of the scientific community is recognizing the shortcomings of the current system for assigning responsibility for research advances. Having done so, it might be of interest to survey individuals from laboratories associated with particular examples of investigative achievements and obtain assessments of individual contributions. The extent of variation in the observations of involved individuals could be informative. Correlations of credit assessments with status (i.e., PI, postdoc, graduate student, research associate, or assistant) would also be of interest. One criterion that might be used to identify key contributors is to ask, in analogy to systematic mutation of amino acids intended to define the residues responsible for the binding of a ligand, would the ultimate advance have been possible (or significantly delayed) if a particular individual had been absent from the team? Of course, this process cannot be as definitive as the analogous one involving mutation nor deletion of amino acids in a ligand-binding protein. In conclusion, the crucial point is not that nominal leaders are necessarily awarded too much credit for success when it occurs, although they certainly can be, but that the task of attributing credit for success in a manner that reasonably reflects actual magnitudes of responsibility for achievement, in all of its diverse guises, is potentially complex and challenging. This awareness must include recognition of the inevitably necessary but inevitably difficult assessment of how different types of contributions can be quantitatively transformed into a common causal currency so as to apportion rewards fairly and appropriately. Given the rather tangible consequences of assignments of credit, it should not be the case that such attributions are made, as I suspect is currently commonplace, with inadequate recognition of the complexity of the task, inconsistent criteria, and inappropriate intrusion of the distortions generated by institutional imperatives. Competing interests None.
233
Author’s contributions NSG conceived the arguments and wrote the manuscript.
Author’s information NSG is Professor of Pathology at Case Western Reserve University and Director of the Histocompatibility and Immunogenetics Laboratory of University Hospitals Case Medical Center in Cleveland, Ohio.
Acknowledgments I thank Peter Harte and Eugene Koonin for critical feedback.
References [1] A. Eyre-Walker, N. Stoletzki, The assessment of science: the relative merits of postpublication review, the impact factor, and the number of citations, PLoS Biol. 11 (10) (2013) e1001675, http://dx.doi.org/10.1371/journal.pbio.1001675. [2] J.A. Eisen, C.J. MacCallum, C. Neylon, Expert failure: re-evaluating research assessment, PLoS Biol. 11 (10) (2013) e1001677, http://dx.doi.org/10.1371/journal.pbio.1001677. [3] H.R. Bourne, The writing on the wall, Elife 2 (2013) e00642. , http://dx.doi.org/ 10.7554/eLife.00642 (Epub 2013 Mar 26). [4] H.R. Bourne, A recipe for mediocrity and disaster, in five axioms, Elife 2 (2013) e01138, http://dx.doi.org/10.7554/eLife.01138 (Print 2013. PubMed PMID: 23878729). [5] H.R. Bourne, A fair deal for PhD students and postdocs, Elife 2 (2013) e01139, http:// dx.doi.org/10.7554/eLife.01139 (PubMed PMID: 24137543; PubMed Central PMCID: PMC3787295). [6] Schekman R: How journals like Nature, Cell and Science are damaging science. The Guardian, December 9 (2013). http://www.theguardian.com/commentisfree/2013/ dec/09/how-journals-nature-science-cell-damage-science (last accessed 10/29/14). [7] Pringle P: Notebooks shed light on an antibiotic’s contested discovery. The New York Times, June 11 (2012). http://www.nytimes.com/2012/06/12/science/ notebooks-shed-light-on-an-antibiotic-discovery-and-a-mentors-betrayal.html?hpw (last accessed 10/29/14). [8] B. Lemaitre, http://www.behinddiscoveries.com/mixedfeelings2011 (last accessed 10/29/14). [9] B. Lemaitre, E. Nicolas, L. Michaut, J.M. Reichhart, J.A. Hoffmann, The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults, Cell 86 (6) (Sep 20 1996) 973–983. [10] Southwick F: All’s not fair in science and publishing. The Scientist 2012, 16(18):9. http://www.the-scientist.com/?articles.view/articleNo/32287/title/All-s-Not-Fairin-Science-and-Publishing/. [11] Rajan TV: The queen bee syndrome. The Scientist 2002, 16(18):9. http://www.thescientist.com/yr2002/sep/opin_020916.html. [12] Falcon, Andrea, Aristotle on Causality, Edward N. Zalta (Ed.)The Stanford Encyclopedia of Philosophy (Winter 2012 Edition) (2012) URL = bhttp://plato.stanford.edu/ archives/win2012/entries/aristotle-causality/NN. [13] E. di Cera, Site-specific analysis of mutational effects in proteins, Adv. Protein Chem. 51 (1998) 59–119. [14] G. Weber, Protein Interactions, Chapman and Hall, New York, 1992. [15] N.S. Greenspan, E. Di Cera, Defining epitopes: it's not as easy as it seems, Nat. Biotechnol. 17 (10) (1999) 936–937. [16] R.E. Hawkins, S.J. Russell, M. Baier, G. Winter, The contribution of contact and noncontact residues of antibody in the affinity of binding to antigen. The interaction of mutant D1.3 antibodies with lysozyme, J. Mol. Biol. 234 (4) (1993) 958–964. [17] P.A. Patten, N.S. Gray, P.L. Yang, C.B. Marks, G.J. Wedemayer, J.J. Boniface, R.C. Stevens, P.G. Schultz, The immunological evolution of catalysis, Science 271 (5252) (1996) 1086–1091. [18] R.H. Frank, P.J. Cook, The Winner-Take-All Society: Why the Few at the Top Get So Much More Than the Rest of Us, Penguin Books, New York, 1995. [19] A. Casadevall, F.C. Fang, Winner takes all, Sci. Am. 307 (2) (2012) 13.
Contents lists available at ScienceDirect
Blood Cells, Molecules and Diseases journal homepage: www.elsevier.com/locate/bcmd
Review
Protein thermodynamics and the cognitive ecology of biomedicine Neil S. Greenspan ⁎,1 Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106-7728, USA
a r t i c l e
i n f o
a b s t r a c t
Article history: Submitted 16 January 2015 Accepted 21 January 2015 Available online 30 January 2015
Assessments of scientific contributions critically influence decisions about grant funding and academic promotion. Unfortunately, there is a tendency for more junior and less assertive individuals to receive less credit than deserved. Acknowledgement of the complexity of relationships among researchers and the different modes of contributing to scientific progress could improve this situation. The thermodynamics of ligand binding is arguably among the most quantitative and empirically validated theoretical frameworks that permit precise apportionment of “credit” to multiple interacting entities that collectively account for a biologically relevant outcome, in this case, receptor–ligand complex formation. The process for assigning credit for research advances to individual researchers might benefit from emulating this thermodynamic thought process by recognizing that contributions of equal quantitative significance can be of different types and can originate through indirect effects. If the hypothesis that some categories of research contribution are frequently under-valued is correct, then calling attention to this state of affairs and providing an alternative way to conceptualize the task of credit attribution has the potential to begin altering the status quo. A beginning step to improving our credit attribution process would be the empirical investigation of accounts of contributions to particular scientific advances from all research team members. © 2015 Elsevier Inc. All rights reserved.
(Communicated by M. Narla, DSc, 21 January 2015) Keywords: Scientific advance Credit attribution Cooperation Cause Protein thermodynamics
Contents Background . . . . . . . . . . . . . Presentation of hypothesis . . . . . . Testing and implications of hypothesis Competing interests . . . . . . . . . Author’s contributions . . . . . . . . Author’s information . . . . . . . . Acknowledgments . . . . . . . . . References . . . . . . . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
Background In attending research seminars over the past twenty-five years, I have on multiple occasions listened to an eminent biomedical scientist describe how a postdoc or graduate student ignored his or her advice and thereby obtained a remarkable result. While some of these scientistsin-training may have reaped the benefits appropriately associated with
⁎ Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106-7288, USA. Fax: +1 216 368 1357. E-mail address: [email protected]. 1 Courier Service: Room 5130, Wolstein Research Building, 2103 Cornell Road, Cleveland, OH 44106-7288, USA.
http://dx.doi.org/10.1016/j.bcmd.2015.01.013 1079-9796/© 2015 Elsevier Inc. All rights reserved.
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
231 232 233 233 233 233 233 233
their significant contributions, there are sometimes unfortunate disparities in the ratio of reward to achievement for such junior researchers and even for more senior investigators working as members of research teams or as members of collaborations encompassing two or more laboratories. The pressure to work in teams has increased with the rise of expensive, highly sophisticated, high-throughput technologies that demand diverse skills and substantial expertise for optimal implementation and quality control as well as data acquisition, processing, presentation, and interpretation. Recent publications have called attention to significant limitations in traditional practices in the biomedical research community pertaining to the numbers of trainees, grant reviews, and manuscript reviews [1–6]. My purpose below is to call attention to and stimulate discussion
232
N.S. Greenspan / Blood Cells, Molecules and Diseases 54 (2015) 231–233
about limitations in standard practices for the attribution of credit for scientific advances. An interesting historical instance of the scenario alluded to above came to public attention with new information about the discovery of streptomycin, the first antibiotic effective against infection by Mycobacterium tuberculosis [7]. The standard account gave virtually all of the credit to Selman Waksman, who won a Nobel Prize for the discovery in 1952. Relevant documents uncovered relatively recently suggest, however, that Albert Schatz, a graduate student with Waksman at the time that streptomycin was identified, was actually the individual most directly responsible for the isolation of the antibiotic. Waksman may deserve a portion of the credit for developing the overall research framework within which Schatz operated or for arranging for testing of the compound after the initial isolation, but it can be argued that Schatz deserved a substantially greater share of the credit than he actually received. A more recent example of what is alleged to be a somewhat similar episode came to light in the aftermath of the announcement of the 2011 Nobel Prizes. A biomedical researcher in France, Bruno Lemaitre, alleged an injustice in connection with the awarding of the 2011 prize for Physiology or Medicine to his former research colleague and one-time administrative superior, Jules Hoffmann [8]. Dr. Lemaitre was the first author of the study that dramatically demonstrated the critical role of the drosophila protein, Toll, in host defense against fungal infections [9]. This highly consequential paper helped to initiate a major new sub-field of research focused on innate immune receptors. The preceding does not consider even more disturbing instances in which an idea is shared freely in the context of anticipated collaboration and the party receiving the information pursues the same investigational goals surreptitiously. An alleged case of this sort of ethically substandard behavior is described by Southwick [10]. Or consider the case, based loosely on a real situation about which I was informed, of a junior tenure-track faculty member whose grant proposal is effectively hijacked by a more senior colleague to whom the junior investigator reports. The justification offered for the transfer of PI status to the more senior individual, who did not conceive or initiate the line of inquiry in question, was “strategic grantsmanship.” Of course, the junior faculty member in this situation would undoubtedly ask, “Strategic from whose perspective?”. As the above vignettes suggest, there is reason to question the adequacy of the standard, often reflexive, thinking used in assigning responsibility for important scientific results. Another aspect of the problem relates to investigators, often but not exclusively women, who work in a highly collaborative manner with a primary focus on answering scientific questions and less focus on career advancement within an institution or on the sort of self-promotion often required for building an independent reputation [11]. My point is not that principal investigators, the typical recipients of the bulk of the credit for new findings, are always or necessarily excessively rewarded. I fully acknowledge the extensive physical and intellectual effort required to establish a research program and initiate a particular line of investigation. However, the distribution of credit for biomedical research progress should be more fully informed by an awareness of the potential complexities of interactions among researchers. I suggest that assessments of how researchers contribute to scientific advances can be usefully informed, in a metaphorical sense, by the patterns of thinking established for assessing the interactions among the subunits that constitute biological macromolecules. Presentation of hypothesis In studying the process of ligand binding from a biophysical perspective, it is sometimes of interest to apportion the “credit” for the interaction to the various participating subunits of the receptor, the ligand, or both. In more technical language, assuming for ease of discussion that we are dealing with protein–protein interactions, the goal is to
quantitatively determine the contributions to the free energy of complex formation (i.e., the net free energy driving the noncovalent association of receptor and ligand) attributable to individual amino acids of either molecular participant. While this cognitive exercise is not generally of direct use to most biomedical scientists, and is therefore likely to be of rather modest interest to many of them, what might be called “the logic of attribution” employed in this biophysical context applies much more broadly. The central issue is how to partition causal responsibility for an event or process that is the outcome of numerous participating elements that potentially influence one another. Similar issues arise at many levels of biological organization from the atomic and molecular scales of receptor–ligand interactions all the way “up” to the interactions among the sometimes functionally diverse members of research teams and well beyond to much larger collections of interacting agents. In the current era, there are extremely few individuals who truly function as solo investigators. Yet, both institutional and individual career trajectories can be substantially affected by the particulars of how credit for research team achievements is attributed. A key point that should be more widely appreciated is that causal attributions can involve different precise meanings for “caused,” an issue that can be addressed with less emotion in the setting of the biophysics of ligand binding. Before describing relevant aspects of the thought process for partitioning energetic contributions of individual amino acids of receptors and ligands, it is useful to explicitly consider that there can be multiple senses for the word “cause.” Over two millennia ago, Aristotle recognized four types of causes: material, efficient, formal, and final [12]. Applying this perspective to asking how a physical object, such as a table, has come to exist, causes can include: 1) the raw materials used to build the table, 2) the labor required for assembling the materials into the form of the table, 3) the blueprint or plan delineating the design of the table, and 4) the purpose motivating the builder or assembler to acquire the necessary materials and then prepare and implement the plans. We needn’t stick precisely to the Aristotelian scheme to benefit from appreciating the different ways in which individuals can advance a research project. What becomes clear in analyzing the energetic roles of individual amino acids is that different sorts of contributions can be identified and measured and the same amino acid can take on varied roles in different, but closely related, receptor–ligand complexes [13–15]. So, for example, an amino acid of the receptor, let us say an antibody to a viral protein, that is positioned in the center of the interface with viral antigen, would be likely to make multiple direct contacts with one or more amino acids of that antigen. Due to these multiple contacts, which could include any combination of one or more van der Waals contacts, hydrogen bonds, charge–charge interactions, and hydrophobic interactions, this receptor subunit may contribute substantially to the enthalpic component of the free energy of complex formation. Another receptor residue that does not make contact with the viral protein could contribute to the free energy of complex formation by virtue of a somewhat indirect molecular mechanism, such as being relatively fixed in position in the unbound state but highly mobile in the bound state, thereby adding to the entropic component of binding. Another possibility is that a non-contact receptor residue serves to crucially position a contact residue so that it makes maximally favorable contacts with the antigen. Evidence consistent with the preceding hypothetical scenarios comes from studies, for example, of two different antibodies that were subjected to systematic mutation in the hopes of increasing the affinities for their respective cognate antigens. Different research groups discovered that, unexpectedly, all of the mutations associated with improved affinity affected non-contact residues [16,17]. Therefore, the magnitude of an energetic increment is not necessarily reflective of whether the effect is direct or indirect or of whether its mechanism of contribution is readily apparent.
N.S. Greenspan / Blood Cells, Molecules and Diseases 54 (2015) 231–233
Furthermore, a single substitution at a precise position in a polypeptide chain can alter the manner by which an unmodified amino acid contributes to the energetics of receptor–ligand interaction, even “flipping” its net effect from positive to negative or vice versa [13]. The preceding can be true even if the relevant unchanged residue is distant from the mutated one in the primary and tertiary structures of the protein [14]. Testing and implications of hypothesis Applying these insights to the current-day teams that perform biomedical research, it is not always clear that individuals other than nominal team leaders receive credit and rewards quantitatively commensurate with their intellectual or physical contributions to ultimate success. At many levels within and beyond institutions, there are often forces, such as those relating to the demands of institutional or organizational public relations that dictate a preference for a highly visible and readily recognized recipient of multiple accolades and rewards. Preference for such readily recognized “heroes” is now widespread. Thus, academic medical institutions have evolved along with the rest of American culture towards what economists Robert Frank and Philip Cook have called a “winner-take-all” model [18,19]. The first step to rectifying this deficiency in the standard practices of the scientific community is recognizing the shortcomings of the current system for assigning responsibility for research advances. Having done so, it might be of interest to survey individuals from laboratories associated with particular examples of investigative achievements and obtain assessments of individual contributions. The extent of variation in the observations of involved individuals could be informative. Correlations of credit assessments with status (i.e., PI, postdoc, graduate student, research associate, or assistant) would also be of interest. One criterion that might be used to identify key contributors is to ask, in analogy to systematic mutation of amino acids intended to define the residues responsible for the binding of a ligand, would the ultimate advance have been possible (or significantly delayed) if a particular individual had been absent from the team? Of course, this process cannot be as definitive as the analogous one involving mutation nor deletion of amino acids in a ligand-binding protein. In conclusion, the crucial point is not that nominal leaders are necessarily awarded too much credit for success when it occurs, although they certainly can be, but that the task of attributing credit for success in a manner that reasonably reflects actual magnitudes of responsibility for achievement, in all of its diverse guises, is potentially complex and challenging. This awareness must include recognition of the inevitably necessary but inevitably difficult assessment of how different types of contributions can be quantitatively transformed into a common causal currency so as to apportion rewards fairly and appropriately. Given the rather tangible consequences of assignments of credit, it should not be the case that such attributions are made, as I suspect is currently commonplace, with inadequate recognition of the complexity of the task, inconsistent criteria, and inappropriate intrusion of the distortions generated by institutional imperatives. Competing interests None.
233
Author’s contributions NSG conceived the arguments and wrote the manuscript.
Author’s information NSG is Professor of Pathology at Case Western Reserve University and Director of the Histocompatibility and Immunogenetics Laboratory of University Hospitals Case Medical Center in Cleveland, Ohio.
Acknowledgments I thank Peter Harte and Eugene Koonin for critical feedback.
References [1] A. Eyre-Walker, N. Stoletzki, The assessment of science: the relative merits of postpublication review, the impact factor, and the number of citations, PLoS Biol. 11 (10) (2013) e1001675, http://dx.doi.org/10.1371/journal.pbio.1001675. [2] J.A. Eisen, C.J. MacCallum, C. Neylon, Expert failure: re-evaluating research assessment, PLoS Biol. 11 (10) (2013) e1001677, http://dx.doi.org/10.1371/journal.pbio.1001677. [3] H.R. Bourne, The writing on the wall, Elife 2 (2013) e00642. , http://dx.doi.org/ 10.7554/eLife.00642 (Epub 2013 Mar 26). [4] H.R. Bourne, A recipe for mediocrity and disaster, in five axioms, Elife 2 (2013) e01138, http://dx.doi.org/10.7554/eLife.01138 (Print 2013. PubMed PMID: 23878729). [5] H.R. Bourne, A fair deal for PhD students and postdocs, Elife 2 (2013) e01139, http:// dx.doi.org/10.7554/eLife.01139 (PubMed PMID: 24137543; PubMed Central PMCID: PMC3787295). [6] Schekman R: How journals like Nature, Cell and Science are damaging science. The Guardian, December 9 (2013). http://www.theguardian.com/commentisfree/2013/ dec/09/how-journals-nature-science-cell-damage-science (last accessed 10/29/14). [7] Pringle P: Notebooks shed light on an antibiotic’s contested discovery. The New York Times, June 11 (2012). http://www.nytimes.com/2012/06/12/science/ notebooks-shed-light-on-an-antibiotic-discovery-and-a-mentors-betrayal.html?hpw (last accessed 10/29/14). [8] B. Lemaitre, http://www.behinddiscoveries.com/mixedfeelings2011 (last accessed 10/29/14). [9] B. Lemaitre, E. Nicolas, L. Michaut, J.M. Reichhart, J.A. Hoffmann, The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults, Cell 86 (6) (Sep 20 1996) 973–983. [10] Southwick F: All’s not fair in science and publishing. The Scientist 2012, 16(18):9. http://www.the-scientist.com/?articles.view/articleNo/32287/title/All-s-Not-Fairin-Science-and-Publishing/. [11] Rajan TV: The queen bee syndrome. The Scientist 2002, 16(18):9. http://www.thescientist.com/yr2002/sep/opin_020916.html. [12] Falcon, Andrea, Aristotle on Causality, Edward N. Zalta (Ed.)The Stanford Encyclopedia of Philosophy (Winter 2012 Edition) (2012) URL = bhttp://plato.stanford.edu/ archives/win2012/entries/aristotle-causality/NN. [13] E. di Cera, Site-specific analysis of mutational effects in proteins, Adv. Protein Chem. 51 (1998) 59–119. [14] G. Weber, Protein Interactions, Chapman and Hall, New York, 1992. [15] N.S. Greenspan, E. Di Cera, Defining epitopes: it's not as easy as it seems, Nat. Biotechnol. 17 (10) (1999) 936–937. [16] R.E. Hawkins, S.J. Russell, M. Baier, G. Winter, The contribution of contact and noncontact residues of antibody in the affinity of binding to antigen. The interaction of mutant D1.3 antibodies with lysozyme, J. Mol. Biol. 234 (4) (1993) 958–964. [17] P.A. Patten, N.S. Gray, P.L. Yang, C.B. Marks, G.J. Wedemayer, J.J. Boniface, R.C. Stevens, P.G. Schultz, The immunological evolution of catalysis, Science 271 (5252) (1996) 1086–1091. [18] R.H. Frank, P.J. Cook, The Winner-Take-All Society: Why the Few at the Top Get So Much More Than the Rest of Us, Penguin Books, New York, 1995. [19] A. Casadevall, F.C. Fang, Winner takes all, Sci. Am. 307 (2) (2012) 13.