Abstract
Philosophers of science diverge on the question what drives the growth of scientific knowledge. Most of the twentieth century was dominated by the notion that theories propel that growth whereas experiments play secondary roles of operating within the theoretical framework or testing theoretical predictions. New experimentalism, a school of thought pioneered by Ian Hacking in the early 1980s, challenged this view by arguing that theory-free exploratory experimentation may in many cases effectively probe nature and potentially spawn higher evidence-based theories. Because theories are often powerless to envisage workings of complex biological systems, theory-independent experimentation is common in the life sciences. Some such experiments are triggered by compelling observation, others are prompted by innovative techniques or instruments, whereas different investigations query big data to identify regularities and underlying organizing principles. A distinct fourth type of experiments is motivated by a major question. Here I describe two question-guided experimental discoveries in biochemistry: the cyclic adenosine monophosphate mediator of hormone action and the ubiquitin-mediated system of protein degradation. Lacking underlying theories, antecedent data bases, or new techniques, the sole guides of the two discoveries were respective substantial questions. Both research projects were similarly instigated by theory-free exploratory experimentation and continued in alternating phases of results-based interim working hypotheses, their examination by experiment, provisional hypotheses again, and so on. These two cases designate theory-free, question-guided, stepwise biochemical investigations as a distinct subtype of the new experimentalism mode of scientific enquiry.
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Notes
Scientific theory has many connotations and definitions, [(National Research Council Report, 2008) pp. 25–37]. This paper defines a scientific theory as a unifying framework that explains a large body of observational and experimental data and is also capable of making testable predictions (Shou et al., 2015). A related term, hypothesis is defined here as a proposition not based on fact that is raised to explain a natural phenomenon prior to its testing. Model is defined in this paper as a reality-approximating instrument for the building of theory (Keller Fox, 2000; Morrison, 1998).
“The subtlety of nature is far beyond that of sense or of the understanding: so that the specious meditations, speculations, and theories of mankind are but a kind of insanity, only there is no one to stand by and observe it." [(Bacon, 1620/1902), Book I, Aphorism X].
"The syllogism consists of propositions; propositions of words; words are the signs of notions. If, therefore, the notions (which form the basis of the whole) be confused and carelessly abstracted from things, there is no solidity in the superstructure. Our only hope, then, is in genuine induction." [(Bacon, 1620/1902), Book I, Aphorism XIV; italics mine].
“As in Mathematicks, so in Natural Philosophy, the Investigation of difficult Things by the Method of Analysis, ought ever to precede the Method of Composition. This Analysis consists in making Experiments and Observations, and in drawing general Conclusions from them by Induction, and admitting of no Objections against the Conclusions, but such as are taken from Experiments, or other certain Truths. For Hypotheses are not to be regarded in experimental Philosophy” [(Newton, 1730/1952), p. 404].
"The first and most obvious distinction between Observation and Experiment is, that the latter is an immense extension of the former. It not only enables us to produce a much greater number of variations in the circumstances than nature spontaneously offers, but also, in thousands of cases, to produce the precise sort of variation which we are in want of for discovering the law of the phenomenon; a service which nature, being constructed on a quite different scheme from that of facilitating our studies, is seldom so friendly as to bestow upon us." [(Mill, 1882), Book III, p. 471].
Hume’s original argument was: “… not only our reason fails us in the discovery of the ultimate connexion of causes and effects, but even after experience has informed us of their constant conjunction, it is impossible for us to satisfy ourselves by our reason, why we should extend that experience beyond those particular instances, which have fallen under our observation. We suppose, but are never able to prove, that there must be a resemblance betwixt those objects, of which we have had experience, and those which lie beyond the reach of our discovery.” [(Hume, 1739/2012), Book I, part III, Section 6].
However, Hume also appeared to have adopted a form of induction when, in rejecting claims for miracles, he stated that: “nothing is credible which is contradictory to experience, or at variance with the laws of nature”. Mill took this to be an argument in defense of induction [(Mill, 1846), p. 375], or as put by Babbage: “whatever is contradictory to a complete induction is incredible” [(Babbage, 1864), p. 488].
“Theory dominates the experimental work from its initial planning up to the finishing touches in the laboratory” [(Popper, 1959/2002), p. 90].
“The theoretician puts certain definite questions to the experimenter, and the latter, by his experiments, tries to elicit a decisive answer to these questions, and to no others.” [(Popper, 1959/2002), p. 89].
Braithwaite took the formulation of Kepler’s laws as an example of hypothetico-deductive thinking: “[Kepler succeeded] by thinking of general hypothesis from which particular consequences are deduced which can be tested by observation” [(Braithwaite, 1953), p. X].
A 2007 US National Academies of Sciences report ‘‘The Role of Theory in Advancing 21st Century Biology’’ by the Committee on Defining and Advancing the Conceptual Basis of Biological Sciences in the 21st Century: http://dels.nas.edu/resources/staticassets/materials-based-on-reports/reports-in-brief/role_of_theory_final.pdf.
“Some profound experimental work is generated entirely by theory. Some great theories spring from pre-theoretical experiments. Some theories languish for lack of mesh with the real world, while some experimental phenomena sit idle for lack of theory” [(Hacking, 1983), p. 159].
“…let us not pretend that the various phenomenological laws of solid phase physics required theory – any theory – before they were known” [(Hacking, 1983), p. 165].
Hacking’s edict has been preceded by Ernest Nagel’s (1961) proclamation that experimental law “has a life of its own, not contingent on the continued life of any particular theory” [(Nagel, 1961), p. 87]. However, according to Galison, whereas Nagel saw experiments as basal foundations in a hierarchy that culminated in theory, Hacking thought that experimentation often has motivation and momentum that are not subordinated to theory [(Galison, 1995), p. 24].
Theory-free explorations are to be done by experiments “…without premature reflection or any subtlety” [(Bacon, 1620/1902), Book II, aphorism XI].
Footnote 1 lists the definitions in this paper of theory, hypothesis, and model.
Elie Zahar analogously and much more expansively argued that to attain full understanding of some case studies in physics, historians and philosophers of science should be acquainted with relevant methodological and technical experimental details (Zahar, 1978).
In recognition of their achievements the Cori’s were each awarded the Nobel Prize in 1947. For their personal and professional biographies see (Cohn, 1992; Larner, 1992); their respective Nobel Prize lectures: Carl Cori—https://www.nobelprize.org/prizes/medicine/1947/cori-cf/lecture/; Gerty Cori – https://www.nobelprize.org/prizes/medicine/1947/cori-gt/lecture/; and an American Chemical Society National Historic Chemical Landmark homage:
http://www.acs.org/content/acs/en/education/whatischemistry/landmarks/carbohydratemetabolism.html.
For Sutherland’s personal and professional biography see (Blumenthal, 2012; Cori, 1978) and Sutherland’s 1971 Nobel Prize lecture: https://www.nobelprize.org/prizes/medicine/1971/sutherland/lecture/
Among Sutherland’s many collaborators were Theodor Rall, Walter D. Wosolait, Jacques Berthet, Thèodore Posternak, Ferid Murad, Peter R. Davoren, Reginald W. Butcher, and G. Alan Robison.
Glycogen is actually a branched polymer. This paper focuses only on the degradation of the linear sections of this polysaccharide and the enzyme-catalyzed debranching of glycogen is not discussed.
Under appropriate substrate concentrations phosphorylase also acted in reverse to polymerize glucose-1-phosphate units back to glycogen (Cori and Cori, 1939, 1940, 1943; Cori et al., 1939b). However, the high intracellular concentration of inorganic phosphate in vivo inhibits this synthetic reaction. The actual glycogen synthesizing enzyme, glycogen synthase, was discovered some years later (Leloir and Cardini, 1957).
For Green’s lifetime contributions see (Colowick, 1958).
In his years in Washington University Sutherland published research papers on glycogen synthesis, (Colowick and Sutherland, 1942; Sutherland et al., 1941) isolation of glucagon and studies of its glycogenolytic activity, (Sutherland and Cori, 1948, 1951; Sutherland and de Duve, 1948; Sutherland et al., 1949b) phosphoglucomutase, (Sutherland, 1949; Sutherland et al., 1949a, 1949c) and glucagon-stimulated liver phosphorylase, (Sutherland & Cori, 1951; Sutherland, 1951b).
The Coris attracted to the Washington University Department of Biochemistry some remarkable younger investigators. Among Sutherland’s contemporaries in the department were the future Nobel Prize laureates Severo Ochoa; Luis Leloir; Arthur Kornberg; Edwin Krebs; and Christian De Duve and leading biochemists such as Herman Kalckar, Victor Najjar, Rollo Park, Sidney Colowick, and Theodore Posternak. Retrospectively commenting on the scientific milieu in the department, Sutherland wrote: “…I believe that kind of stimulating environment, with the necessary “critical mass” of young and talented investigators, with the opportunity for the free exchange of ideas, is an important ingredient in the making of scientific progress. Such an environment existed at Washington University…" [(Sutherland, 1992), p. 5].
Until the mid 1950s hormone-stimulated glycogenolysis was studied in whole animals, in isolated muscle tissue, or in liver slices. None of these experimental systems could be probed for molecular details of hormone action. Although it was uncertain at the time that construction of a working cell-free system was achievable, Sutherland was insightful in reasoning that only a dissectible in vitro system could potentially disclose such details.
While Cori was initially skeptical of Sutherland’s proposed approach, he retrospectively expressed high praise for his exceptional intuition and experimental prowess [(Cori, 1978), p. 324]: “What we see at work here is a sort of hunch or secret insight plus tenacity, the ability of differentiating between important and unimportant observations, absolute reliance on the accuracy of one's results and a prodigious memory—all qualities that characterize the successful bench scientist and that Sutherland possessed in large measure.".
Krebs and Fischer were awarded the 1992 Nobel Prize for their discovery of reversible protein phosphorylation as a biological regulatory mechanism.
In that Sutherland actualized his original intent of using purified enzymes in combination with a cell-free system (2.1.4).
The discovery that the particulate cell fraction, (later identified as cell membranes) was essential for phosphorylase activation, was serendipitous. As later told, (Sutherland, 1992) this fraction was initially thought to be dispensable cell debris. However, centrifugation of the murky homogenate to remove the alleged debris resulted in unanticipated loss of phosphorylase activation by the supernatant fraction.
A similar exercise of separating and recombining resolved subfractions of a cell-free system was also the key first step in the discovery of ubiquitin-mediated system of protein degradation (2.2.6).
The heat-resistant mediating factor was unlikely to be a protein since most proteins are inactivated at 100 °C. Likewise, as that factor passed through a dialysis tube, it appeared to have a molecular size that was much lower than that of most proteins (Rall et al., 1957).
Patricia Woolf detailed the history of this landmark discovery (Woolf, 1975).
The expertise and advise of Leon Heppel was also instrumental in the early phases of the decryption of the genetic code by his fellow NIH investigator Marshall Nirenberg [(Fry, 2016), pp. 427–428 and 448–449].
Sutherland originally named the enzyme adenyl cyclase. This paper uses its current name, adenylyl cyclase.
Later studies revealed that lipophilic steroid and thyroid hormones do traverse the outer cell membranes and interact with specific intracellular cytoplasmic or nuclear receptors.
The idea of existence of hormone-specific receptors endured for more than 70 years as a theory in need of experimental substantiation, [see for instance (Sutherland and Rall, 1960), pp. 292–294]. It was only in the 1970s that specific receptors were physically isolated.
The rationale for a sequence of activations of different enzymes is that each step further amplifies the initial signal. For instance, suppose that adenylyl cyclase produced a single molecule of cAMP. This molecule then activates enzyme X that synthesizes 10 molecules of product x which next activate enzyme Y that in turn produces 100 molecules of product y. Thus, in this example, the initial cAMP signal was amplified × 100-fold.
Beside phosphorylation, phosphorylase kinase activation is also mediated by calcium ions. Discussion of this type of regulation of the kinase activity is beyond the scope of this paper.
For their discoveries of G-proteins mediated signaling Rodbell and Gilman were awarded the Nobel Prize in 1994.
This section examines the history of the discovery of the ubiquitin-mediated system of protein degradation in eukaryotes. Lacking ubiquitin, prokaryotes have no ubiquitin-mediated protein breakdown system.
Trained in the laboratory of Harold C. Urey, the discoverer of Deuterium, Rittenberg was well versed in the use and separation of stable non-radioactive isotopes that were used in Schoenheimer’s studies.
Quasi selective labeling of long or short-lived proteins was attained by, respectively, feeding radioactive amino acids to cells for long or short periods of time or by exposing cells to amino acid labeled with two distinguishable isotopes for long and short times [reviewed by (Goldberg and Dice, 1974; Schimke and Doyle, 1970)].
Lifetimes of proteins were more accurately expressed as half-lives, i.e., the time needed to degrade half of the initially present molecules.
For Hershko’s biography see: https://www.nobelprize.org/prizes/chemistry/2004/hershko/biographical/.
Hershko, Ciechanover, and Rose were awarded the 2004 Nobel Prize in Chemistry in recognition of their discovery of the ubiquitin-mediated system of protein breakdown.
Dissectible in vitro systems had been vital tools in the successful resolution of the protein biosynthesis machinery, (Rheinberger, 1993, 1997, 2006; Zamecnik, 1960, 1984) and in the discovery of cAMP (2.1.5). Hershko came to appreciate the potential of a cell-free system in the earliest stages of his PhD training when he studied the effects of polyamines and Mg+2 ions on protein synthesis in such system, a study that was the subject of his very first publication [(Hershko et al., 1961) and personal communication].
Reticulocytes are precursor cells to mature erythrocytes. Already devoid of nucleus and mitochondria, they overwhelmingly produce globins, the proteinaceous components of hemoglobins. Abnormal mutated globins may occur naturally or can be artificially produced by feeding reticulocytes analogs of amino acids or puromycin that by prematurely terminating protein translation affects synthesis of globin fragments.
For Ciechanover’s biography see: https://www.nobelprize.org/prizes/chemistry/2004/ciechanover/biographical/.
To be degraded, the tritium labeled globin had to be partially denatured. In later experiments this substrate was replaced by other purified proteins that were labeled with 125I, a radioactive isotope of iodine.
Rose, a renowned expert on enzymic mechanisms, had long-standing theoretical (but not active) interest in protein degradation. After meeting Hershko at a Fogarty Symposium in 1976, he invited him to spend a sabbatical in his laboratory (Kresge et al., 2006). As work on the protein degrading system progressed in subsequent years, Hershko and Ciechanover made repeated work visits to Philadelphia where their collaboration with Rose came to a head with the discovery of the ubiquitin-mediated protein degradation system. For Rose’s biography see: https://www.nobelprize.org/prizes/chemistry/2004/rose/biographical/.
Biochemists who have made significant contributions at different stages of the work included Hanna Heller, Sarah Elias, Sarah Ferber, Rachel Katz-Etzion, Esther Eytan, Esther Leshinsky, Deborah Ganoth and Yuval Reis of the Hershko laboratory, and Jessie Warms, Arthur Haas, Keith Wilkinson, and Cecile Pickart of the Rose laboratory.
As occasionally happens in experimental biochemistry, luck played a role in the facile isolation and then purification of APF-1. Being a rare heat-resistant protein, APF-1 was greatly purified by heating Fraction I and removing by centrifugation the bulk of the denatured irrelevant proteins. A subsequent single purification step yielded homogenous APF-1.
Subsequent experiments largely substantiated the hypothesis. Three types of enzymes, E1, E2, and E3 were isolated and shown to successively catalyze conjugation of ubiquitin to protein substrates (2.2.9). Also, deubiquitinating enzymes (DUBs; isopeptidases) that sever the isopeptide bond of ubiquitin and protein were identified. Some of these enzymes act to salvage incorrectly conjugated proteins (2.2.11). Breakdown of the protein substrates was found to be conducted by the multimeric proteasome complex (2.2.11).
Covalent bonding of ubiquitin to the E1 enzyme proceeded in two steps: (1) ubiquitin + ATP ubiquitin→ ~ AMP + PPi (2) ubiquitin ~ AMP + E1-(SH)→ E1-S ~ ubiquitin + AMP, where: ~—high energy bond; PPi—pyrophosphate; E1-(SH)—sulfhydryl group in E1; E1-S ~ ubiquitin—thiolester of E1 with ubiquitin. These reactions were analogous to the activation of amino acids prior to their charging onto transfer RNA, (Zamecnik, 1984). Hershko became acquainted with this type of activation reaction when he used an in vitro protein synthesis system in his very first research project, performed while he was still a student of medicine (Hershko et al., 1961).
A later discovered second ATP-consuming junction was hydrolysis of ubiquitin tagged proteins at the proteasome (2.2.11).
Here again the strategy of using highly purified proteins proved to be productive. All three enzymes were isolated by their affinity binding to columns of immobilized purified ubiquitin and differential elution from the columns.
Over 600 different E3 ubiquitin ligases were found in time to be encoded in the human genome. Each ligase is specific to one or several protein substrates (2.2.11). Hershko and associates were first to demonstrate direct binding of one type of E3 ligase (E3) to a protein substrate and to characterize the substrate binding site in that enzyme (Hershko et al., 1986).
Ubiquitin residues are polymerized by formation of isopeptide (amide) bonds between carboxy end of a distal ubiquitin and -amino group of a preceding ubiquitin molecule.
These enzymes were later recognized to be regulatory subunits of the proteasome.
26S, 20S and 19S are the respective apparent sedimentation coefficients of the whole complex and its subunits.
The ballooning interest in the field is illustrated by the steep increase over time of the number of PubMed listed articles that had ‘ubiquitin’ as keyword: 43, 2128, and 5666 papers in the years 1985, 2003, and 2020, respectively.
Ubiquitin is degradation signal in the three major kinds of autophagy-lysosome systems: Macroautophagy in which misfolded proteins and dysfunctional organelles are transported to the lysosomes, (Kocaturk and Gozuacik, 2018); microautophagy under which cytosolic components are engulfed and transported to the lysosomes, (Oku and Sakai, 2018); and chaperone-mediated autophagy in which degradation tags and chaperones facilitate crossing of the lysosomal membrane by degradation-destined proteins, (Kaushik and Cuervo, 2018). Specifics of conjugation of ubiquitin and ubiquitin-like proteins to substrates and to components of the autophagy systems are beyond the scope of this article and are reviewed elsewhere (Chen et al., 2019).
In vitro systems that successfully served as essential experimental platforms in this and other historical cases as described, continue today to be vital instruments for the unraveling mechanics of complex biochemical systems. For instance, recent probing of the circadian clock of Cyanobacteria was performed in constructed in vitro whole-clock system that was composed of isolated protein components. Maintaining autonomous oscillation for long periods of time, this system enabled monitoring of the function of each individual module of the clock, (Chavan et al., 2021).
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The author is indebted to Dr. Avram Hershko for insightful discussions, comments on the manuscript and donation of facsimiles of his laboratory notes. The perceptive comments of the two anonymous reviewers and of Dr. Iris Fry are gratefully acknowledged.
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Fry, M. Question-driven stepwise experimental discoveries in biochemistry: two case studies. HPLS 44, 12 (2022). https://doi.org/10.1007/s40656-022-00491-1
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DOI: https://doi.org/10.1007/s40656-022-00491-1