The author poses an alternate set of ideas concerning paradigms, normal science, research traditions and scientific revolution on the basis of the unique and inherently distinctive development of molecular biology and genetics; for, a new set of conceptual tools concerning scientific progress are required for an adequate understanding of how biological processes were elucidated under the scientific auspices of the central dogma of the genetic code. This essay concentrates on a limited study of three aspects in genetics: the study of chromosome structure, dynamics and function, reverse transcriptases, and the discovery of RNA catalysts. In attempting to analyze the key moments of discovery in these processes, Venkatesan distinguishes between Kuhnian and Laudanian notions of science and how molecular biology configures into them and attempt to put forth a set of ideas that may not necessarily conflate the two but provide further insight into their treatises on the nature of scientific revolution of which they discuss at length.

Paradigm Shifts and New Worldviews: Kuhn, Laudan and Discovery in Molecular Biology

Priya Venkatesan

<1> In a 1953 issue of the scientific publication Nature, Francis Crick and James Watson, put forth an elucidation of the molecular structure of nucleic acid, the component of DNA, also known as deoxyribonucleic acid (Watson and Crick, 1953). In their groundbreaking study, they revealed that DNA is double helical chain composed of purinic and pyramidal bases:

We wish to put forward a radically different structure for the salt of deoxyribose nucleic acid. This structure has
two helical chains each coiled round the same axis’Ä¶
The two chains (but not their bases) are related by a dyad
perpendicular to the fibre axis. Both chains follow
right-handed helices’Ä¶but run in opposite directions.
(Watson and Crick, 1953)

These simple and elegant statements brought about a revolutionary moment in the founding and development of the sciences of molecular biology, genetics and biochemistry. Watson and Crick discovered the essential structure of the molecule of heredity, DNA. Utilizing this model, subsequent studies could reveal how the molecular workings of a cell followed the direction of the blueprint of the cell, DNA. In the process of discovering the biological importance of information as stored in DNA, the central dogma of molecular biology was established: coded genetic information stored in DNA is transcribed into messenger RNA and subsequently translated into protein. Biological research laboratories, however diverse and eclectic in focus, are universally predicated on this principle. Thus, Watson and Crick's description of the characteristic structure of DNA led to an understanding of the mechanisms of DNA replication and transcription.

<2> Watson and Crick received the Nobel Prize for their discovery and every genetics textbook refers to this elucidation as the starting point for the description of biological processes. As the fields of genetics and molecular biology developed, experimental techniques became more refined and sophisticated. However, molecular biologists never relinquished their elemental debt to the work of Watson and Crick. The formerly cryptic nature of DNA was made tangible; the work of the laboratory, formerly scattered and confused before Watson and Crick's finding, was now focused and directed. Knowledge of the DNA construct afforded new possibilities in determining the processes of cell components, such as the nucleus, the endoplasmic reticulum and most importantly, chromosomes, the material in which DNA is packaged.

<3> Other scientists previously put forth alternate structures of DNA, but had ultimately failed in this regard in that their structures conflicted with the hard data of X-ray diffraction studies, the very studies that Watson and Crick utilized in determining the structure of DNA. The science of molecular biology predates Watson and Crick's discovery. The term was first used in 1938 by Warren Weaver of the Rockefeller Foundation [1 ]. The field, however, only began to flourish after the revelation of the physical structure of DNA. Now, such a vast amount of information has been accumulated that it is almost impossible to keep up with every experiment being conducted.

<4> The landmark discovery of Watson and Crick ushered in a new phase of normal science, to use the term put forth by Thomas Kuhn in his Structure of Scientific Revolutions, that continues. Normal science, according to Kuhn is characterized by puzzle-solving, the mode of scientific experimentation in which scientists address problems that have known solutions. A scientist studying gene expression tries to discover how proteins are involved in inducing genes; a scientist studying chromosome dynamics attempts to determine which proteins confer mitotic cell stability. These are just some of the many innumerable examples in which Kuhn's notion of normal science plays out in the everyday life of the laboratory. Some projects are more risky than others; however the expected outcome is publication.

<5> The history of discovery in molecular biology encompasses the paradigmatic notion of the genetic transfer of information while simultaneously allowing for anomalies. Larry Laudan in his Progress and Its Problems points out some of the shortcomings of the notions of normal science and paradigm. He argues that Kuhn never resolves the issue of the relationship between paradigms and theories and that normal science does not address conceptual problems that arise in science. A research tradition he asserts would lead to the "adequate solution of empirical and conceptual problems."

<6> I would like to pose an alternative set of ideas concerning paradigms, normal science, research traditions and scientific revolution on the basis of the unique and inherently distinctive development of molecular biology and genetics. A new set of conceptual tools concerning scientific progress are required for an adequate understanding of how biological processes were elucidated under the scientific auspices of the central dogma of the genetic code. I would like to concentrate on a limited study of three aspects in genetics: the study of chromosome structure, dynamics and function; reverse transcriptases; and the discovery of RNA catalysts. In attempting to analyze the key moments of discovery in these processes, I hope to distinguish between Kuhnian and Laudanian notions of science and how molecular biology configures into them and to attempt to put forth a set of ideas that may not necessarily conflate the two but provide further insight into their treatises on the nature of scientific revolution of which they discuss at length. Furthermore, I would like to contend that the constant reification of scientific theory, the tendency of new findings to contradict and change our worldview, does not reduce the truth-value of scientific investigation, but rather reflects its commitment to truth. The central dogma of molecular biology, which states that pathway of biological information from DNA to RNA to protein is linear and that each player in the pathway has specific roles, is challenged by new discoveries. These discoveries, however, do not supplant the central dogma and its concomitant tenets, but create anomalies that must be considered within the context of normal science and research traditions.

Chromosome Structure, Genetic Mapping and the C-value Paradox

<7> To begin, I must now elaborate upon a discussion of the organization of the eukaryotic genome. In the study of the organization of chromosomes, much effort has been directed to the mapping of the genome. Genome mapping is defined by determining the location of DNA in the chromosome under study. Genes are localized on specific positions in the chromosome at points called loci and these points are confined to specific regions on the chromosome. This type of genetic mapping is done by linkage studies, i.e. mating species with different phenotypes and counting the progeny and determining the incidence of crossovers through examination of the progeny. (Morgan, 1911). This method has been especially successful with the organism Drosophila. Other techniques have been employed to assign human genes to specific chromosomes or another. In mapping human genes a technique called somatic cell hybridization has played an important role. (Barsky, c1960). Somatic cell hybridization is the fusion of human and mouse chromosomes in which human chromosomes are lost randomly. When gene products are synthesized on these few remaining chromosomes, they are assigned a position on these chromosomes. This is called synteny testing [2 ].

<8> Underlying the study of the mapping of genes is the C-value paradox. The C-value paradox states that excess DNA exists in a chromosome that is not essential to the development of the chromosomes of higher species, such as eukaryotes. In actuality, the majority of DNA in a chromosome is considered to be "junk DNA" that does not contain genes and therefore does not code for proteins. Studies of chromosome material have been limited to DNA that encodes for genes. This junk DNA mainly consists of repeated sequences of DNA, termed repetitive DNA. A location on the chromosome known as the centromere harbors much of this repetitive, non-protein producing DNA (Willard, 1990). Efforts to find, map and assign genes to loci have been directed by the paradigm of the C-value paradox (Gall, 1981). It has been assumed there were no known genes located on the centromere. Research devoted to finding genes there has been very limited.

<9> However, evidence is now emerging, particularly in the laboratory with which I am affiliated, that there are viable genes in the centromere that code for mRNA transcripts (Venkatesan, Jasinskas, and Hamkalo, unpublished results). Rather than the use of somatic cell hybridization (such as synteny testing), these new studies relied on a new set of techniques. We used a probe isolated from centromeres of mouse chromosomes by laser dissection and we hybridized this probe with colonies of mouse DNA clones. After finding the clone, its DNA was isolated, digested and blotted with the probe to establish the validity of the clone as a piece of DNA from the centromere [3 ]. After sequencing, it was determined that genes did exist in the centromere and that the centromere was not simply a repository of junk, repetitive DNA that has no function. This is an anomaly relative to the paradigm of the C-value paradox; however, the idea of centromeric genes does not challenge the normal science of the existing efforts to map and pinpoint genes on locations of the chromosomes that do not contain repetitive DNA. New research might be devoted to finding further genes in centromeres by similar methods of mapping and then be incorporated into the current paradigm. However, an alternate research tradition might emerge whereby new methods of discovering the anomaly of centromeric genes are incorporated alongside traditional means of finding genes. Here, we might return to the Laudan's emphasis on problem-solving and research traditions versus the puzzle-solving aspects of normal science that Kuhn expostulates on. According to Laudan, " a research tradition is a set of general assumptions about the entities and processes in a domain of study, and about the appropriate methods to be used for investigating the problems and constructing the theories in that domain." (Laudan, p. 81).

<10> But, has the C-value paradox been challenged? The C-value paradox is not technically a theory in that it does not specify concepts or ideas upon which science is conducted; however, it underlies the assumptions that guide the research of finding and mapping genes. If the existence of centromeric genes shows that junk DNA actually encodes for genes useful for the development of higher organisms, then experimental adjustments would have to be made by scientific community in acknowledging that. Kuhn would maintain that "normal science does not aim at novelties of fact or theory’Ä¶new and unsuspecting phenomena are, however, repeatedly uncovered by scientific research." (Kuhn, pg. 52). In a sense, normal science has uncovered an anomaly; however this discovery was not so anomalous as to precipitate a crisis and abandon the paradigm. Puzzles involving the mapping of genes on chromosomes would take place concomitantly with the mapping of centromeric genes. However, in contrast Laudan asserts that every major period in the history of science is characterized by "the coexistence of numerous competing paradigms." (p. 74) According to Laudan, "a successful research tradition is one which leads, via its component theories, to the adequate solution of an increasing range of empirical and conceptual problems." (p. 82). In the case of the study of chromosomes, problems have been solved, not via theories, but through experimental techniques. A change in experimental rationale took place in the finding of centromeric genes, which took into consideration a contradiction of the assumptions behind the C-value paradox. A new research tradition came into place. According to Laudan, there are times when two research traditions can be "amalgamated," producing a synthesis. Science can work under different research traditions, one research tradition being the finding of genes in non-repetitive DNA and the other being the mapping of genes in repetitive regions of the chromosome. The synthesis would be that there are not only genes in non-repetitive portions of chromosomes but are also interspersed within repetitive regions of chromosomes.

<11> However, one could argue that the mapping of genes constitutes normal science and the discovery of centromeric genes is an anomaly that does not serve as an adequate challenge to the paradigm of the C-value paradox. The C-value paradox is a tenet that underscores the difficulty of finding useful DNA, since the majority of DNA in chromosomes consists of junk DNA. It still forms the presumptive basis of research conducted in the search for genes and is an organizing paradigm around which rules are generated concerning experimental methodology. Puzzles can be still solved with meaningful solutions, the puzzles in this case being the search for useful genes. There is a whole scientific culture and mode of experimental life surrounding the mapping of genes that is cognizant of the limitations of the C-value paradox.

<12> In short, Laudan's emphasis on the problem-solving ability of the C-value paradox and how discoveries contradicting it generate different research traditions that can be synthesized. Kuhn's emphasis on normal science and the emergence of an anomaly, do not affect in a wholesale manner the experimental conduct of molecular biologists. Nor do they precipitate a crisis in the revolution in genetics wrought by the discovery of the structure of DNA and the genetic code, of which the C-value paradox is a successor.

<13> However, what neither Kuhn nor Lauden's theories can accomodate is the change in experimental techniques that brought about the discovery of centromeric genes and that affected the landscape of the milieu of mapping genes. Rather than merely being conceptual and empirical problems surrounding the solving of problems within certain theoretical frameworks, the ability to find centromeric genes attests to the methodological problems that dictate the experimental confines of finding genes. The new methods and experiments employed in finding centromeric genes added to the existing repertoire of research techniques in the discovery of novel genes. The actual materials and methods, and not simply the empirical observations and results, constitute the "amalgamated" research tradition [4 ]. Experiment, rather than theory, enhanced problem-solving efforts. A new mode of investigation comes into being that does not revolve around the paradigm of the C-value paradox. Rather, a competing corollary emerges in which it could be stated that the majority of DNA in chromosomes is not junk DNA.

<14> Yet, it is not an incompatible corollary. According to Kuhn, a choice between competing paradigms "proves to be a choice between incompatible modes of community life." (p.94). Geneticists will be mapping genes on chromosomal loci using traditional methods such as lod scores and somatic cell hybridization, and simultaneously fishing for centromeric genes using new techniques and methods [5 ]. These "modes of life" are not incompatible, though based on contradictory assumptions. However, the differences in experiment are sufficient to bring about changes in the ways scientists think about the location of genes, how they are expressed, and the significance of their protein products when located in newly-researched areas of chromosomes, such as in centromeres and other repetitive regions.

Reverse Transcriptases and Revolution in the Paradigm of the Genetic Code

<15> The study of chromosome mapping reveals how certain scientific discoveries lead to concomitant methods of experimentation. The C-value paradox, in the search for centromeric genes in repetitive DNA, is now questioned and may be ultimately abandoned by molecular geneticists. The discovery [of anomalies] has also challenged other vastly held tenets of molecular biology, one example being the information transfer inherent in the genetic code. The genetic code, in Watson and Crick's model, is based on the supposition of a one-way passage of the information from DNA to RNA to protein. This paradigm forms the foundation of research into the chemical processes of cells. DNA is transcribed into RNA and RNA is translated into protein. Whatever moleculare biological events take place molecularly, their discovery is based on the presumption of the primacy of the genetic code.

<16> Genetic information is held in the sequence of bases in DNA. Genetic information that is expressed as a polypeptide sequence must be translated from the four-letter language of nucleotides into the 21-letter language of proteins. This translation takes place via an intermediary transcription product, mRNA. The sequence of information in the genetic code is as follows:

Diagram 1

This process is ubiquitous. The initial elucidation of the structure of DNA led to studies to determine how it functions in processing information. In other words, scientists attempted to determine how RNA is made from DNA, and what molecules are involved in the mechanism of translation. What eradicated the sanctity of the genetic code was the discovery of retroviruses and reverse transcriptases which struck at the heart of the singular one-way passage of information of the genetic code.

<17> A reverse transcriptase is an enzyme capable of synthesizing DNA on an RNA template. This enzyme is also called RNA-directed DNA polymerase, and it was discovered by Howard Temin and David Baltimore in the early 1960s. Temin proposed that RNA, which serves as the genetic material of certain animal tumor viruses (also known as retroviruses), is initially transcribed into DNA, which then serves as the template for replication and transcription of RNA during viral infection (Temin, 1972). In other words this transfer of information takes place:

Diagram 2

<18> Temin's proposal concerning reverse transcriptase was largely ignored because it contradicted the previously accepted notion that genetic information flows only from DNA to RNA [6 ]. However, when it was proven that DNA was synthesized in these viruses and served as an intermediate molecule, the notion of reverse transcriptases became more accepted. Later, Temin would subsequently isolate reverse transcriptase; the enzyme was later shown to be utilized by the HIV virus to replicate its RNA genome into DNA that subsequently inserted itself into the genome of Helper T-cells (Joshi and Joshi, 1996).

<19> Reverse transcriptases were employed in recombinant DNA techniques. They are used in the creation of cDNA libraries, i.e. repositories of genomes through the production of DNA from mRNA, a pervasive method in current molecular biology [7 ]. While the initial finding of reverse transcriptases met with resistance, the acquiescence with which it ultimately met attests to the flexibility of widely accepted ideas in the scientific field. Reverse transcriptases were an anomaly that became incorporated into the paradigm of the genetic code. After a momentary period of crisis, all that resulted was a change from diagram (1) to diagram (2). Geneticists and molecular biologists began to realize that the genetic code was not an invincible tenet that was beyond fallibility. According to Kuhn, "Anomaly appears only against the background provided by the paradigm’Ä¶ the anomalies that lead to paradigm change will penetrate existing knowledge to the core." (p. 65). However, what Kuhn's theories do not allow for is the adaptability of paradigms. Inherent in the genetic code is the predicate that information flows in a certain manner. However, there is nothing a priori manifest in the genetic code that would preclude that information may proceed in an alternate, even opposite direction.

<20> I would like to contend that there is the aspect of mutability within a paradigm. What once may be a product of imagination may well become fact. The existence of reverse transcriptases proves that adage. Furthermore, the puzzle-solving ability of molecular biologists was augmented by their discovery, since, as will return to below, they led to the use of cDNA libraries as a functional tool in genome experimentation.

<21> Larry Laudan would argue that "’Ä¶one of the major factors influencing the entrenchment of any element of a research tradition is in conceptual well-foundedness. The core assumptions of any given research tradition are continuously undergoing conceptual scrutiny." (p.100) There is surely a conceptual modification entailed by the discovery of reverse transcriptases. It was now known that genomic material can lie within RNA molecules as well as DNA molecules and information transfer can take place from RNA to DNA. The former conception of DNA as the unique entity of heredity is now would jointly held with RNA.

<22> However, reverse transcriptases, through their reversal of the information pathway of the genetic code, not only rocked the theoretical foundation of molecular biology. They caused a methodological revolution as well. The employment of cDNA libraries as a potent tool in biological experimentation added to the repertoire of recombinant DNA techniques. Hybridization of the entire set of genes in an organism could now be accomplished with the advent of the use of reverse transcriptases, since the cDNA library could be encoded from the isolated mRNA set from an organism.

<23> Moreover, viruses containing reverse transcriptases were tumor viruses that had transforming potential (i.e. could they make a cell cancerous) stimulated more excitement in the study of these polymerases. The viruses were also discovered to be oncogenic in that they induced malignant growth in cells and tissues they infected (Temin, 1972). Temin's initial reports that DNA was actually synthesized during infection led to a tremendous amount of work on these viruses and their role in tumor production [8 ].

<24> In assessing the significance of the discovery of reverse transcriptases, one could surmise that a "mini-revolution" in molecular biology took place in which a research tradition of the genetic code was forever changed conceptually. However, the theoretical framework of molecular biology remained intact, concomitant with methodological shifts in the experimental paradigm. While Kuhnian notions of paradigm shift and integration of anomaly are applicable, Laudan's explanation that the core assumptions of any research tradition constantly undergo conceptual scrutiny duly pertain to the discovery of reverse transcriptases and the genetic code. The transformation of the parameters of the genetic code point to the plasticity of assumptions behind a research tradition. It also indicates the flexibility of paradigms and the normal science they engender, a normal science in which the presumptive model is able to adapt to emerging discovery.

RNA Enzymatic Activity and the Revolution in the Conception of Catalysis

<25> Reverse transcriptases attest to the adaptability of research traditions. They led to a change in experimental method and methodology. However, their existence did not precipitate a wholescale overthrow of the factual foundation of molecular biology. DNA was still considered to be a double-helical molecule with base pairs that form nucleotides and in most organisms, DNA is transcribed into RNA, and then translated to protein. This still forms the basis of most genetic research.

<26> In the next example I will offer, of the discovery of RNA catalysts, a paradigm shift took place within the conceptual confines of an important premise in molecular biology. Protein, once thought to be responsible for chemical heredity, was also thought to be the only source of catalytic material in life systems, i.e. enzymes were proteins or all enzymes are composed of proteinaceous material. A revolution occurred over the next few years with the discovery of ribozymes, RNA molecules that could catalyze reactions as manifested by self-splicing. RNA could splice, or remove, the introns (extraneous genetic material, also called intervening sequences) that it contained [9 ]. The discovery of these unique RNA molecules came through investigation of an organism called Tetrahymena by Tom Cech at the University of Colorado, Boulder.

<27> Cech writes in his article on RNA catalysts in the journal Gene:

Because RNA is chemically and structurally dissimilar from protein, the finding of catalytic activity in RNA was initially surprising. Quantitative measurements of reaction rates show that RNA can be as efficient a catalyst as protein. On the other hand, the potential versatility of RNA to catalyze diverse types of reactions has only begun to be explored. Understanding the efficiency and versatility of RNA as a catalyst helps us evaluate origin-of-life scenarios involving self-replicating RNA, and may explain why RNA catalysis remains important in contemporary cells. (Cech, 1993).

Cech maintains that RNA serves as an appropriate entity for catalysis and forms essential activities as an enzyme in the cell. They are a necessary part of the life functions of the cell. Their evolutionary significance is also mentioned whereby Cech denotes self-replicating RNA as the origin of life since the beginning of nucleic acids.

<28> In his Nobel lecture, Cech addressed the methodological nature of the implications of RNA catalysts and how their discovery met with the same resistance that protein enzymatic activity met with. The revolutionary nature of his finding is alluded to in this passage in terms of his ascribing catalytic activity to genetic material.

As more and more examples of protein enzymes were found, it began to appear that biological catalysis would be exclusively the realm of proteins. In 1981 and 1982, my research group and I found a case in which RNA, a form of genetic material, was able to cleave and rejoin its own nucleotide linkages. This self-splicing RNA provided the first example of a catalytic active site formed of ribonucleic acid. (Cech, 1990)

In the following excerpt from an article in Science, Cech directly refers to RNA being catalysts, and the processes of enzymatic reactions are not exclusive to proteins.

Proteins are not the only catalysts of cellular reactions; there is a growing list of RNA molecules that catalyze RNA cleavage and joining reactions. The chemical mechanisms of RNA-catalyzed reactions are discussed with emphasis on the self-splicing ribosomal RNA precursor of Tetrahymena and the enzymatic activities of its intervening sequence RNA. Wherever appropriate, catalysis by RNA is compared to catalysis by protein enzymes. (Cech, 1987)

This fundamental assumption of the nature of enzymes radically changed. If RNA could be enzymes, the next question that remains to be asked is how they play a dual role in as a source of genetic information and as catalysts of their intervening sequences. RNA, now a transmitter of the genetic code of DNA through the process of transcription, is now known to have catalytic activity. How could these two disparate functions be assimilated into a single molecule with the definite structure of nucleotides or bases? A paradigmatic shift took place in which the conception of what it signifies to be a catalyst underwent remarkable modification, following Cech's assertion that RNA and protein are chemically and structurally different but that both have enzymatic qualities. The parameters under which the RNA molecule was studied also changed. If the RNA molecule in Tetrahymena had self-splicing capabilities, then the nature of RNA had to be further characterized.

<29> This can also be framed in Laudanian terms. One might suggest that what took place in the discovery of RNA catalysts was a change of worldview. Laudan writes: "A highly successful research tradition will lead to abandonment of that worldview which is incompatible with it, and to the elaboration of a new worldview compatible with the research tradition. (Laudan, 101). This new worldview of RNA catalysis was then embraced by biologists and geneticists alike and incorporated into textbooks, review articles and cited frequently in publications. It generally became accepted that RNA was an enzyme and the product of transcription.

<30> Furthermore, the theoretical underpinnings of the study of RNA were now modified in light of its dual functional rule. The conceptual framework used to be that RNA served as a molecule of transfer information; this had now changed. A research tradition in line with a new theoretical framework was now being reconciled with an old worldview. This resolution came about through what Laudan terms by "forging a new worldview which could be reconciled with the scientific research tradition." (Laudan, p. 101). Laudan asserts that success of any theory and research tradition depends on its ability to solve both old and new problems.

<31> Kuhn maintains that crisis is the basis for the emergence of new scientific theories. A crisis in the perception of the natural world concerning structure and function accompanied the discovery of RNA catalysts. It was thought that only proteins with amino acid structures could function as enzymes. Now, nucleotides could serve that purpose. Nucleotides and amino acids are such disparate structures (as Cech mentions) that it seemed almost unimaginable that they could occupy the same functional status. A new theory of enzymatic activity emerged that encompassed the paradoxical role of nucleic acids and amino acids: RNA, as well as protein, can be enzymes.

<32> Yet, unlike the case of centromeric genes and reverse transcriptases, a methodological change did not take place. RNA molecules were not subsequently employed as laboratory catalysts, and the ribozyme from Tetrahymena was not further isolated for this purpose. However, the notion that the Kuhnian concepts of paradigm shifts, assimilation of anomaly, and crisis, and Laudanian notions of research traditions and world-view, converge in an analysis of the discovery of RNA catalysts. This points to the recondite and multifarious ways in which one can approach dialectical movements in science. The anomaly of ribozymes became incorporated into a new worldview concerning the nature of enzymes. Furthermore, normal science changed in such a manner in that researchers now devoted their efforts into finding other examples of RNA catalysts. New puzzles came into being which now had to be solved: With the elucidation of RNA molecules came concomitantly a newfound determination of their potential enzymatic capability.

Conclusions: Kuhn, Laudan and Kitcher: Molecular Biology and the Validity of the Truth-Claim Ontology of Science.

<33> Kuhn argues in The Structure of Scientific Revolution that science is not cumulative and progressive in the traditional sense. He attacked notions of the history of science as being a linear trajectory of discovery, whereupon one discovery logically lead sto the next discovery that mirrors nature more accurately. Laudan, in a sense, makes distinctions between himself and Kuhn, opposing Kuhn's notion of normal science with his description of research traditions, but likewise relinquishes the "classical connections between progress, rationality and truth." To make this decision, Laudan argues that "it involves the assessment of specific cases drawn from the history of science; whether science as a whole is rational and progressive depends’Ä¶upon whether a set of individual choices of theories and research traditions has exhibited progress and rationality." (Laudan, p. 127). Are the competing theories and research traditions in molecular biology progressive in their modifications? Have the changes in normal science that I have characterized in the discovery of anomaly in molecular biology led to merely another period of normal science, or do they form a continuous period of change in which each discovery led to a more objective claim to truth?

<34> In Advancement of Science,Philip Kitcher contends that the "legend" of science as being a progressive history of truth-claims in which science advanced rationally is still a valid picture of activities of scientists. He eschews the sociological and historical argument that science is just a belief, like any other beliefs, and also the argument that scientists are not privileged bearers of truth about nature.

<35> Does the delineation that I have just propounded sustain Kitcher's argument, in which he tries to dismantle Kuhnian and Laudanian conceptions of scientific history and progress, or converge with Kuhn's and Laudan's descriptions of normal science and research traditions, in which rationality, truth and progress are arguable notions when one undertakes a sociological history of science?

<36> Taken in a case by case manner, the discovery of centromeric genes, reverse transcriptases and RNA catalysts serves to illustrate the changing empirical and conceptual nature behind the workings of molecular biology. These findings had a huge impact on the way science is conducted. They went beyond the realm of ordinary discovery within the confines of normal science. (Both reverse transcriptases and RNA catalysts elicited Nobel prizes for their discoverers). They affected in a wholesale manner the general framework of the scientific conceptualizations of molecular biology. These discoveries challenged normal science and research traditions in such a manner that the current paradigm either required modification or revision. I have talked about these processes in the context of Kuhnian paradigm shifts and Laudanian changes in research traditions and worldviews, with their concomitant implications for normal science and problem-solving respectively, and tried to draw new insights on the nature of scientific practices, particularly concerning molecular biology. However, does this dismantle Kitcher's argument?

<37> I would argue cautiously that it does not: the advances of genetics in the previously described processes are indicative of set of discoveries marked by historical correspondence with nature and claim to truth. Centromeric genes form a postscript to the C-value paradox; reverse transcriptases modify the parameters of the genetic code and RNA catalysts redefine the notion of enzymatic activity. Each of these activities of scientific endeavor can be seen as historical developments that converge on truth. In a sense my analysis of Kuhnian and Laudanian notions center around how they should be modified in the realm of molecular science, and these qualifications may be the result of a view that scientific progress is more aligned with Kitcher's view of science. I argue that paradigms are flexible and that experimental methodologies change as a result of new discoveries, as well as theoretical frameworks. Anomalies add to the richness of puzzle-solving within normal science and out of crisis new scientific theories emerge. Research traditions become incorporated alongside new research traditions that accompany modifications of scientific theory. However, each discovery that I delineated was a result of the initial revolution that accompanied the discovery of the structure of DNA.

<38> Kitcher explains: "Many scientific concepts’Ä¶undergo a cumulative process of refinement." (Kitcher, p. 139). Refinement may be the adequate word to describe what happened to the maxims and tenets of molecular biology concerning the examples of centromeric genes, reverse transcriptases and RNA enzymes. The statements that they serve to challenge are not immediately abandoned. The C-value paradox is still conveyed in textbooks, the pathways of the genetic code are still depicted as a one-way transfer of information and most enzymes are viewed as proteins. However, this does not jeopardize the truth-claim of the discoveries of centromeric genes, reverse transcriptases and RNA catalysts.

<39> Kitcher continues: "Contemporary science provides a picture of the physiological-physical-psychological relation between human cognitive systems and nature, and we are able to use this picture to appraise and improve our performance." (Kitcher, p. 139). Nature is in this case consists of unobservable genes, the entities of chemical heredity. With the discovery of the structure of DNA the first physical picture that provided the psychological basis for portraying the entity of gene became accessible. Subsequently molecular biologists were able to construct a fruitful science cognitively. Discoveries accumulated that improved upon each other; a more accurate picture of nature resulted without undermining the truth-claim character of the science as a whole. Overall, I would hope that this depiction of examples drawn from molecular biology would offer an epistemological assessment of how a science integrates challenges to its foundations, redefines the boundaries of how it is practices and how it ultimately progresses.

"It is producing not the known, but the unknown," Molecular Biology: Postmodern or Not?

<40> The previously discussed examples of scientific discovery in molecular biology exemplify the dialectical nature of postmodernism and science today. Molecular biology in some ways is postmodern in other respects is not. For example, the refinement of the Kuhnian notion of paradigm shift and Laudanian concept of new worldviews encompasses what Jean Franˆßois Lyotard in the Postmodern Condition terms as the "search for instabilities." (Lyotard, 53). Instability marks the nature of research and scientific discovery is predicated upon this instability. "Research that takes place under the aegis of a paradigm tends to stabilize." (Lyotard, p. 61). As Lyotard explains, discovery is "unpredictable."

<41> However, the significance of centromeric genes, reverse transcriptases and RNA catalysts within the framework of paradigms and worldviews is that it simultaneously contradicts the foundations of science and paradoxically legitimizes it as well. As Lyotard states, "But what never fails to come and come again, with every new theory, new hypothesis, new statement or new observation is the question of legitimacy. For it is not philosophy that asks this question of science, but science that asks it of itself." (Lyotard, p. 54). These discoveries destabilize the basic tenets of research and yet are accepted as true and assimilated within the demarcations of scientific knowledge. This is because they advance scientific research without overthrowing the underpinnings of established paradigms through modern sensibilities rather than in a postmodern sense. In other words, the truth-claim character of science is not put into question even in light of this postmodern analysis.

<42> Within the confines of molecular biology, the existence of paradigm shifts and new worldviews attest to their flexibility and mutability and the emergence of new forms of methodology and experimentation. It is this adaptability that transforms the potential postmodern character of science as embodied by molecular biology into legitimate scientific knowledge that defies narrative. Furthermore, this new conceptual format develops as a result of the inherent characteristics of molecular biology. Science continually redefines itself and in the process legitimates itself and validates it truth-claim accessibility. It has a tenuous, contradictory relationship with the human sciences: it weakens and negates its power and yet simultaneously exemplifies its methodology. As Lyotard states, "The people debate among themselves about what is just or unjust in the same way that the scientific community debates about what is true or false; they accumulate civil laws just as scientists accumulate scientific laws; they perfect the rules of consensus just as scientists produce new 'paradigms' to revise their rules in light of what they have learned." (Lyotard. p. 30).

<43> Yet, discovery in molecular biology meets the postmodern criteria of argument through falsification. As Lyotard states, "[A statement of science] is never secure from 'falsification.' The knowledge that has accumulated in the form of already accepted statements can always be challenged. But conversely, any new statement that contradicts a previously approved statement regarding the same referent can be accepted as valid only if it refutes the previous statement by producing arguments and proofs." (Lyotard, p. 26). The shifts in paradigm and the emergent new worldviews in molecular biology consisted of new scientific knowledge that challenged previously accepted ideas and changed the foundational basis of methodological experimentation. Furthermore, these findings (of centromeric genes, reverse transcriptases and RNA catalysts) , accepted through argumentation and evidence, are not protected from being contradicted. This underscores the postmodern nature of pivotal discovery in molecular genetics. As Lyotard continues, " The game of science thus implies a diachronic temporality, that is, a memory and a project. The current sender of a scientific statement is supposed to be acquainted with previous statements concerning its referent and only proposes a new statement on the subject if it differs from the previous one." (Lyotard, p. 26). Memory involves the theories of the C-value paradox, the genetic code and the nature of enzymatic function while the project consists of how these theories ultimately underwent paradigm shifts, the concept of which is privy to modification. It may just be that it essential to molecular biology that the new statements it generates are intrinsically contradictory and different from previous ones. Genetics may exemplify the characteristics of post-modern science with its "catastrophes and pragmatic paradoxes," as Lyotard would put it.

<44> Yet, finally, it is legitimacy that is at stake here. Lyotard maintains that the rules by which science plays is underscored by language games. However, it is not the games of language that are integral to new discovery, but the foundational premise of paradigm shifts and new worldviews as put forth by Kuhn and Laudan. Puzzle-solving and research traditions are still the basis of modern science and embody their performativity and effectiveness. As an intellectual institution, molecular biology and genetics encourage new observations, theories and findings and this is what is inherent in their language. Discovery, in essence, is welcomed, the field of the unknown encompasses the field of the known and truth is still validated as the outcome of science.

References

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Cech, T.R. Biosci Rep (1990) Nobel lecture. Self-splicing and enzymatic activity of an intervening sequence RNA from Tetrahymena. Jun; 10(3):239-61 3.

Cech TR. Science (1987) The chemistry of self-splicing RNA and RNA enzymes. Jun 19; 236 (4808):1532-9.

Klug, W.S. and Cummins, M.R. Essentials of Genetics. (Prentice Hall) Saddleriver, 1999.

Kuhn, T.S. The Structure of Scientific Revolutions. (University of Chicago Press). Chicago, 1962.

Laudan, Larry. Progress and Its Problems. (University of California Press). Los Angeles, 1977.

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Lyotard, Jean-Franˆßois. The Postmodern Condition. (University of Minnesota Press). Minneapolis, 1979.

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Notes

[1] Malacinski and Friefelder, Essentials of Molecular Biology, p. 4. [^]

[2] Somatic cell hybridization is one of many ways to map genes on chromosomes. It relies on the fact that two cells in culture can be induced to fuse into a single hybrid cell. In this case, a human and mouse cell are fused, creating a hybrid. The hybrid cell contains two nuclei in a common cytoplasm. Eventually, the nuclei fuse together creating a synkaron. In the case of the human-mouse hybrid, human chromosomes are lost randomly until eventually the synkaron has a full complement of mouse chromosomes and only a few human chromosomes. The rationale is this: if a specific human gene product is synthesized in a synkaron containing one to three human chromosomes, then the gene responsible for that product must reside on one of the human chromosomes remaining in the hybrid cell. Other methods of chromosomal mapping include in situ hybridization in which a probe (a sequence of DNA that is complementary in base sequence to the region of DNA to which is going to be hybridized) is hybridized to a region of the chromosome. The area of the chromosome to which it hybridizes is the region where the gene is localized. [^]

[3] The techniques described here are routine methods in recombinant DNA technology and are related to methods of mapping. A probe is created whereby a sequence of DNA has base complementarity to another sequence of DNA. The rationale in this instance is that probe derived from the centromere has base complementarity or homology to genes in a library( the entire complement of genes in an organism). This is called hybridization. If this probe hybridizes to a portion of DNA in the library it indicates that there are genes on the centromere. The portion of DNA in the library becomes a clone, which is subject to further analysis. This clone is isolated and purified and "blotted" or transferred onto a membrane. This is known as Southern blot procedure. The probe derived from the centromere (the same probe used in hybridizing the library) is hybridized with this membrane that has the clone on it. If the probe hybridizes with the clone, this can be detected and confirms that the clone is a centromeric gene. [^]

[4] This thesis has also been articulated in Naomi Oreskes' Rejection of Continental Drift, Wise's Energy and Empire and Steven Shapin and Simon Schaffer's Leviathan and the Air Pump. [^]

[5] Lod (logarithmic of odds) score method is a statistical approach utilizing pedigree data to determine if two genes are linked, or if the position of two genes (called loci) are on the same chromosome. [^]

[6] Klug and Cummins, Essentials of Genetics, p. 366. [^]

[7] cDNA libraries are commonly used in what is termed cDNA cloning. It differs from genomic libraries in that it represents the sequences of DNA in the genome that are expressed. Only genes that are expressed are transcribed into mRNA . Since reverse transcriptase can synthesize DNA from a complementary strand of RNA, DNA can be created from a RNA template. Once the RNA strand is created by the reverse transcriptase enzyme, it czn be degraded and the resultant new DNA strand can serve as a template for its own replication. This double-stranded cDNA molecule can then be cloned into vectors and inserted into bacterial colonies to create a cDNA library. [^]

[8] It was subsequently determined that the infecting agent in many tumors were oncogenic viruses that possessed these reverse transcriptases. Working with the RNA-containing oncogenic Rous sarcoma virus, Temin determined that DNA is synthesized by RSV during infection. He announced these results in 1970 and found that other workers, using a mouse leukemia virus had arrived at the same conclusion. Reverse transcriptase has since been found in all RNA oncogenic viruses, which are called retroviruses since they reverse the flow of genetic information. (Klug and Cummins, Essentials of Genetics, p. 366-7). [^]

[9] Introns, also known as intervening sequences, are portions of DNA considered unnecessary for the translation of protein from mRNA. Once the introns are excised from an mRNA molecule, the remaining molecules are termed exons. The exons are joined together and are then translated into protein. Introns exist in mRNA molecules and are excised out by an elaborate enzymatic mechanism known as intron splicing. Ribozymes have the capacity to splice its own introns through an intermolecular reaction that connects two different RNA molecules. Because it possesses this inherent enzymatic mechanism of self-splicing, ribozymes are also known as catalytic RNA. [^]