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Library of Congress Cataloging-in-Publication Data Watson, James D. Molecular biology of the gene / James D. Watson, Cold Spring Harbor Laboratory, Tania. Brief Contents Author: James D. Watson | Tania A. Baker | Stephen P. Bell | Alexander Gann | Michael Levine | Richard Losick. Molecular Biology of the Gene. F T H. E D I T I O N. James D. Watson. Cold Spring Harbor. Laboratory. Tania A. Baker. Massachusetts Institute of Technology .
Algis Valiunas James D. Watson is the most famous American scientist since J. That his name will roll throughout history in tandem with that of Francis Crick, his English collaborator at the Cavendish Laboratory in Cambridge, does not diminish its luster, and may even enhance it somewhat. For an achievement like the discovery of the structure and basic function of DNA, there is glory enough to go around. It might indeed be too much for a single man to shoulder. Watson and Crick are certainly an inseparable pair in the public mind, and the association has even confused some persons who clearly ought to know better. Mott was flummoxed.
Mattison, Berwyn F. Letter from Berwyn F. Lecture Notes. Klug, Aaron.
Letter from Francis Crick to Robert L. Letter from Francis Crick to Fritz Lipmann. Letter from Francis Crick to Marshall W. Lipmann, Fritz. Letter from Fritz Lipmann to Francis Crick. Letter from Francis Crick to Jacques Monod. Charles C. Thomas, Publisher, Journal of Molecular Biology 3, : Sound Recording.
Letter from Francis Crick to Severo Ochoa. Ochoa, Severo. Letter from Severo Ochoa to Francis Crick. Nirenberg, Marshall W. Letter from Marshall W. Nirenberg to Francis Crick. Pauling, Linus. Letter from Linus Pauling to Francis Crick. Bhargava, P. Letter from P. Perutz, Max F. Medical Research Council of Great Britain.
Her Majesty's Stationery Office, Weaver, Warren.
Letter from Warren Weaver to Francis Crick. Letter from Francis Crick to Carl C. Letter from Francis Crick to Warren Weaver. Lindegren, Carl C. Letter from Carl C. Lindegren to Francis Crick. Lerman, Leonard S. Letter from Leonard S. Lerman to Francis Crick. Letter from Francis Crick to Leonard S. International Congress of Biochemistry 6th, , . Crick, Francis, and Leslie E. Letter from Francis Crick to Alexander Rich.
Khorana, H. Letter from H. Tables available in molecular biology textbooks e. For example, CAC codes for histidine. Only a few exceptions for these coding relations have been found, in a few anomalous cases see the list in a small table in Alberts et al. In contrast, genetic information refers to the linear sequence of codons along the DNA, which in the simplest case are transcribed to messenger RNA, which are translated to linearly order the amino acids in a protein.
With the genetic code elucidated and the relationship between genes and their molecular products traced, it seemed in the late s that the concept of the gene was secure in its connection between gene structure and gene function. The machinery of protein synthesis translated the coded information in the linear order of nucleic acid bases into the linear order of amino acids in a protein.
In the late s, a series of discoveries by molecular biologists complicated the straightforward relationship between a single, continuous DNA sequence and its protein product. Overlapping genes were discovered Barrell et al. And split genes were found Berget et al. In contrast to the colinearity hypothesis that a continuous nucleic acid sequence generated an amino acid chain, it became apparent that stretches of DNA were often split between coding regions exons and non-coding regions introns.
The distinction between exons and introns became even more complicated when alternative splicing was discovered the following year Berk and Sharp A series of exons could be spliced together in a variety of ways, thus generating a variety of molecular products.
Discoveries such as overlapping genes, split genes, and alternative splicing forced molecular biologists to rethink their understanding of what actually made a gene…a gene Portin ; for a survey of such complications see Gerstein et al. These developments in molecular biology have received philosophical scrutiny.
Molecular biologists sought to discover mechanisms see Section 2. Also, conceptualizing DNA as an informational molecule see Section 2. Finally, the concept of the gene see Section 2. Experimentation also figured prominently in the classical period see Section 3. Because of this, I have long felt that the future of molecular biology lies in the extension of research to other fields of biology, notably development and the nervous system.
Brenner, letter to Perutz, Along with Brenner, in the late s and early s, many of the leading molecular biologists from the classical period redirected their research agendas, utilizing the newly developed molecular techniques to investigate unsolved problems in other fields. Francois Jacob, Jacques Monod and their colleagues used the bacteria Escherichia coli to investigate how environmental conditions impact gene expression and regulation Jacob and Monod ; discussed in Craver and Darden ; Morange Ch.
The study of behavior and the nervous system also lured some molecular biologists. Finding appropriate model organisms that could be subjected to molecular genetic analyses proved challenging. And at Cambridge, Sydney Brenner developed the nematode worm, Caenorhabditis elegans, to study the nervous system, as well as the genetics of behavior Brenner , ; Ankeny ; Brown In subsequent decades, the study of cells was transformed from descriptive cytology into molecular cell biology Alberts et al.
Molecular evolution developed as a phylogenetic method for the comparison of DNA sequences and whole genomes; molecular systematics sought to research the evolution of the genetic code as well as the rates of that evolutionary process by comparing similarities and differences between molecules Dietrich The immunological relationship between antibodies and antigens was recharacterized at the molecular level Podolsky and Tauber ; Schaffner ; see also the entry on the philosophy of immunology.
And the study of oncogenes in cancer research was just one example of molecular medicine Morange b. The molecularization of many fields introduced a range of issues of interest to philosophers. Inferences made about research on model organisms such as worms and flies raised questions about extrapolation see Section 3. And the reductive techniques of molecular biology raised questions about whether scientific investigations should always strive to reduce to lower and lower levels see Section 3.
The number of base pairs varies widely among species. For example, the infection-causing Haemophilus influenzae the first bacterial genome to be sequenced has roughly 1. The history of genomics is the history of the development and use of new experimental and computational methods for producing, storing, and interpreting such sequence data Ankeny ; Stevens Frederick Sanger played a seminal role in initiating such developments, creating influential DNA sequencing techniques in the s and s Saiki et al.
In the mid s, after the development of sequencing techniques, the United States Department of Energy DoE originated a project to sequence the human genome initially as part of a larger plan to determine the impact of radiation on the human genome induced by the Hiroshima and Nagasaki bombings. While the human genome project received most of the public attention, hundreds of genomes have been sequenced to date, including the cat Pontius et al.
One of the most shocking results of those sequencing projects was the total number of genes defined in this context as stretches of DNA that code for a protein product found in the genomes. The human genome contains 20, to 25, genes, the cat contains 20, genes, the mouse 24,, and rice 32, to 50, So in contrast to early assumptions stemming from the classical period of molecular biology about how genes produced proteins which in turn produced organisms, it turned out that neither organismal complexity nor even position on the food chain was predictive of gene-number.
And the human genome project itself has turned its attention from a standardized human genome to variation between genomes in the form of the Human Genome Diversity Initiative Gannett A related challenge was making sense of the genetic similarity claims. Does this finding tell us anything substantive about our overall similarity to pumpkins Piotrowska ?
To help answer such questions, genomics is now supplemented by post-genomics. There is ongoing debate about what actually constitutes post-genomics Morange , but the general trend is a focus beyond the mere sequence of As, Cs, Ts, and Gs and instead on the complex, cellular mechanisms involved in generating such a variety of protein products from a relatively small number of protein-coding regions in the genome. Post-genomics utilizes the sequence information provided by genomics but then situates it in an analysis of all the other entities and activities involved in the mechanisms of transcription transcriptomics , regulation regulomics , metabolism metabolomics , and expression proteomics.
Developments in genomics and post-genomics have sparked a number of philosophical questions about molecular biology. Since the genome requires a vast array of other mechanisms to facilitate the generation of a protein product, can DNA really be causally prioritized see Section 2.
Similarly, in the face of such interdependent mechanisms involved in transcription, regulation, and expression, can DNA alone be privileged as the bearer of hereditary information, or is information distributed across all such entities and activities see Section 2.
Concepts in Molecular Biology As the history above reveals, key concepts in molecular biology are mechanism, information, and gene. Hence, major tasks for philosophers of molecular biology have been and continue to be analyzing the concepts of mechanism, information, and gene in order to understand how they have been, are, and should be used. Discovering the mechanism that produces a phenomenon is an important accomplishment for several reasons.
First, knowledge of a mechanism shows how something works: elucidated mechanisms provide understanding. Second, knowing how a mechanism works allows predictions to be made based upon the regularity in mechanisms. For example, knowing how the mechanism of DNA base pairing works in one species allows one to make predictions about how it works in other species, even if conditions or inputs are changed.
Third, knowledge of mechanisms potentially allows one to intervene to change what the mechanism produces, to manipulate its parts to construct experimental tools, or to repair a broken, diseased mechanism. In short, knowledge of elucidated mechanisms provides understanding, prediction, and control. Given the general importance of mechanisms and the fact that mechanisms play such a central role in the field of molecular biology, it is not surprising that philosophers of biology pioneered analyzing the concept of mechanism see the entry on mechanisms in science.
Starting in the s, a number of philosophers focused squarely on how the concept of a mechanism functions in science generally and molecular biology specifically. A number of characterizations of what a mechanism is have emerged over the years Bechtel and Abrahamsen ; Glennan ; Machamer, Darden, and Craver Phyllis McKay Illari and Jon Williamson have more recently offered a characterization that draws on the essential features of all the earlier contributions: A mechanism for a phenomenon consists of entities and activities organized in such a way that they are responsible for the phenomenon.
In short, the double helix of DNA an entity with an organization unwinds an activity and new component parts entities bond an activity to both parts of the unwound DNA helix. DNA is a nucleic acid composed of several subparts: a sugar-phosphate backbone and nucleic acid bases.
When DNA unwinds, the bases exhibit weak charges, properties that result from slight asymmetries in the molecules. These weak charges allow a DNA base and its complement to engage in the activity of forming hydrogen weak polar chemical bonds; the specificity of this activity is due to the topological arrangements of the weak polar charges in the subparts of the base.
Ultimately, entities with polar charges enable the activity of hydrogen bond formation. After the complementary bases align, then the backbone forms via stronger covalent bonding. The mechanism proceeds with unwinding and bonding together activities new parts, to produce two helices newly formed entities that are more or less faithfully copies of the parent helix. Scientists rarely depict all the particular details when describing a mechanism; representations are usually schematic, often depicted in diagrams.
A mechanism schema is a truncated abstract description of a mechanism that can be instantiated by filling it with more specific descriptions of component entities and activities.
This is a schematic representation with a high degree of abstraction of the mechanism of protein synthesis, which can be instantiated with details of DNA base sequence, complementary RNA sequence, and the corresponding order of amino acids in the protein produced by the more specific mechanism.
Molecular biology textbooks are replete with diagrams of mechanism schemas. A mechanism schema can be instantiated to yield a description of a particular mechanism.
In contrast, a mechanism sketch cannot yet be instantiated; components are as yet unknown. Sketches have black boxes for missing components or grey boxes whose function is known but whose entities and activities that carry out that function are not yet elucidated. Such sketches guide new research to fill in the details Craver and Darden Historians of biology have tracked the entrenchment of information-talk in molecular biology Kay since its introduction.
The question for philosophers of biology is whether an analysis of the concept of information can capture the various ways in which the concept is used in molecular biology e. Stephen Downes helpfully distinguishes three positions on the relation between information and the natural world: Information is present in DNA and other nucleotide sequences.
Other cellular mechanisms contain no information. DNA and other nucleotide sequences do not contain information, nor do any other cellular mechanisms.
These options may be read either ontologically or heuristically. A heuristic reading of 1 , for instance, views the talk of information in molecular biology as useful in providing a way of talking and in guiding research.
And so the heuristic benefit of the information concept can be defended without making any commitment to the ontological status Sarkar Indeed, one might argue that a vague and open-ended use of information is valuable for heuristic purposes, especially during early discovery phases in the development of a field. Stegmann does explicitly allow that components other than nucleotide sequences might contain what he calls instructional information.
However, his only example is a thought experiment involving enzymes linearly ordered along a membrane; nothing of the sort is known to actually exist or even seems very likely to exist. Stegmann calls this the sequentialization view. On his account, DNA qualifies as an instructional information carrier for replication, transcription and translation. The sequence of bases provides the order.
The hydrogen bonding between specific bases and the genetic code provide the specific kinds of steps. And the mechanisms of replication, transcription, and translation yield certain outcomes: a copy of the DNA double helix, an mRNA, and a linear order of amino acids. For more on this topic, see the entry on biological information. She argues that information is ubiquitous. She defines information as follows: a source becomes an informational input when an interpreting receiver can react to the form of the source and variations in this form in a functional manner.
She claims a broad applicability of this definition. The definition, she says, accommodates information stemming from environmental cues as well as from evolved signals, and calls for a comparison between information-transmission in different types of inheritance systems — the genetic, the epigenetic, the behavioral, and the cultural-symbolic.
On this view, genes have no theoretically privileged informational status Jablonka Kenneth Waters argues that information is a useful term in rhetorical contexts, such as seeking funding for DNA sequencing by claiming that DNA carries information. As discussed in Section 2. Talk of information is not needed; causal role function talk is sufficient. Investigations of reduction and scientific change raised the question of how the concept of the gene evolved over time, figuring prominently in C.
Over time, however, philosophical discussions of the gene concept took on a life of their own, as philosophers raised questions independent of the reduction debate: What is a gene?
And, is there anything causally distinct about DNA? For a survey of gene concepts defended by philosophers, see Griffiths and Stotz , An example will help to distinguish the two: When one talked about the gene for cystic fibrosis, the most common genetic disease affecting populations of Western European descent, the Gene-P concept was being utilized; the concept referred to the ability to track the transmission of this gene from generation to generation as an instrumental predictor of cystic fibrosis, without being contingent on knowing the causal pathway between the particular sequence of DNA and the ultimate phenotypic disease.
The Gene-D concept, in contrast, referred instead to just one developmental resource i. A second philosophical approach for conceptualizing the gene involved rethinking a single, unified gene concept that captured the molecular-developmental complexities. Returning to the case of cystic fibrosis, a PMG for an individual without the disease referred to one of a variety of transmembrane ion-channel templates along with all the epigenetic factors, i.
And so cystic fibrosis arose when a particular stretch of the DNA sequence was missing from this process. Relatedly, philosophers have also debated the causal distinctiveness of DNA. Consider again the case of cystic fibrosis. A stretch of DNA on chromosome 7 is involved in the process of gene expression, which generates or fails to generate the functional product that transports chloride ions.
But obviously that final product results from that stretch of DNA as well as all the other developmental resources involved in gene expression, be it in the expression of the functional protein or the dysfunctional one.
Thus, a number of authors have argued for a causal parity thesis, wherein all developmental resources involved in the generation of a phenotype such as cystic fibrosis are treated as being on par Griffiths and Knight ; Robert ; Stotz Waters , see also his entry on molecular genetics , in reply, has argued that there is something causally distinctive about DNA.
Causes are often conceived of as being difference makers, in that a variable i. So RNA polymerase is a difference maker in the development or lack of development of cystic fibrosis, but only a potential difference maker, since variation in RNA polymerase does not play a role in the development or lack of development of cystic fibrosis in natural populations. The stretch of DNA on chromosome 7, however, is an actual difference maker.
That is, there are actual differences in natural human populations on this stretch of DNA, which lead to actual differences in developing or not developing cystic fibrosis; DNA is causally distinctive, according to Waters, because it is an actual difference maker. Advocates of the parity thesis are thus challenged to identify the other resources in addition to DNA that are actual difference makers. Recently, Paul Griffiths and Karola Stotz have responded to this challenge by offering examples in which, depending on context, regulatory mechanisms can either contribute additional information to the gene products or create gene products for which there is no underlying sequence.
Thus, according to Griffiths and Stotz, to assign a causally distinctive role to DNA, as Waters does, is to ignore key aspects of how the gene makes its product. Molecular Biology and General Philosophy of Science In addition to analyzing key concepts in the field, philosophers have employed case studies from molecular biology to address more general issues in the philosophy of science, such as reduction, explanation, extrapolation, and experimentation.
For each of these philosophical issues, evidence from molecular biology directs philosophical attention toward understanding the concept of a mechanism for addressing the topic.
Theory reduction pertains to whether or not theories from one scientific field can be reduced to theories from another scientific field. In contrast, explanatory reduction often united with methodological reduction pertains to whether or not explanations that come from lower levels often united with methodologies that investigate those lower levels are better than explanations that come from higher levels.
Philosophical attention to molecular biology has contributed to debates about both of these senses of reduction see the entry on reductionism in biology.
Philosophy of biology first came to prominence as a sub-specialty of philosophy of science in the s when it offered an apparent case study by which to judge how theories from one field may reduce to theories from another field.
The specific question was: might classic, Mendelian genetics reduce to molecular genetics? Even though Schaffner and Hull were engaged in a debate over theory reduction, they simultaneously admitted that the question of formal theory reduction was rather peripheral to what scientists actually did and studied Schaffner b; Hull And indeed, while the theory reduction debate was playing out, a number of philosophers of biology switched attention from scientific theories to the stuff in nature that scientists investigated.
William Wimsatt argued for a shift in the reduction debate from talk of relations between theories to talk of decompositional explanation via mechanisms. And Lindley Darden and Nancy Maull focused attention on the bridges between fields formed by part-whole relations, structure-function relations, and cause-effect relations.
This shift in attention was a precursor to understanding the philosophy of science through the lens of mechanisms. Darden, building on the work of Machamer, Darden, and Craver , has more recently returned to the question of how Mendelian and molecular genetics are related and viewed it through this lens Darden Rather than understanding the relationship as one of reduction, she suggests they can be understood as relating via a focus on different working entities often at different size levels that operate at different times.
Thus, the relation was one of integration of sequentially operating chromosomal and molecular hereditary mechanisms rather than reduction. For an alternative but still integrative reading of the relationship between classical genetics and molecular biology that focuses on their shared functional units, see Baetu Reduction can also be about explanation and methodology.
That is, reduction can be about using reductive methodologies to dig down to lower levels because the thought is that this exercise leads to more reductive explanations and more reductive explanations are better than explanations at higher levels.
Rosenberg 4 Hence, the task of this explanatory reduction is to explain all functional biological phenomena via molecular biology.
This particular debate can be understood as an instance of a more general debate occurring in biology and philosophy of biology about whether investigations of lower-level molecular biology are better than investigations of high-level systems biology Baetu a; Bechtel and Abrahamsen ; De Backer, De Waele, and Van Speybroeck ; Huettemann and Love ; Marco ; Morange ; Pigliucci ; Powell and Dupre On this deductive-nomological account Hempel and Oppenheim , an explanation of particular observation statements was analyzed as subsumption under universal applying throughout the universe , general exceptionless , necessary not contingent laws of nature plus the initial conditions of the particular case.
Philosophers of biology have criticized this traditional analysis as inapplicable to biology, and especially molecular biology. Since the s, philosophers of biology have questioned the existence of biological laws of nature. Smart emphasized the earth-boundedness of the biological sciences in conflict with the universality of natural laws. Without traditional laws of nature from which to derive explanations, philosophers of biology have been forced to rethink the nature of scientific explanation in biology and, in particular, molecular biology.
Two accounts of explanation emerged: the unificationist and the causal-mechanical. Philip Kitcher , developed a unificationist account of explanation, and he and Sylvia Culp explicitly applied it to molecular biology Culp and Kitcher An explanation of a particular pattern of distribution of progeny phenotypes in a genetic cross resulted from instantiating the appropriate deductive argument schema: the variables were filled with the details from the particular case and the conclusion derived from the premises.
Working in the causal-mechanical tradition pioneered by Wesley Salmon , , other philosophers turned to understanding mechanism elucidation as the avenue to scientific explanation in biology Bechtel and Abrahamsen ; Bechtel and Richardson ; Craver ; Darden a; Glennan ; Machamer, Darden, and Craver ; Sarkar ; Schaffner ; Woodward , There are differences between the various accounts of a mechanism, but they hold in common the basic idea that a scientist provides a successful explanation of a phenomenon by identifying and manipulating variables in the mechanisms thereby determining how those variables are situated in and make a difference in the mechanism; the ultimate explanation amounts to the elucidation of how those mechanism components act and interact to produce the phenomenon under investigation.
As mentioned above see Section 2. There are several virtues of the causal-mechanical approach to understanding scientific explanation in molecular biology.
Molecular biologists rarely describe their practice and achievements as the development of new theories; rather, they describe their practice and achievements as the elucidation of molecular mechanisms Craver ; Machamer, Darden, Craver Another virtue of the causal-mechanical approach is that it captures biological explanations of both regularity and variation.
Unlike in physics, where a scientist assumes that an electron is an electron is an electron, a biologist is often interested in precisely what makes one individual different from another, one population different from another, or one species different from another.
Philosophers have extended the causal-mechanical account of explanation to cover biological explanations of variation, be it across evolutionary time Calcott or across individuals in a population Tabery , Difference mechanisms are regular casual mechanisms made up of difference-making variables, one or more of which are actual difference makers see Section 2.