Molecular Biology

Summary

Molecular biology is the study of biological processes at the level of molecules, particularly the nucleic acids DNA and RNA and the proteins they encode. The field consolidated rapidly in the early 1950s after Rosalind Franklin’s X-ray crystallography work at King’s College London, and Watson and Crick’s 1953 double-helix model built from that data, overturning the assumption that protein carries heredity and demonstrating that the genetic code sits in the sequence of DNA’s four chemical bases. Within two decades, molecular biology had redrawn oncology, pharmacology, and clinical education. It also raised philosophical questions that remain unresolved: whether life can be fully explained by physics and chemistry, what a “gene” is when the majority of the genome was long dismissed as “junk DNA,” and what it means to find language-like codes operating without any evident author.

Origins: From Chemistry to Life

The intellectual origins of molecular biology lie in three near-simultaneous recognitions made in the mid-twentieth century, each by someone working at the edge of their discipline.

Archibald Garrod began the first of these in 1897 when he identified alkaptonuria as an “error of metabolism,” combining biochemistry with Mendelian inheritance to explain disease in a synthesis Porter calls farsighted but notes “went largely unnoticed” at the time.(Porter, 1997) Garrod’s concept of inborn errors, in which specific enzyme deficiencies block specific metabolic steps, would later become the foundational logic of molecular medicine, but it arrived before the machinery to develop it existed.

The second recognition came in 1943, when Oswald Avery demonstrated at the Rockefeller Institute that DNA, not protein, carries the hereditary message. Using purified DNA extracted from virulent pneumococcus bacteria, Avery and his colleagues produced a permanent heritable change in non-virulent bacteria, establishing that the nucleic acid itself constituted the genetic material.(Maddox, 2003) Erwin Chargaff responded to Avery’s results by analyzing the base composition of DNA across species, discovering in 1949 that adenine and thymine always appear in equal proportions, as do cytosine and guanine, a “curious correspondence” he could not explain but which became a constraint any structural model would have to satisfy.(Maddox, 2003)

The third recognition was Erwin Schrödinger’s 1943 Dublin lectures, published as What Is Life?. Schrödinger, a physicist, proposed that genes are irregular crystals whose aperiodic arrangement encodes hereditary information, and that life itself can be defined as “negative entropy”: matter that resists decay by consuming energy from its environment.(Maddox, 2003) The molecular biologist Gunther Stent later called What Is Life? the “Uncle Tom’s Cabin of biology,” because it expressed biological problems in the language of physics and drew a generation of postwar physicists into biology.(Maddox, 2003) William Astbury at Leeds had already taken X-ray diffraction images of DNA fibres before the war, correctly determining that the bases lie flat, stacked like pennies 3.4 Ångströms apart, a measurement that would prove constant through every subsequent structural attempt.(Maddox, 2003)

Rosalind Franklin arrived at King’s College London on 5 January 1951, leaving coal research to work on biological molecules. Maddox notes the difference tersely: “Coal does not make more coal, but genes make more genes.”(Maddox, 2003)

The Structure of DNA

The technical difficulty of determining DNA’s structure was not simply organizational. It required bringing together methods that had developed in separate disciplines, and the scientists who solved it worked at the intersections of those disciplines, sometimes productively, sometimes in competition.

Franklin’s contribution at King’s was a specific technical advance before it was anything else. By controlling the humidity inside her X-ray camera through salt solutions, she demonstrated that DNA exists in two physically distinct forms: the hydrated “B” form, longer and thinner, and the dry, crystalline “A” form, which could be converted back to B simply by restoring moisture.(Maddox, 2003) No previous experimenter had identified this transition or understood its implications for interpretation. The division of labor that King’s director J. T. Randall imposed on the group assigned Franklin the A form with the Signer DNA (a high-molecular-weight preparation from Rudolf Signer of Berne that produced exceptional diffraction diagrams(Maddox, 2003)) and assigned Wilkins the B form.(Maddox, 2003)

At the Naples conference in May 1951, Wilkins showed the first clear X-ray diffraction slide of DNA: “a sharp discrete set of reflections” that demonstrated a regular, mappable structure. James Watson was in the audience and was convinced.(Maddox, 2003) Linus Pauling had announced the alpha helix structure of proteins that same spring, establishing model-building as a viable approach to macromolecular structure and prompting Francis Crick to observe that “helices were in the air.”(Maddox, 2003)

Watson attended Franklin’s November 1951 colloquium at King’s and took no notes. He misunderstood her account of the water content cloaking the phosphates on the outside of the molecule, and the model he and Crick constructed the following week placed the phosphates on the inside. Franklin identified the error instantly: DNA is “a thirsty molecule,” and Crick later accepted that “I did not know enough chemistry to know that things like sodium are highly likely to be hydrated anyway.”(Maddox, 2003) The error also traced to Watson’s flawed memory of Franklin’s data.(Maddox, 2003)

Watson and Crick’s 1953 double helix was the result that reoriented biology. Porter frames it directly: it “overturned the assumption that protein was the transmitter of inheritance and opened genetics as a field of clinical medicine.”(Porter, 1997) After Franklin’s death in 1958, Bernal’s obituary in Nature noted that her contribution consisted in “the technique of preparing and taking X-ray photographs of the two hydrated forms of deoxyribonucleic acid and by applying the methods of Patterson function analysis to show that the structure was best accounted for by a double spiral of nucleotides.”(Maddox, 2003)

Canguilhem offers an epistemological analysis that explains why this discovery required so many hands and disciplines. The deciphering of DNA’s structure by Watson and Crick, he argues, required not just genetics and biochemistry but also x-ray crystallography, electron microscopy, radioisotope tracing, and information theory. Each discipline had to be brought into structural relation with the others before the problem could be formulated, let alone solved.[cang-ir88-ch05-009] A DNA crystal, he writes, is a “superreal,” non-natural object, the product of “considerable technical and theoretical labor,” the latest in a series of new scientific objects invented since the end of the nineteenth century, including the cellular extract, the intermediate metabolite, the Drosophila gene, and the culture of mutant bacteria.[cang-ir88-ch05-006]

Molecular Biology and Cancer

The connection between molecular biology and cancer was not immediate. It ran through virology, chromosomal studies, and statistical genetics before converging on the oncogene concept.

Peyton Rous had discovered in 1910 that a filterable cell-free agent taken from chicken tumors could transfer sarcomas to healthy chickens, providing the first experimental evidence that viruses cause cancer. He waited fifty-five years for the Nobel Prize.(Mukherjee, 2010) In the same period, Theodor Boveri proposed in 1914, based on sea-urchin experiments, that cancer results from abnormal chromosomal combinations within the nucleus, imagining “a new class of genes” capable of driving uncontrolled cell division, the structures that would later be called oncogenes.(Mukherjee, 2010)

The molecular mechanism linking these observations arrived when Howard Temin and David Baltimore independently discovered reverse transcriptase in 1970, demonstrating that RNA tumor viruses could convert their RNA genome into DNA. This overturned what had become known as the central dogma of molecular biology and explained how a viral gene could permanently integrate into a host cell’s chromosome.(Mukherjee, 2010)

Harold Varmus and J. Michael Bishop then showed in 1976 that the src oncogene in Rous sarcoma virus originated from a normal cellular proto-oncogene present in all vertebrate cells. “Src,” Varmus wrote in 1976, “is everywhere.” The implication was that cancer genes are not foreign intrusions but mutated versions of normal growth-regulating genes.(Mukherjee, 2010) Janet Rowley had confirmed the chromosomal specificity of this process in 1973 when she found the same 9:22 translocation in every single case of chronic myelogenous leukemia she examined: not random chromosomal chaos but a specific, reproducible abnormality.(Mukherjee, 2010)

Alfred Knudson arrived at the complementary concept in 1971 from statistics alone. His analysis of retinoblastoma inheritance patterns led him to propose the two-hit hypothesis: for certain cancer-causing genes, two mutational events are required to provoke uncontrolled division, distinguishing anti-oncogenes (tumor suppressors) from the proto-oncogenes that Varmus and Bishop were working on simultaneously.(Mukherjee, 2010) Robert Weinberg isolated the first human oncogene directly from a bladder cancer cell in 1982, confirming that mutated endogenous ras encoded a permanently hyperactive protein.(Mukherjee, 2010)

Mukherjee summarizes the two-class model that emerged: cancer represents a confluence of activated proto-oncogenes (“jammed accelerators” driving uncontrolled division) and inactivated tumor suppressor genes (“missing brakes” removing growth-inhibitory signals).(Mukherjee, 2010) The deeper insight, as Varmus framed it in his Nobel lecture drawing on Beowulf, was that the cancer cell is “a distorted version of our normal selves,” not an alien invasion but an internal rebellion of the organism’s own regulatory machinery.(Mukherjee, 2010) The Rous sarcoma virus, in Mukherjee’s reading, turns out to have been “an accidental courier for a gene that had originated in a cancer cell — a parasite parasitized by cancer.”(Mukherjee, 2010)

Philosophical Implications

Molecular biology’s success produced a philosophical challenge that no amount of experimental data resolves on its own. It concerns the relationship between the molecular level of description and the phenomena that medicine must address: health, disease, regulation, and death.

Canguilhem’s analysis in Ideology and Rationality in the History of the Life Sciences identifies what he calls “thematic conservation”: the persistent return, across all epochs of biological thought and through all shifts in content, of ideas about self-preservation, regulation, and normality. Aristotle’s teleology, Descartes’s mechanism, Stahl’s animism, Claude Bernard’s homeostasis, and the genetic code’s “errors” all invoke the same underlying contrast between normal and abnormal function. For Canguilhem, this pattern is not coincidental. It reflects the structural situation of biology as a science that must grapple with sickness and death. “Physics was produced, sometimes at risk of life and limb, by living things subject to sickness and death,” he writes, “but sickness and death are not problems of physics. They are problems of biology.”[cang-ir88-ch06-010]

Twentieth-century biochemistry, Canguilhem argues, reached a conclusion opposite to what nineteenth-century organic chemists had anticipated. Rather than abolishing the distinction between living and nonliving, it established that living things exist in “unstable equilibrium,” maintaining order through constant borrowing of energy from the environment, and that the concepts of regulation and homeostasis are required to explain this, not reducible away from it.[cang-ir88-ch06-007] The proliferation of “auto-” prefixed terms in modern biology (auto-organization, auto-reproduction, auto-regulation, auto-immunization) reflects this epistemological necessity: living systems are open to their environments and maintain organization both because of and despite that openness, a situation that “alone suffices to distinguish biology from physics.”[cang-ir88-ch06-008]

Modern genetics established the normal/abnormal distinction at the molecular level, but it did not dissolve it. Gene mutations that block chemical syntheses by altering enzyme catalysts are interpreted as “errors in reading the genetic message.” Canguilhem notes this use of “error” does not return biology to medieval notions of monsters as mistakes of nature. Rather, “the new science of living things has not only not eliminated the contrast between normal and abnormal; it has actually grounded that contrast in the structure of living things themselves.”[cang-ir88-ch06-009]

Canguilhem also identifies a paradox in Pasteur’s refutation of spontaneous generation: by demonstrating rigorously that like produces only like, Pasteur simultaneously strengthened confidence in life’s continuity from life and heightened skepticism toward any doctrine of species transmutation, thereby impeding Darwinism.[cang-ir88-ch05-007] This is a general epistemological pattern: major advances in one direction can, for structural reasons, obstruct advances in an adjacent direction.

Narby approaches molecular biology from a different angle. He identifies a “blind spot” in how the discipline frames its own objects. Jacques Monod, a Nobel-winning molecular biologist, stated the field’s foundational commitment clearly: “The cornerstone of the scientific method is the postulate that nature is objective,” meaning the systematic denial that phenomena can be interpreted in terms of purpose or intention.(Narby, Jeremy, 1998) Yet the technical vocabulary of molecular biology is saturated with purposive language: proteins and enzymes are described as “miniature robots,” ribosomes as “molecular computers,” cells as “factories,” and DNA itself as a “text,” a “program,” a “language.”(Narby, Jeremy, 1998) As linguist Roman Jakobson pointed out, coding systems with a four-letter alphabet forming meaningful three-letter words had previously been considered “exclusively human phenomena,” that is, phenomena requiring the presence of an intelligence to exist.(Narby, Jeremy, 1998) Narby’s point is not that molecular biologists are wrong but that calling 97 percent of the genome “junk DNA” reveals, as he puts it, the field’s readiness “to belittle the unknown,” where “mystery DNA” would have been equally accurate and more honest.(Narby, Jeremy, 1998)

Because physicists and chemists had “dematerialized” matter, Canguilhem writes, biologists were able to explain life by “devitalizing” it, studying life under laboratory conditions as far as possible as though it were nonlife. This practice is both the discipline’s strength and the source of the tensions its philosophy must address.[cang-ir88-ch05-010]

Molecular Biology and Medical Education

The molecular revolution reshaped what medical schools taught and who taught it. Ludmerer identifies three converging changes in American academic health centers by the 1980s.

First, the preclinical sciences stopped being separate disciplines. Techniques such as recombinant-DNA methodology were used by investigators across all scientific departments, and teaching and research in all the basic science subjects became “interrelated and sometimes indistinguishable from each other.”(Ludmerer, 1999) By 1980, over 1,000 disorders resulting from defective gene products had been identified, compared with only 15 in 1960. That scale required a new kind of genetic medicine that departments organized around organ systems were not structured to deliver.(Ludmerer, 1999)

Second, clinical investigation became molecular. Physician-scientists in clinical departments increasingly adopted the same reductionist approaches as workers in the basic sciences, and the “forefront of clinical investigation” shifted away from bedside observation toward molecular mechanism.(Ludmerer, 1999)

Third, this shift created a disconnect. The molecular revolution dramatically advanced basic biomedical science while simultaneously creating “a profound disconnect between research, teaching, and patient care” within academic health centers, eroding the traditional physician-scientist role that had held basic and clinical work together.(Ludmerer, 1999) The bench had moved further from the bedside precisely because both had become more sophisticated.

Human Notes Zone

[Space for Thomas’s clinical and pedagogical notes on molecular biology.]

Molecular Biology

Molecular Biology

Summary

Origins: From Chemistry to Life

The Structure of DNA

Molecular Biology and Cancer

Philosophical Implications

Molecular Biology and Medical Education

See Also

Human Notes Zone

Sources