We’ve discovered the secret of life.
—Francis Crick, said on February 28, 1953
Nobel Prize winner 1962
Gene sequencing is not the solution. The solution is good (Bio)- chemistry. Sequencing genes isn’t proving to be particularly useful in fighting diseases such as cancer and diabetes and much of the research being done on these subjects is irrelevant. You could sequence 150,000 people with cancer and its not going to cure anyone. It might give you a few leads, but it’s not the solution. The solution is good (bio)-chemistry. Most of the (genetic) experiments we do are irrelevant. We’re not going to cure cancer (and diabetes) by doubling the money. We’re going to do it by being more intelligent.
—James D. Watson, March 25, 2013
Nobel Prize winner 1962
Salk Institute, San Diego, California
Seminar March 25, 2013
There is no symbol of science more iconic than the double helix of DNA, the 1953 identification and description of this structure by James Watson, an American, and Francis Crick, an Englishman from Cambridge University, was thought to be monumental.
On April 6, 1928, James D. Watson was born in Chicago, Illinois. He eventually became a molecular biologist, geneticist, and zoologist who is best known for his co-discovery of the structure of DNA in 1953 with Francis Crick.
He was the only son of Jean Mitchell and James D. Watson, a tax collector of English descent. His mother’s father, Lauchlin Mitchell, a tailor, was from Glasgow, Scotland, and her mother, Lizzie Gleason, was the child of Irish parents from the town of Tipperary, Ireland. Raised Catholic, he later described himself as “an escapee from the Catholic religion.” Watson said, “The luckiest thing that ever happened to me was that my father didn’t believe in God.”
Watson attended public school and graduated ahead of his peers. He was fascinated with bird watching, a hobby he shared with his father, so he considered a career in ornithology. Watson appeared on the radio show Quiz Kids, which was a show that challenged bright children with pointed questions. Because of the unique admission policies of the University of Chicago and university president Robert Hutchins, Watson was accepted at age 15 as a full-time student.
After reading Erwin Schrodinger’s book What Is Life in 1946, Watson changed his major and professional direction from ornithology to genetics. In 1947 Watson earned his B.S. degree in Zoology from the University of Chicago and in his autobiography Avoid Boring People, Watson described the University of Chicago as an “idyllic academic institution” where he was instilled with the skills for critical thought and “an ethical compulsion not to suffer fools who impeded his search for truth.”
In 1947 Watson left Chicago and entered graduate school at Indiana University to study under the 1946 Nobel Prize winner, Herman Joseph Muller, who, in landmark publications in 1922, 1929, and in the 1930s, formulated the basic properties of the heredity molecule that Schrodinger ultimately presented in his 1944 book.
Watson, Crick, and Maurice Wilkins were awarded the 1962 Nobel Prize in Physiology/Medicine “for their discoveries concerning the molecular structure of nucleic acids and its significance for information transfer in living material.”
In 1950 Watson received his PhD degree from the University of Indiana with his thesis “The Biological Properties of X-Ray Inactivated Bacteriophage.”
Following studies at the University of Chicago and Indiana University, he worked at the University of Cambridge’s Cavendish Laboratory in England, where he first met his future collaborator and friend Francis Crick.
In 1956 Watson was appointed a junior member of Harvard University’s Biological Laboratories with the responsibility to promote research in molecular biology; he held the post until 1976.
Between 1988 and 1992 Watson was associated with the National Institutes of Health, and during this period he contributed to the establishment of the Human Genome Project.
Watson has written numerous books, including the textbook, The Molecular Biology of the Gene (1965) and his bestselling book, The Double Helix (1968), which documented the events leading to the discovery of the DNA structure (it was edited by Gann and Witkowski and reissued in a new edition in 2012: The Annotated and Illustrated Double Helix).
In 1968 Watson became the director of the Cold Spring Harbor Laboratory (CSHL) on Long Island, New York, where he expanded its level of funding and research. At CSHL, he redirected the facility’s research emphasis to the study of cancer. In 1994 he was appointed to the post of president and served in that capacity for ten years, when he was then appointed to the post of chancellor, in which capacity he served until 2007.
In his memoir, Avoid Boring People: Lessons from a Life in Science, Watson referred to his academic colleagues as “dinosaurs,” “deadbeats,” “fossils,” “has-beens,” “mediocre,” and “vapid.” Steve Shapin in Harvard Magazinenoted that Watson had written an unlikely Book of Manners, noting the skills necessary at different times in a scientist’s career; he wrote that Watson was known for aggressively pursuing his own goals at the university. E.O. Wilson once described Watson as “the most unpleasant human being I had ever met,” but in a later TV interview, said that “he considered them to be friends, and their rivalry at Harvard was old history.”
In early October 2007 Watson was about to begin on a UK book tour to promote the memoir. He was interviewed by Charlotte Hunt-Grubbe at CSHL for the Sunday Times Magazine to highlight the beginning of his tour.
During the interview Hunt-Grubbe broached the subject of race and intelligence and Watson replied that he was “inherently gloomy about the prospect of Africa, because all of our social policies are based on the fact that their intelligence is the same as ours—whereas all the testing says ‘not really,’ and I know that this ‘hot potato’ is going to be difficult to address.” He said his hope was that everyone is equal, but he countered this by saying that “people who have to deal with black employees find this not true.” He said that you should not discriminate on the basis of color, because “there are many people of color who are very talented, but don’t promote them when they haven’t succeeded at the lower levels.”
Because of the public controversy, on October 18, 2007, the Board of Trusties at CSHL suspended Watson’s administrative duties. On October19th Watson released an apology and on October 25th, Watson resigned his position as chancellor. In 2008 Watson was appointed chancellor emeritus of CSHL. In a 2008 BBC documentary, Watson stated, “I have never thought of myself as a racist. I am mortified by it. It (the interview) was the worst thing in my life.”
DNA or deoxyribonucleic acid is the material that contains the genetic instructions or blueprints (scripts) for all living organisms: humans, horse, fruit fly, bacteria, corn, oak tree, etc.
Prior to Watson and Crick, the existence of DNA was known, but some genetic experts were highly skeptical that it contained genetic material. What was left to be done was to find out what the DNA structure actually looked like.
Watson and Crick created DNA models out of sticks and balls, not unlike Tinker toys. They originally operated under the incorrect belief that DNA was a triple helix.
While Watson and Crick have been credited with the elucidation of the structure of DNA, it is a fact that they built their understanding of the DNA structure on the work of others, including Linus Pauling (recipient of two unshared Nobel Prizes), who theorized that DNA was a triple helix, and British biophysicist Rosalind Franklin, who in 1952 used a painstaking technique referred to as x-ray diffraction to make a famous three dimensional image of DNA.
Photographs produced by the X-ray crystallography method are not actually pictures of molecules. The spots and smudges were produced by X-rays that were diffracted as they passed through crystalized DNA. Crystallographers use mathematical equations to translate the resultant patterns from the spots to translate the patterns to the three dimensional shapes of the molecule.
Watson and Crick based their double helix model of DNA on data that they were able to extract from Franklin’s X-ray diffraction photo. They interpreted the pattern of spots on the X-ray photograph to mean that DNA was helical in shape. Based on Watson’s recollection of the photograph, he and Crick deduced that the helix had a uniform width of 2 nanometers (nm), with its nitrogenous bases stacked 0.34 nm apart. The width of the helix suggested that it was made up of two strands, contrary to the three strands that Pauling had proposed.
Using molecular models made of wire, Watson and Crick began building scale models of a double helix that would conform to the X-ray measurements and what was then known about the chemistry of DNA. After failing to make a model that placed the sugar-phosphate chains on the inside of the molecule, Watson tried putting them on the outside and forcing the nitrogenous bases to swivel to the interior of the double helix.
Imagine this double helix as a rope ladder having rigid rungs, with the ladder twisted into a spiral. The side ropes are the equivalent of the sugar-phosphate backbones, and the rungs represent pairs of nitrogenous basses. Franklin’s X-ray data indicated that the helix made one full turn every 3.4 nm along its length. Because the bases were stacked just 0.34 nm apart, there were ten layers of base pairs, or rungs on the ladder, in each turn of the helix. This configuration made sense because it put the relatively hydrophobic nitrogenous bases in the molecule’s interior and away from the surrounding aqueous medium.
The nitrogenous bases of the double helix are paired in specific combinations: adenine (A) with thymine (T), and guanine (G) with cytosine (C). It was primarily by trial and error that Watson and Crick arrived at this key feature of DNA. At first, Watson theorized that the bases paired like-with-like; for example, A with A and C with C. However, the model did not match with the X-ray diffraction data, which showed that the double helix had a uniform diameter.
Adenine and guanine are purines, nitrogenous bases with two organic rings. In contrast, cytosine and thymine belong to the family of nitrogenous bases known as pyrimidines, which have a single ring, making the purines A and G approximately twice as wide as the pyrimidines C and T. A purine-purine pair would be too wide and a pyrimidine-pyrimidine pair would be too narrow to justify the 2 nm diameter of the double helix. The solution was to always pair a purine with a pyrimidine.
Watson and Crick reasoned that there must be additional specificity of pairing dictated by the structure of the bases. Each base has chemical side groups that can form hydrogen bonds with its appropriate counterpart: adenine can form two hydrogen bonds with thymine and only thymine; guanine forms three hydrogen bonds with cytosine and only cytosine. By default A can only pair with T, and G can only pair with C.
The Watson-Crick double helix model fully explained Chargaff’s rules: Chargaff found a peculiar regularity in the ratios of nucleotide bases. In the DNA of each species he studied, the number of adenines approximately equaled the number of thymines, and the number of guanines equaled the number of cytosines. In human DNA, the four bases are present in the following percentages – A = 30.9% and T = 29.4%; G = 19.9% and C = 19.8%. The A = T and the G = C equalities, later referred to as Chargaff’s rules, was unexplained until the proposal of the double helix.
Wherever one strand of a DNA molecule has an A, the partner strand has a T; and a G in one strand is always paired with a C in the complementary strand. Therefore, in the DNA of any organism, the amount of adenine equals the amount of thymine, and the amount of guanine equals the amount of cytosine. Although the base-pairing rules dictate the combinations of nitrogenous bases that form the “rungs” of the double helix, they do not restrict the sequence of the nucleotides along each DNA strand. Therefore, the linear sequence of the four bases can be varied in countless forms, and each gene has a unique base sequence.
Franklin was the X-ray crystallographer that actually took the photograph that enabled Watson and Crick to deduce the double helical structure of DNA. Franklin died of cancer when she was 38 years of age. Her colleague, Maurice Wilkins, was a co-recipient of the 1962 Nobel Prize along with Watson and Crick for co-discovering the double helical structure of DNA in April 1953. Franklin was not included in the award because the Nobel Committee does not award the prize posthumously.
In April 1953 Watson and Crick shocked the scientific community with an article that was given a one page announcement in the British journal Nature (see Watson, J.D. and Crick, F.H.C.: “Molecular Structure of Nucleic Acids: A Structure for Deoxynucleic Acids.” Nature.171(1953), p.738.). The paper reported their molecular model for DNA: the double helix, which has since become the symbol of molecular biology. The value of the Watson and Crick model was that its structure posited the basic mechanism of DNA replication. They ended their landmark paper with the following paragraph: “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.”
We now know that in humans the double helix in the nuclei of each cell and that each somatic (body) cell contains 46 pairs of chromosomes and that the sperm and the egg each has 23 pairs (one pair maternal and the other paternal). The DNA molecule contains the information that determines what each individual looks like (e.g., blue eyes, blond hair, black skin, gender, etc.) and directs cellular functions including enzymatic, respiration, repair, and reproduction.
It has been calculated that if the 46 segments of DNA in one cell were to be uncoiled, connected end to end, and laid out flat it would be approximately seven feet long. The resulting ribbon would be so thin that its details could not be visualized except perhaps by an electron microscope. Calculations then reveal that if the sum total of an individual’s DNA were placed end to end it would stretch from the earth to the moon 500,000 times. Another way to grasp the immensity of information stored in one individual’s DNA would be to create a type-written format that would completely fill the entire Grand Canyon 50 times.
It is estimated that the human body is made up of 50 to 70 trillion cells. Cells are the basic building blocks or bricks that are found in a wide range of tissues, such as the liver, brain, cartilage, skin, kidney, heart, thyroid, gonads, etc.
In the perfect world, the normal genetic controls keep the various cell types, their anatomy, their physiology, and their directed functions on the rails. Unless a stick is put into the spokes, peoples’ liver is not found in their skull and they will have two eyes appropriately located.
It’s quite remarkable when you think about it, because all of the tissues of plants and animals start with two cells: the sperm and the egg. When the egg is pierced by the sperm and is “fertilized” the new organism becomes a zygote.
The zygote divides and produces a daughter cell, and they each divide, and then there are four, and this is repeated again and again. What makes the process so remarkable is that after a short period of time—minutes in fruit flies, hours in chicken eggs, and days in humans—the cells begin to differentiate and specialize, form different tissues and organs, and all from the single zygote cell!
The British Liver Trust points out that the liver brags of over 500 functions, including managing food that has been digested and absorbed from the gastrointestinal tract, disarms toxins, produces bile to support absorption of lipids and fat soluble vitamins, and 497 other tasks.
Hemoglobin carries oxygen throughout the vascular system; kidneys filter the blood and produce urine; the brain and spinal cord stores memory and interpret light and images, tastes and smells, and drive motor functions; the lens in the eye focuses light on the retina; and muscles move the entire body; —all from one complete zygote.
The initial mistake was that geneticists believed that the “genetic code” was a blueprint, like the blueprint of a building, and it didn’t matter if the construction company was American, Chinese, Irish, Mexican, or South African because the resulting building would be exactly alike, since it used the same raw materials and the same blueprint, and as a result would be invariably the same building.
Well, it turns out that the gene and the genetic code is not a blueprint, but is instead a “script” that is easily modified, interpreted, or differentiated by actors, directors, and producers. So this is epigenetics rather than genetics!
The DNA is the script, the basic information—the code. Nessa Carey posits in chapter 3 “Life as We Knew It” in The Epigenetics Revolution:
If DNA is a code, then it must contain symbols that can be read. It must act like a language. This is exactly what the DNA code does. It might seem odd when we think how complicated we humans are, but our DNA is a language with only four letters. These letters are known as bases, and their full names are adenine, cytosine, guanine, and thymine. They are abbreviated to A, C, G, and T. One of the easiest ways to visualize DNA mentally is as a Zip(per).
One of the most obvious things that we know about a zip(per) is that it is formed of two strips facing each other: this also true of DNA. The four bases of DNA are the teeth of the zip(per). The bases on each side of the zip(per) can link up to each other chemically and hold the zip(per) together. The two bases facing each other and joined up like this are known as a base-pair. The fabric strips that the teeth are stitched on to on a zip(per) are the DNA back bones. There are always two backbones facing each other, like two sides of the zip(per), and DNA is therefore referred to as double-stranded. The two sides of the zip(per) are basically twisted around to form a spiral structure—the famous double helix.
On March 25, 2013, James Watson gave a lecture to an invitation-only academic gathering at the Salk Institute in San Diego, California, almost sixty years after the announcement that he and Francis Crick had identified and mapped out the double helix structure of DNA.
Watson’s lecture was a far cry from the heady days of 1953 when he and Crick believed they had identified the very “secret to life itself.” With obvious disappointment, Watson declared that “gene sequencing is not the answer to solving the problems of human health, and much of the research currently being conducted is irrelevant!”