Undoubtedly one of the greatest scientific advancements of mankind occured in 1953 when Francis Crick and James Watson discovered that deoxyribonucleic acid, or DNA, was a double helix (Crick Papers, Franklin Papers). Last month, James Watson received the entire sequence of his genome. How is it possible for 50 years to span theorizing proteins as the keeper of hereditary information to personal genome sequencing? The comparison is not unlike that of the technological advancement from the first brief flight taken by the Wright brothers to the moon landing over 60 years later. Arguably, the impact of determining the structure of DNA is even greater than that of space travel.
In 1953, although Oswald Avery had shown the that DNA carries hereditary information in bacteria 9 years earlier, most scientist believed proteins had to carry this information (Crick Papers, Franklin Papers). Proteins were composed of up to 20 different amino acids while DNA was composed of only 4 nucleic acids. Proteins could be a variety of sizes, shapes and compositions while DNA seemed to be too simple. The structure of DNA was not known, although several top scientists, including Linus Pauling, a two-time Nobelaureate, were competing for that discovery. Nor was it known how proteins could retain hereditary information and transfer that information during cell division. Watson and Crick had combined their knowledge of genetics, chemistry, X-ray crystallography and biochemistry and set out to solve the structure of DNA without manipulating any actual DNA. Pauling had earlier discovered that proteins can form alpha helices, leaving the thought of helical forms in the ether as a structural possibility. Indeed, Pauling and Watson and Crick all developed three-stranded helical models of DNA, although Watson and Crick revised theirs before publishing. Previously, Alexander Todd had found that the DNA backbone was comprised of alternating phosphates and deoxyribose sugars. Separately, Edwin Chargaff found that the nucleic acids adenine (A) and thymine (T) were always in equal proportion in DNA, as were the nucleic acids guanine (G) and cytosine (C). The final piece of the puzzle, X-ray crystallography done primarily by Rosalind Franklin and with the assistance of Maurice Wilkins, was given to Watson and Crick by Wilkins without Franklin’s knowledge and showed Crick that DNA had a helical structure much like a corkscrew. With a tip from visiting collegue Jerry Donohue, that the commonly known structures of thymine and guanine were actually incorrect, Watson was able to assemble the first model of DNA. An A paired with a T was about the same size as a G paired with a C. This not only paired DNA strands in a double helix but put the nucleic acids on the inside of the helix. To fit appropriately Crick theorized one strand would have to run antiparallel to the other. Crick’s wife sketched the first diagram:
The implications of this finding are extraordinary and outlined in a paper published a month after the initial announcement of DNA’s structure (Crick Papers, Franklin Papers). DNA was able to copy itself exactly, never losing the starting information, because each strand could prime the second. In a dividing cell each of the two new cells would have one strand of the original DNA paired with a new strand of DNA. No hereditary information would be lost in cell division since A and T were always paired as were G and C.
Although Watson and Crick did not do their own DNA manipulations they were able to experimentally create a model by piecing together data that seemed to be insiginificant or unrelated to each other (Crick Papers, Franklin Papers). Although the scientific climate at the time led them and most men to be dismissive of Franklin, Watson and Crick have since admitted fault for their attitude. Franklin herself held no grudge against them since they were unaware of Wilkins’ deceit. Watson, Crick and Wilkins later received a Nobel Prize for this work, after the community accepted DNA was the carrier of genetic information. Franklin, however, had died and was not eligible for the Nobel Prize based largely on her data.
How does Watson feel about this year’s advancement? “I am thrilled to see my own genome.” he recently told the New York Times (Wade, The New York Times). He has opted not to know the status of a gene known to contribute to Alzheimer’s disease, apolipoprotein E, however. That choice is the epitome of personal genome sequencing. Instead of talking to genetic counselors about the risk of some forms of heart disease or cancer, for instance, a person could find out the status of genes known to contribute to those diseases and choose to be more or less vigilant about diet and exercise. Additionally, potential parents could learn if they are carriers for diseases like cystic fibrosis and hemophilia before conceiving.
Is this actually possible for real people right now (Harmon, The New York Times)? Not quite. Watson’s entire genome was sequenced at a cost of $1 million. Currently, Stephen Hawking, Larry King and others are having their genomes sequenced for a tenth of that cost. Goals are to get a complete genome for $1000 in a few years. Currently, $1000 can give you the sequence to the most useful 1% of the genome. Scientists contend that the more people who have a complete genome sequenced the more information will be available to compare ancestry, health, personal success, appearance and preferences with genes and gene combinations. Does everyone who likes the color blue have a gene dictating so? Likely not. However risk-takers may have similar gene sets. As may mathematicians or actors. More importantly, collections of personal genomes along with health histories can help researches pin down disease-causing genes.
Decoding the entire genome and taking advantage of gene therapy, a process that hopes to switch a faulty gene for a correct, or wild type, one in specific organs may be far off, however (Human Genome Project Information). The last 50 years have brought us the discovery of unique genes, of ‘junk’ DNA, and of the promoters, or regulatory areas of genes (necessary so pancreatic cells can respond to glucose to produce insulin and so neurons can respond to acetylcholine to fire a synape, or so a pancreatic cell can function as such and not a neuron [since both cells contain a complete genome]). Genes can be spliced (or stuck) into vectors and popped into cells in culture to see how their sudden presence changes the cell behavior (a technique used frequently in cancer research). We now know how many genes are regulated. Global regulation of the genome, such as methylation, has been discovered. Methylation binds DNA tightly to prevent gene expression and is frequently decreased overall in tumors to allow unregulated gene expression, although tumor suppressor genes are frequently methylated more to allow tumor progression. Chromosomes can be stained to determine if breakage and rejoining has occured. And the amplification of specific regions of DNA is possible. This techinique, polymerase chain reaction (PCR), is indispensible in modern molecular biology. Paternity tests and forensics are the most widely known applications of PCR but researchers can use PCR to determine if a gene is present or deleted, if expression of the gene is increased or decreased, and if a person has a specific mutation. Today we know that the human genome contains about 30,000 genes, half of which have unknown functions. We know that only 2% of the genome codes for genes and that about 50% is ‘junk’ or structural regions. We know now that DNA can copy itself or serve as a primer for mRNA and that mRNA can then leave the nucleus of the cell to direct protein production. We know that our genome has many similarites to flies and plants, but that the regulation of our genome is more complex and allows for our unique existence.
Finding the structure of DNA has led to an information boon that has revolutionized, really, created, modern molecular biology (Harmon, The New York Times; Wade, The New York Times). Sequencing the genome has made genetic work much easier, and comparative genomics—the comparison of thousands of genomes complete with biographical information could give us answers to why some people are shy and why some people are outgoing. The argument of nature versus nurture may finally be put to rest, although I suspect science will find it is as suspected all along and nature and nurture both contribute to our personalities; much like diet and genes can affect the risk heart disease or cancer.
The Francis Crick Papers, National Library of Medicine. http://profiles.nlm.nih.gov/SC/Views/Exhibit/narrative/doublehelix.html
The Rosalind Franklin Papers, National Library of Medicine. http://profiles.nlm.nih.gov/KR/Views/Exhibit/narrative/dna.html
Wade, Nicholas. “Genome of DNA Discoverer is Deciphered.” The New York Times. June 1, 2007.
Harmon, Amy. “6 Billion Bits of Data About Me, Me, Me!” The New York Times. June 3, 2007.
“The Science Behind the Human Genome Project.” Human Genome Project Information. http://www.ornl.gov/sci/techresources/Human_Genome/project/info.shtml
