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
Although published observations of autistic behavior date back to the 18th century it was not until 1943 that that disease was named (CDC). At that time Dr. Leo Kanner conducted a study of 11 children noting “autistic disturbances of affective contact”. The term autistic was coined about 30 years before to describe a condition marked by “a tendency to view life in terms of one’s own needs and desires”.(Random House Unabridged Dictionary) Around the same time Dr. Hans Asperger completed a study of 400 children noting similar behavior (CDC). The result was the classification of Autistic Spectrum Disorders (ASD) including autistic disorder, Asperger’s Syndrome, and pervasive developmental disorder-not otherwise specified. ASDs affect approximately 1 in 150 children in all races, ethnicities and socioeconomic groups equally (CDC, Beaudet, Maimburg, Cantor, Nagarajan). Autism is four times as likely to affect males as it is to affect females.
Autism is a developmental disability that is not related to intellectual capacity (CDC, Beaudet, Maimburg, Cantor, Nagarajan). Children affected with autism have difficulty with social interaction, communication, relating and understanding feelings and sensations, and paying attention. Autistic children may also have different ways of learning and may accomplish harder tasks, such as multiplication or reading words, before easier tasks such as number identification or letter pronunciation. Children with autism may be uncomfortable being touched and prefer solitude and undeviating routines and repetitive behaviors. A difficulty identifying appropriate feelings in a situation, personal space, body language and tone of voice are also symptoms common in ASDs. Verbal skills range from no language skills to relatively normal language skills although a person with an ASD may not recognize the natural ebb and flow of a conversation and stick to one personal topic for long periods of time. ASD symptoms are limited to social interaction and communication skills although they may be present along with another disorder such as mental retardation, epilepsy, Fragile X syndrome, tuberous sclerosis, congenital rubella syndrome or untreated phenylketonuria. Asperger’s syndrome is usually differentiated as a mild version of autism although the range of abilities and spectrum of symptoms in autistic disorder can be quite broad.
Since the symptoms for ASDs are so wide ranging it is important for infants and toddlers to complete standard screening tests (CDC). One-third to one-half of parents with autistic children notice symptoms by the child’s first birthday, with 80-90% noticing symptoms by the second birthday. The child may not have any difficulty with walking or other motor skills and show an ability to complete puzzles or other intellectual activities on par with their age group but they may not be able to play pretend or focus on objects or people. The child may also stop gaining skills or lose skills as a toddler. Early screening tests will help to identify those symptoms that may suggest autism (most children are diagnosed by age 4-5) in time to start behavioral therapies, currently the only treatment for ASDs. Some doctors may suggest talking to a nutritionist about diet changes that can help control symptoms and behavior. Similarly, some benefits have been seen with massage therapy, homeopathy, dance, or meditation. It is important to discuss alternative therapies with a doctor to prevent malnutrition or potentially harmful therapies. Currently, about one-third of autistic patients receive an alternative therapy although up to 10% may be harmful. Medication may also be given to control hyperactive energy levels, depression, seizures, attention deficiencies, or self-injurious behavior that frequently occur with autism or linked disorders.
ASDs are described as highly heritable although the genetic basis is unknown (CDC, Beaudet, Nagarajan). Simply put, a person with an autistic disorder may pass the condition to their child but may not have inherited the disease from a parent. De novo, or new, mutations occur in a number of genes that have been shown to be linked to autism (about 10-20% of cases). These mutations may be caused by environmental factors, although those are largely unknown. Another way of looking at ASD inheritance can be shown in twin studies. With identical twins, one twin affected with an ASD means the other has a 75% chance of being affected. A fraternal twin, however, has only a 3% chance of being affected if their twin is affected. Similarly, if a family has one child with an ASD there is a 2-8% chance of the second pregnancy producing a child with autism. Finding a genetic cause can be complicated. The cause may or may not be inherited. It may or may not be the result of a genetic mutation or environmental cause in the womb (thalidomide, for example). What other factors can contribute to ASDs if genetics and environment do not account for all the cases? Some cases can be explained by a different kind of change to DNA, what is called an epigenetic change. Genetic changes to DNA are considered changes to the sequence of DNA by deletion, duplication or base-pair change. Epigenetic changes to the DNA cover the way DNA is packaged in a cell’s nucleus. Each cell contains about 6 feet of DNA, clearly too much to fit in a cell without a highly-regulated packaging method (Hypertextbook). (Since every body has about 10 trillion cells the total DNA in every person can make about 70 trips to the sun and back). One method is called methylation and basically winds the DNA so tightly that the genes can not be expressed (CDC, Beaudet, Nagarajan). Methylation is common in cancer cells where most genes are hypomethylated, or turned on, while tumor suppressor genes (the brakes on tumor development) are hypermethylated. What this means for autism and other psychiatric disorders is that some genes the brain cells need for normal function are perfectly normal but locked away. One such gene can cause enough disruption to the brain to cause autism, schizophrenia or other psychiatric disorders. Altered methylation patterns have been linked to autistic patients with older fathers (Cantor) and some cases of assisted reproduction (such as IVF) (Maimburg); although, one study shows a decreased chance of autism after the rise of assisted reproduction. This study accounts for the cases where the assisted reproduction caused altered methylation. While it is not always known how methylation patterns in the brain cells are altered it is thought to occur early in development. Diagnostic tests are in development to identify these patients (Nagarajan). Likewise, drugs to undo methylation are in development and may be used to treat these subset of patients.
Not all cases of autism can be explained and no one explanation covers all cases. The broad range of symptoms and abilities in autistic patients is reflected in the many cellular causes of autism. Currently the best treatment for children with an ASD is an early diagnosis and behavioral intervention with medical treatment for those symptoms that require it.
Centers for Disease Control, http://www.cdc.gov/ncbddd/autism
Random House Unabridged Dictionary, Random House, Inc, 2006
Beaudet, Arthur L. Autism: highly heritable but not inherited. Nature Medicine. Vol. 13 No. 5, p. 534-6, 2007
Maimburg, Rikke D. and M. Vaeth. Do children born after assisted conception have less risk of developing infantile autism? European Society of Human Reproduction and Embryology. p.1-3, 2007
Cantor, RM. et al. Paternal age and autism are associated in a family-based sample. Molecular Psychiatry. Vol. 12. p. 419-423, 2007
Nagarajan, R.P. et al. Reduced MeCP2 expression is frequent in autism frontal cortex and correlates with aberrant MECP2 promoter methylation. Epigenetics. Vol. 1, No. 4, p. 172-182, 2006.
Hypertextbook, http://hypertextbook.com/facts/1998/StevenChen.shtml
