The $100 Genome?

Our human genomes are contained within 23 pairs of chromosomes comprised of DNA. It was 70 years ago in 1953 that Watson and Crick first solved the physical structure of DNA, a groundbreaking achievement that earned them the Nobel Prize. They showed that DNA is a long chain molecule with two strands wound around each other in the canonical double helix. Each strand consists of only 4 nucleotides designated A, C, G, and T. There is a very specific pairing between the nucleotides on opposite strands with A always paired with T and C paired with G (Fig. 1) . Like the 26 letters of the Roman alphabet that can be arranged in enormous variety to spell all the words in the English languages, combinations of the 4 nucleotide letters form all the genes that define each of us. Variations in our individual genes confer our unique physical attributes and contribute to everything from our daily health to our longevity. Knowing the sequence of the entire genome of each person would be extremely useful for optimizing individualized health care, but each human genome contains 6 billion base pairs, and generating the information has been cost-prohibitive on a wide scale. However, that is a goal that is rapidly becoming feasible with advancing sequencing technology.

This history of DNA sequencing begins in the 1970s when two different research groups first developed methods for actually reading the sequence of nucleotides in a piece of DNA. Allan Maxim and Walter Gilbert* invented a complex chemical method for deciphering a DNA sequence while Frederick Sanger and colleagues utilized an elegant enzymatic approach for their sequencing technology. Gilbert and Sanger each received the 1980 Nobel prize in Chemistry for these advances, but Sanger’s approach ultimately proved simpler and easier to automate and it became the foundation of modern sequencing technology. However, the initial implementations of Sanger’s technology were slow and expensive. For example, it took a 13-year worldwide effort of many laboratories (from 1990 to 2003) and $3 billion to generate the first complete human genome sequence. While an extraordinary and vastly important achievement for understanding human biology, it clearly was not a process that could be applied to individuals in the healthcare arena. Remarkably, subsequent engineering advances and refinements to Sanger’s concept have produced incredibly sophisticated sequencing machines that have increased the speed and decreased the cost of sequencing by orders of magnitude. Only 20 years after the first complete human genome sequence the current cost per genome sequence is now under $1000 and can be completed in just days. Further advances that are nearing commercialization promise to decrease the cost even further to $100 per genome done in 1 day, a price and speed that makes it feasible for anyone to have their genome sequence added to their medical record.

Knowledge of an individual’s complete genome sequence can help forecast disease risks, identify problematic mutations, and potentially tailor the most effective and beneficial lifestyles (e.g. diet and exercise). Generating a person’s genome sequence early in life could provide a blueprint for maximizing health and preventing diseases. In addition, the genome sequence can be used to predict optimal medications for treating certain conditions and illnesses. Individualized genetic assessment is performed for some cancer drugs, but the efficacy of most common drugs is based on their general properties for humans, not on their specific effects on an individual. Personalized genetic information may someday be used to precisely determine which drug to use rather than randomly testing several possible candidates on each patient. Lastly, these new technologies can sequence the entire genome from single cells. Not only is this invaluable for scientific studies looking at the biology of cell-to-cell variations, but it also has immediate applications in cancer treatment. Tumors are usually complex, heterogeneous mixes of cells with different mutations that have arisen during cancer formation and tumor growth. Being able to sequence different individual cells from a patient’s tumor will provide a more thorough picture of the genetic diversity in the tumor and the most effective therapeutic approach for destroying that tumor. If the scientific and medical advances over the next 20 years are anything like those of the last two decades we should see genome sequencing and genetic medicine becoming an integral part of typical clinical practice with a multitude of benefits to us all. That’s a cheerful thought to start 2023. Happy New Year’s to all my readers.

* I met Dr. Gilbert in 1975 during my first semester in graduate school when he came to give a seminar in my department. Prior to his visit, my advisor called me into his office to inform me that I needed to attend the seminar because Dr. Gilbert was smarter than he and I put together and that his seminar was certainly going to be spectacular. As a brash and confident young graduate student, I was skeptical about my advisor’s assessment of how much smarter Dr. Gilbert could be than me until I saw his presentation. As my advisor predicted, his seminar on his new DNA sequencing method was brilliant, stunning, revolutionary, and a tour de force of organic chemistry so far beyond me that I could only sit and be humbled by this world-class intellect. During my scientific career, I’ve had the pleasure of meeting around 15 different Nobel Prize winners, but I’ll always remember Dr. Gilbert as one of the most dazzling scientists I’ve ever encountered.

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