Sequenced: The Human Genome – 10 Years Later

Michael Convente February 17, 2011 0

Ten years ago a momentous achievement in science was completed – the sequencing of the human genome. Initially started as a publicly-funded venture, the Human Genome Project eventually morphed into a public vs. private competition, both pursuing the same goal but for very different reasons. Each group succeeded and published their results in the scientific journals Nature and Science, respectively. (access required) Much was expected from the completion of the human genome sequence, from advances in research to the development of personalized medicine. And while progress in the research community has been staggering, the promise of a genomics revolution has largely been unmet. Ten years is an eon in the timescale of research science. We have gained massive amounts of knowledge in the past decade, but we still have much to learn. And perhaps most relevant, we still have much to debate about how best to use and safeguard the knowledge we have uncovered. This final task requires an informed and engaged citizenry, so I hope you will join me below the fold to become a part of this integral group.


First, a brief history lesson about Deoxyribonucleic Acid – or better known to us all as DNA. The concept that organisms possess some factor that can be passed on from one organism to another, termed a "transforming principle", was developed from the work of bacteriologist Frederick Griffith. In 1928, Griffith discovered that injecting into mice a combination of a dead virulent strain of bacteria with an alive benign strain killed his animals. Since the virulent strain of bacteria was dead at the time of injection, some compound from it must have been transmitted to the alive bacteria, transforming it into a virulent strain, thus leading to his animals' death. The identity of this transforming principle would be revealed as DNA in 1944 by a trio of scientists. And finally, in 1953 scientists James Watson and Francis Crick would publish (warning – PDF) the structure of this hereditary molecule. For their discovery, the duo, along with Maurice Wilkins, would receive the 1962 Nobel Prize in Physiology or Medicine. A wave of research followed these forefathers of modern genetics. The central dogma of biology – DNA –> RNA –> proteins – was developed soon after the structure of DNA was published. Scientists were able fill in the molecular blanks missing from the works of pioneers such as Charles Darwin and Gregor Mendel. It started to become clear that it was our DNA sequence that made us us. Efforts to sequence a genome of a biological entity first proved successful in 1977 following the completion of the Bacteriophage virus φX174 genome. The methods underlying the rudimentary sequencing technology used were vastly primitive compared to the advanced machines of modern times, which made the final result that much more remarkable. Soon, the genomic sequencing of common model organisms including Escherichia coli and Saccharomyces cerevisiae (a type of budding yeast) were initiated. As advances were made in characterizing numerous features of these model organisms, including their development, homeostasis mechanisms, and evolution, it became clear that in order for scientists to take the next step in their research, the human genome must be sequenced entirely.




A $3-billion dollar joint venture between the United States Department of Energy and United States National Institutes of Health to sequence the human genome formally started 1990. The Human Genome Project consisted of a massive consortium of scientists across the globe, yet even with hundreds of researchers working on the project it was expected to take 15 years to complete. Progress was slow for the first several years, as the technology failed to meet the intense demands of the project. The rate of progress finally started to increase in 1998 when the publicly-funded venture gained some fierce competition from the private sector.

J. Craig Venter, a cavalier scientist and entrepreneur with a harsh reputation and strong ego, was unsatisfied with the NIH's progress. Not only did he believe he had a new method of sequencing (called "Shotgun Sequencing") that was better and faster than the pairwise end sequencing method used by the NIH, he believed that he could complete the human genome sequence for a fraction of $3-billion cost. The scientists at the NIH had reason to take Dr. Venter seriously; researchers working for his start-up Celera Corporation were fast on the trails of the university researchers. This troubled the leading researchers at the Human Genome Project for two reasons. First, all scientists have a little bit of an ego, and if history were to repeat itself, the team that finished first would get all the credit. Second, and much more concerning to scientists, was the plan of Celera Corporation to patent the entire human genome, which could have devastating effects for biomedical research. This controversy has extended beyond Celera Corporation, and I will touch more on it below.

As the year 2000 dawned, it became clear that the sequencing of the human genome would be finished well before 2005, the initial projected date of completion. A potential clash between bio-research and bio-enterprise was avoided when in March 2000 President Clinton announced that the human genome could not be patented and should be shared freely among the research community. In an unexpected turn of events, Dr. Venter and his team at Celera accepted this announcement (though surely with disappointment) and backed off of plans to patent any portion of their revealed sequence. In early 2001, 11 long years after the initiation of the Human Genome Project, both the NIH and Celera Corporation published their respective sequences in the high-impact journals Nature and Science. The impact of the completed human genome was enormous, and within the copious amount of data were some very surprising results. First, it was assumed that due to our extreme complexity and advancement over fellow mammals, humans had many more genes (sequences of DNA that code for proteins, the essential molecular building blocks of cells, tissues, and organs) than lesser animals. Some estimates even went as high as 100,000 genes. Therefore, it was extremely surprising to learn that this…

…has the same number of genes as this.

What became evident after the completion of the human genome was that our ability to construct different gene products through mechanisms such as alternative splicing is enhanced compared to lesser animals. Another surprising result was that out of our 3 billion base pairs of DNA, only about 1.5% codes for proteins. At the time the genome sequence was completed, this other 98.5% was referred to as "junk DNA", but one of the advances since 2001 has been the discovery that non-coding DNA can have a profound impact on coding DNA. Nevertheless, when you read reports that we're 97-98% similar to orangutans or other hominids yet are confused why we look a good bit different, now you will know why – the differences in DNA sequence are heavily weighted in the DNA that actually codes for proteins.

All of the above findings are fascinating, but what did they eventually mean for the fields of research and medicine? The advancements in the research community as a result of the completed human genome were vast. With the completed human genome at hand (along with the completed genomes of other model organisms), researchers could now delve into the field of molecular evolution. Finally, biologists would have the data necessary to track the evolution of protein sequences, with a concept that protein domains or even specific amino acids (the building blocks of proteins) that were conserved throughout multiple species must be critical for a life process. This foundation has held true throughout biology, as researchers have found that mutating a highly conserved amino acid often leads to non-functional protein. The completion of the human (and mouse genome) has allowed researchers to develop transgenic mouse models for which to study the pathogenesis of numerous diseases. The revelation that mice and humans contain almost the exact same number of genes has further validated the use of mouse models in studying human disease.

However, while the impact on research science has been profound, the promise of a genomics revolution for medicine has yet to emerge. Largely, the completion of the human genome has enlightened scientists and physicians, though therapeutic methods as a result of this enhanced knowledge have been predominantly absent. Having the entire human DNA sequence at hand has allowed physicians to map out specific mutations for cancers. This information, in combination with previous knowledge about the overall pathways that a specific mutated gene reside in, have aided scientists to accurately predict which medicines will work for patients, and perhaps more importantly, which ones won't. Overall, this enables recommendations for medicines that affect biology at the pathway level, which more often than not aids in patient treatment and helps bring down the costs associated with prescriptions of ineffective medicines. However, what hasn't come to fruition is the notion of "personalized medicine", the idea that individual treatment plans can be compiled based on an individual's DNA sequence. The problem is two fold. The first – being able to completely sequence an individual's DNA content – is getting closer and closer to being resolved. An effort that took over a decade and cost a total of over $3-billion can now be finished in a matter of weeks and for far cheaper. This is still not good enough for clinical use, but scientists have predicted that within another decade, the field of genomics will be essentially "dead", as it will be feasible, quick, and cost-effective to sequence everyone's full DNA code.

Gleevec, an anti-cancer drug developed in the late 1990s, is one rare example of a medicine targeting specific cancer-causing mutations in patients.

Problem number two, which involves the development of personal pharmaceuticals, is a lot more troublesome. As a quick piece of background, the way a lot of medicines work is that they specifically bind proteins and prevent them from performing their normal function. When a protein is mutated, this binding pocket is often perturbed. Since the same type of cancer can be caused by literally hundreds of different mutations within a large gene, the amount of different protein conformations is very high. Thus, in order to ensure a perfect fit, a different molecule will have to developed for every single gene mutation. Some will have cross-reactivity, but the effectiveness will vary from patient to patient. It already costs billions of dollars for pharmaceutical companies to develop medicines that will benefit thousands, if not millions of patients. Ironically, the same completed genome that allows for cost reduction among broad medicines leads to astronomical costs for personalized medicines. While gene therapy and gene replacement remains in its very early stages (not to mention its bio-ethical implications), it likely is where the field of personalized medicine is going.

Lastly, the completion of the human genome and ability for us to easily sequence bits of or entire individual genes has far-reaching implications in regard to health insurance and DNA "ownership". With our exponentially increasing public research database, scientists and physicians are now able to look into our genetic future. Common mutations are now known for diseases including Parkinson's, Alzheimer's, Huntington's, Sickle Cell Anemia, and Cystic Fibrosis, just to name a few, and we have the ability determine whether an individual is affected. For many of the aforementioned diseases, their symptoms don't manifest well into adulthood. This raises a major bio-ethical question regarding knowledge of future (and in most cases, certain) disease. How would I feel if I knew it was certain I would get Alzheimer's disease in my elder years? If it's determined I have Cystic Fibrosis, should I have children knowing that the chances they will have the disease are vastly increased? These difficult but important decisions are reasons why physicians have been hesitant to embrace the field of personalized medicine. Unfortunately, many people just don't know enough about genetics to fully understand the impact of knowing what our genes say. As we have seen throughout history, fear of the unknown is a powerful emotion, and some experts are anxious that many people won't be able to emotionally handle potentially devastating genetic news.

This concern is even more prominent now that commercial DNA sequencing services exist, such as 23andMe. I myself have used the 23andMe service for both curiosity sake and family importance (of which I will write about here at soon), but with my background in molecular biology, I am able to comprehend the implications of what my results said. As I mentioned above, the reasoning behind the private investment to sequence the human genome stems from the ability to patent all sequenced genes. Thankfully, President Clinton listened to scientific community and declared the patenting of the entire human genome unallowable. However, the patenting of specific genes was not unheard of, even while the Human Genome Project was moving along. In the 1990s, a collaboration between a biotech company called Myriad Genetics and the University of Utah produced key research on the tumor suppressor genes BRCA1 and BRCA2, which are commonly associated with breast cancer. In order to capitalize financially on their findings, Myriad Genetics filed for patents on the sequences of both genes. These patents were granted in 1997 and 1998. Since breast cancer is a very common disease affecting millions, the number of labs studying BRCA1 and BRCA2 would be in the hundreds, if not thousands. For over a decade, every year a lab conducted research on either of these two genes, it would have to pay Myriad Genetics a royalty fee. Perhaps more concerning, if a woman wanted to know her risks for breast cancer related to her BRCA1 and BRCA2 gene sequences, she would have to pay $3,000 for the genetic test. In 2009 a trademark complaint was made against Myriad Genetics, and a court nullified all of Myriad's patents. In an elegant defense of the laws of nature, the ruling judge wrote the following:

"The information encoded in DNA is not information about its own molecular structure incidental to its biological function, as is the case with adrenaline or other chemicals found in the body…this informational quality (of DNA) is unique among the chemical compounds found in our bodies, and it would be erroneous to view DNA as 'no different' than other chemicals previously the subject of patents….DNA, in particular the ordering of its nucleotides, therefore serves as the physical embodiment of laws of nature – those that define the construction of the human body…the preservation of this defining characteristic of DNA in its native and isolated forms mandates the conclusion that the challenged composition claims are to unpatentable products of nature."

The case is still in litigation, as Myriad Genetics has filed an appeal. The final ruling will have far-reaching implications into the scope and economics of research and medical care. Overall, the impact of the Human Genome Project has been immense. As a graduate student in cell and molecular biology, the availability of the entire human genome has empowered my lab's research and that of countless labs across the world. The field of molecular evolution has vindicated the prior work of anthropologists and evolutionary biologists that relied solely on fossil records and observable trait analysis. Research on genetic diseases has become much more focused, as geneticists now have a database to link identified mutations to specific genes. The emergence of commercial sequencing services has bridged the gap between research and medicine, with a little bit of fun mixed in as well. And while the progress toward personalized medicine has been slower than initially expected, the field is definitely moving in that direction. Because of this transition, it is paramount that proper and accurate science education remains at the forefront of any school curriculum. Hopefully you all have learned a great deal by reading this diary and will be able to add your educated opinion into the ring in regard to the future of personalized medicine and what it means for our overall care.

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