The Human Genome turns ten years old this summer. Ten years ago President Clinton and British Prime Minister Blair announced that a draft copy of all 3 billion letters of the genetic code had been finished. The combined public and private effort cost nearly $3 billion and took eleven years. Ten years after completion, what progress has science achieved for these efforts?
Learning to Read
First a bit of background: each cell in our body carries within it nearly the exact same set of instructions as every other cell in our body- instructions for how to grow and function. These instructions are encoded in a double-stranded twist of molecules called DNA. This incredibly long molecule is made of an ordered series of four smaller molecules: adenine, thymine, guanine and cytosine, or A, T, G, C for short. The genetic code, or sequence of As, T, Gs and Cs, is 99.9% similar among all humans [1]; the remaining 0.1% contributes to the differences in our appearance and predisposition to disease or health. Scientists want to understand this code and how its instructions are carried out so they may one day be able to predict and prevent diseases in those people who are likely to get them.
After completing the draft copy of this sequence ten years ago, scientists and policy makers imagined it would be straightforward to improve human health; Bill Clinton stated in 2000, “Genome science […] will revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases.” However, understanding how the genetic code influences disease was and is more challenging than expected. Many puzzles remain to be solved; some people have the same genetic sequence for a region of DNA that influences a disease, but only a portion of them will eventually get the disease. Why is this?
Translating the Text
DNA, although being entirely composed of As, Ts, Gs and Cs, it is not uniform throughout its length. Less than 2% [2] of DNA actually codes for proteins, the major actors in a cell. Disturbances in these “protein-coding” regions can lead to diseases, but surprisingly, people with the exact same sequences in these regions can have extremely variable disease states. It is now known that most diseases can’t be explained by the sequences of the coding regions alone. The answer seems to lay in the rest of the DNA- the non-coding sequences. This used to be called “junk” DNA, but it actually plays a much more important role than was previously thought. Some of this non-coding DNA helps regulate how much of a specific protein is produced, other parts help to keep the DNA from being degraded, and the majority of it is still mysterious. Increased knowledge of the functions of this kind of DNA will further our understanding of how it impacts human health.
Another reason that the human genome has been slow to provide clinical results is that diseases are actually much more complicated than we had anticipated. Except for a few specific cases (e.g., some breast and ovarian cancers [3]), most diseases are caused by changes in more than one part of the genome. Each change slightly increases or decreases a person’s risk of developing a disease but there is usually no “smoking gun”. Consequently, most individuals wouldn’t benefit from having their genome sequenced right now; we still don’t know how differences in sequence affect human health. However, we are making massive improvements in our understanding. How? Paradoxically, by sequencing more people.
Hitting the Books
Each small change in sequence results in extremely small differences in the probability of getting a disease. So in order to see the pattern in the genetic code behind each disease, we need to sample many people with the disease. Currently, the cost of sequencing a human genome is roughly $30,000 but the price has been dropping exponentially over the last 20 years [4]. In fact, a company called GnuBio was just founded with the stated goal of sequencing a genome for $30 [5]. This kind of technology bodes well for clinical sequencing being relevant for individual patients in the next 10 years.
Perhaps where sequencing technology has made the most impact is in the laboratory. It is now standard procedure to sequence DNA from bacteria, mouse, and human tissue among others; the genome sequences are the structures onto which scientists hang each new piece of knowledge they discover. A more detailed knowledge of these sequences provides a way to tie discoveries in model organisms to diseases that affect humans. Once scientists isolate a gene and its function in an organism like a fruit fly, they search through a map of the human genome to find a sequence that is very similar. Scientists then use this as a starting point to understand the gene in humans.
Ten years on and the enormously expensive Human Genome Project has had a modest impact on the treatment of human diseases, but a significant impact on how science is conducted and on the understanding of the interaction of DNA and disease. That foundational knowledge is constantly expanding and will gradually allow science to make life a little better for all of us.
Rishi Jajoo, PhD Student, Harvard Medical School
References:
1. http://www.ornl.gov/sci/techresources/Human_Genome/project/info.shtml#draft
2. http://www.ornl.gov/sci/techresources/Human_Genome/project/info.shtml#draft
3. http://www.cancer.gov/cancertopics/factsheet/Risk/BRCA
4. http://synthesis.cc/2008/06/learning-curves-and-genomics-thoughts-on-the-future-of-sequencing.html
5.
Links of interest:
Nation Human Genome Research Institute Human Genome Project site with informative resources:
http://www.genome.gov/10001772
New York Times Article on Human Genome draft anniversary:
http://www.nytimes.com/2010/06/13/health/research/13genome.html?_r=1&scp=1&sq=%22human%20genome%22&st=cse
New York Times Article on Human Genome draft anniversary with graphics:
http://www.nytimes.com/2010/06/15/business/15genome.html?ref=business
Wellcome Trust Sanger Institute Human Genome Project site:
http://www.sanger.ac.uk/about/history/hgp/