Focus
Student Scene
February 12, 2001
 Photo by Jeff Cleary |
Don't Stop Now: There's Still a Lot to Be Learned About the Human Genome
By Heather Ettinger"So now that the human genome sequence is finished, will it be hard for you to find a job?" a friend asked Heidi, a former HMS graduate student. It was June 2000, and the Human Genome Project and Celera Genomics had recently announced that they had compiled a "working draft" of the human genome.
Heidi's response was shock. Was this the message that had reached the public? Did the public think that there was no more work to be done? Did they know that sequence was of only one individual? Heidi, of course, knew that not only was the human genome not completely sequenced and assembled but also that once it was complete there was still much work to be done. For example, the mammoth task of annotating the genome, deciphering which sequences are genes, and determining the function of these genes, still remained.
During the week of Feb. 12 the complete sequence of the human genome and scientists' comments about it are being published in the journals Science and Nature. This represents an unprecedented accomplishment. In the excitement generated by this milestone, however, an important message should not be lost: the published sequence represents only five individuals, so the human genome is far from being complete. Many other individuals' genomes need to be sequenced before we even begin to have a good representation of what the human genome is.
The Victory Paradox
The completion of the genome has been compared to our landing on the moon. Though we reached the moon, we didn't capitalize on that feat as we might have to make further scientific investigations and discoveries on lunar missions. The danger now is halting our progress in characterizing and understanding the human genome just because we have reached an exciting goal.The recent completion of the sequencing of a strain of the enterohaemorrhagic Escherichia coli O157:H7 offers an extreme example of the surprises and challenges we may find upon sequencing other individuals' genomes. E. coli O157:H7 is a virulent and pathogenic version of the same bacterial species that lives symbiotically in our gastrointestinal system and that is used daily in the lab. Since the first documented outbreak in 1982, O157:H7 has become an increasing public health hazard, killing dozens of people each year.
Upon completion of the laboratory E. coli K-12 genome, researchers set out to sequence the genome of its deadly counterpart. The goal was to understand what made these bacteria different from one another so drugs could be designed to prevent or treat infection. Researchers were expecting only one or a few changes in E. coli O157:H7 to give it its nasty properties. They were completely shocked to find that the genomes were very different.
The virulent O157:H7 contains approximately 1,300 genes not found in nonpathogenic K-12 strains. In addition, of the genes that the two did have in common, approximately 75 percent differed by at least one amino acid. The two genomes, in fact, are so different that scientists are now questioning whether these two bacteria should really be considered the same species.
Digging Diversity
I am certainly not suggesting that sequencing many individuals' genomes will reveal that we are not the same species. The variation among humans will not be nearly as great as between these two bacteria. So what lesson does the sequencing of the E. coli O157:H7 genome have for the human genome? It's that we are not always good at predicting nature's intricacies. We do not know what lies ahead. It is best to be cautious about the conclusions we draw from just a handful of individuals' genomes.As it stands now, the genomes sequenced by the genome projects lack diversity. In fact, one scientist has said that the Human Genome Project could be called the "Western Nation Genome Project" since it does not include genomes from people in countries such as India or China. It will be important to sequence genomes from different cultural or demographic populations. But it will be equally, if not more, important to sequence many individuals from seemingly similar cultural or geographic backgrounds. According to an article published in Science, "Genetic differences of populations from different continents represent only about 10 percent of human genetic diversity" while "more than 80 percent of genetic variation is between individuals of the same population." (Oct. 15, 1999, Vol. 286, pp. 451-453).
Tailor-made Drugs
The sequencing of many individuals' genomes has far-reaching consequences. Identifying the genetic variations is essential for the branch of genomics dubbed pharmacogenomics, which aims at tailoring pharmaceuticals to individuals by understanding how genetic variations contribute to an individual's drug response. The sequencing of many genomes may also reveal much about our past since it can help identify migration patterns of ancient peoples.Just as the sequencing of many genomes will reveal differences, it will reveal similarities. Many cultural anthropologists and geneticists have used genetic variation to support the idea that there really are no human races, but instead a "virtual continuum of genetic variations." (Science Oct. 23, 1998, Vol. 282, pp. 654-655). Documenting these similarities has the profound potential to change human relations.
Misconceptions about the human genome project don't just lie with members of the public like Heidi's friend. The scientific community faces the risk of disregarding the lack of diversity of the current genome projects. The Human Genome Diversity Project, formally organized in 1993 and designed to sequence the genomes of people from all over the world, has been dramatically reduced in size and scope. Scientists now speak of proteomics, not genomics; genomics is no longer the hot topic. And there are journal articles about science and life in the "post-genomic" age.
I would argue that we are still living in the age of genomics. The next step, proteomics, promises to provide a wealth of information, but we should not forget that there is still a wealth of diversity to be discovered. To deny the human genome this diversity would be truly a misuse of our capabilities.
Heather Ettinger has just completed work on her PhD in the HMS Biological and Biomedical Sciences program in biological chemistry.