"So, what do you know about the Human Genome Project?"
The Human Genome Project impacted upon my life with a horrible silence, as I faced my interrogator. It was the first question I couldn't find an answer for, in this the most extremely important interview of my life, for my top choice university. On leaving the interview room, all that I could think about was how I had managed to fumble such an important question. I was surprised by how much I had to learn!
At first I believed that the Human Genome Project1 should have particular relevance to me, as I have a genetic disease. It was only when I had considered the matter further that I realised that this was not necessarily the case. In fact, the anomalous gene I inherited from my mother was first identified and sequenced2 some seven years ago! So what does the sequencing of all the other genes that make up humans really mean to me? Well, for a start -- I'm more than just my one funny gene -- along with all the rest of the people in the world I share all the other genes in the genome!
But living with a genetic disorder is not easy. The numerous treatments available, though effective in many ways, didn't quite help my bones to grow straight. Even before the publicity of the Human Genome Project, and the announcement of the first draft sequence3, my parents had been eager to help with the research effort for the syndrome called X-Linked Hypophosphatemia, in which the PHEX gene is affected. Three years ago our family participated in a project that tried to correlate the effect of mutations in the PHEX gene with the severity of the bone disorder4. This research certainly showed that we had a mutation in that particular gene but like that of most families, it was different from every other one known. So we're all unique, even though we share a unique disorder . Yet I'm convinced that it is possible to draw some parallels between recent work on our unique gene and the impact of work on the entire human genome.
As with my syndrome, an initial key to understanding has to be identification. With the first draft of the human genome before us, we are for the first time able to step back and look at our entire biological landscape, and thereby begin to identify what intrinsically makes us human. Similarly, the identification of the gene for XLH was the first step to understanding the basic biology of my own genetic disorder.
Intriguingly, the science that contributed to the discovery of my gene was different in approach from that which allowed the whole genome to be sequenced. For my gene, it was a case of narrowing in on one target; the Hyp consortium2 looked at many different families affected by XLH, and made a cDNA library with markers on either side of the gene. Deletions or mutations in their PHEX gene meant that it would not hybridize with the normal gene. By contrast, the Human Genome Project team widened out to look at bits of all the possible normal human DNA fragments cloned in bacteria, and then carefully piecing them together, while the Institute for Genomic Research used a 'shotgun' approach, sequencing lots of tiny pieces of DNA directly and then using a computer to check for overlaps5. Either way, both my gene, and the rest of the human genome, have been effectively sequenced.
Once the basic draft of the human genome was known, many different pieces of interesting information could be gathered, information as basic as the absolute number of genes that make us! In the human genome there are only some 27,000 - 40,000 genes, a far cry from the 100,000 originally predicted6. This information indicates that we are less genetically superior, in terms of gene number, than we once believed. It has to be incredibly humbling, to us arrogant humans, to realise that 90% of our genes are similar to those of mice! We can conclude that it's not the number of genes, but rather the ways in which we use them, that contributes in a major way to what makes us human -- the issue is quality, not quantity. Other discoveries, including the remarkable finding that only 1.5% of our genome represents the coding region of our genes, compared to the 50% which represents apparently only 'junk' DNA, must inevitably lead to more questions. And more questions can only lead to more answers.
In a manner similar to the information derived from simple identification, many rare genetic disorders (of which at least 4000 are known7) can benefit from the identification of the genes that are affected in these conditions8. Identification of any particular anomaly must open the flood-gates for a whole range of ground-breaking technologies and research discoveries. The genome sequence will act as a major diagnostic tool to help convincingly to diagnose genetic disorders of all kinds, as well as providing a starting point in development of therapeutic medicines.
Of course, we know that there are many ethical considerations that are involved in these sorts of diagnostic genetic tests. Like its counterpart in the United Kingdom, the Genetic Interest Group, which has dealt comprehensively with these issues9, the Genetic Alliance, an international consortium of genetic disease networks, is deeply involved in helping to raise and answer these questions, which range from pre-natal testing to insurance contingencies10. Similarly, individual rare disease organisations, like the XLH Network11 which was set up as a world-wide support system to help deal with the condition I share with 1 in 20,000 people around the globe, are making their own considerations about the use of these tests, like the newly announced genetic test for XLH provided by a commercial company12. It is a matter of mixed emotions on my part to consider that a test for my syndrome could be used to identify an affected baby before it is born; no doubt some people would choose not to have had babies like me.
But the common hope is that identification of particular genetic codes may lead to a better understanding of the specific genetic disorder. Happily, new research into my disorder has shown very recently that the affected PHEX gene, normally a cell-surface associated endopeptidase, can be reconstituted in soluble form to cleave a malfunctioning hormone which is probably the key to phosphate leakage13 and therefore poor bone development. This information could lead to new treatments and prevention of some of the major effects of XLH. In a similar way, for example, a soluble enzyme which should be the product of the affected gene in another rare, and fatal, genetic disorder, the so-called Type II Glycogen Storage Disease, is now entering final clinical trials to evaluate its efficacy as a treatment in preventing the death of young babies with this syndrome14.
And so, for the many thousands of genetic disorders, will the identification of the relevant mutated gene lead to a cure, and will these cures make much of a difference to the general world population? Individually, these genetic disorders might seem very rare, but if you add them all up, you actually get a significant proportion of all childhood diseases15. So therefore, it seems that understanding these diseases is sure to have a major impact on many many people. Just what the answer will be, for each disorder however, must depend on what the gene product is, and how accessible it may be to treatment.
In addition to the use of recombinant proteins made from correct genes inserted into bacterial, yeast, eukaryotic cells or even animals16, as for Glycogen Storage Disease, even more dramatic possibilities for future treatment of genetic disorders lie in the direct approaches like gene therapy -- inserting the correct gene into the body that is affected, and germ line therapy -- inserting the correct gene into either a sperm or an egg17. I myself probably won't benefit from either of these treatments, as I have almost finished growing, but who knows whether these sorts of genetic methods will be available to my younger brother, who is also affected, or, if either of us have them, to our children? The clinical research rushes ahead almost faster than we can grow up!
These treatments, however, will be expensive, and individual by their very nature, and therefore mostly unavailable to the poorest people of the world. And genetic disease affects everyone, not just the rich! For example, my own syndrome, XLH, affects poor black people from South Africa18 just as badly as wealthy people in Scandinavia or America or Brazil19. Most of the world will therefore be in the position, as with medicines for AIDS20, of looking into the windows of wealth-financed good health. It is hard to imagine how the advent of gene-based medicines will immediately affect most of the world's people, many of whom (as we are constantly reminded on the television news) need such basic things as clean water before they can even think of moving towards sophisticated medicines and treatments.
But in the developed world, which counts people who are able to afford such medical approaches, individualised medicines must be the wave of the future, as individual genes are identified and their functions are understood. The challenge for the pharmaceutical companies, and the governments which regulate their activities, will be even greater than those of today, as they will need to develop their medicines to work with a global market of individuals, rather than a market of globally affected groups. This challenge is formidable, and it is one that I expect to continue to grapple with, on a personal and a public level as I move toward a career in medicine. Since I know what it is like to be a genetic subject, perhaps I will have a better concept of this new individualised medicine, than those who are only part of a 'normal' group!
As for my interview -- the panel decided that I was more than just the sum of my genetic information, and the outcome was good. They made me a conditional offer of a place at university. It's all up to me, now, not just my genes, whether I get the final grades that will open up new worlds in which to work.
1. Historical overview of the Human Genome Project
(http://www.georgetown.edu/research/nrcbl/scopenotes/sn17.htm)
2. The HYP consortium. 1995. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nature Genetics 11:130-136.
3. Press Pack for the Announcement of the Rough Draft of the Human Genome
(http://www.wellcome.ac.uk/en/1/awtpregnm.html)
Also: Press Release from the National Human Genome Research Institute
(http://nhgri.nih.gov/NEWS/initial_sequencePR.html)
4. Filisetti, D., Ostermann, G., von Bredow, M., Strom, T., Filler, G., Ehrich, J., Pannetier, S., Garnier, J-M., Rowe, P., Francis, F., Julienne, A., Hanauer, A., Econs, M.J., and Oudet, C. 1999. Non-random distribution of mutations in the PHEX gene, and under-detected missense mutations at non-conserved residues. Eur. J. Human Genetics 7:615-619.
5. 'On your marks' News feature in New Scientist online archive 23 May, 1998 (http://www.newscientist.com/ns/980523/ngenes.html)
6. 'Less is more' News feature New Scientist 17 February, 2001. pp 6-7.
Also: Press Release from the National Human Genome Research Institute
(http://www.nhgri.nih.gov/genome_sequence.html)
7. The Wellcome Trust web pages (http://www.wellcome.ac.uk/en/1/awtpregnmbrs.html)
8. The Sanger Centre's work on identifying genes in various genetic diseases
(http://www.wellcome.ac.uk/en/1/awtpregnmsan.html)
9. Genetic Information Group web pages (http://www.gig.org.uk) Response to the discussion document, 'Whose hands on your genes?'
10. Genetic Alliance website (http://www.geneticalliance.org)
11. XLH Network website (http://xlhnetwork.ncl.ac.uk)
12. 'What does genetic testing mean to us?' Discussion document created by the XLH Network (http://www.btinternet.com/~elphagreen/XLH/genetictest.html)
13. Boileau, G., Tenenhouse, H.S., DesGroseilliers, L., and Crine, P. (2001)
Characterization of PHEX endopeptidase catalytic activity : identification of parathyroid-hormone-related peptide 107-139 as a substrate and osteocalcin, Ppi and phosphate as inhibitors. Biochem. J. 355:707-713.
14. 'Interview with Paul Kaplan', 29 March, 2001. As linked through the Association for Glycogen Storage Disease web site (http://www.agsd.org.uk) or directly (http://www.cix.co.uk/~embra/ipa/interview.html)
Also: Wraith, E. (2000) Glycogen storage disease. Biological Sciences Review 13:22-26.
15. Scriver, C.R. (1984) An evolutionary view of disease in man. Proc. R. Soc. Lond B 220:273-298.
16. Bulleid, N. (2001) Tailor-made proteins. Biological Sciences Review 13:2-6.
17. National Human Genome Research Institution publication: The possibilities for treating genetic diseases (http://www.nhgri.nih.gov/Policy_and_public_affairs/Communications/Publications/Maps_to_medicine/how.html)
18. Basu, D., Pettifor, J.M., Kromberg, J.G.R. (2001) X-Linked hypophosphatemia in a South African population. (ABSTRACT)
International Bone & Mineral Society webpage describing IBMS conference in Madrid, June 2001 (http://www.ibmsonline.org/meetings/meet.htm)
19. The XLH Network Geographical Profile of Members
(http://xlhnetwork.ncl.ac.uk/Cases.html)
20. Opinion Interview: Yusuf Hamied with K.S. Jayaraman discussing the price of AIDS medicines in Africa. New Scientist 31 March, 2001 pp 42-45.