The Human Genome Project, countdown to completion

Jody Boeckel

Copyright 1999

Imagine having the recipe to make a human being. Knowing its entire genetic make-up from beginning to end. Sounds far fetched, well it isnít with the latest scientific achievements in sequencing the Human Genome. Itís only a question of how far we will take this information to get an understanding of its full potential.

The Beginnings:

Long before there was a formal Human Genome Project (HGP), the Department of Energy (DOE), the National Institute of Health (NIH) and some of their predecessor agencies were interested in developing more sensitive methods to detect changes in our genetic make-up, induced by ionizing radiation, and to begin understanding the related health effects due to this type of exposure. It has been know for some time that the genetic-information containing deoxyribonucleic acid (DNA) is the molecule in the cell that is the most sensitive to the effects of radiation and other pollutants, even at low levels. One can only begin to imagine the impact it will have, in the pharmaceutical, and medical fields as well as how research will change, once we have our complete genetic make-up spelled out.(www.ornl.gov/hgmls/publicat/judges/aren.html)

In 1984, researchers got together at a conference to discuss a single question. The question being asked was if modern DNA research provided an adequate way of detecting genetic mutations. Particularly, if there was sufficient evidence to indicate an increasing mutation rate in those people and their descendants, who survived the Hiroshima and Nagasaki bombings. The overwhelming conclusion was, not yet, and so this was the underlying question-answer series that sparked the idea for the formation of the Human Genome Project. (www.ornl.gov/hgmis/publicat/tko/01_forword.html)

In 1988, the DOE and the NIH signed a memorandum joining them in a combined effort to sequence the human genome. Then just two years later, on October 1, 1990 the official clock began counting down, signaling the journey and adventure to sequence the entire human genome. (New England Journal of Medicine, July 1, 1999)

It was evident that once this project was completed it would furnish a highly detailed and accurate genetic reference guide that others could use to build on, without having to repeat the sequencing process from scratch. Originally the goal of the project was to have a completely sequenced genome within15 years. Due to improved sequencing techniques and the increased competition generated by the private sector, a "highly accurate" version of the human genome is set to be completed by the year 2003. (http://cnn.com/HEALTH/mayo/9908/19/human.genome/) Coincidentally, that is the 50Th anniversary of the discovery of the double helix structure of DNA preformed by Watson and Crick. (Science, Oct.23, 1998, v.282)

According to Dr. David I. Smith, Director of the Mayo Clinicís Cancer Genetics Program, 90% of the project should be finished by early April year 2000. (http://cnn.com/HEALTH/mayo/9908/19/human.genome/) This preliminary version will contain varying lengthed gaps in the sequence, because some sections need to be manually sequenced instead of using the automated method. Even this premature version will provide enough information for researchers to begin work on their own projects. (Chronicle of Higher Education, July 19, 1999)

Basics behind the project:

The HGP has turned into an international, private and public drag race, costing billions of dollars, with seemingly endless possibilities to what accomplishments and discoveries that will be a direct result of its completion. The completely sequenced DNA or what some have termed our "genetic blueprint", will provide us the necessary information and an adequate resource data base, to begin our understanding of some of the critical differences that makes us phenotypically and genotypically different from one another. (BioEssays 1999,v21 121-130) The DNA sequence of one person is approximately 99.9% identical to that of another person. DNA is what makes up the 23 pair of chromosomes each person has. (www.ornl.gov/hgmls/publicat/judges/aren.html)

Chromosomes are composed of long threads of DNA, tightly packaged in our cells, containing thousands of genes arranged like beads on a string. Genes are short pieces of DNA that provide cells with the proper information as to what protein(s) they are to produce and in what amounts. These hereditary instructions are spelled out by the use of 4 different nucleotides or bases: adenine (A), thymine (T), guanine (G), and cytosine (C). (www.ornl.gov/hgmis/publicat/tko/04_exploring.html) The DOE and NIH along with some private companies are in the process of sequencing 80,000 to 100,000 genes over the next several years. (http://cnn.com/HEALTH/mayo/9908/19/human.genome/) That would account for approximately 6 billion base pairs, 3 billion coming from each parent, constituting our genetic library. (www.ornl.gov/hgmls/publicat/judges/aren.html) To give you an idea of the enormous amount of information involved here, that is enough information to fill an estimated 1,000 Manhattan telephone books, or approximately 1 million pages of written text. That would take approximately 26 years of reading 24 hours a day seven days a week, to finish this mammoth pool of information.

Genetic disease:

During cell division, the double stranded helical DNA begins to unwind, allowing each strand to start synthesizing a complementary strand of DNA. This is where the greatest chance for a mistake is likely to occur. A single mistake or mutation in the replication process could lead to a number of problems in the cell. Many normal and pathogenic characteristics are determined by an allelic variation in a single gene, inherited according to the Mendelian laws. (Nutrition Reviews, may, 1999, vol. 50, No.5) A misspelling found in the instructions to a cell could force it to start producing the wrong protein(s) or cause the cell to start producing too much or to little protein, offsetting the homeostatic balance a cell tries to maintain. This misspelling of the genetic code can be the direct cause of disease, or can increase a persons likelihood of contracting a disease. (http://cnn.com/HEALTH/mayo/9908/19/human.genome/) Defective genes are directly linked to an estimated 4000 heredity human diseases such as Cystic fibrosis, and Huntingtonís disease. (www.ornl.gov/hgmis/publicat/tko/02_why.html) A single misplaced base for example, is sufficient to afflict someone with sickle cell anemia, a disease where humans contain an abnormal hemoglobin type causing the red blood cells to have a sickle shape, which in turn blocks blood flow. (http://cnn.com/HEALTH/mayo/9908/19/human.genome/)

For most of us though, our interest is focused on the more common diseases, those inflictions that we struggle to control on a day-to-day basis. Cancer, heart disease and some psychiatric disorders are caused by complex interactions of genetic error and some sort of environmental influences. (http://cnn.com/HEALTH/9906/11/human.genome/) The mapping of all genes and the identification of the proteins encoded by these genes, will pave the way for more-effective therapies and a means of prevention. (www.ornl.gov/hglms/publicat/primer/prims.html)

The HGP will aid scientists in understanding how and why disease such as Hypertension and Multiple Sclerosis are so effective in setting up their disease conditions. Discoveries made by the HGP will help design programs of prevention rather than treatment. People will have a better idea of their risks and be able to make changes to decrease these risks. Medications will soon be prescribed that are especially designed for your specific genetic disposition, increasing the effectiveness of the treatment. (http://cnn.com/HEALTH/9906/11/human.genome/)

Projects implications and ramifications:

In addition to the projects many implications for medicine, it will also provide a better understanding of what really affects human health. A precise means of disease diagnosis, a more rapid characterization of genetic damage and the repair processes needed to fix the damage, are just a few expectations of the HGP.

This international project is creating technologies and providing resources that can be applied to the characterization of other living organisms genome. The appeal of this approach to biology is evident by the establishment of genome projects for several microbes, genetically engineered hybrid crops, insects and several mammal species. The information gained from these other genome projects will, in turn, provide important new practical applications towards energy conservation, environmental protection, agriculture development, and some industrial processes. Generation after generation, evolution has conserved the biochemistry that worked well for the simplest organisms and has adapted this biochemistry to respond to changing environmental conditions. The genes that determine structure and function for similar single cell organisms are often similar, in sequence and products, to those that determine the structure and function of human cells. By studying simple cells and simple organisms, we will better understand comparable structures and functions in our cells. (www.ornl.gov/hgmls/publicat/judges/aren.html)

Scientist knew that new sequencing technology was needed to help speed up the completion of the HGP. One vitally important sequencing advancement was the development of the automated fluorescent-based DNA sequencing technique that has quadrupled the efficiency of the HGP. Prior to the HGP, scientists had to look at each and every chromosome, to find a particular gene of interest, a process that could take10 years or more, depending on the nature and complexity of this gene. The HGP will drastically decrease this time by providing a comprehensive map of all our genetic information, allowing scientist to turn their attention to figure out the geneís interaction and function instead of tying to figure out the genes sequence (http://cnn.com/HEALTH/mayo/9908/19/human.genome/)

A spin off from the HGP is the Microbial Genome Initiative, formulated in 1994, to sequence the genomes of bacteria. The bacterial genome would play a big role in areas such as energy production and its uses, environmental remediation, industrial processing and waste reduction. As a result of the microbial genome initiative, we have already completed the sequence genome of two fundamental microorganisms, Escherichia coli, and Saccharomyces cerevisiae or "bakers yeast". (Science, Oct 23,1998,v.282) Another microbe of interest is Deinococcus radiodurans, which thrives despite being exposed to extremely high levels of ionizing radiation, and has the ability to repair the radiation-induced damage to its DNA. It is likely that weíll be able to insert foreign DNA into this microbe, allowing it to digest extremely toxic organic materials, aiding us in our waste management problems. This will provide a quicker, more cost-effective, simpler way to handle the cleanup of such things as oil spills, nuclear reactor accidents or other dangerous chemical mishaps. Structural studies have been started to learn how and the mechanism behind which these unique proteins are allowing these organisms a means of surviving in such adverse conditions that would prove lethal to most other creatures.

Discoveries as a result of the project:

In 1995, the highest resolution physical maps for human chromosomes 16 and 19 were completed by the Los Alamos National Laboratory and the Lawrence Livermore National Laboratory. (www.ornl.gov/hgmis/publicat/tko/04_exploring.html) The chromosome 19 map has shown evidence of the DNA repair genes HHR23A, ERCC2, and XRCC1, and the characterization of the genetic defect underlying the cause of Alzheimerís disease, Myotonic Dystrophy, and at least one form of Migraine headaches. It has also described the extremely unusual genetic mechanism by which, aberrant triplet repeats contribute to the onset of Huntingtonsís disease and at least eight others diseases.

Genes mapped to chromosome 16 include those causing Crohnís disease, Battenís disease, Fanconiís anemia, Polycyctic Kidney disease, and several forms of breast and prostate cancer. (www.ornl.gov/hgmls/publicat/judges/aren.html)

ELSI issues and the debate that follows:

The HGP from the onset was destined to stir up a difference in opinion about how to deal with information made available by this project. This has lead to the establishment of a program devoted to the ethical, legal, and social implications (ELSI) as a direct result of the genome project. The HGP has committed 5% of its annual research budget to help the ELSI program with funding. (New England Journal of Medicine, July 1, 1999)

One goal of the ELSI program is to address the consequences of the vastly growing genetic information and protocols on individuals and society. Another necessary goal is to recognize and develop appropriate policy options to address and solve the future ELSI issues that are sure to arise.

The list of ELSI issues is relatively long and in one way or another, have some legal ramifications tied to them. One of these issues is the "fair" use of genetic information. The lawyers, judges, and juries will have to be DNA experts to understand some of the evidence presented in courtrooms in the post-genome era. Cases involving paternity determination, forensic DNA evidence and criminal prosecutions will be made possible by advancements made by the HGP. Discrimination includes that of age, sex, race and now genetic discrimination. (www.ornl.gov/hgmls/publicat/judges/aren.html)

Another ELSI issue is dealing with the privacy implications of personal genetic information, used in places such as work, school or used to influence an adoption proceeding. Imagine being in a disease condition, you may not want to know some of the risks or implications of this disease, but others such as your insurance company, your employer, or the Government may want this information for there own use. Congress has already begun legislation and debate to come up with answers to these issues. The Health Insurance Portability and Accountability Act, offers a bit of protection due to the loss of health insurance because of the use of genetic information.

Other ELSI issues deal with genetic literacy and the understanding of genetic information, particularly the information related to extremely complex conditions that involve multiple genes or some genetic-environmental interactions. Genetic-environmental interactions are linked to heart disease, diabetes, mental illness, and some cancers. This is the most complex of ELSI issue because the science behind the gene-environmental interactions is poorly understood, but there has been an increased interest, by scientists in this area, so the ELSI members have already began looking into this issue more in depth. (www.ornl.gov/hgmls/publicat/judges/aren.html)

The genomic information has already been made public through the use of the Internet. There are some that believe this information should be controlled by private companies, limited by patents, licenses and contained in secret databases. The private companies that provided millions of dollars towards the HGP, making it possible to shorten the completion time, want the human genome information to remain with them. The NIH, the Genome Research Institute, and many others believe this information should be available to everyone. (http://cnn.com/HEALTH/9906/11/human.genome/)

One of the hottest and most controversial topics is the right to patent the human genome. Does someone have the right to own the human genome? Should this be totally public information that anyone can look-up and have access to. These are just some of the subjects you will see in the headlines over the next few years. (www.ornl.gov/hgmls/publicat/judges/aren.html)

In my opinion:

I believe the HGP will be useful and advance science in a direction that will better the human way of life. I see the project as being a valuable tool to help us solving many of our problems related to crime, disease, and will provide the understanding to many biological interactions. I do believe we need to proceed with caution and think this through before we cause trouble for ourselves. I believe that much attention has been paid to fully understand what could be controversial or trouble areas. Most people get concerned about something once we start messing nature, and so I believe this information will be used correctly because people are concerned about some of the possibilities of misuse.

Conclusion:

The HGP is fulfilling its expectations as the single most important project in biology and biomedical sciences that has already changed biology and medicine. (Science, Oct 23,1998,v.282) New genome maps will be completed, narrowing the gap between form and function and uncover additional insight into the behavior of biological systems. (Nutrition Reviews, may, 1999, vol. 50, No.5) It will also provide a new way to approach disease, with a better means of treatment but most importantly will be used as a preventative tool. Legal and legislative communities have the possibility to be proplexed with the volume and complexity of some of the issues they soon will face. What to do with this information, how to store it and who should be allowed access, are all questions that will need addressing.

References

http://www.ornl.gov/hgmis/publicat/tko/01forword.html
http://www.ornl.gov/hgmils/publicat/judges/drell.html
http://cnn.com/HEALTH/mayo/9908/19/human.genome/
http://cnn.com/HEALTH/9906/11/human.genome/
http://www.ornl.gov/hgmis/publicat/primer/prim2.html
http://www.ornl.gov/hgmis/publicat/tko/02.why.html
BioEssays 1999,v.21, 121-130
http://www.ornl.gov/hgmis/publicat/tko/04 exploring.html
The Chronicle of Higher Education, July 16, 1999
The New England Journal of Medicine, July 1, 1999
Science, Oct. 23, 1998, v. 282

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