Chapter 2                                    

Definition and Background

2.1. Definition :

The Human Genome Project (HGP) is possibly the most important, interesting and really inspirational Human achievement. It is also a technological victory, and many described it as more significant than the invention of the wheel or landing the man on the moon. This code “Human Genome” is the essences of mankind’s life and as long as Human exist, this information is going to be important and will be utilised.

It is an international effort where around 25 international scientific research laboratories collaborate to achieve complete characterisation of the Human Genome, (International Human Genome Consortium, 2001). The nucleus of the Human cell contains 46 chromosomes (23 pairs); 44 autosomes and 2 sex chromosomes as seen in Fig (1)

These 46 chromosomes constitute the Human Genome. This Genome contains about 30.000-40.000 genes (functional genes), which make up only about 3% of the total genetic material, as recently discovered (Ventor, et al 2001; International Human Genome Consortium, 2001). The rest of the DNA is referred to as junk genes.

The first aim of the HGP was to determine the location of all 40.000 genes on the 46 chromosomes. The second aim, which follows from the first one, is the determination of the base sequence of the Genome and eventually to identify the function of the genes. To find the location of the gene, a process known as mapping is adopted, and sequencing is to determine the base sequence of the gene.

The dimensions of the project are difficult to imagine due to delicate and sophisticated processes involved. This is mainly due to the huge size of DNA molecule. It is estimated that the length of DNA molecule in each cell in our body is around 2 meter. Given the fact that Human body has an average of 100 trillion cells, thus if all the DNA in our body are attached to each other and stretched, it will reach the moon and back to earth eight thousand times.  

To simplify the ethos of Human Genome Project (HGP), it will help to draw the following analogy :

If we magnify the size of the nucleus of the Human cell to the circumference of the earth, then one chromosome would have the dimension of a country. A gene would have the dimension of a city. The base pairs would have the equivalent of the population of that city, Fig (2). In this “world of the cell” scientists are looking for approximatly 30.000-40.000 genes (cities) to locate them on the 46 chromosomes (countries) and ultimately to find out the sequence of a line of 3 billion bases (inhabitants). 

Fig (2) distribution of chromosomes and genes

 (red colour within the chromosomes refer to the functional genes

 which form arond 3% of the total genetic materials, whereas the

 rest of DNA is referred to as junk genes)

2.2. Historical Background :

After the Second World War and specifically after the American nuclear bombs were dropped on Hiroshima and Nagasaki on August 6, 1945. The world conscience was stirred to the horrific effects on Japanese population in these two cities. A Japanese estimate in 1968 concluded that as many as 250,000 citizens of Hiroshima had either been killed outright or had died of radiation sickness within five years. The consequence of that incidence still has implications on generations to come due to its effect on genetic material. Since that time the Department of Energy (DOE) in the United States and its predecessor agencies had been interested in finding and developing sensitive methods to detect the tiny changes that take place in the genetic material by ionising radiation and its implication on health (US DOE programme Report 1990).

It has been reported by many research articles that the DNA molecule (genetic material) is the most sensitive part of the cell that is easily altered or damaged by radiation even in small doses (Cleaver and Borek, 1993).

As the information were gathered since the discovery of the DNA molecule Fig (5), in addition, further discoveries and new technologies were developed that led to better understanding of the DNA molecule and its functions in staggering base. Since the 1980s the ideas arose to sequence the entire Human Genome systematically, and with this idea arose the HGP. It was recognised early on that once this project was completed, it would furnish a “comprehensive reference source” that others could build on without having to repeat the research from scratch.

In addition DOE have been charged with pursuing a deeper understanding of the potential health risk posed by energy use and by energy-production technologies. Most of radiological health hazards research stem from studies supported by DOE and its agencies. Among these investigations are long standing studies of the survivors of the atomic bombings of Hiroshima and Nagasaki. Much has been learnt about the consequences of exposure to high doses of radiation. On the other hand, many questions remain unanswered; in particular, we have much to learn about how low doses produce their insidious effects. When present in low but significant amounts, toxic agents such as radiation or mutagenic chemicals work their mischief in the most subtle ways, altering only slightly the genetic instructions in our cells.

The consequences can be heritable mutations too slight to produce discernible effects in a generation or two but in their persistence and irreversibility, deeply troublesome nonetheless (US DOE programme Report 1990).

Until 1980’s the science in Molecular Biology was not developed enough to detect at first hand these tiny changes to the DNA molecule that encode our genetic programme. Sophisticated technologies were needed that could detect a change in one “word” of the programme, among perhaps a hundred millions.

In 1984 DOE and the international commission for protection against environmental Mutagenes and Carcinogens convened meeting jointly. The question was first seriously asked : Can we or should we sequence the whole Human Genome ? Is it possible to develop a high technology where we obtain a word by word copy of the entire genetic script for an average Human being and thus to establish a benchmark for detecting the elusive mutagenic effect of radiation and cancer-causing toxins ?

To answer these questions a workshops were held in 1985 and 1986. A DOE advisory group, the congressional office of Technology Assessment and by the National Academy of Science, studied these issues. The matter was also debated publicly and privately among biologists themselves. In the end, a consensus emerged that they should make a start.

The DOE have an earliest interest in Human Genome and did have fully equipped national laboratories, in addition to its capability to conduct multidisciplinary projects, which make it ideal for such endeavour. This huge project will undoubtedly benefit from the contribution of different disciplines, engineering, physics, chemistry, computer science and mathematics. Thus with the infrastructure in place and with a particular interest in the ultimate results, the DOE in 1986 was the first Federal Agency to announce and to fund an initiative to pursue a detailed understanding of the Human Genome.

This interest in Human Genome was not restricted to the DOE. Many institutes; National Institutes of Health, the Cold Spring Harbor Laboratories and the Howard Hughes Medical Institute sponsored many workshops on Human Genome project.

In the 1988 the NIH (National Institutes of Health) joined in the pursuit, and in the fall of that year, the DOE and NIH signed a memorandum of understanding that laid the foundation for a concerted interagency effort.

But to look into the history of the HGP in term of molecular techniques that facilitated the achievement of this project refer to table (1), which reveal the chronology of research that led to the completion of mapping and sequencing of the Genome.

2.3. Aims of the Human Genome Project :

The completion of mapping and sequencing of all Human Genome is nothing less than a biochemical revolution. Like silicon valley pirates who reverse- engineering a computer chips to steal a competitor’s secrets, Genetic Engineers are decoding life’s molecular secrets and trying to use that knowledge to reverse the natural course of disease. DNA in their hand has become both a blueprint and a drug, a pharmacological substance of extraordinary potency that can treat not just symptoms or the diseases that cause them, but also the imperfections in the DNA that make people susceptible to a disease. The ability to change and manipulate genes could eventually change every aspect in our life : what we wear, what we eat, how we live how we die, how we treat the diseases and in general how we see ourselves in relation to our fate, other living organisms and the environment.

There were a lot of debate and disapproval from wide spectrum of scientists and institutions regarding the money allocated to be spent on the project. The budget for the project was initially $3 billion. Some of the arguments that were posed were, if this money spend wisely there will be no homeless or unemployed in America. So how to justify this huge budget ? Though other scientists consider this is a bargain science compared to Manhattan project “Nuclear bomb” which cost $18.5 billion or Apollo project, which cost $115.3 billion as the value of dollar today. But to find a reasonable answer to this justification, one might burrow the following analogy used by Steve Jones (1993) : When Royal Admiralty send HMS Beagle to south America when Darwin was on board, not because they were interested in evolution theory. The very controversial theory which Darwin published after his voyage in his famous book in 1859 “The origin of the species by natural selection” or the preservation of the favoured races in the struggle for life. The British government was interested in one thing : They knew that the first step to understand and ultimately to control the world was to make a map of it! That was the purpose of HMS Beagle voyage. This is still probably the purpose of Human Genome Project to seek control over Human body!.

Among other Goals, which could be sub grouped under this umbrella, are :

2.3.1. Develop the needed technologies to map the Genome :

Human Genome consists of 46 chromosomes which can be seen at the level of light microscope, a procedure currently used by clinical cytogenetic laboratories all over the world as seen in Fig (1). Analysis of chromosomes at such level can reveal some information such as Down’s syndrome where we can see 3 copies of chromosome 21 instead of normal 2 copy as in Fig (3), or gender of the individual whether XY chromosome or XX chromosomes are seen.

Whereas the sequencing of the DNA will supply 10 million times as much information as chromosome pattern; a very large improvement (Cantor, 2000). Thus sequencing the Human Genome with its 3 billion base pairs was aimed and would be an enormous task. Early in the Genome project, the prospect of dealing with such very large numbers led its policy makers to decide to rely on a continuing evolving technology. Taking this approach, the project during its first five years plan to invest very heavily in improving technology of mapping and sequencing which will ultimately reduce costs and invest very little in large scale DNA sequencing, which was very expensive. In the second phase, the next five years, the technical advances of the first five years will pretty much have to be repeated; the methods have got to become more efficient and reliable by at least another factor of ten. By then, the Genome will have been mapped and the sequencing can begin. In the last five years of the project, somewhere, somehow, the rest of the Genome will be sequenced and all the genes will likely be found (Cantor, 2000).

This investment in technology and due to “shotgun” DNA-linking strategy developed by Celera Genomics in 1998 forced the public-funded initiative to pick up the pace and make it possible to speed the process and reduce the time significantly from 15 years to 10 years.

2.3.2.  Develop technology for functional Genomics :

To study the function of a gene, we need to destroy or alter the gene and then observe the resulting phenotype as was done earlier with the fruit fly Drosophila melanogastra during 1920s and onwards. But this sort of experiments can’t be done on human beings, exactly like trying a new drug, has to be tried first on experimental animals to evaluate its effect before prescribing for public use. Hence the need for a series of models of genomic projects for experimental animals. Comparative genomics is the key to understand the Human Genome, as Celera Genomic president Graig Venter said, “Comparative genomics is going to be the single most important tool forward” (Withgott, 2001). Celera sequenced the lab mouse, Mus musculus.

In February, 2001, and comparing the Genome of the Human and mice will facilitate our understanding of the genetic basis of Human diseases. There is a striking similarity between Human and mouse chromosomes (Rubin and Barsh, 1996) as in Fig (4).

Nuclear Genome of some 40 species have been fully sequenced so far: most bacteria, but the list includes five nonhuman Eukaryotes; the mouse, fruit fly, nematode worm, Arabidoposis mustard plant and baker’s yeast ((Withgott, 2001).

The importance of this comparative study will help in finding the function of 40% of Human genes, which are completely unknown, as well as help in confirmation of the function of other gene which we think we know!. Joseph Nadeau at the Case Western Reserve University School of Medicine in Cleveland, Ohio, is leading a project called the International Mouse Mutagenesis Consortium. The aim of this project is to mutate every one the 30.000 or so mouse gene to see what their functions are and ultimately utilise this knowledge for Human purposes. This is the beginning and not the end of the genomics era, says Francis Collins, director of the Human Genome project, “There is a lineup of organisms with their hands raised, saying “Sequence me next!” Collins says. As we do so, he adds, we should look to “some of the less-trammelled parts of the evolutionary tree”.

The following table shows some examples of Genome sizes of some model organisms :

Table (2) Genome size of some model organisms

2.3.3. Map and sequence the Genome working draft (3 billion letter) : which is more than 95% completed and published in two of the best International Journals, British Nature on 15/2/01 and American Science on 16/2/01. Still some gaps need to be filled along the Genome. It has been estimated that it would take over nine years to read this letters in aloud voice. If written out, the Genome would fill about 200 volumes, each the size of a telephone directory. Other estimate put the size of Human Genome equivalent to 134 complete sets of Encyclopaedia Britannica.

2.3.4. Biological data to track down any Human Genome : The Genome Data Base (GDB), Genome Sequence Data Base (GSDB) and the National Centre for Genome Resources (NCGR) are DOE-supported HGP database which work together to provide access to all scientists to the Human Genome. The purpose is to establish a standard data where the scientists, researchers and doctors can refer to track down any gene of interest.

2.3.5. The ultimate goal to discover all the 30.000-40.000 genes : All the genes need to be discovered, and render them accessible for further biological study. Currently we know roughly around 60% of the total Genome, but need further confirmation of their function. About 40% of the Genome not known at all.

2.3.6. Unlock the secrets of life processes : Exploring the whole Genome will facilitate our understanding of the biochemical underpinning of our sense and memory; development and ageing; similarities and differences.

2.3.7. Studying the ethical, legal and social implications of HGP : In depth knowledge of all the function of the genes will have huge impact on individual, society and the environment in terms of ethical, legal, social and religious implications.