Driving Science into the 21st Century
What is the human genome?
The human body contains about 100 trillion cells. Most of these cells contain a nucleus (red blood cells do not have nuclei). Each nucleus has 23 pairs of chromosomes, formed during conception when 23 individual chromosomes from each parent come together to form the new offspring.
Our chromosomes are made up of thousands of genes, which determine who we are - our traits and characteristics. The term "human genome" describes all the genes found in the human body. This is estimated to be between 50,000 and 100,000. Just of few thousand human genes have been identified. They are difficult to locate because they are found in packages of 23 pairs of chromosomes.
Genes use deoxyribonecleic acid (DNA) to make proteins and it is these proteins that tell our body how to behave - whether to grow brown hair, to be short or tall, to develop diabetes or not, and perhaps, to develop cancer or not. DNA is made up of very small chemical components called nucleotides. Each nucleotide contains sugar, a phosphate group and molecules containing nitrogen. There are four types of molecules, labeled A, C, G, and T (abbreviations for adenine, guanine, cytosine and thymine). The instructions to make these proteins are spelled out in specific codes of these molecules.
All species have this same four-letter alphabet in every cell in their bodies. There are 3 billion pairs of nucleotides in our bodies, or 20,000 - 50,000 in each gene.
If our strands of DNA were stretched out in a line, the 46 chromosomes would extend more than six feet. If the six-foot length of the 100 trillion cells could be stretched out, it would be 600 trillion feet, or over 113 billion miles. That is enough material to reach to the sun and back 610 times.
What is gene sequencing?
Gene sequencing is the decoding device - it tells us how to decode the gene, and give us the exact order of the molecules in our DNA.
In 1971, scientists learned to cut the DNA into smaller, more manageable pieces. This meant scientists could locate specific genes within sequences and could position them on a map. Mapping the genes was just the beginning - more detailed sequencing is required to further analyze and understand the genome. Sequencing is decoding the gene to learn the exact order of nucleotides. If you think of a strand of nucleotides, the letters are like beads on a string, which are laid out in a specific order. Gene sequencing determines the correct order of these "beads".
The English alphabet has 26 letters, and we consider it a tremendous achievement when a child learns the alphabet, and then learns to put the letters together to form words and phrases. Understanding our genetic sequences is like learning a new language and reading new words, one that no one in the world knows - yet.
Knowing the correct order is important, when you are looking for the cause of disease. When the order of the molecules is incorrect, you have a mutation, which can - but not always - lead to disease.
Sequencing is not the same as genetic mapping or the study of genetics. The study of genetics is determining the function of genes and how they interact in living organisms. Genome mapping is locating genes within the DNA. Sequencing is analyzing the structure of the DNA and order of the molecules A, C, G and T.
How will genome science revolutionize cancer prevention and therapy?
Until the 1950's, surgery was the only treatment available for those with cancer. When radiation therapy was introduced in the 1950's, it was used extensively, together with surgery, to reduce or eliminate local (primary) tumours or to control pain in more advanced cases of cancer. In the late 1960's, the use of combination chemotherapy lead to cures of advanced, extensive disease. This breakthrough built on the platform of local tumour control and cure achieved with surgery and radiation. At present, our available therapies permit a cure rate of approximately 50% for all cancers. The past two decades have seen the benefits of early detection as a means of maximizing the benefits of local therapy (breast and cervical cancer) and the incremental gains of hormonal and chemotherapy given in an adjuvant setting (breast and colon cancer).
Today, cancer treatment is on the verge of the next major breakthrough - potentially that with the greatest overall impact: applying genome science to cancer medicine. Scientists around the world agree that cancer is a genetic disease. If half the cancer cases in the world can be cured without understanding the genetic basis of cancer, imagine what might be achieved if such knowledge were available. Indeed, the only real prospect, short of luck, to achieve the remaining 50% of cancer cures, is to harness and apply the genetics of cancer.
How is cancer a genetic disease - what does this mean? Traditionally, we think of genetic diseases as hereditary disorders passed from one generation to another (e.g. haemophilia). While certain cancers have a hereditary basis (e.g. familial retinoblastoma), this is a relatively uncommon circumstance. The majority of cancers, particularly those in adults, arise as a result of cumulative events within the genome. These events, known as mutations, result in an abnormal configuration of DNA, the genetic code within the nucleus of the cell. As a result, aberrant signals arise and lead to disturbed cellular behaviour. Cancer is basically a disease of abnormal cell growth and proliferation, invasion of host tissue(s) and metastasis (spreading) to sites distant from original site. Every aspect of the malignant process - growth, proliferation, invasion and metastases - has a genetic basis. Accordingly, there will be a genetic basis for controlling or reversing the sequential, cumulative events that result in cancer.
In the future, researchers will be able to read the genetic structure of a single cell, identify the difference between normal and cancer cells, and follow genetic changes that cause cells to become cancerous. They will also be able to uncover specific cell changes that are precursors to cancer, making early detection techniques more effective.
Gene sequencing is a means to an end. Information about the genome will lead to the development of gene therapies and products that will prevent abnormal gene functions. There are many potential therapies that will be produced including drugs designed for correcting abnormal genes, drugs that specifically interfere with incorrect message sent by genes (called anti-sense genes) and drugs that create an ineffective environment preventing spread of cancer cells in metastatic cancers (cancers that have spread).
The recently discovered BRCA1 and BRCA2 genes are providing important insights ways that mutations influence the development of breast cancer. In certain circumstances, BRCA 1/2 mutations appear to confer a strong predictive risk of developing breast cancer, in other circumstances they appear to contribute, but only with other changes, to an increased susceptibility for cancer. Recent work has linked the BRCA 1 and 2 genes to regulatory events within the cell proliferation cycle. It is also becoming clear that mutations in regulatory genes are related to a wide variety of human diseases, eg cystic fibrosis, asthma, obesity, coronary artery disease, osteoporosis, etc. Thus, the applications of gene sequencing stand to benefit the whole of human medicine - indeed, all life sciences, as well as cancer medicine.
The Genome Sequence Centre: the cancer focus
An essential component of the cancer research program is to investigate three specific objectives:
- First, identify the critical mutations associated with particular cancers
- Second, align this information with current prognostic determinants in relations to current treatments (surgery, chemotherapy and radiation therapy)
- Third, correlate mutations with clinical outcomes and identify specific molecules as preferred targets for drug development for therapeutic intervention or diagnosis.
The Genome Sequence Centre has the capability to achieve these objectives through the strong medical and research support of the BC Cancer Agency and the BC Cancer Research Centre.
The BC Cancer Agency will supply genetic material for sequencing. This material will include:
- Molecular fingerprinting of certain cancers such as breast, lung, lymphomas, prostate and leukemia where it is possible to follow the disease from the early to advanced stage and correlate this information with the clinical progression of the disease.
- The hereditary cancer program is currently investigating breast cancer in the B.C. population, but will soon expand to include other common cancers when the cancer-prone genes are identified. These families and the database associated with them may prove to be a powerful investigative tool for cancer control strategies. This will open a new area of screening for the Agency.
- The Genome Sequence Centre will have an immediate impact in the area of neurological research by sequencing brain DNA, provided by Dr. T.B. Snutch of the Biotechnology Lab at the University of British Columbia.
- Fungal pathogens in humans threaten those whose immune systems have been compromised, such as cancer and AIDS patients. The Genome Sequence Centre could have an immediate impact in this area, as there has been no sequencing of this material to date. DNA libraries are available for fungal pathogens important to BC and Canada, such as the fungus cryptococcus neoforman, which causes meningitis.
- Information from the Genome Sequence Centre will be integrated with the vast epidemiological database managed by the BC health care system.
BC Cancer Agency and the BC Cancer Research Centre - a history of research success and new treatments
Over the past 60 years, the BC Cancer Agency and the BC Cancer Research Centre have been recognized as international leaders in cancer research, diagnosis and treatment. The cancer control system (prevention, early detection, diagnosis, treatments, research and education) has been continuously refined and improved since 1935. The benefit of this system for the people of B.C. is the lowest cancer mortality rates in Canada - 11 per cent lower overall than the rest of the country. This is more remarkable in view of the fact that B.C. also has the highest incidence of cancer in Canada.
In addition to benefiting from a well-organized cancer care system, British Columbians also benefit from discoveries made here in the province. The close connection of the BCCA and the BCCRC means that discoveries made in the lab can be quickly translated into patient care, more quickly than anywhere else.
Some examples of leading research for diagnosis and treatment:
- bone marrow transplantation research
- the development of the Light Induced Fluorescence Endoscope (LIFE) which has been used to identify and treat early cancerous lesions of the airways (lung cancer),
- the development of an automated cervical screening system (ACCESS) to reduce cervical cancer mortality through detection of early lesions
- the application of intermittent hormone therapy in the management of prostate cancer
- new therapeutic programs including gene therapy of melanoma and liposome-delivery systems for chemotherapy agents
- the Provincial Screening Mammography Program, and
- a model for examining the design of systemic therapy based upon principles of cellular resistance through mutation and the application of alternating non-cross resistant therapies to overcome such resistance.
The BC Cancer Agency and Research Centre have many links to the biotechnology industry. In fact, three of the province's largest biotechnology companies (ranked by number of biotech employees) are associated with the BCCA: Xillix Technologies Corp, Inex Pharmaceuticals Corp. and StemCell Technologies Inc. There is also a close link with QLT Phototherapeutics Inc.
To complement and advance the Research Centre's ability to continue this type of research and development, the Genome Sequence Centre will become an important component of the overall basic research program in cancer genetics, developmental biology, differentiation and molecular biology.
The Human Genome Project
Genomics is the science that decodes genes of all living organisms. It is a relatively new field for science and research, with tremendous potential for discovery, innovation and breakthrough for science, medicine and technology. Genome is the term used to describe the full complement of DNA.
The Human Genome Project is a worldwide research effort to analyze the structure of human DNA and determine the location and sequence of the estimated 100,000 human genes. This analysis is called DNA or gene sequencing. The information generated by this project will be the source book for biomedical science in the 21st century. It began ten years ago, motivated by the knowledge that a complete inventory of human genes will provide new clues and routes to diagnose and treat many of the 4000-plus genetic diseases that afflict humans, including cancer, heart disease, diabetes, Huntington's disease and others. It will also be applicable to other life sciences such as agriculture, forestry or fisheries.
The first decade of work on the Human Genome Project has been devoted to developing technology and to determining the DNA sequences of several important organisms: bacteria, yeast and C.elegans (a laboratory worm). This work has been important to our understanding of cancer, due to totally unanticipated discoveries that cancer-causing genes in humans have a close relationship with genes in other organisms.
Laboratories in France, Germany, Japan, the United Kingdom and the United States are beginning to work on the project, launching a full-scale effort to sequence the human DNA. This is an enormous task. There are 3 billion base pairs of nucleotides. A collaborative effort is essential to complete this project. With current resources, it is expected to take another 10 years to complete the sequencing of the human DNA.