Graphics: Fan Sozzi

Company Profile

Name: Xenon Genetics Inc.
Location: Burnaby, BC
Type: Biopharmaceutical
Date Founded: 1996
Ownership: Private
Employees Total: 95

Basis for Research/Technology

"Genomics-based drug discovery"

Background- A Brief Introduction to Genetics

Characteristics such as hair colour, eye colour, height and many others are said to be inherited or "passed on" from parents to children. Genetics is the field of science dedicated to studying the structure and function of genes, and how certain traits are inherited⁵.

		Figure 1. The human karyotype.

Traits are determined in large part by an organism's genes. A gene is a section of DNA that encodes a particular protein or nucleic acid (DNA or RNA) that carries out some function in the cell: it is the hereditary material that is passed on from one generation to the next. The entire set of genes in an organism is known as the genome. The genome is made up of several long molecules of DNA containing many genes, known as chromosomes. In humans, each cell normally contains 46 chromosomes, half from one parent, half from the other. There are 22 pairs of chromosomes and two sex chromosomes: two X chromosomes in females, one X one Y in males⁵.

Recently, the sequencing of the human genome was completed, providing us with a blueprint of all the genes encoded by our DNA.

The particular set of genes that an individual acquires from its parents is known as its genotype⁵. This remains constant throughout life and is generally unchanged by environmental events. However, the environment does affect how every organism develops and functions. For example, a person with tall parents likely has a genotype that encodes genes necessary for becoming tall as well; however, if that person lacks proper nutrition while growing or suffers from hormonal defects, he or she may not reach his/her full potential height. The form taken by some traits (such as tallness) in specific individuals is called a phenotype. Phenotype is determined in part by the genotype of the individual and in part by the environment to which they are exposed. Thus, the observable properties of an organism are produced by the combination of the genotype and its interaction with the environment⁵. This means that a single genotype can produce different phenotypes, depending on the environment in which the organism develops.

For instance, identical twins have the same genotype, but could develop different phenotypes for certain traits if they were separated at birth and grew up in very different environments. Their adult heights might differ depending on their nutrition while growing up and other environmental factors.

		Figure 2. Comparison of identical twins. (Image Source: reproduced from "Genetics" - reference 5)

On the other hand, the same phenotype can be produced by different genotypes, depending on the environment. For example, certain people all living in the same region with a prevalence of a specific disease may all become resistant even though they have different genotypes. The way their bodies acquire resistance may differ slightly due to genetic differences, but the overall observable trait of resistance is similar.

All humans have very similar sets of genes that specify in a general sense how we develop and function. However, there can be many different forms of a given gene; for example, the genes for eye colour are slightly different between people with brown eyes and those with blue eyes. (Note: eye colour is actually determined by a combination of several genes, but for the purpose of this example we will assume it is controlled by a single gene⁵.). These slightly different forms of the same gene are called alleles. Every person has two alleles for any given gene, one inherited from their mother and another from their father. In some cases, the alleles are identical, but they can also be slightly different. Individuals in which both alleles are the same are said to be homozygous for that gene. Individuals that have two different alleles of a particular gene are said to be heterozygous for that gene.

Although each person can only have up to two different alleles of a gene, in a population the total number of different alleles for a single gene can be large. This overall collection of alleles for all the genes in a population is known as the gene pool⁵. Some of these different alleles are dominant, meaning that the allele and its corresponding phenotype will be expressed whether one copy is present (heterozygous) or two copies are present (homozygous)⁵. Others alleles are recessive, meaning that the allele and its phenotype will only be expressed if two identical copies are present in the cell (homozygous)⁵. This phenomenon is well-illustrated in one of the first famous genetics experiments of Gregor Mendel with pea plants. Just like humans, pea plants also inherit one set of genes from each parent plant. In peas, there is a gene that controls the outside appearance of the peas. One allele results in smooth peas, the other for wrinkled peas. The allele for wrinkled peas is said to be recessive to the allele for smooth peas. Thus, the gene for smooth peas is said to be dominant. If the plant receives two alleles from its parent plants that both encode smoothness (homozygous for the "smooth" gene), the peas will be smooth. Similarly, if the new plant receives two alleles for the recessive "wrinkled" gene (homozygous for the "wrinkled" gene), the peas will be wrinkled. However, if the plant receives one gene for smooth peas from one parent, and the gene for wrinkledness from the other (heterozygous), the resulting peas will be smooth since the smoothness allele is dominant to the wrinkledness allele.

Most of the time the situation is much more complex than the example of Mendel's peas. Many characteristics are controlled by the effects of more than one gene working together, all of which may also interact with the environment. Such characteristics are known as complex traits and may not completely follow rules of dominance and recessiveness⁵.

Genetics has shown that genes are the root cause of many diseases. Some diseases such as cystic fibrosis are caused by mutations in a single recessive gene that can be passed on to offspring. Since the diseased allele is recessive, the child will only develop the disease if he/she receives the same mutated allele from both parents^5,6. In other diseases, a gene or a combination of several genes may be involved in a much more complicated and indirect way; for example, certain people may be made more susceptible to some diseases depending on the genetic alleles they carry, and environmental influences can finally "cause" the diseases to develop. Some examples of these "complex traits" include susceptibility to heart disease, hypertension, diabetes, asthma, various forms of cancer and infections.

		Figure 3. Location of various genetic diseases. (Image Source: reproduced from "An Introduction to Genetic Analysis" - reference 2)

How Xenon uses genetics for drug discovery

Xenon Genetics studies small, isolated populations of people who descended from a few individuals who left one area to settle another for political, religious, or social reasons. These populations are known as "founder populations"^{3, 5}. In any population, all the different alleles for all the genes that members of a given community collectively share are known as the gene pool. Although the founder populations may eventually become quite large, the gene pool of the population is derived from the genes present in the original founders and remains small. Generations of relative isolation mean that everyone in the community tends to share more alleles than individuals from larger populations. This is a result of non-random mating (also known as inbreeding). The result of non-random mating is a decrease in the frequency of heterozygotes; in others words, people are more likely to share identical alleles and be homozygous for many genes since no new alleles are being introduced from people outside the population⁵.

Generally, non-random mating can be harmful to a population because recessive, deleterious alleles become homozygous, at which point their effects are expressed. The main recognized founder populations in the world are those of French-speaking Quebec, Finland, Sardinia, Iceland, Costa Rica, the northern Netherlands, Newfoundland, and several discrete ethic groups, including Ashkenazi (Eastern European) Jews and certain populations in India. Already studies of these groups are shedding light on the roots causes of many disorders, from schizophrenia to hereditary colon cancer and metabolic disorders³.

CLICK HERE TO READ THE STORY OF TRISTAN DE CUNHA

Xenon has a broad network of clinical collaborations around the world that provide access to the DNA and clinical information from more than thirty of such historically isolated founder populations. They study these multiple populations and track genetic information to discover the basis of certain genetic diseases. Because the founder populations share more genetic information, it is easier to track genetic mutations through generations. As well, particular phenotypic traits (i.e. symptoms of diseases), if they exist in the population, will be more evident because of the homozygosity of the population, and therefore more easily associated with the underlying gene defect. This makes identifying disease genes much faster. In many diseases, more than one gene or many mutations in a single gene can be involved in causing the disease, and this is made more obvious by studying multiple populations^3,6.

Xenon has a second platform for gene discovery called "Extreme Genetics" designed to identify the root causes of complex diseases involving more than one gene, or a combination of genetic and environmental factors. By looking at populations with rare genetic disorders that represent extreme forms of common human diseases, insight is gained into biological pathways common to both forms of the underlying disease. For example, a rare eye genetic disease called familial exudative vitreoretinopathy (FEVR) causes defects in blood vessel formation (called angiogenesis) in the peripheral retina, leading to blindness. Xenon scientists were able to identify a gene called Frizzled-4 as the root cause of the FEVR phenotype⁴. While the FEVR disease is rare, Xenon expects that studying its effects will lead to insights into other diseases that also show defects in angiogenesis. These include much more prevalent diseases such as cancer, cardiovascular disease and common diseases of the eye's retina such as diabetic rhetinopathy. The Extreme Genetics technique has already identified a new gene (HSF4) that is implicated in one of the most common form of hereditary childhood cataracts (a prevalent cause of blindness in children and adults) by studying a group of Chinese families that have high incidences of cataracts^1,6.

Click here to learn how to identify and map a gene to its specific location (called a locus) on the chromosome.

Applications

Cardiovascular disease: This is the number one killer in the western world. About half of all patients suffering from coronary artery disease* have low levels of HDL-cholesterol ("good cholesterol"). This is a condition that greatly increases the risk of coronary disease, for which there is no treatment. This disorder has a large genetic component to it, and Xenon is using its founder populations to search for the underlying genetic causes. Once uncovered, these genes could be potential targets for the development of new drugs to control the disease. The goal of Xenon's program is to develop small molecule compounds that will raise HDL-cholesterol. In August 1999, Xenon scientists discovered the gene for the protein called ABCA1, a transporter protein that is mutated in families with Tangier's disease* and a related disorder, familial hypoalphalipoproteinemia*. Both these diseases are characterized by low HDL-levels and premature cardiovascular disease. Furthermore, scientists showed that mutations in the ABCA1 gene lead directly to an inability to regulate levels of HDL-cholesterol. Now, in collaboration with the company Pfizer, many compounds are being screened to see if they interact with ABCA1 to elevate HDL levels. One of these could potentially be developed into a drug to raise HDL levels and control cardiovascular disease.

Central Nervous System diseases: There is a large, unmet need for new drugs in this area of medicine. For example, one third of patients with depressive illness do not respond to any of the drugs currently available. Xenon is targeting areas of neuroscience including epilepsy, sleep, depression and incontinence using its gene-discovery platform to investigate the genetic elements underlying these conditions. To date, it has identified several drug target genes for epilepsy in humans and is close to identifying genes involved in incontinence.

Metabolic Diseases: The diseases being targeted in this area include defects in iron metabolism, diabetes and obesity. Hemochromatosis is a common genetic disorder resulting in over-retention and build-up of iron stores in cells leading to multi-organ failure. Currently, the only treatments include phlebotomy (blood-letting) and chelation therapy (IV treatment to remove heavy metals from blood), both of which are costly and can cause further complications in patients. Xenon is trying to identify small molecules that can reduce body iron stores to normal levels through identification of genes involved in transport.

Diabetes and obesity are also great problems in the western world, with the number of patients increasingly yearly. While insulin can alleviate some of the symptoms of diabetes in many patients, others are not sensitive to its effects: drugs are needed to enhance insulin sensitivity. Current obesity drugs are aimed at suppressing appetite to reduce intake, but have the major drawback of ceasing to be effective after a few months. The goal with these diseases is to uncover novel genes associated with their occurrence and develop new molecular therapies. Human genetic studies with large families in Europe and South Africa who have high occurrences of diabetes are underway in an attempt to identify these genes.

Commercial Products:

None to date.

Website:

http://www.xenongenetics.com/

Other companies doing similar work:

Galileo Genomics
http://www.galileogenomics.com/

GeneSeek
http://www.geneseek.com/

Myriad Genetics
http://www.myriad.com/

idGENE Pharmaceuticals
http://www.idgene.com/

References

1. Bu L. et al. Mutant DNA-binding domain of HSF4 is associated with autosomal dominant lamellar and Marner cataract. Nature Genetics. 2002. 31:276-278.
   
2. Griffiths AJF, Miller JH, Suzuki DT, Lewontin RC, Gelbart WM. An Introduction to Genetic Analysis, 6th ed. 1996. W.H. Freeman & Co.: New York. pp.5.
   
3. Lewis, R. 2001. Founder Populations Fuel Gene Discovery. The Scientist 15(8): 8.
   
4. Robitaille J. et al. 2002. Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. Nature Genetics. 32: 326-330.
   
5. Russell, P.J. Genetics, 5th ed. 1998. Benjamin/Cummings Publishing Company Inc.: Menlo Park CA. Pp. 18-41, 714-743.
   
6. Xenon Genetics website.
     http://www.xenongenetics.com/

Links

NCBI website on "Genes and Disease"
  http://www.ncbi.nlm.nih.gov/disease/

Founder populations in Sardinia, Italy provide genetic links to heart disease
  http://www.ama-assn.org/sci-pubs/amnews/pick_02/hlsc0225.htm

The Serrastretta database of founder populations in Southern Italy - study of Familial Early Onset Alzheimer's Disease
  http://biologia.unical.it/arles/Bruni.htm

Founder populations and breast cancer
  http://breast-cancer-research.com/content/pdf/bcr36.pdf

Mapping genes for complex traits in founder populations
  http://hg-wen.uchicago.edu/pubs/ober101.pdf

Human Genome Project website
  http://www.genome.gov/page.cfm?pageID=10001694

Human Genome Project Information from the US Department of Energy
  http://www.ornl.gov/hgmis/