Beginners guide to genetics: Past, present, and future

In the last article of our series, the Genetics Group, coordinated by Osvaldo Mutchinick, deals with the history of genetics and how future research will impact diagnosis and treatment of diseases

Diagnosis

Cytogenetics

In 1956, three years after the discovery of the double helix, Tjio and Levan established the correct number of chromosomes heralding the start of chromosome analysis. Three years later, Lejeune found that Downs syndrome resulted from a numerical chromosomal abnormality--an extra chromosome 21. In 1973, Turner syndrome (45, X0) and the Philadelphia chromosome, a (9;22) translocation responsible for chronic myeloid leukaemia, were discovered. These genetic advances resulted from the ability to do G and R banding, which allowed scientists to identify chromosomes by dyeing them to produce their characteristic dark and light bands.1

As research continued, other diagnostic tools appeared. Techniques such as fluorescent in situ hybridisation and in situ hybridisation allowed detection of nucleotide sequences. Both of these use probes--DNA fragments marked with fluorescent dye--that recognise homologous sequences in the target DNA.2 For example, a probe that recognises the Philadelphia chromosome can search a patients leukocytes to see if they have chronic myeloid leukaemia. If the chromosome is present, the probe will attach or hybridise and the fluorescent dye can be seen using a special microscope. Multicolour karyotyping or chromosomal painting uses a similar technique to fluorescent in situ hybridisation. Probes are marked with a different coloured dye to paint each chromosome a different colour; this highlights any chromosomal aberrations.3

The study of chromosomes is becoming easier. Automatic analysers are being developed to allow better and faster diagnosis of chromosome related diseases. In specialties such as oncology, chromosomal alterations will be rapidly diagnosed, improving prognosis and therapeutic approaches.3

Genome

Another area in genetics that has developed rapidly is molecular genetics, particularly by the completion of the human genome project. The evidence that DNA contained genetic material came from bacteria in 1944, when scientists noted that changes in DNA resulted in transformation into another bacterium. But 1953 provided a milestone in genetics. Two scientists at Cambridge University deduced the double helix structure of DNA. Many advances came in future years, but an important one was the sequence of mitochondrial DNA in 1981. After this, scientists began to think that maybe the human genome could be sequenced, and the first proposal was made by the US Department of Energy. In 1986, Kary Mullis, a Californian scientist, described a tool that allowed millions of a determined segment of a genome to be copied. The polymerase chain reaction allowed genes to be studied in detail to discover if any mutations had occurred.

BSIP/LAURENT/SPL

It's a FISH of the fluorescent
in situ hybridisation variety

The Human Genome Project started officially on 1October 1990 in the United States. Japan, France, Germany, and the United Kingdom later joined the project. Besides working out the genetic sequence in the human genome, it also analysed the genomes of other living organisms. The first was the bacterium Haemophilus influenzae in 1995 and the first multicellular organism was Caenorhabditis elegans, a nematode, in 1998. By June 2000 the human genome was sequenced,45 and a big political, social, ethical, and religious debate ensued and still goes on.

One of the most surprising results was that the total number of human genes was only half that expected, and only a few more than Caenorhabditis elegans.6 This begged the question: what allows humans so many different characteristics when 99% of our genome is the same as chimpanzees? And why are there so many variations between humans, when 99.9% of our genomes are the same? The answer must lie in that remaining 0.1%.

It used to be thought that one gene codes for one protein, but scientists now think that a human gene must produce many different proteins. This is achieved by post-transcriptional and post-translational modifications.2 Genes will code for approximately 300000 to 400000 proteins. Research needs to develop from describing the genes to what their products do--genomics becomes proteonomics and poses a greater challenge. In knowing the gene and the function of the protein products, the possibilities will be unlimited. Whereas genetics has focused on diseases with a low prevalence in the past, it may be used to prevent diseases that cause a great burden to Western societies, such as coronary artery disease and diabetes mellitus.

This knowledge will make medicine more predictive and preventive. The possibility of knowing an individuals predisposition to diseases will allow doctors to recommend lifestyle modification or medical treatment, flagging up other ethical considerations. If we know that someone is at risk of disease it may affect job prospects or insurance.

Treatment

Advances in genetics will affect treatment options. It will help scientists to figure out what it is, in that 0.1% of the genome, that means some people present adverse effects and others do not. Pharmaceutical companies are investing huge sums of money on research to find diseases and their related genes to produce drugs. This, pharmacogenomics, with all the economic implications, will reduce side effects and will make treatment more efficient.7

Gene therapy is the genetic modification of cells to produce a therapeutic effect. This is done by modification of cultured cells or by modification of in vivo cells. In the beginning, gene therapy focused on treating single gene disorders; the objective was to replace the mutated copy with a healthy gene. This has been attempted in patients with cystic fibrosis and Duchenne muscular dystrophy, but the results are still not satisfactory.

Gene therapy has three important components: a therapeutic gene, a vector (often a virus) that allows delivery of the gene to cells, and a device to deliver gene therapy. The greatest problem is finding a vector, which has limited the possibilities of gene therapy. However, new viruses are being created to help deliver genetic material.

Currently, stem cells are the most realistic genetic therapy available. They are packed to go genes not needing a vector. The principles have existed for a long time. For example, in haematological malignancies, bone marrow transplantation repopulates a persons bone marrow. Stem cells have different origins--the embryo, umbilical cord, and adult stem cells. They are simply cells waiting for signals to become something. Since the nucleus holds all the information, in theory a stem cell could become a hepatocyte or a neuroglia cell with the appropriate signals. One of the most promising therapies are adult stem cells, since they are free of all ethical and religious debate. These are found in many places in an adult, such as bone marrow, skin, and the nervous system, and remain inactive. These pluripotential cells have the ability to differentiate into many types of cells. For example, bone marrow adult stem cells have been turned into hepatocytes and myocardium cells. Functional improvement has even been noted in patients with acute myocardial infraction that receive adult stem cells. The big problem of stem cells is signaling--this is how, and which, different molecules make adult stem cells migrate and differentiate to different tissues.

Osvaldo Mutchinick chief,

Heidy Arrieta associated researcher,

Juan Morales associated researcher,

Jazmin Arteaga resident in medical genetics,

Rodrigo Macias resident in medical genetics,

Regina Gomez-Palacio resident in medical genetics,

Leonora Luna social worker,

Nancy Monroy laboratory researcher,

Adrian Gonzalez, social service, The Genetics Group at the National Institute of Medical Sciences and Nutrition Salvador Zubiran Tlalpan, Mexico
Email: grangeroloco@hotmail.com


studentBMJ 2005;13:89-132 March ISSN 0966-6494

1. Collins S. McKusick VA. Implication of the Human Genome Project for medical science. JAMA 2001;285:540-4.
2. Gonzales AJ, Arrieta HR, Mutchinick OM. A beginners guide to genetics: the basics. studentBMJ 2004;12:316-7. (September 2004.)
3. Varella M. Molecular cytogenetics in solid tumors: laboratorial tool for diagnosis, prognosis and therapy. Oncologist 2003;8:45-58.
4. McPherson JD, Marra M, Hillier L, Waterston RH, et. al. A physical map of the human genome. Nature 2001 Feb 15;409(6822):934-41.
5. Venter JC. A part of the human genome sequence. Science 2003;299:1183-4.
6. Bumol T, Watanabe A. Genetic information, genomic technologies, and the future of drug discovery. JAMA 2001;285:511-55.
7. McKusick VA. The anatomy of the human genome. JAMA 2001;286:2289-95.

   

           

Responses published this month Articles Responses EDUCATION Beginners guide to genetics: Past, present, and future       Osvaldo Mutchinick et al (March 2005) Dr.Pinakini K Shankar (February 25, 2005) Read this response EDUCATION Beginners guide to genetics: Past, present, and future       Osvaldo Mutchinick et al (March 2005) Dr.Pinakini K Shankar (February 25, 2005)       Assistant professor, M.D, Department of Pharmacology, Melaka Manipal Medical college, Manipal pimochi@yahoo.co.in Dear editor, Rapid progress in genome science and a glimpse into its potential applications have spurred observers to predict that biology will be the foremost science of the 21st century.As rightly described by the author this is the era of pharmacogenomics.I would also like to add on that not only the scientists have unravelled the human genome by the Human Genome project which was completed in June 2000, the complete genomes of at least 88 microorganisms, most of it are human pathogens have also been sequenced. In a country like India where microbial disease account for a significant number cases,pharmacogenomics has presented a tremendous oppurtunity and challenge for its diagnosis, prevention and treatment.The information obtained from these genetic sequences are phenomenal.Diagnostic tool development, and vaccine design can be aided by knowing which portion of the pathogen are important antigenic determinants. Important genes conferring resistance to antibiotics can be detected, and this information may be used to choose the appropriate antibiotic therapy. Genetics also finds application in Forensic Medicine to identify individuals. Forensic scientists scan about 10 DNA regions that vary from person to person and use the data to create a DNA profile of that individual (called as DNA fingerprint). They can be used to identify potential suspects whose DNA may match evidence left at crime scenes, exonerate persons wrongly accused of crimes,identify crime and catastrophe victims, to establish paternity and other family relationships,to identify endangered and protected species as an aid to wildlife officials (could be used for prosecuting poachers)and to match organ donors with recipients in transplant programs. Thus Genomics offer a wide array of hope in the future of mankind.