Archive for January, 2006

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Human Epigenome Project

January 15, 2006

The American Association of Cancer Researchers have published a blueprint for a comprehensive international Human Epigenome Project. According to the authors –

“The goal of the HEP (Human Epigenomic Project) is to identify all the chemical changes and relationships… that provide function to the DNA code, which will allow a fuller understanding of normal development, aging, abnormal gene control in cancer and other diseases, as well as the role of the environment in human health.”

The proposed structure involves a “low-resolution scan” of a large group of samples to get a general picture of the epigenome. And then focused, detailed mapping of a handful of high-interest ‘reference epigenomes’. The AARC wants the project to happen in conjunction with the existing European and Japanese efforts.

The researchers claim that the technology necessary for high-throughput mapping of the epigenome is within sight. The most promising approach involved –

“The so-called ChIP/chip methodology, in which intact chromatin – the complex of DNA and histones – is immunoprecipitated (brought out of solution using antibodies that recognize specific histone modifications) and analyzed on microarray “chips.” Modifications of DNA are also tracked on chips, following treatment with enzymes that recognize sites of methylation. Impressive accounts of success with these methods were presented at the workshop.”

I love this idea and hope that it gains momentum. The existing European effort hopes to have 10% of the human epigenome mapped by fall 2006. An international effort, with considerable American support, could move much much faster (to state the obvious). I agree with the statement in the report that, ultimately, the Human Epigenome Project could have a bigger impact than the Human Genome Project Especially in fields like psychiatry that have not benefitted from gene sequence based approaches.

I can see a few obstacles that might interfere with cooperation with the Europeans. As of now, Epigenomics AG, a German molecular diagnostics firm, stands to patent all of the MVPs identified by the Human Epigenome Project. During the Human Genome Project, the US Government was vehemently opposed to Celera’s patenting of genetic information. Assuming that the US government’s position hasn’t changed on this topic, it may be difficult to get public funding for a project involving the Europeans.

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Gene Therapy

January 8, 2006

Gene therapy is a technique for fixing genetic disorders by inserting cloned genetic material into cells to repair or replace dysfunctional genes. Currently there are four approaches to gene therapy:

  • A functional gene is inserted (nonspecifically) into the genome to take cover for a nonfunctional gene. This is the most common approach.
  • An abnormal gene is replaced by a normal gene through homologous recombination. (see gene-targeting)
  • The abnormal gene is repaired through specific reverse mutations, which returns the gene to normal function.
  • Gene regulation can be altered by inserting promoters or interrupting promoters.

How it works
The most common gene therapy approach is to use a functional gene to replace a dysfunctional disease causing gene. The gene is inserted into a target cell via a vector. Vectors are biological agents that transfer genetic material from one cell to another. Currently, ‘domesticated’ or genetically-modified viruses are the most common type of vector.

Viral vectors infect the target tissue and insert the designated genes into the host cells. For example, gene therapy for diabetes would target the cells of the pancreas responsible for insulin production. If the therapeutic gene is expressed, the cell is able to produce the protein or proteins that it had been missing – alleviating the genetic disorder.

Common Viral Vector Classes:

  • Retroviruses – A type of virus that has an RNA genome and reverse-transcribes double stranded DNA that can be integrated into the host genome.
  • Adenoviruses – Viruses with with double-stranded DNA genomes. Adenoviruses are responsible for many mundane human illnesses such as the common cold.
  • Adeno-associated viruses – Virus with a single stranded DNA genome. They are unique in that they can incorporate their genetic material into a specific place – chromosome 19.
  • Herpes simplex viruses – Viruses with double stranded DNA genomes that solely target genomes. Their specificity makes them particularly useful as vectors for neuronal diseases.

Some researchers are investigating nonviral vectors. This approach takes advantage of natural cellular processes such as endocytosis. For example, some scientists are exploring the use of artificial lipid globules to introduce the transgenes into the cell. A similar strategy is to attach the transgene to a cell membane receptor agonist. When the agonist binds to the receptor it initiates endocytosis, delivering the transgene into the cell. So far these delivery systems are not as effective as the viral vector systems.

One intriguing new approach is the creation of an artificial 47th chromosome to introduce into the target cells. Because the transgene no longer has to be incorporated into one of the cells natural chromosomes, there is no risk of insertional mutations. This approach has the added advantage of not interfering with the cells pre-existing expression pattern. Furthermore, because this strategy uses a whole chromosome, Very large amounts of genetic material can be added allowing for more sophisticated design. Also the chromosome could potentially be designed in a way that would avoid an immune reaction. However, the size of the transgenic element, creates additional difficulty in getting it inot the nucleus of the target cell.