About CGE

Tim Starr, Post Doctoral Fellow

"In David Largaespada's lab we study the genetics of cancer using mouse models.  One of the main projects in our lab is searching for unknown gene mutations that cause cancer.  We use an engineered mammalian transposon, first developed in Perry Hackett's lab, to randomly mutate genes in a forward genetic screen for oncogenes and tumor suppressor genes. The goal of this research is to identify more genes and proteins that could be targeted by therapeutic drugs for battling cancer."

What is the Center for Genome Engineering all about?

Here are some examples of what we're doing:

Biomedical genetics and genomics:
Our researchers are identifying genes to cure diseases

With the completion of the human genome sequence, scientists now know every A, T, G, and C that comprises each of the 23 pairs of human chromosomes.  Although many human genes have been identified, others remain to be discovered.  Especially important is the identification of those genes, which when broken (or mutated), cause diseases such as cancer or diabetes.

Identifying disease-causing genes is the first step in curing human genetic disease.  Since humans possess a set of genes similar to the genes in organisms like fish and mice, scientists can make rapid progress in understanding human gene function by studying these model organisms.  The framework provided by model organisms is particularly helpful when combined with methods to specifically dissect gene function.
CGE scientists are at the forefront of developing new approaches for exploring the functional landscape of the vertebrate genome and the role of genes in disease processes.  Dr. Largaespada, for example, has developed a powerful method using the Sleeping Beauty (SB) transposon to perform unbiased somatic  cell mutagenesis to identify cancer genes in mice.  In this approach, SB is mobilized, and if it ‘jumps’ into a gene involved in cancer, a tumor develops.  Members of Dr. Largaespada’s lab then isolate DNA from the tumor and extract the newly mobilized SB to identify the disease gene.

Using SB, the Largaespada lab has identified known and novel cancer genes for sarcoma, leukemia, gastrointestinal cancer and hepatocellular carcinoma.  Many other genes remain to be identified.  Once the genetic framework underlying cancer is understood, it will be possible to develop and test new therapeutic strategies.

Gene Therapy:
Our researchers are using vectors to cure genetic diseases

Gene therapy promises to revolutionize the treatment of disease in the 21st century.  The goal of gene therapy is to restore natural function to the defective or mutated genes that underlie human genetic disease.  Gene therapy differs from current therapeutic strategies that typically involve the intermittent use of drugs.  Because the beneficial effect of gene therapy is sustained, patients can expect a significantly improved quality of life.

The key to effective gene therapy is the safe delivery of therapeutic genes to cells of particular tissues.  Once delivered, the gene expresses a protein that mediates the therapeutic effect.  Normally, genes introduced into cells are expressed only for a short period of time, often a few weeks.  However, if genes are inserted into a cell’s chromosomes, expression can endure much longer, often for the lifetime of the cell.

The McIvor, Hackett, Somia and Largaespada laboratories in the Center for Genome Engineering are developing methods to more effectively insert therapeutic genes into chromosomes.  One approach uses the SB and Tol2 transposons, the former of which was developed at the CGE.  In contrast to the viral vectors that are currently widely used for gene therapy, transposons are not known to elicit adverse immune reactions and therefore promise to be safer for patients.

In CGE laboratories, SB has been used to cure several genetic diseases in mice, including Hemophilias A and B, hereditary tyrosinemia type I, α1-antitrypsin deficiency and mucopolysaccharidosis I disease.  The current goal of gene therapy research in the CGE is to raise the efficiency of the transfer of transposons into cells, to direct DNA delivery to specific cell types, and to scale up delivery to larger animal models such as the dog as a prelude to clinical trials in humans.

Precision Genome Engineering:
Our researchers are targeting genes for therapy

Transposable elements like Sleeping Beauty have proven invaluable for identifying human disease genes and for delivering therapeutic genes in gene therapy.  In the field of genome engineering, however, one tool is sorely lacking: the ability to make precise insertions, deletions, or substitutions in genes located on chromosomes.  Such precision genome engineering is referred to as gene targeting.

Fundamentally, gene targeting is a DNA swapping reaction.  A DNA fragment carrying a desired sequence is introduced into a cell, and it replaces the existing copy of the gene.  To enhance the efficiency of gene targeting, a chromosome break is created at the site of modification (the target).

The Voytas lab has implemented a method of gene targeting that works at high efficiency.  Enzymes called zinc finger nucleases (ZFNs) are used to generate the chromosome break at the target.  ZFNs have two components: a DNA recognition domain (a zinc finger array) and a nuclease that cleaves the chromosome.  Zinc finger arrays can be designed to recognize any site in the genome, thereby making it possible to modify any chromosomal sequence.

Applications of ZFN-mediated gene targeting are numerous.  For example, gene targeting provides a new way to conduct gene therapy: defective genes are simply corrected to cure disease.  In plant agriculture, gene targeting can be use dto create crops with novel traits, such as disease and herbicide resistance.  Gene targeting promises to fundamentally change the way we conduct genetic research, because it gives scientists unprecedented flexibility in their ability to manipulate the genetic code.