Genetics at the Forefront

Genetics at the Forefront

The growth of genetics in state-of-the-art medicine was evident at Cleveland Clinic’s 2015 Medical Innovation Summit. In fact, among the Top 10 Medical Innovations selected by summit leaders this year, four were related to genetics. Consult QD asked Charis Eng, MD, PhD, Chair and founding Director of Cleveland Clinic’s Genomic Medicine Institute, for her viewpoint on these four fascinating innovations. (Click on headlines below to watch video on each subject.)

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Genomics-based Clinical Trials

By upending a 50-year-old research model that can be slow, inefficient and expensive, genomics-based clinical trials promise to increase the speed and flexibility of the research process and guide patients more quickly to promising treatments.

Dr. Eng’s take: “This is an important consequence of somatic genomic testing in cancer, in which we look for acquired (“somatic”) mutations, not those that are inherited. Based on the genomic profile of a tumor that we establish through next generation DNA sequencing, we can now identify the most common genomic changes in a patient’s cancer and select the best treatment. So instead of tossing chemotherapeutic agents at cancer patients like a weed killer that kills everything, we can identify which chemotherapeutics will be most effective for a particular patient’s particular cancer that carries a specific mutation or mutations. Genomics-based clinical trials are definitely accelerating clinical research and treatment. We are finding out more quickly if a cancer responds better to a treatment, and whether that response is more durable with fewer side effects.”

CRISPR for Gene Editing

Thanks to a new, inexpensive technology called CRISPR, laboratories around the world are now able to edit genes in single cells to organisms – from human cancer cells to mice. CRISPR, which stands for “clustered regularly interspaced short palindromic repeats,” can identify and remove mutated genes from a DNA strand for as little as $30. While altering human genes remains controversial, it is clear that CRISPR has tremendous potential to impact the course of human disease.

Dr. Eng’s take: “An individual’s genome has approximately 30,000 genes, which function as the body’s business plan. A major error in that business plan is a mutation. When a sporadic cancer occurs, the cancer cell hijacks the body’s business plan and alters it.

“With CRISPR, one can precisely edit an error in the business plan. Currently, the research community can edit in a mutation in gene X or completely remove gene Y and look at the consequences in non-human animal models of disease. Very powerful. In reverse, technically, one can equally well remove the mutation from specific gene X and hence, ‘correct’ a mutation. CRISPR can be used to make knockout mice very quickly and much more inexpensively than previously. The problem with this generation of CRISPR-mediated mutations is that they may introduce some off-target effects, adding a variant or two in the gene you are trying to edit, and that’s bad. It is fine for research at present, but we shouldn’t even be thinking of using CRISPR in humans right now. We need to keep in mind ethical and societal issues.”

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When might CRISPR be available for clinical use? “To treat a cancer that has a mutation, the first trials could begin within five years,” Dr. Eng predicts, warning, “Again, keeping ethical and societal responsibility front, right and center.”

Cell-free Fetal DNA Testing

Studies show that Cell-free Fetal DNA Testing more accurately predicts Down’s, Edwards’ and several other syndromes than standard blood tests and ultrasound.

Dr. Eng’s take: “We are using this method now in prenatal testing as standard-of-care, and it has already been a boon for medical practice. It is huge. In the past, chorionic villus sampling (CVS) was used to test for genetic defects in a fetus, but CVS has side effects such as spontaneous abortions and fetal defects. This new technology allows us to test miniscule amounts of fetal DNA circulating in the mother’s blood stream. This is called next generation sequencing (NGS), or massively parallel sequencing. It is a technology that brings more certainty to parents everywhere, with no dangerous side effects.”

Dr. Eng adds: “Cell-free fetal DNA testing should only be performed in the setting of pre-test and post-test genetic counseling.”

Cancer Screening via Protein Biomarker Analysis

Protein biomarker analysis focuses on changes in the structure of certain proteins circulating in the blood. In contrast to examining genetic mutations, which can indicate the risk of cancer, the new tests give real-time information on cancer’s presence. In 2016, a new biomarker platform is hitting the market that should offer more accurate cancer screenings and more chances of early detection.

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Dr. Eng’s take: “Right now, biomarkers in general are not very accurate for cancer screening. Carcinoembryonic antigen (CEA) and cancer antigen 125 (CA 125), for example, are useful for clinicians when following the progression of certain cancers and for showing how well a cancer is responding to treatment. But they are not useful screening tools.

“Genes are the master molecules that produce and direct proteins. Some believe that looking at the protein, the end product, might be more effective than looking at gene mutations to predict cancer development.

“We are waiting for these new highly accurate new biomarkers. They will look for changes in protein structure – and not just whether the protein elevated or depressed. For instance, a protein that looks like a box instead of a sphere, or a teardrop instead of cruciform, and we hope this will provide us with a predictor of disease. We should be able to detect even the most minute difference in protein structure, instead of waiting for a biomarker in the bloodstream to cross a certain threshold.

“I suspect that in time, we might employ a combination of proteomic and genomic markers to screen for cancer and other diseases.”