Tag Archives: health

Metabolomics and Precision Medicine

Advancing Precision Medicine: Genomics, Metabolomics, and Clinical Trials

Monday, October 12 was the evening of an interesting talk at BIOCOM. Teresa Gallagher, founder of the San Diego Clinical Research Network (SDCRN) introduced the moderator of the event, Arnold Gelb, MD, Senior Medical Director at Halozyme. Rather than attempt to summarize all of the topics examined, the goal of this blog is to give a sampling of some of the areas discussed during the event.

Deterministic versus probabilistic genetics

The first speaker of the evening was Amalio Telenti, MD, PhD, Head of Genomics at Human Longevity, Inc. His talk touched on the ever-present nature vs. nurture debate. Do our genes determine a particular characteristic or merely influence the probability of developing that characteristic? In the world of whole genome sequencing, this can be described as deterministic versus probabilistic genetics.

In general, a deterministic trait would be something like Tay-Sachs Disease: if you have two copies of the gene for this condition, you have a better than 99% chance of developing the disease. A probabilistic trait is one with many genes that influence it, like height. Outside factors like disease and diet also affect how tall an individual grows. Hence, height is a probabilistic trait.

Telenti predicted that genomics will not revolutionize all aspects of medicine; but some medicine will be revolutionized profoundly; clinical trials will benefit the most. Genomics will be employed to stratify patient populations both before studies are commenced and after all the data is collected. Ideally genomics will be utilized to both determine who benefits from a drug and who should not take the drug.

Metabolomics combines genetics and environment

Steve Watkins, PhD, Chief Technology Officer of Metabolon spoke next. Metabolon specializes in metabolomics, offering comprehensive measurements of small molecules such as glucose, cholesterol, cortisol, and amino acids in a CLIA-certified lab.

Metabolites reflect the integration of genetic and environmental influences on an individual. Diseases can be prevented and diagnosed by checking on an individual’s metabolites. Response to disease treatment can be monitored by testing metabolites. Metabolomics is emerging as an effective tool in precision medicine.

Metabolomics integrates the effects of the environment with the effects of genetics

A person’s genome and environment affect their metabolome. Used with permission from Metabolon.

Watkins shared that Proceedings of the National Academy of Sciences recently published a study led by Baylor University’s Tom Caskey, MD. Caskey comprehensively tested the metbolites of many patients with no frank disease. Metabolon’s platform spotted underlying health issues not previously noticed in the patients’ genetic data.

For example, Patient 3905 had very high levels of sorbitol and fructose, but no clinically significant mutation was reported in their genome. Looking back at the genomic data for that individual, a mutation in the fructose pathway indicating “fructose intolerance” was discovered. This mutation had been overlooked previously. When discussing these results with the patient, the patient simply stated that fruit bothered him, so he refrained from eating it.

In the same study, Patient 3923 carried a gene for Xanthinuria type 1. He showed no symptoms of the disease such as kidney stones, suggesting the gene was not penetrant (or not expressed), leaving the patient symptom-free.

In conclusion, Watkins stated that metabolomics can be used in a number of ways:

1) By identifying pathways of interest for genetic assessment

2) By revealing non-penetrance of genes suspected of being deleterious

3) By enabling monitoring and understanding of metabolic conditions

Which drugs to use in cancer treatment?

The final speaker for the evening was Nicholas Schork, PhD Professor and Director of Human Biology at the J. Craig Venter Institute. He focused on emerging themes of design for precision medicine trials.

Schork presented several novel ideas. One was the idea of vetting algorithms for the treatment of cancers based on the mutations the cancers carry. Some hospitals already use this method, begging the question of who has the best algorithm for cancer treatment. As Schork points out, this has led to some interesting conversations with the FDA. He envisions clinical trials in the future for the evaluation of algorithms for cancer treatment with existing drugs, in direct contrast to the conventional clinical trial, usually designed to assess the effectiveness of a new drug.

In all, this was an exciting presentation of cutting-edge research and future directions in precision medicine.

Treating Cancer in the Genomic Era

Revolutionizing Cancer Treatment

by DeeAnn Visk

We have all had “ah-ha” moments. I had one on October 15, 2013 listening to Dr. Razelle Kurzrock illustrate a new way of thinking about cancer and cancer drug development. Historically, cancers are categorized by the organ in which they originate. With the advent of genomic sequencing, cancers can now be grouped by the mutations they contain. Thinking about cancer in this way will revolutionize how this disease is treated therapeutically, researched in academia, targeted by drug companies, and conceptualized in clinical trial design.

This epiphany occurred at the recent meeting of the Southern California Chapter of Women In Bio at Janssen Labs, while listening to Dr. Kurzrock, one of three excellent speakers at the meeting.

Director of Clinical Trials, Moores Cancer Research Center

Dr. Razelle Kurzrock, Director, Center for Personalized Cancer Therapy

Dr. Kurzrock pointed out that, while the light microscope was invented in 1590, it is still used today to diagnose cancer. While current cancer therapies are not quite as ancient, treatment for many cancers has not changed for up to 20 years. This is shocking, given the enormous strides in technology that have occurred in the last two decades. Most importantly, we need to change the paradigm of thinking of cancer as an organ-centric disease. Molecular abnormalities in cancer are not associated with the cancer’s organ of origin. Hence, we should treat cancers based on their molecular profile, not on where they originated in the body.

Now that the genomic era is upon us…

we can analyze the molecular signature of each cancer. Clinical trials need to be redesigned to be mutation-centric, not drug-centric. Multiple genetic markers should be employed to diagnose and classify cancers.

Generally, clinicians are entrenched in their way of thinking, which presents an obstacle to this kind of fundamental change. To paraphrase Max Planck, science progresses one funeral at a time. Regrettably, medicine also seems to progress this way. Previous ways of thinking about cancer have become so ingrained that many are not even aware of their underlying assumptions.

The concept of classifying cancer by mutational profile will also impact cancer research. How many times have you heard of a laboratory studying breast cancer, or prostate cancer, or liver cancer? Several more times than you hear about a laboratory studying a particular mutation in a cancer biomarker like the epidermal growth factor receptor (EGFR), I’ll bet.

Further areas of inertia include applications for new drugs submitted to the Food and Drug Administration (FDA). No application for an investigational new drug study (IND) has ever been filed based on a treatment targeted at a mutation in a cancer (of any kind), rather than treatment of a cancer in a specific organ. This situation persists despite the fact that the FDA has indicated it would be open to INDs using this approach.

Need a new paradigm for treating cancers.

Hope for new cancer treatments–turning in a new direction.

I hope the idea of classifying cancers by the mutations that drive them, not the organ in which they originate, changes how cancers are treated. Dr. Kurzrock did an excellent job of articulating and advocating for these changes. Employing old-school approaches to cancer is so engrained that we are often unaware of these underlying assumptions. Rethinking cancer biology certainly has changed how I would respond to a loved one being diagnosed with cancer. I would seek out a forward-thinking doctor, willing to utilize this new paradigm from the onset, not waiting for last-ditch efforts once the cancer re-occurs.

Challenging the current methods for treatment, research, and drug development will not be easy, given with the institutional barriers that remain. Financial interests of the institutions involved will need to be realigned with this new paradigm. Either that or we need AIDS-activist-like protests to spur on this change in thinking. In the end, as with AIDS, it may be patient advocacy groups that can best bring about this change in thinking in the medical, pharmaceutical, research, and regulatory communities.

The views expressed here are solely those of DeeAnn Visk are not necessarily those of Women in Bio, AWIS-SD, Janssen Labs, NPR, or your local NPR station. A special thanks to Nurith Amitai for her especially helpful editing.

This article was previously published in the January/February 2014 edition of the Association for Women in Science San Diego Chapter Newsletter.

DeeAnn Visk, Ph.D., is a freelance science writer, editor, and blogger. Her passions include cell culture, molecular biology, genetics, and microscopy. DeeAnn lives in the San Diego, California area with her husband, two kids, and two spoiled hens. You are welcome to contact her at deeann.v@cox.net

The long and the short of your telomeres

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The long and the short of your telomeres

A friend of mine, Bonnie, sent me an interesting site, which offers to determine the length of your telomeres (pronounced tea/low/mirrors). My initial response, given that telomeres shorten with age, was that the test would only tell you what you could already know by looking at your birth certificate: your age.

Telomeres length indicates wear and tear on your chromosomes; like the tread depth on your tires. Each time a cell divides, the end of the chromosomes (telomere) generally gets shortened. Normally, a cell can only divide so many times before the telomeres on the chromosome ends are too short to allow any more replications and the cell dies.

TeloMe, the company in question, will determine the length of your telomeres. This can be used as a starting point to monitor how healthy you are living; you can make life style choices to lengthen your telomeres such as limiting caloric intake, not smoking, eating lots of fruits and vegetables, and getting regular exercise. Hmmmm…What do peer-reviewed articles in reputable journals say? Querying the PubMed database with the word “telomere” leads to 14,000+ papers. Yikes! That’s a lot to review.

This is fluorescent microscope image of chromosomes (DNA, in blue) with the telomeres in yellow.

Fortunately, there is another company, Telome Health(TH)—no relationship with TeloMe, as per a phone call to TH’s offices—that has nicely gathered a “short” list of 155 peer-reviewed papers on telomeres. There is strong evidence for the shortening of telomeres being a bad thing. You can shorten the rate at which your telomeres are shortened. However, I am not convinced that there is way to lengthen your telomeres.

So should I get my telomere length tested?

So if you really want to go ahead and test the length of your telomeres you have my permission. Personally, I would go with the already established company, Telome Health. The company is well established and certified to do the testing as a clinical diagnostic test.

Or if you want to do it the less expensive way, take care of yourself:

1) Eat nutritious healthy meals

2) Get regular sleep

3) No smoking

4) Get regular exercise

5) Take Omega-3 fats

6) Reduce stress in your life

Basic, good living will keep you healthy. This just helps to explain why and gives you a way to track it.