Genomics Advances: The Quest for Personalized Medicine

LINDA HARDER

Personalized medicine is hardly a new concept. For decades, physicians have sought to identify inherited risk factors to better predict and prevent disease. Nonetheless, major advances in the field of genomics are paving the way for a far more sophisticated and widespread approach to personalized medicine.

Claire Fraser, Ph.D., director of University of Maryland School of Medicine’s Institute for Genome Sciences, acknowledges, “Nothing has been more important in medicine than family history. But because DNA sequencing has advanced so much in the past seven to eight years, and the cost of genome sequencing has come down to the point where we’ve crossed a price barrier, it’s not science fiction to think that genomics-based tests will be available in every hospital and many doctors’ offices in the future.”

Dr. Fraser foresees a time when people routinely may have their DNA sequence analyzed as children or young adults, and then refer back to that information in their medical records for life. “The biggest bottleneck today is finding DNA sequence variants that are actionable,” she says. “But that will change. In the future, physicians will likely go back into their patients’ DNA sequence data on an ongoing basis for guidance on the most effective treatment for each individual.”

Genomics’ Role in Personalizing Treatment

There are a number of areas where genomics is bringing added value by identifying the best treatment for a given patient. Dr. Fraser remarks, “The low hanging fruit has been in cancer treatment, where specialists are folding in genomic information to better diagnose and treat many cancers. We’ve learned that not all prostate or breast cancer is the same, and that women with BRCA1 and 2 genetic variations are also at higher risk for ovarian cancer. But we have a long way to go. The decision about lumpectomy versus mastectomy may be easier in 10 years.

“We’re using genomic tools to do molecular profiling, to further sub-classify specific tumors,” she adds.

“Although we don’t always have enough information to know when to recommend a specific treatment based on the underlying genetic variants associated with a specific tumor yet, we will.”

Where Dr. Fraser sees genomics making the greatest contribution is as a source of additional information to help physicians make decisions. She explains, “If a physician sees two 40-year-old patients, both of whom repeatedly have elevated cholesterol levels, which one should be started on a statin? If the genomic information is available, it could be revealed that one patient has five to six DNA sequence variants that put them at higher risk for an adverse cardiovascular event, thus indicating they should start treatment with a cholesterol-lowering drug sooner, while for the other patient, watchful waiting is appropriate. In most situations, genetic data doesn’t provide a black and white answer, but it should allow for more informed treatment decisions.”

The Microbiome

One burgeoning area of genomics research is the human microbiome – the plethora of microorganisms found in the gut, skin and vagina. The human genome is comprised of about 23,000 genes, while our gut microbiome alone contains an astonishing 3.3 million genes from bacteria and viruses.

This field is one of Dr. Fraser’s particular areas of expertise. She points out, “Over the past 10 to 15 years, we’ve developed new approaches to study our microbial partners. Only 10% of cells in and on the human body are actually human – the other 90% are non-human microorganisms.”

Research is just beginning to uncover the role of these microorganisms in health and disease, and reveal how their influence extends beyond our gut. In contrast to old-school thinking that the immune system evolved to control microorganisms, there is now evidence that these microbes co-evolve with, and contribute to, immunological, metabolic and neurological processes.

“One theory is that the gut microbiota in healthy individuals exist in perfect equilibrium and keep inflammation in check,” explains Dr. Fraser. “An imbalance in this equilibrium may trigger a cascade of events that affects immune cells circulating throughout the body. For example, a change in microbial colonization of the gastric tract has been found to be associated with celiac disease and inflammatory bowel disease.”

Dr. Fraser notes, “The bacterial composition of our gut may protect against or contribute to many disorders. Currently, several clinical trials are investigating the effects of probiotics. I think in the near future, we’ll look at the microbiome as an important measure of health, and patients will provide a routine fecal sample at their annual history and physical for evaluation of the status of the gut microbioma.

Community Types of Microbiota

“We’ve found that two to three community types are present in the human gut,” she continues. “Each human has one of these community types, which share common functional capabilities such as the metabolism of carbohydrates and fats, but which may differ in the ways they metabolize drugs and other compounds we ingest, including potential carcinogens. These microbial communities are very active metabolically, and large numbers of bacterial metabolites likely serve as signals to us as their hosts. If we eat glucose, for example, we suspect that our gut microbiota contribute to the overall response to release insulin.

As discussed in “Stopping Infectious Diseases” in the November/December 2013 issue of Maryland Physician, fecal transplantation is emerging as an accepted method to restore healthy microbial communities in patients with Clostridium difficile-associated diarrhea, and perhaps eventually other inflammatory bowel diseases. Says Dr. Fraser, “This opens up an alternative approach to treating immune diseases that may complement drug therapies that modulate immune pathways.”

Even plant viruses, which contribute as much as 95% of the viral DNA in the human gut, may be involved in human health and disease. In the future, they may help explain why smokers’ risk of certain neurodegenerative diseases, such as Parkinson’s or Alzheimer’s, is lower – one of the few pieces of good news for smokers.

Dr. Fraser speaks to the link between our microbiome and nutrition, explaining, “As we better understand how our gut microbes function, we can move towards a nutrigenomic approach to diet and health. Incorporating all of this genomic data into one’s medical practice has huge potential, but is also hugely challenging.”

Americans Suffer Diminishing Microbiome Diversity

A number of microbiome studies show that following use of a broad-spectrum antibiotic, some individuals’ gut communities are never restored to what they looked like prior to administration of the antibiotic. The hypothesis is that the complexity of the human microbiota is diminishing due to the collateral damage that occurs following exposure to antibiotics in our food supply, growing use of antibacterial soaps and sanitizers, and limited exposure to bacteria early in childhood.

“Unfortunately, we appear to pass this reduced diversity in our microbiota on to our children,” laments Dr. Fraser. “Studies have compared U.S. infants to those in developing countries and found that our microbial communities are far less diverse, and therefore inherently less stable than theirs. The first few years of life are a critically important time because the immune system is maturing. If we’re not exposed to microbes, our immune systems may come to view them as foes and we can develop problems such as asthma later in life. For example, studies have shown that the best way to decrease asthma in children is to have a dog or cat.

“There are even some intriguing links between gut microbiota and autism,” Dr. Fraser adds. “Perhaps the rise of ADHD will be found to link, at least in part, to microbiomes.”

Identifying Positive Genes

While most of the focus today is on identifying genetic factors that increase our risk for disease, there is a growing search for genetic factors that keep us healthy. “We tend to think about genetics’ negative effects,” observes Dr. Fraser, “yet it also has positive impacts. One of my University of Maryland colleagues, Dr. Scott Devine, is studying a group of centenarians in a search for longevity genes. They’ve found a few hundred sequence variants that may contribute to longevity. Some of these have been mapped back to known pathways with the very real possibility that we can find protective alleles. At least one protective allele for breast cancer has been identified.”

Studies by the Einstein Institute and Boston University also have identified favorable alleles, such as variants of APOC3, IGF-r and CETP that are associated with a lower risk of heart disease, diabetes and dementia.

With the potential for genomics to do everything from replacing amniocentesis to understanding the environmental triggers for rheumatoid arthritis, Dr. Fraser sums up the current state of genomics by noting, “The field is moving quickly, so stay tuned. Physicians will soon begin to incorporate all of this genomic data into their practice.”

UPDATE- APRIL 1, 2014

Researchers at the Institute for Genome Sciences at the University of Maryland School of Medicine have been awarded a research program contract from the U.S. Food and Drug Administration (FDA) to sequence, assemble, and annotate a population of bacterial pathogens using two high-throughput sequencing (HTS) technologies in support of the expansion of a vetted public reference database.

The continued development of HTS technologies for accurate identification of microorganisms for diagnostic use will have significant impact on human healthcare, biothreat response, food safety, and other areas. Developing a comprehensive, curated database of microbial genome sequences and associated metadata will serve as a valuable reference to evaluate and assess HTS-based diagnostic devices. Leading the sequencing and analysis phases of the project, the Genomics Resource Center (GRC) at the Institute is a cutting-edge genomic sequencing and analysis center with a long history of high-quality microbial genomics research that has sequenced and analyzed more than 5,000 microbial genome sequences in just the past five years.

The genome sequencing will use two HTS platforms, Illumina and Pacific Biosciences, and multiple genome assembler software packages and assembly QA/QC pipelines to assemble and validate the resulting draft genome sequences. By using two complementary sequencing platforms, GRC researchers will be able to cross-validate consensus sequences to generate the highest possible genome sequence accuracy. The comprehensive, curated database to which these annotated genome sequences will be added will enable high confidence confirmation of in vitromicrobial pathogen identification. This database will be accessible through the collection of the National Center for Biotechnology Information (NCBI)’s public domain databases. The combination of genomic data and metadata will help to advance the goal of developing HTS-based in vitrodiagnostics and the assessment of their potential.

The GRC was formed to serve the global genomics and bioinformatics communities, and its reputation is built on both its deep history in sequencing, genomics and analysis, and its end-to-end service level from initial project consultation through publication. The GRC is led by Luke Tallon, scientific director and founding leader of the GRC, and Lisa Sadzewicz, administrator director of the facility. “We are excited to contribute our genome sequencing and analysis expertise to this important project with the FDA,” says Tallon.

“This database will be an important reference for the scientific and medical diagnostic communities,” says Claire Fraser, PhD, Director of the Institute for Genome Sciences. “We have worked with federal agencies and global scientific partners to sequence and analyze an extensive population of bacterial pathogens since our Institute launched in 2007 and are pleased to develop this reference database with the FDA.”

“The Institute for Genome Sciences is truly unique to an academic medical university because it houses cutting-edge sequencing technologies overseen by internationally renowned experts in the field who are deeply engaged in the research enterprise,” says E. Albert Reece, MD, PhD, MBA, vice president for medical affairs at the University of Maryland, and John Z. and Akiko K. Bowers distinguished professor and dean of the University of Maryland School of Medicine. “This award recognizes the strength of the University of Maryland School of Medicine’s genomics program, which will make significant contributions to better identifying and, ultimately, treating infectious diseases.”

Claire Fraser, Ph.D., director of University of Maryland School of Medicine’s Institute for Genome Sciences. IGS uses large-scale, cutting-edge experimental and computational tools to better understand gene and genome function in health and disease, to study molecular and cellular networks in a variety of model systems, and to generate data and resources of value to the international scientific community.


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One Comment

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