Mayo Clinic researchers put genomics into action to advance individualized medicine

By Susan Murphy

For the first time, a team of scientists led by the National Institutes of Health has finished sequencing an entire human genome — all of the roughly 3 billion bases of DNA. This accomplishment comes nearly two decades after the Human Genome Project decoded 92% of the sequence. The new research fills in the missing 8%, which is critical to understanding how DNA differs from person to person.

Researchers at Mayo Clinic Center for Individualized Medicine say the landmark achievement could one day bring further insights into genetic diseases, and advance individualized medicine.

"It's an important milestone," says Eric Wieben, Ph.D., director of the center’s Medical Genome Facility, where researchers are working to harvest information from the human genome sequence and ultimately translate genomic findings into patient care.

Dr. Wieben led his team in sequencing 365 terabases (365,000 billion bases) of DNA in 2021 — some of which helped pinpoint a definitive diagnosis for roughly 30% of patients with undiagnosed genetic diseases.

Dr. Wieben says the completed human genome sequence adds previously missing regions that are highly repeated in humans and will be a valuable reference that could open the door for mapping more human genomes in their entirety.

"I believe it will provide a comprehensive framework that will enable cost-effective sequencing for lots of different cell types of males and females within different ethnic groups to further advance our knowledge of genomic variation," Dr. Wieben says. "Once we begin to accumulate enough data, we're going to have a better idea of which of these highly repeated sequences have an influence on the disease process," he adds. 

A complete human genome contains 3 billion bases of DNA that are tightly bound into chromosomes in the nucleus of each of the body's cells. Most people have 23 pairs of chromosomes, and each chromosome contains many genes — the basic units of heredity. Some genes provide instructions for making proteins, which play many critical roles in the body, including the work in cells that regulate the body's tissues and organs. This is also where most known disease-causing mutations occur.

Dr. Wieben says significant progress has been made, but much work remains to be accomplished. He quotes one of the leaders of the original Human Genome Project in saying that deciphering a genome is like getting all the pieces of a Boeing 747 in a big box with no instructions and figuring out how to put it together.

"You couldn't put it together, and you wouldn't understand how it could fly," says Dr. Wieben, who has dedicated his career to investigating the human genome. He says his work is driven by helping patients, and by his fascination with the regulation of gene expression in different cell types and its link to health and disease.

He says part of the complexity of the genome lies in the 6-foot-long coiled DNA strands that are packed strategically into every cell's nucleus. 

"It's extremely thin, and it has to get highly organized to fit in there,” says Dr. Wieben. “And you must consider the arrangements between different segments of DNA on a chromosome: How do they fold and what difference does that make? And what proteins are binding to different DNA elements? And how do they regulate what turns a gene on and off? There are just an awful lot of nuanced things."

Researching beyond DNA to paint the full picture

Mayo Clinic has spent decades exploring and sequencing the human genome, allowing physicians to tailor a range of therapies to a patient's genetic makeup.

Konstantinos Lazaridis, M.D, the Carlson and Nelson Endowed Executive Director for Mayo Clinic's Center for Individualized Medicine, says there are many more secrets of life embedded in the human genome code that still need to be unlocked, including hidden biological patterns in the molecular architecture.

Dr. Lazaridis says the key to accelerating new discoveries and medical advances lies in building on the successes of sequencing the human genome.

“We value and celebrate this tremendous progress in decoding the complete sequencing of human DNA,” Dr. Lazaridis says.

He is leading his team in focusing on "multi-omics" data, combined synergistically with the proven value of genomic knowledge and discoveries, in their search for answers. This includes proteomics, the study of proteins in a cell; microbiome, the study of bacteria, fungi, protozoa and viruses that live inside the body; and metabolomics, the study of metabolites to identify the underlying causes of diseases.

Dr. Lazaridis also is zeroing-in on the human exposome — the measure of all the exposures of  people in their lifetime and how those exposures relate to health.

"We believe that a profound understanding of environmental contributors to disease and health, when combined with genomics, could lead to vast improvements in knowledge of the causes and risk factors for many diseases."

Dr. Lazaridis says the center is advancing the idea of sequencing the genome of every Mayo Clinic patient. He envisions that one day all patients will be offered an omics testing kit — even before they come to the practice — to collect their saliva, urine, stool or hair. This collection will provide a detailed DNA health analysis. 

"This is how we'll understand why cancer develops in an individual and how to treat it, or what led to a patient's rare disease and how to customize a therapeutic," Dr. Lazaridis says. "Our collaborative efforts will ultimately result in life-saving innovations for our patients. That is our singular focus."

A version of this article was originally published on the Mayo Clinic Center for Individualized Medicine blog.