The dawning of the age of genomic medicine, finally

LA JOLLA, California - When President Bill Clinton announced in 2000 that Craig Venter and Dr. Francis Collins of the National Human Genome Research Institute had succeeded in mapping the human genome, he solemnly declared that the discovery would "revolutionize" the treatment of virtually all human disease.

The expectation was that this single reference map of the 3 billion base pairs of DNA -- the human genetic code -- would quickly unlock the secrets of Alzheimer's, diabetes, cancer and other scourges of human health.

As it turns out, Clinton's forecast was not unlike President George Bush's "mission accomplished" speech in the early days of the Iraq war, said Dr. Eric Topol of Scripps Translational Science Institute, which is running a meeting On the Future of Genomic Medicine here March 6-7.

Thirteen years after Clinton's forecast, even Venter acknowledges that mapping the human genome has had little clinical impact. "Yes, there's been progress, but we all would have hoped it would have been more rapid," he said in an interview in his offices this week.

But that is finally changing.

"We are at an inflection point," said Collins, who now directs the National Institutes of Health. In a telephone interview, he said he never expected an "overnight, dramatic impact" from sequencing the human genome, in part because of cost.

Recently, a combination of lower-cost sequencing technology and a growing list of wins in narrow corners of medicine are starting to show that genomic medicine is on the verge of delivering on at least some of those early claims.

Recent advances in sequencing have been "pretty stunning" and genomics is "just on the threshold" of delivering results, Venter told Reuters.

Although much is left to be learned about the genome, scientists believe knowing a person's genetic code will lead to highly personalized treatments for cancer, better predictions for diseases in babies and help unlock the puzzle of mysterious genetic diseases that currently go undiagnosed and untreated.

Venter is staking his latest entrepreneurial venture on that expectation. Earlier this week, he announced formation of a new company, Human Longevity Inc., to undertake a massive project: sequencing 40,000 human genomes a year in a search for new therapies to preserve health and fight off diseases, including cancer, heart disease and Alzheimer's.

To do that, Human Longevity will use two HiSeq X Ten machines and has an option to buy three more. The sequencers, made by Illumina Inc., can map a single genome for as little as $1,000.

Collins' government-funded Human Genome Project spent $3 billion and took 13 years to sequence the human genome.

Breaching the $1,000 genome could prove to be a watershed. At that cost, said Illumina Chief Executive Jay Flatley, ambitious projects like Venter's are economically feasible and clinical results more achievable.

"We've still only scratched the surface of what the genome holds," he said. "What we need to do now is get hundreds of thousands to millions of genomes in databases with clinical information," he added.

MAKING A DIFFERENCE

Advances in sequencing equipment and the advent of next-generation sequencing has transformed the work Dr. Elizabeth McNally does as director of the Cardiovascular Genetics Clinic at the University of Chicago.

In seven short years, she said, her group has gone from testing just one gene at a time to testing 60 to 70 genes and she is moving quickly into whole genome sequencing.

McNally points to the case of Jeanne Sambrookes - a patient who is alive today because of these advances.

As a child, Sambrookes often noticed the distinct, hunched posture of her mother, her aunt and her grandmother as they struggled to climb a flight of stairs.

Sambrookes had been very athletic as a young teen, but as she matured, she noticed a heaviness in her legs. By age 20, running left her tired. At 40, she needed a pacemaker, just like her mother did at that age.

"I started thinking there is something to this," said Sambrookes, now 56, who lives in Michigan City, Indiana.

After some dead ends, she found McNally, who cast a wide net, testing for more than two dozen genes that could account for Sambrookes' heart and muscle problems.

The culprit turned out to be a mutation in a gene called Lamin that causes Limb-girdle muscular dystrophy. The disease can cause weakness and wasting of the muscles between the shoulders and knees. The mutation can also cause electrical disturbances of the heart.

McNally recommended Sambrookes replace her pacemaker with an implantable cardiac defibrillator that could protect against sudden cardiac death.

That proved to be the right call. Last August, Sambrookes' heart stopped three times. Each time, the defibrillator shocked her back to life.

"She literally tried to die three times," McNally recalls of her patient. "It still takes my breath away."

Although McNally uses panels of 70 to 80 genes in her clinic, she has started experimenting with whole genomes. With the reduced cost of gene mapping, whole gene sequencing is a potentially cheaper, more powerful tool.

The reduced cost of mapping is cutting the cost of research, too -- another factor that could speed clinical outcomes. McNally's team recently published a paper in the journal Bioinformatics in which she used Beagle, a supercomputer housed at Argonne National Laboratory, to analyse 240 full genomes in about two days. Such an endeavour normally takes months.

"That dramatically decreases the cost associated with analysis because we sped up the time," said McNally.

CORNERS OF MEDICINE

Dr. Jay Shendure, associate professor of Genome Sciences at the University of Washington in Seattle, said the impact of gene sequencing is beginning to emerge in specific areas -- after a startup period that was longer and narrower than expected.

"I do think there are these corners of medicine, which are important ones, that may happen relatively quickly," he said.

A key example is the use of a pregnant woman's blood to see if her foetus may have trisomies -- chromosomal abnormalities associated with Down syndrome and other disorders.

"Almost overnight, sequencing is in the process of taking over as the primary means of screening for trisomies in at-risk populations, and maybe eventually to everyone," Shendure said.

The clinical results are promising. A trial of Illumina's test published last week in the New England Journal of Medicine found about 3.6 per cent of standard tests for trisomies had false positive results, compared with 0.3 per cent with Illumina's Verify test.

That means fewer women would need to go through invasive follow-up diagnostic tests using amniocentesis or chorionic villus sampling, both of which can cause miscarriages.

If the tests become routine practice, Goldman Sachs analyst Issac Ro estimates the market could reach $6 billion a year.

Venter's new company, Human Longevity, has picked cancer as its first sequencing target. Working with the University of -California, San Diego, the company plans to sequence the genomes, as well as the tumours, of every cancer patient treated at UCSD's Moores Cancer Center.

Collins calls cancer a "disease of the genome" and notes that genomics has revealed cancer to be a collection of different mutations, all of which contribute to its growth.

Drug companies have responded with treatments that block aberrant pathways, an approach called precision medicine.

"That's happened pretty quickly because of this window that DNA sequencing has provided," said Collins.