In part I of this series, I summed up Alan Guttmacher’s 30,000-foot view of pediatric medicine, highlighting how much has changed in a few short decades. Guttmacher, director of the National Institute of Child Health and Human Development, used to be deputy and acting director of the National Genome Research Institute, and his vision of the future of pediatrics is informed by genomics and genetics.
Today, 1,700 single-gene traits (like cystic fibrosis and sickle-cell disease) have had their disease-causing genes identified. Complex traits like diabetes and autism, caused by an interplay between multiple genes, not to mention environmental factors, have been much harder nuts to crack. As of around 2005, we’d found genes for about 30 of these complex traits – but only in animals. In humans, only 8 genes were known.
But that’s changing rapidly. Genome-wide association studies (GWAS) have become a powerful tool for finding genes involved in common, complex traits, rapidly scanning the complete genomes of many people to find variations in DNA that track with those diseases. In 2002, GWAS for just one disease cost $10 billion, but the International HapMap Project, completed in 2005, dramatically reduced the size of the task, yielding a cost today of about $800,000 per disease.
To see the progress, compare the number of genes for complex traits that had been mapped to their chromosomes — in 2006 versus the 4th quarter of 2010 (click to enlarge these two images):
Now check out the red line below — the one that goes almost straight up — another way to show the dramatic progress we’ve made in finding complex-trait genes:
GWAS has great potential to give new insights into disease biology. Take age-related macular degeneration, a major cause of blindness. GWAS identified three causative genes that might never have been thought of otherwise – inflammatory genes that changed people’s thinking about the disease.
Meanwhile, the cost of whole-genome sequencing continues to go down — from $100 million in 2001 to about $10,000 today. With next-generation technologies, we’re now in hot pursuit of the $1,000 genome.
But that’s not all. There’s also epigenetics – the myriad of ways in which environmental factors modify our genome and influence gene activity. “Childhood appears to be a key period for this,” said Guttmacher. (See our recent post on epigenetics and developmental disorders for example.)
And there’s this to consider: “Most of the DNA you’re carrying isn’t yours,” Guttmacher says. It belongs to microbes you’re harboring in your different organs. The NIH’s Human Microbiome Project is seeking to catalog these communities in the nose, mouth, skin, GI tract and urogenital tract.
Guttmacher predicts that pediatrics in the future will have a large anticipatory component. The seeds of many adult illnesses are already germinating in childhood: one study, for example, found that elderly people with bronchitis tended to have frequent chest infections in childhood.
So here’s the vision: From birth, newborns will have their genomes sequenced. They could then be followed for biomarkers (which will have by then been discovered) indicating very early onset of disease, that would trigger the start of treatment.
So take a newborn baby named Sue, born prematurely. She develops necrotizing enterocolitis, a common complication in preemies. Her intestinal microbiome reveals a unique microbial cause. High-throughput drug screening has identified a new class of medications effective against this organism, and Sue’s genome indicates she will tolerate the medication well. Complications are averted.
Since Sue’s genetic profile indicates an increased sensitivity to dog dander, the family gets a cat instead, warding off asthma. She’s regularly monitored for Crohn’s disease, since her genetic profile indicates increased risk – and at age 13, she tests positive for an early biomarker. A small molecule, discovered through high-throughput screening, can prevent the onset of the disease by blocking a receptor expressed in her bowel, and Sue remains healthy. Her increased genetic risk for early heart attack is similarly countered with lifestyle changes and a targeted medication.
This is the direction in which medicine is moving – a personalized approach based on each individual’s genetic makeup, with properly targeted drugs and a focus on prevention. It may become a reality in our children’s lifetimes.