With a maternal family history crackling with stories of batty, addle-brained aunts and uncles who all died in their mid-50s, Doug Whitney knew that early onset Alzheimer’s disease was the culprit when his mother forgot how to make her signature pumpkin pie one Thanksgiving when Whitney was 21.
But the Oklahoma native felt impervious to Alzheimer’s, which claimed 10 of 14 siblings in his mother’s clan long before people spoke freely about dementia. It wasn’t until 1995, when his older brother Roger was diagnosed with the scourge at age 49 that Whitney connected the dots to realize that he — along with his two children — might also be genetically vulnerable.
“I was prepared at the time to die at 55,” he recalls. “We didn’t know for sure if I had the gene, but after I hit 50 and didn’t have symptoms, I figured I was in the clear.”
Whitney was right — and wrong. DNA testing in 2011 revealed he did indeed inherit a mutation in one of his presenilin (PSEN) genes, an error normally guaranteeing the development of early onset Alzheimer’s disease. Yet the 66-year-old Washington state resident, retired from a long career in the Navy, is more than a decade past the point he should already have died from the disease.
Whitney somehow escaped his genetic sword of Damocles. He is healthy despite carrying a known pathogenic mutation. He is an enigma — and just the type of person who could help researchers identify protective genes that somehow cancel out the effects of bad mutations.
Researching Healthy People
Representing an array of potential health conditions, Whitney and others like him are attracting growing scrutiny from researchers around the globe. An increase in gene sequencing efforts is fueling projects aimed at identifying resilient individuals.
This emerging approach flips a once-standard research paradigm on its head: Instead of focusing solely on gene mutations that trigger disease, scientists are now also looking closely at healthy people with disease-causing mutations to find pivotal clues about how to protect against or prevent illness.
“More than a decade of looking at the ‘exciting’ targets discovered by looking at individuals with disease made me appreciate that maybe it would be better to identify those genes that prevent people from having disease,” explains Stephen Friend, a co-founder of the Resilience Project, a year-old collaborative effort, led by the Icahn School of Medicine at Mount Sinai in New York, to understand human DNA patterns that influence inherited diseases. The project aims to analyze the genetic material of 1 million people all over the world. “We’ve had the frustration of seeing how hard it is to start from an anchor point of ‘This is a gene that causes disease.’ Starting with ‘This is a gene that protects you from disease’ is a more rational point,” Friend believes.
“But the audacity of thinking that we could go in and identify why someone doesn’t have a disease has been both expensive and at the edge of doable,” adds Friend, who is also the president of Sage Bionetworks in Seattle, a nonprofit advocating open-data policies. “It’s now becoming technologically possible to find those individuals.”
An Ethical Slant
Studying the health or physiological effects of a disabled gene is nothing new. Researchers have practiced “reverse genetics” on mice and other lab animals by creating “knockouts” — disabling both copies of a gene and then asking what consequence it has. But animal results don’t always translate to humans. And it’s considered unethical to engineer genes in people. So finding natural human knockouts has become the next logical step.
“The number one benefit of mouse studies is we can engineer the types of mutations in mice that would never appear naturally in humans,” notes Daniel MacArthur, a human genomics researcher leading the Human Knockout Project at Massachusetts General Hospital and the Broad Institute of Harvard and MIT.
Teaming with diverse groups of collaborators, MacArthur has conducted extensive research indicating that the average healthy person has about 20 genes in which both copies are knocked out. MacArthur’s efforts have been among the most seminal in the field. By analyzing the exomes, the approximately 20,000 genes that code for proteins, in more than 90,000 people, his team uncovered about 200,000 variants that naturally disable genes. Investigators around the world sequenced these exomes in a variety of disease-focused projects.
For example, a 2014 study of more than 36,000 Finns by MacArthur and others, published in the journal PLoS Genetics, indicates that people lacking the LPA gene may be protected from heart disease; another mutation that’s carried in one gene copy by more than 2 percent of Finns may prompt fetuses with two copies to miscarry.
Efficiencies of Scale
Because of the relative scarcity of human knockouts, however, searching for them in the general population is somewhat inefficient. That’s why scientists are targeting “enriched” populations, such as the Finns, a historically isolated group with roots in the small numbers of settlers who moved to Finland four millennia ago and married close genetic relatives.
In other cultures, particularly in the Middle East, unions between blood relatives as close as first cousins are routine. Capitalizing on this, a U.K. project called the East London Genes and Health (ELGH) study is sequencing the DNA of 100,000 South Asians because up to 40 percent of Pakistanis and 10 percent of Bangladeshis in East London have parents hailing from the same extended family. They also suffer twice the average rate of death from heart disease and five times the rate of type 2 diabetes.
“Work done by the ELGH project and other investigators suggests that about half are knockouts for at least one rare gene,” MacArthur explains. “This makes these groups a really powerful source of human knockouts.”
Scientists say that beyond deciphering the still obscure functions of thousands of genes, one of the ultimate goals of human knockout research is to develop drugs that protect people from illness, essentially mimicking the disabling effects of loss-of-function genes.
Based on research by Helen Hobbs and Jonathan Cohen from the University of Texas Southwestern Medical Center in Dallas, for example, drugmakers are set to begin marketing compounds targeting the PCSK9 gene in hopes of slashing the incidence of heart attacks and strokes. One such treatment, Praluent (alirocumab), was approved by the FDA in July. The pair found that people with mutations blocking one copy of this gene have radically lower levels of cholesterol.
“PCSK9 is the poster child for the use of naturally occurring loss-of-function variations to identify genes that could be good targets for drugs for common disease therapy,” says MacArthur, who unwittingly stumbled into human knockout research as an undergraduate student 15 years ago and never changed course. “It’s a very powerful approach.”
Even diseases of aging — a universal condition with the accumulation of enough birthdays — could eventually be targeted by drugs based on human knockouts, according to Mark Gerstein, a professor of biomedical informatics and co-director of the Yale Computational Biology and Bioinformatics Program. Numerous bodily functions designed to aid in reproduction — such as weight gain during puberty — turn against us if they continue when we are older, he says, leading to a shortened life span.
“There may be a gene that, if it’s knocked out, slightly hinders your fitness for reproduction, but dramatically improves your longevity,” Gerstein says. “The theory is certainly incontrovertible at this point.”
Dodging a Genetic Bullet
Whitney fervently hopes a drug will soon be found to counteract the presenilin gene’s strong odds of causing early Alzheimer’s — not for him, but for his 43-year-old son, who also carries the mutation. (His 41-year-old daughter has tested negative.) Ten of Whitney’s 63 maternal cousins have succumbed to the disease and five more are currently fighting it.
Meanwhile, his children, six remaining siblings, and many extended family members have enrolled in the DIAN study (Dominantly Inherited Alzheimer Network), an international registry established in 2008 and based at Washington University of St. Louis. The DIAN study tracks those at genetic risk for the disease. Two of Whitney’s sisters have tested negative for the mutation, and the rest of his siblings don’t yet know their mutation status and aren’t required to be tested to participate in the research.
However, all are past the point at which their affected relatives developed early Alzheimer’s, which accounts for less than 1 percent of all cases. Researchers are still trying to figure out which factors allowed Whitney to dodge the disease despite having a presenilin gene mutation, he says.
“I find it utterly fantastic that none of my other siblings have shown symptoms yet. They all had a 50-50 chance of acquiring the mutation, and it doesn’t stand to reason that they would all escape it,” adds Whitney.