At 6 months old, the signs of Shay Emma Hammer's epilepsy were subtle - eye blinks and tremors in her tiny hands. She missed developmental milestones - rolling over, sitting up, crawling, walking.
An EEG, which measures the brain's electrical activity, showed what her parents and her doctor already knew. She was having epileptic seizures. But, as is often the case with infant-onset epilepsy, her symptoms and development fit no known pattern. Her disease couldn't be given a name or a cause.
Pediatric neurologist Dr. Dinesh Talwar treated her with drugs that worked on children with similar symptoms, using trial and error to find a combination that, for a time, seemed to work.
At age 4, the seizures worsened.
"It's hard to watch someone having a seizure, said Shay's father, Michael Hammer. "They are pretty scary looking things. We got used to them. She had hundreds of seizures over the course of her life."
Shay developed autism and scoliosis. She wore a brace and needed 24-hour care.
The Hammers' insurance company paid for limited genetic testing - looking for already-known causes of seizures. "They did three or four, and they came back negative," Hammer said.
So he decided he would find the source of Shay's disease himself.
Hammer, an associate professor of ecology and evolutionary biology at the University of Arizona, is an expert in population genomics. You've probably read about his detective work.
He directs the University of Arizona's Human Genomics Core, which traced the origins of half a million people for National Geographic's Genographic project.
His lab's pioneering work on the Y chromosome has pushed its origins back 300,000 years. It discovered that humans bred with other hominids in Africa, long before their dalliances with Neanderthals.
"Here I am doing all this high-tech gene stuff. I said, 'Why not my family?' "
It took longer than usual to receive approval from the human-subjects committee at the university.
"Some of the faculty here were trying to find a way to dissuade me. They worry that you've lost your objectivity," Hammer said.
But he wanted answers. His lab sequenced the entire genome of Hammer, his ex-wife, Susanne, his son, Isaac, and Shay.
No illusions of a cure
Hammer had no illusions about finding a cure for Shay's epilepsy or halting the regression in her development.
"She had more speech at 4 than she did at 12. She had a good vocabulary and would thumb through magazines naming things but would talk in three- or four- word phrases," Hammer said.
"Going into Shay's world was like living between the second-hands of the clock. You just had to shut off your world and slow things way down and just sit with her and let her point to things she wanted you to interact with."
She walked, slowly, and would use a wheelchair for longer strolls in the park or the mall. When she was little, a favorite destination was the merry-go-round at Tucson Mall.
"She loved to jump on a little trampoline or go into the pool with her water wings. From the outside, it looked like caregiving 24/7. Most people would say, 'That's a lot of work.' It just wasn't.
"Being with Shay was such a lovely time and space. She was just so innocent and unworldly. She had one foot in this world and one not."
Shay died on March 1, 2011, at age 15.
Sudden Unexpected death
A syndrome called Sudden Unexpected Death in Epilepsy affects one in 1,000 epilepsy patients.
For children with early and continuing seizures, the rate is much higher, the Epilepsy Foundation says.
"I never really expected it to happen, but she was at a higher risk," said Hammer. "It is this mysterious sort of shutting down of the relationship between brain, heart and lungs."
Hammer slept with a baby monitor by his head. He didn't hear anything that night. There was no evidence of a seizure.
"I was just devastated," said Hammer. "I didn't know if I wanted to go on, but I wanted to know, 'What's the cause?' 'Did I have anything to do with it?' 'Is there anyone out there like my daughter?' "
Hammer's lab found the source of Shay's epilepsy.
Shay was found to have a "de novo" mutation, one that hadn't been passed from mother or father, didn't exist in her brother and hadn't been previously indicated in epilepsy.
It was a "copying error." We all have 50 to 100 mutations in our genome that weren't passed on from mother or father. Mutations can provide an evolutionary advantage. Most times, they are innocuous. In rare instances, they trigger disease.
In Shay's case, follow-up studies of the effect of the mutation in laboratory tests at other universities, showed that it was capable of disrupting the electrical signals sent to the brain.
It was an answer - and an incentive to do more.
"We had done this for Shay and there are other families out there suffering. If we can do it for one, we can do it for all. I just felt that was what Shay would want me to do."
Hammer proposed another study, using whole-exome sequencing, a new method that captures most of the protein-encoding regions of the genome by examining less than 2 percent of it. It is cheaper and faster.
Talwar found 10 families among his pediatric neurology practice to volunteer for the study. Hammer's lab sequenced the exome of mother, father and patient in each case.
The results were "shockingly successful," in Hammer's words. The study identified the probable genetic source of severe childhood epilepsy in 7 of 10 subjects. Three were brand-new identifications.
A comfort to a handful
For now, said Hammer, the results are simply a comfort to a handful of families such as his.
"Families who have children with disabilities, even if there is no cure, they want an answer," he said.
That may not sound like much, but to parents who wonder about the cause of their child's debilitating disease, it can be life-changing.
Talwar said he has seen spouses blaming each other for providing an inherited trait, for doing something unhealthful during pregnancy or for failing to treat a fever immediately. The blame "doesn't make sense," he said, but it happens.
For Ann Wilhelm of Phoenix, the study provided more than comfort.
Her daughter, Ashley, had a childhood much like Shay's - early seizures that became more violent and impeded her development.
The Wilhelms said "yes" easily when Talwar told them about the study. "We had talked to our insurance company about a genetic study. They wouldn't pay," Wilhelm said.
The study found a mutated gene related to one that causes Dravet syndrome.
"Finally," said Wilhelm. "Now the blame's not on my husband or me. Neither one of us had that gene."
"We were also concerned about our 20-year-old son. Do his children have to worry? At least we know it's not genetic. Something happened and now we can deal with it and hopefully the doctors can come up with something to treat it."
Their daughter, now 15, is doing better under Talwar's care, she said. "He has been amazing. We absolutely love him."
Seven novel mutations found
This first study found seven novel mutations. Subsequent studies will increase the likelihood of "double hits" - patients with the same mutation, said Krishna Veeramah, an associate scientist at Arizona Research Labs.
Veeramah, lead author of a research paper published in the journal Epilepsia about the findings, said that will allow researchers to pursue the mechanics of those disease-causing mutations - leading to better treatment.
"That's going to happen very quickly as the pace of whole-exome sequences increases," he said.
Hammer, at age 59, is preparing to change the focus of his research to make that happen.
He and his co-researchers would like the University of Arizona to establish a genomic medicine center that would pair genetic testing with counseling, studies and clinical treatment for epilepsy and other diseases.
It is the kind of medicine that will be standard in the future, says Dr. Robert P. Erickson. So why not start now?
Erickson was the genetic counselor on Hammer's study team, helping with the protocols and consent forms, counseling patients and working with the doctors who treated them.
Routine genomic screenings
Talwar said genomic screenings should be done routinely. Insurance companies are only hurting themselves by refusing them, he said. They pay for MRIs and other tests that could be made unnecessary.
The tests themselves are affordable and getting more so - about $1,000 for whole-exome sequencing and $5,000 for the entire genome.
Tests alone aren't enough, however.
Interpretation of the results requires a team of specialists. Not all doctors are well-schooled in genomics and not all genomics researchers have medical knowledge.
Patients need counseling and protocols need to be developed about what they should be told. There are privacy issues that become complicated when insurance pays for the tests.
Erickson has been practicing genetic medicine for most of his career. He is now a professor emeritus of pediatric genetics at the UA. He continues to see patients in his "retirement." It's not a job, he said, but an "avocation."
He expects genomic testing to be routine for everyone in the very near future, beginning in the womb.
Periodic screening will recur at stages, he said.
Counseling is a critical part of that, he said. "We have to make it clear to the patient that we're not going to tell them everything, just things that are medically actionable."
Dr. Fernando Martinez, the pediatrician and asthma researcher who heads the UA's Bio5 research institute, said the UA has "enormous interest in the idea of putting everyone together who is interested in genetics and genomes and human disease."
He said he has already encouraged Hammer to relocate his lab to Bio5, to create a more intimate link with researchers and clinicians at the UA College of Medicine and its affiliated health centers. He said new leadership at the Medical College is extremely interested in the field.
"In the end, initiatives like this are headed by well-trained, enthusiastic scientists." Finding that enthusiasm in a nationally known researcher like Hammer, he said, "is like a present from heaven."
Martinez knows a little bit about personal motivation in scientific research. His own, groundbreaking research into the causes and treatment of asthma were inspired by his mother's lifelong battle with respiratory disease.
He said Hammer's initial success is encouraging. "He's already demonstrated he can find the causes of these rare diseases. The next step is to make some more successes."
Hammer, whose lab is now on the main campus in space provided by the Department of Ecology and Evolutionary Biology, said he is reluctant to break up the synergy he has created there. But he understands the need to work more closely with his new contacts in neurology and pediatric medicine and to branch out into other areas of medical research.
He and Erickson recently teamed with medical researchers at the UA to propose a center for genomic medicine at the UA.
Hammer's most immediate task is finding funds to help a growing number of families with severely epileptic children who have contacted him in the weeks since his results were published - about a dozen so far.
He is seeking federal certification of his lab that would allow him to offer medical testing for a fee.
He is raising money through the UA Foundation to continue his research and to pay for whole-exome testing for families who can't afford the fees.
The success of the first study and the impact it has had on the families involved, motivates him to do more.
"I have to persevere," he said. "I want to help families. Maybe it's my way of staying involved with my daughter. Her legacy lives on through my work and my craft."
Contact reporter Tom Beal at firstname.lastname@example.org or 573-4158