Science
WASHINGTON, D.C. — Every illness is its own story — a 30-year-old man with kidney failure but no clear diagnosis, a paraplegic woman with a bowel problem doctors can't heal, a young woman with aggressive late-stage breast cancer.
A new way to treat such patients is developing in which their very individuality is part of the cure. It's a specialized type of genetic testing and a team approach to patient care designed to help diagnose and treat patients with complex medical problems — patients who might otherwise be left grappling with nameless diseases, unclear health futures or the prospect of imminent death.
"It's called individualized medicine or personalized medicine. The terms are interchangeable," said Dr. Gianrico Farrugia, director of the Mayo Clinic's Center for Individualized Medicine, who works with colleagues at Mayo centers in Minnesota, Arizona and Florida.
The trick: They use the human genome to determine a patient's unique genetic profile.
"And then we tailor care for them," Farrugia said.
The approach is seen as an antidote to what is too often a mass approach to medicine. In addition to seeing clinical specialists for their disease, patients and their families have access to a team of other support staff — pathologists, scientists, bioethicists, genomic counselors, bioinformatics specialists and lab technicians.
The Individualized Medicine Clinic sees two types of patients: those with advanced cancer and those the clinic calls medical odyssey patients, who have conditions other doctors have not been able to diagnose.
Blood testing (usually involving the patient and one or more immediate family members), biopsies and other diagnostic tests are run, and genetic counseling is required. Blood and tissue samples are sent to scientists at Baylor College of Medicine for a complex type of genetic testing called whole-exome genetic sequencing. The process can take months, but it eventually reveals which genes in a patient's DNA are tripping things up.
Most genetic testing performed these days looks at one gene or a group of known genes, but whole-exome sequencing analyzes a person's constellation of genes — about 21,000 genes — and the coding regions within them.
This type of testing really works, said Dr. David Goldstein, a professor of molecular genetics and microbiology and biology and the director of the Center for Human Genome Variation at Duke University. He said it's particularly beneficial to use in children with rare diseases that are difficult to identify.
"They come into the clinic, and something's really wrong, and the clinical geneticist is pretty sure its genetic but doesn't know what it is," he said. "They look through their entire genome and compare it with their parents'."
And that's where they can find answers, he said.
"In some cases, this approach is identifying entirely new syndromes," said Goldstein. Because it looks at a person's whole genome, he added, it can identify genetic mutations that families aren't looking for, and family genetic counseling is key.
For Denis Keegan, whole-exome sequencing helped put a name to his disease. His doctors at the clinic discovered a mutation in an inherited gene that explains why his 30-year-old kidney is failing him.
"Since I didn't have any idea what the hell was going on with my body, I said, 'Let's do it.' I hoped the prognosis would change, but I kind of knew it wouldn't. The biggest thing was to find out what was wrong with me," said Keegan, who lives in Cincinnati and was diagnosed with kidney disease at 16 with a form that his doctors couldn't identify.
He and his wife, Lindsay Keegan, 30, married five years and thinking about having a family, wanted to know whether it was something he could pass on to a child. They suspected the answer was yes because his father also has kidney disease and has undergone a transplant. Keegan's only brother, who does not have kidney symptoms, and their dad were tested too, and a mutation of the FN1 gene was discovered in the family. His illness: fibronectin glomerulopathy.
"I have a 50-50 chance of passing it on," Denis Keegan said.
Lindsay Keegan said they were assigned a genetic counselor, who talked with them before and after the test. She explained that knowing about the affected gene will help them make an informed decision about having children and that in vitro fertilization is an option.
"It's an ongoing conversation," she said, and they said they are holding off on expanding their family for now.
Denis Keegan learned that his condition isn't linked to an immune-system issue, so immunosuppressant drugs won't help him, but that certain diet and lifestyle choices could benefit his health.
Farrugia said sequencing is also used for other reasons — for example, helping pinpoint why some patients have dangerous reactions or don't respond to standard drugs for serious illnesses, like cancer and gastrointestinal problems, his area of expertise.
Individualized medicine is being used in other ways too. In one patient, a paraplegic woman who had a serious bacterial infection that can cause severe diarrhea and even life-threatening inflammation of the colon, Mayo doctors found a genetic mutation that showed her body didn't metabolize the medication normally used to heal the condition.
"We were able to carry out a fecal microbiome transplant that resulted in complete healing of her colon in three days," said Farrugia.
For another patient, individualized care is giving her peace of mind, a safety net for the future. Breast-cancer survivor Holly Boehle, from Grand Rapids, Mich., visited the Mayo Clinic for a second opinion after being diagnosed with an aggressive form of breast cancer in January.
She agreed to participate in the Mayo Clinic's breast-cancer genome-guided therapy study (the Beauty Project) which aims to help physicians tailor chemotherapy to breast-cancer patients based on their individual genomes and the genomes of their tumors. Patients are paired with mouse avatars — mice that are injected with and grow the patient's tumor — that can help scientists identify the best treatment for each person.
Boehle's tumor responded well to the standard chemotherapy treatment and to surgery, so she didn't need a tailor-made drug, but she says the genetic information the Mayo Clinic obtained will be there in case her cancer returns and she requires a stronger arsenal of drugs to fight it.
"Let's say the cancer returns 10 or 15 years down the road. They'll be able to see how my tumor tissue responded to the mice on different medications," said Boehle.
"We hope she remains in remission and it's the end of the story. But if she were to progress, we could go and find a new target that isn't standard. For these cancer patients like Holly, we do whole-exome sequencing but also RNA sequencing," said Farrugia.
He said they are practicing a type of medicine that 10 years ago, after the Human Genome Project was completed, many physicians hoped would be commonplace by now. But taking genomics from the lab to the bedside has been slower going than most had hoped.
The slow pace is likely due to a combination of issues, including genetic-test costs, access to testing, health-insurance coverage and unawareness that the testing exists, said Goldstein.
He said whole-exome sequencing is more affordable than is widely perceived by both physicians and patients. "In our hands, the cost of sequencing all genes for a child, mom and dad is $3,000. We are doing the exome sequencing here at Duke. If you use a diagnostic company, it's much more," said Goldstein.
Stan Nelson, a professor in the department of human genetics at UCLA's David Geffen School of Medicine, where whole-exome sequencing has been available to patients for the last two years and is often run on children with unidentified rare diseases that have not been identified through other types of genetic and diagnostic tests, says the procedure costs about $6,000 for a parent and an affected child.
At the Mayo Clinic, the price tag is $21,000 for the total cost of genetic tests, not including consultation and counseling. However, volunteering to be part of a study can reduce costs.
Farrugia said there is no central registry of all of the patients who have undergone genetic testing or whole-genome sequencing. (Most medical centers currently house their own data.) But he estimates that the number is likely in the "thousands of thousands."
He guesses that the number of academic centers doing whole-exome sequencing is in the range of 20 or 30 centers, including those that do the sequencing in-house and those, like the Mayo Clinic, that send the sequencing to an outside lab.
Nelson believes that whole-exome sequencing should be performed earlier instead of being a last effort to identify rare disease and that it could save patients, especially young ones, from going through many other invasive and expensive diagnostic tests.
"We are now moving from the promise of genomics to the practice of genomics,'' Farrugia said. "As we move from the promise to the practice, we want to make sure we're doing what's right for each patient and making sure we're doing the right studies so that what we think will happen, we can prove will happen. That is the next frontier of genomic medicine — moving into the reality of using genomics in everyday life."
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