Beverly Gage writes about being a patient with a disease so rare that she might be the only person in the world who has it. After baffling a series of doctors, she is referred to the NIH. She has her genome sequenced and is diagnosed with an ultra-rare version of an extremely rare disease.
She is, she writes, “a zebra with polka dots.”
Of course there are no treatments. It is difficult to find treatments for relatively common genetic diseases like sickle cell disease, cystic fibrosis, or spinal muscular atrophy.
Thanks to advances in genetic sequencing, researchers can figure out the genomic variants that lead to symptoms in people who do not fit the mold, whose disease doesn’t exist outside of them. We are also discovering that many people with more common diseases that we thought we understood have unique versions of those diseases based on their specific mutations. Cystic fibrosis, for example, affects about 30,000 people in the United States. We used to diagnose it by doing a sweat test. Now we sequence genomes and find that there are more than 2000 different genomic variations on the gene that causes the disease. These variations lead to different manifestations of disease and different responses to therapy.
As we learn more about human genetic variation, we will come to realize that all diseases are rare and that variable responses to treatment often reflect underlying genomic variety. This true in asthma, leukemia, heart disease, and many other diseases.
It is an exciting time to be a researcher but not always a great time to be a patient. Ms. Gage was not comforted when one doctor compared her to a soldier on the battlefield, making sacrifices for the good of others. It is hard to know whether to feel valued or exploited when a researcher tells you that “your cells are like gold to us.”
In some cases, discovery of the gene leads to discovery of effective treatments. Spinal muscular atrophy used to be a death sentence for the 1000 or so children born with it every year in the United States. But now there is a gene-therapy that can offer these children a chance at a normal life. But the price tag - $3M - threatens to break the budgets of insurance companies and government health care systems. The treatment is risky. Some children who get the treatment die.
These new drugs are unlike most medical innovations in the past. They do not represent incremental improvements on existing treatments. They are an entirely new type of treatment for an entirely new way of thinking about disease.
One problem with genomic diagnostic testing is that genomic results are not always accurate. Many people who have positive genomic test results do not have symptoms of the disease that is thought to be associated with the positive test results. Sometimes, when the treatments are risky, it is unclear whether the treatment could be worse than the disease.
These new drugs are unlike most medical innovations in the past. They do not represent incremental improvements on existing treatments. They are an entirely new type of treatment for an entirely new way of thinking about disease. In the past, disease was thought of as a problem for populations of people. Medicine aggregated information from thousands of patients to categorize types of heart disease or cancer or arthritis or dementia. Drugs, then, were tested and deemed successful if they helped more people than they hurt, even though, in most cases, they didn’t help everybody and hurt many people. There was always a balance between risks and benefits based on population data.
For patients like Beverly Gage, however, there are no populations in which to study the drug. Any new treatment will have to be tested on her. The results will be difficult to interpret. She isn’t hopeful. She concludes that we live in an age of diminished expectations “when defeat and discovery so often coexist (and) when we have learned just enough to understand all that we do not and may never know.”