As a 13-year-old seventh grader, Charlie Blotner first began experiencing numbness and tingling in his legs and arms. His parents took him to numerous doctors and specialists, who suggested a simple case of teenage anxiety. When the tingling escalated from once or twice a month to multiple episodes a week, Blotner was finally referred to a neurologist, who scheduled an MRI scan. The result—a brain tumor—was a shock for his parents but something of a relief for Blotner. Finally someone believed he wasn't making up his symptoms.
After five years of watchful waiting, Blotner underwent surgery to remove the tumor and agreed to donate some of the tissue to a research study at the University of California, San Francisco (UCSF). Investigators from UCSF and the Mayo Clinic are looking at gliomas, the most common type of malignant brain tumors, in adults to find better ways to understand and classify their genetic profile. The analysis showed that Blotner had a mutation in the IDH1 gene. Researchers do not fully understand how this mutation causes tumors, but they do know that the average survival time for adults with this mutation is 8.9 years post-diagnosis.
Blotner's surgery was successful, but he knows he may be in a race against time to find a targeted treatment for his tumor should it return. It's a race he may well win—thanks to an emerging field called precision medicine.
The Precision Medicine Initiative
Delivering the right treatment to the right person at the right time is the broad definition of precision medicine, a concept promoted by President Obama when he announced the creation of the Precision Medicine Initiative in his State of the Union address in 2015. Congress, with bipartisan support, passed the 21st Century Cures Act, which included $1.5 billion for this initiative. It was signed into law on December 13, 2016.
Physicians have always aspired to find the right treatment for patients, but precision medicine goes deeper, says Daniel H. Lowenstein, MD, professor of neurology at UCSF. "We recognize that each of us is unique at every level from our genomic makeup (the instruction set we inherit as genes), the molecules made in our genes, and the cell types, to the organs and our overall body, as well as our environmental exposures. Given all those factors, the goal of precision medicine is to come up with treatments for diseases that are as individualized as possible."
Advances in technology—genomic sequencing, high-resolution imaging, more sophisticated tests, the ability to combine data across populations and the world, the computing power to analyze the data—add to researchers' understanding of each individual's makeup and help inform doctors on how to treat each person.
Until relatively recently, patients were placed into broad disease categories—breast cancer or lung cancer, for example. Today, thanks to genetic profiling, patients may be diagnosed with a more specific type of breast cancer such as HER2. Advances in biomarker tests help doctors and researchers identify and diagnose more rare diseases. And more precise diagnoses lead to more specific and customized treatments.
Tools of Precision medicine
Genomic Testing
Ten years ago, Santosh Kesari, MD, PhD, FAAN, professor of translational neuro-sciences and neurotherapeutics at the John Wayne Cancer Institute and Pacific Neuroscience Institute in Santa Monica, CA, who treats some of the most aggressive brain tumors, had few options to offer his patients. Today, thanks to advances in genetic sequencing, he has been able to identify genetic mutations in the tumors of one third to one half of his patients. As sequencing becomes more sophisticated it provides a host of new targets for drug therapies.
A particular mutation may make a tumor more vulnerable to a specific drug. For example, the MGMT gene produces a protein that helps cells repair themselves. It also protects cancer cells from the lethal effects of some chemotherapy, allowing them to proliferate, resulting in tumor growth. In patients with glioblastoma multiforme (GBM), an aggressive brain tumor, a mutation in MGMT can be beneficial because the MGMT repair protein doesn't work as well. In these patients, the chemotherapy drug temozolomide can be more effective because the mutation means the cancer cells cannot repair themselves, and they die.
Dr. Kesari thinks in five to 10 years this level of precise testing, imaging, and treatment in oncology will become routine in many other fields of medicine.
Exome Sequencing
The development of exome sequencing—a partial sequencing of a person's DNA—has allowed doctors to identify genes responsible for specific diseases. For example, cerebellar ataxia, a condition that affects coordination and balance, could be caused by any of more than 600 different genes. Before exome sequencing, finding the exact gene was like looking for a needle in a haystack, says Brent L. Fogel, MD, PhD, FAAN, associate professor of neurology and human genetics at UCLA who researches, diagnoses, and treats genetic forms of ataxia.
Now, instead of looking for a mutation in a person's entire DNA, a researcher can use exome sequencing to look at just the parts of the DNA that code for proteins—the exons. These constitute about 1 percent of a person's DNA and hold the clues to most genetic disorders. By narrowing the test to these precise regions of the DNA, sequencing is now both cheaper and quicker. It also means researchers can identify the proteins likely to be affected by a mutation. When Dr. Fogel and his team suspect a patient has ataxia, they look for mutated protein-producing exons and diagnose and treat him or her accordingly.
For example, one of his patients, a 9-year-old girl, came to him with coordination difficulties so pronounced she would soon need a wheelchair. She had been to many doctors without receiving a diagnosis. After performing exome sequencing, Dr. Fogel discovered she had a mutation in SLC52A2, a gene that controls a protein that transports vitamins, in her case moving riboflavin between cells. After finding the mutated gene, he treated her with high-dose riboflavin, which she will take for the rest of her life. Five years later, she has stabilized, and her symptoms are controlled. Before precision medicine she may have remained undiagnosed and become severely disabled.
While not every diagnosis leads to a direct and successful treatment, just being able to diagnose a particular form of ataxia has tangible benefits, such as being able to make a better prognosis or avoiding treatments that will not work.
Developments in Precision Medicine
Identifying Antibodies
The ongoing discovery of antibodies continues to contribute to precision medicine. In 2007 Josep O. Dalmau, MD, PhD, FAAN, adjunct professor of neurology at the University of Pennsylvania in Philadelphia, and colleagues discovered that anti-N-methyl-D-aspartate (NMDA) antibodies caused a previously undiagnosed and rare form of autoimmune encephalitis, which occurs when the body's own immune system attacks a part of the brain instead of a virus or bacterium.
Since then a team led by Eric Lancaster, MD, PhD, assistant professor of neurology at the University of Pennsylvania, has identified other antibodies that cause forms of autoimmune encephalitis as well as the part(s) of the brain they attack. They have also developed tests to detect proteins in cerebrospinal fluid that will tell them which antibody is attacking which part of the brain.
So far, the University of Pennsylvania team along with teams at the Mayo Clinic and the University of Oxford have discovered 16 new types of autoimmune encephalitis. Each one has a particular risk associated with it, and each has specific implications for treatments. For example, if a patient has anti-NMDA antibodies, she has a 50 percent chance of having a benign ovarian tumor. If a patient has GABAB antibodies, he has more than a 50 percent chance of having lung cancer. Identifying the antibody that causes a form of autoimmune encephalitis can lead to diagnosing and treating more serious underlying diseases or conditions.
As another example, patients who have the POLG gene, which is associated with a severe form of epilepsy, are predisposed to liver failure if exposed to the anticonvulsant valproate, says Bruce H. Cohen, MD, FAAN, director of the Neuro-Developmental Science Center at Akron Children's Hospital in Ohio.
Discovering Ion Pathways
Another advancement is the discovery that certain inherited forms of epilepsy are caused by mutations to the genes controlling ion pathways. These pathways are like tunnels with toll gates through the cell membranes that carry messages from inside the cell to outside and vice versa. Alterations to these tunnels affect how signals travel between neurons in the brain and can cause epilepsy.
Dr. Lowenstein has a patient with epileptic encephalopathy, a particularly severe form of epilepsy, who was found to have a mutation in one of the genes governing ion pathways. Researchers isolated the gene and introduced it into living frog cells so they could test various drugs on those cells. When they found that quinidine, a drug approved by the US Food and Drug Administration (FDA) for arrhythmia, appeared to reverse the effects of the mutation in the cells, the researchers sought approval from the FDA to try the drug on the patient. Because her disease was so severe—she had numerous uncontrollable seizures that were contributing to cognitive and neurologic decline—and the drug was considered relatively safe, her doctors received approval to test the drug, and her epilepsy was remarkably improved. Now she has fewer and less severe seizures.
But the treatments may not work for everyone. The quinidine, which was successful with Dr. Lowenstein's patient, was administered to other patients with mutations to the same gene. The results were mixed—it had no effect on some, little on others, and worked well with still others. The upshot? Simply identifying a mutated gene isn't always enough to deliver a targeted treatment successfully.
"We know patients are not just their biology," says James Giordano, PhD, professor of neurology and chief of the neuroethics studies program at Georgetown University Medical Center in Washington, DC. "They are nested within certain environments." So having a gene mutation may not be enough to trigger a disease. It may require a series of triggers in combination with the original mutation or triggers at particular stages.
Sorting Out Complex Conditions
To determine what causes complicated neurologic conditions, scientists need to identify how genes are expressed over a lifetime and how environmental and psychological triggers, and everything else that affects every person's unique makeup, combine to cause a particular condition. Finding and targeting biomarkers—genetic mutations, antibodies in spinal fluids, abnormal images on MRIs, sugar levels in blood, hormone levels in saliva that can be measured to indicate normal or abnormal bodily processes—may not be enough to solve the problem, says Dr. Giordano. Scientists also have to understand the mechanisms of the condition and validate the biomarker to make sure it really does cause a condition.
That's why using precision medicine for neurologic disorders is complicated, says James Beck, PhD, vice president of scientific affairs at the Parkinson's Disease Foundation, a division of the Parkinson's Foundation. For example, in some inherited cases of Parkinson's disease, a particular gene mutation damages dopamine neurons in the brain, causing their eventual death, but in most cases no obvious mutations in the coding region of the exome are to blame. As scientists come to better understand the part of the genome that includes DNA not turned into genes, they may identify other causes of this common disorder, says Dr. Cohen.
"The brain is a remarkable and complex entity," Dr. Lowenstein says. Because of this, the field of neurology may see gains from precision medicine much later than what has been seen in the field of oncology.
The Future of Precision Medicine
Building a Data Bank
Aggregating data from patients, their family members, and members of the general public could potentially lead to the next big breakthroughs, say Dr. Giordano and Spencer P. Hey, PhD, a precision medicine researcher at Harvard Medical School. Both say the computing tools exist to analyze vast quantities of data.
"The more data we have, the more we can pinpoint various factors that may influence both health and disease," says Dr. Giordano. Ideally, data banks would include information about lifestyle, environment, and social and psychological factors as well as input from exercise trackers such as Fitbit and other wearable technologies, says Dr. Kesari. "With more than just health data, we are more likely to see patterns that may lead to new discoveries."
The Precision Medicine Initiative calls for a voluntary cohort—the All of Us Research Program—of a million people to be set up to share data with researchers and for patients to be able to access any information from their own data. The program has already begun recruiting participants for a beta phase. Later this year the National Institutes of Health will begin voluntary recruitment for the cohort through a dedicated website or through participating health care providers. Anyone in the United States can participate. Patient security and protecting private data are paramount. To join the cohort or to learn more about the privacy and security protections, go to allofus.nih.gov.
Addressing Patients' Concerns
Since his brain surgery, Blotner, now 22, has shared a saliva sample for genomic sequencing with the International Low-Grade Glioma Registry. He hopes this will help researchers discover why some people develop these types of malignant brain tumors. This study will also look into what a diagnosis of low-grade glioma means for patients and how treatments affect their daily activities. To learn more about this study, go to the American Brain Tumor Association website.
Blotner has been working with local project leaders of GBM AGILE, a crowdsourcing data collaboration created by the National Biomarker Development Alliance that is looking for biomarkers and more information about glioblastoma multiforme. He is hoping to find ways to get patients and families involved in this research effort.
"I am one of the first to volunteer to share tissue samples of my brain tumor," he says. "I'm alive because of past research, and if I can contribute to the survival of future patients then I will do just about anything to help."
Not every patient is as willing. Anne Hall, now 58, was diagnosed with Parkinson's disease 10 years ago. A former athlete and chief counsel for the US Department of Health and Human Services and a patient advocate for the Parkinson's Foundation, Hall has participated in several clinical trials, including one involving deep brain stimulation (DBS). She is a strong believer in research and has consented to share some of her information from the DBS trial with other researchers, but she isn't ready to participate in large-scale data collections—not until she knows how the data are going to be shared, how participants can benefit, and what safeguards are in place.
Dr. Giordano agrees with her. At Georgetown University his team is pressing for legislation to protect participants from having their data used against them. In general, he believes that researchers must be open and clear about how the data will be used and by whom. And patients must be able to access any beneficial data if they want.
Some participants might like to know if they have a biomarker that may predict a future condition but others may not, and researchers have to respect that, says Hall. For instance, if she were 25 and part of a data group that found a biomarker for her developing Parkinson's disease in the future, she might not want to know that and live with the worry. On the other hand, if the data uncovered a biomarker for a condition that could be prevented or cured if treated early enough, she might want to know that.
Striking a balance between how big data banks benefit researchers and how they benefit patients may affect how many people are willing to participate.
In the meantime, Blotner and Hall are keeping a close eye on precision medicine, which they both believe holds the key to their futures and the course of their conditions.
