What is a disease? This seemingly abstract and theoretical question is actually among the most practical questions in all of biomedicine. How patients are diagnosed, treated, managed and excused from various social and moral obligations hinges on the answer that is given. So do issues of how research is done and health care paid for. The question is also becoming one of the most problematic issues that those in health care will face in the next decade.
"The revolution in our understanding of the human genome, molecular biology, and genetics is creating a huge--if little acknowledged--shift in the understanding of what a disease is."
That is because the current conception of disease is undergoing a revolutionary change, fueled by progress in genetics and molecular biology. The consequences of this shift in the definition of disease promise to be as impactful as any other advance in biomedicine has ever been, which is admittedly saying a lot for what is in essence a conceptual change rather than one based on an empirical scientific advance.
For a long time, disease was defined by patient reports of feeling sick. It was not until the twentieth century that a shift occurred away from subjective reports of clusters of symptoms to defining diseases in terms of physiological states. Doctors began to realize that not all symptoms of fever represented the presence of the same disease. Flu got distinguished from malaria. Diseases such as hypertension, osteoporosis, cancer, lipidemia, silent myocardial infarction, retinopathy, blood clots and many others were recognized as not producing any or slight symptoms until suddenly the patient had a stroke or died.
The ability to assess both biology and biochemistry and to predict the consequences of subclinical pathological processes caused a distinction to be made between illness—what a person experiences—and disease—an underlying pathological process with a predictable course. Some conditions, such as Gulf War Syndrome, PTSD, many mental illnesses and fibromyalgia, remain controversial because no underlying pathological process has been found that correlates with them—a landmark criterion for diagnosing disease throughout most of the last century.
"Diseases for which no relationship had ever been posited are being lumped together due to common biochemical causal pathways...that are amenable to the same curative intervention."
The revolution in our understanding of the human genome, molecular biology, and genetics is creating a huge--if little acknowledged--shift in the understanding of what a disease is. A better understanding of the genetic and molecular roots of pathophysiology is leading to the reclassification of many familiar diseases. The test of disease is now not the pathophysiology but the presence of a gene, set of genes or molecular pathway that causes pathophysiology. Just as fever was differentiated into a multitude of diseases in the last century, cancer, cognitive impairment, addiction and many other diseases are being broken or split into many subkinds. And other diseases for which no relationship had ever been posited are being lumped together due to common biochemical causal pathways or the presence of similar dangerous biochemical products that are amenable to the same curative intervention, no matter how disparate the patients' symptoms or organic pathologies might appear.
We used to differentiate ovarian and breast cancers. Now we are thinking of them as outcomes of the same mutations in certain genes in the BRCA regions. They may eventually lump together as BRCA disease.
Other diseases such as familial amyloid polyneuropathy (FAP) which causes polyneuropathy and autonomic dysfunction are being split apart into new types or kinds. The disease is the product of mutations in the transthyretin gene. It was thought to be an autosomal dominant disease with symptomatic onset between 20-40 years of age. However, as genetic testing has improved, it has become clear that FAP's traditional clinical presentation represents a relatively small portion of those with FAP. Many patients with mutations in transthyretin — even mutations commonly seen in traditional FAP patients — do not fit the common clinical presentation. As the mutations begin to be understood, some people that were previously thought to have other polyneuropathies, such as chronic inflammatory demyelinating neuropathy, are now being rediagnosed with newly discovered variants of FAP.
"We are at the start of a major conceptual shift in how we organize the world of disease, and for that matter, health promotion."
Genome-wide association studies are beginning to find many links between diseases not thought to have any connection or association. For example some forms of diabetes, rheumatoid arthritis and thyroid disease may be the products of a small family of genetic mutations.
So why is this shift toward a genetic and molecular diagnostics likely to shake up medicine? One obvious way is that research projects may propose to recruit subjects not according to current standards of disease but on the basis of common genetic mutations or similar errors in biochemical pathways. It won't matter in a future study if subjects in a trial have what today might be termed nicotine addiction or Parkinsonism. If the molecular pathways producing the pathology are the same, then both groups might well wind up in the same trial of a drug.
In addition, what today look like common maladies—pancreatic cancer, severe depression, or acne, for example, could wind up being subdivided into so many highly differentiated versions of these conditions that each must be treated as what we now classify as a rare or ultra-rare disease. Unique biochemical markers or genetic messages may see many diseases broken into a huge number of distinct individual disease entities.
Patients may find that common genetic pathways or multiple effects from a single gene may create new alliances for fund-raising and advocacy. Groups fighting to cure mental and physical illnesses may wind up forgetting about their outward differences in the effort to alter genes or attack common protein markers.
Disease classification appears stable to us—until it isn't. And we are at the start of a major conceptual shift in how we organize the world of disease, and for that matter, health promotion. Classic reductionism, the view that all observable biological phenomena can be explained in terms of underlying chemical and physical principles, may turn out not to be true. But the molecular and genetic revolutions churning through medicine are illustrating that reductionism is going to have an enormous influence on disease classification. That is not a bad thing, but it is something that is going to take a lot to get used to.
At age 52, Glen Rouse suffered from arm weakness and a lot of muscle twitches. “I first thought something was wrong when I could not throw a 50-pound bag of dog food over the tailgate of my truck—something I use to do effortlessly,” said the 54-year-old resident of Anderson, California, about three hours north of San Francisco.
In August, Rouse retired as a forester for a private timber company, a job he had held for 31 years. The impetus: amyotrophic lateral sclerosis, or ALS, a progressive neuromuscular disease that is commonly known as Lou Gehrig’s disease, named after the New York Yankees’ first baseman who succumbed to it less than a month shy of his 38th birthday in 1941. ALS eventually robs an individual of the ability to talk, walk, chew, swallow and breathe.
Rouse is now dependent on ventilation through a nasal mask and uses a powerchair to get around. “I can no longer walk or use my arms very well,” he said. “I can still move my wrists and fingers. I can also transfer from my chair to the toilet if I have two of my friends help me.”
It’s “shocking” that modern medicine has very little to offer to people with this devastating condition, Rouse said. But there is hope on the horizon. Yesterday, the U.S. Food and Drug Administration approved Relyvrio, a drug made up of two parts, sodium phenylbutyrate and taurursodiol, to treat patients with ALS.
“This approval provides another important treatment option for ALS, a life-threatening disease that currently has no cure,” said Billy Dunn, director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research, in a statement. “The FDA remains committed to facilitating the development of additional ALS treatments.”
Until this point, the FDA had approved only two other medications—Riluzole (rilutek) in 1995 and Radicava (edaravone) in 2017—to extend life in patients with ALS, which typically kills within two to five years after diagnosis. That’s why earlier this week, Rouse was optimistic about the FDA’s likely approval of a controversial new drug for ALS.
When Relyvrio is taken in addition to Riluzole, it appears to slow functional decline by an additional 25 percent and extend life by another 6 to 10 months, said Richard Bedlak, director of the Duke ALS Clinic. “It is not a cure, but it is definitely a step forward.”
“The whole ALS community is extremely excited about it,” he said the day before Relyvrio’s expected approval. “We are very hopeful. We’re on pins and needles.”
A study of 137 ALS patients did not result in “substantial evidence” that Relyvrio was effective, the agency’s Peripheral and Central Nervous System Drugs Advisory Committee concluded in March. However, after some persuasion from FDA officials, patients and their families, the committee met again and decided to recommend approving the drug.
In January 2019, following an ALS diagnosis at age 58 in October the previous year, Jeff Sarnacki, of Chester, Maryland, was accepted into a trial for Relyvrio. “Because of the trial, we did experience hope and a greater sense of help than had we not had that opportunity,” said Juliet Taylor, his wife and caregiver. They both believed the drug “worked for him in giving him more time.”
In June 2019, Sarnacki chose an open-label extension, offered to patients by drug researchers after a study ends, and took the active drug until he died peacefully at home under hospice care in May 2020, five days after his 60th birthday. A retired agent with the federal Bureau of Alcohol, Tobacco, Firearms and Explosives who later worked as a security consultant, Sarnacki lived about 19 months after diagnosis, which is shorter than the typical prognosis.
His symptoms began with leg cramps in fall 2017 and foot drop in early 2018. A feeding tube was placed in 2019, as it became necessary early in his illness, Taylor said. He also took Radicava and Riluzole, the two previously approved drugs, for his ALS. “We were both incredulous that, so many years after Lou Gehrig’s own diagnosis, there were so few treatments available,” she said.
The dearth of successful treatments for ALS is “certainly not for lack of trying,” said Karen Raley Steffens, a registered nurse and ALS support services coordinator at the Les Turner ALS Foundation in Skokie, Ill. “There are thousands of researchers and scientists all over the world working tirelessly to try to develop treatments for ALS.”
Unfortunately, she added, research takes time and exorbitant amounts of funding, while bureaucratic challenges persist. The rare disease also manifests and progresses in many different ways, so many treatments are needed.
As of 2017, the Centers for Disease Control and Prevention estimated that more than 31,000 people in the U.S. live with ALS, and an average of 5,000 people are newly diagnosed every year. It is slightly more common in men than women. Most people are diagnosed between the ages of 55 and 75.
Most cases of ALS are sporadic, meaning that doctors don’t know the cause. There is about a one-year interval between symptom onset and an ALS diagnosis for most patients, so many motor neurons are lost by the time individuals can enroll in a clinical trial, said Richard Bedlack, professor of neurology and director of the Duke ALS Clinic in Durham, North Carolina.
Bedlack found the new drug, Relyvrio, to be “very promising,” which is why he testified to the FDA in favor of approval. (He’s a consultant and disease state speaker for multiple companies including Amylyx, manufacturer of Relyvrio.)
The “drug has different mechanisms of action than the currently approved treatments,” Bedlack said. He added that, when Relyvrio is taken in addition to Riluzole, it appears to slow functional decline by an additional 25 percent and extend life by another 6 to 10 months. “It is not a cure, but it is definitely a step forward.”
T. Scott Diesing, a neurohospitalist and director of general neurology at the University of Nebraska Medical Center in Omaha, said he hopes the drug is “as good as people anticipated it should be, because there are not too many options for these patients.”
So far, Rouse's voice is holding up, but he knows the day will come when ALS will steal that and much more from him.
ALS is 100 percent fatal, with some patients dying as soon as a year after diagnosis. A few have lasted as long as 15 years, but those are the exceptions, Diesing said.
“If this drug can provide even months of additional life, or would maintain quality of life, that’s a big deal,” he noted, adding that “the patients are saying, ‘I know it’s not proven conclusively, but what do we have to lose?’ So, they would like to try it while additional studies are ongoing.” The drug has already been conditionally approved in Canada.
As his disease progresses, Rouse hopes to get a speech-to-text voice-generating computer that he can control with his eyes. So far, his voice is holding up, but he knows the day will come when ALS will steal that and much more from him. He works at I AM ALS, a patient-led community, and six of his friends have already died of the disease.
“Every time I lose a friend to ALS, I grieve and am sad but I resolve myself to keep working harder for them, myself and others,” Rouse said. “People living with ALS find great purpose in life advocating and trying to make a difference.”
The Friday Five covers important stories in health and science research that you may have missed - usually over the previous week, but today's episode is a lookback on important studies over the month of September.
Most recently, on September 27, pharmaceuticals Biogen and Eisai announced that a clinical trial showed their drug, lecanemab, can slow the rate of Alzheimer's disease. There are plenty of controversies and troubling ethical issues in science – and we get into many of them in our online magazine – but this news roundup focuses on scientific creativity and progress to give you a therapeutic dose of inspiration headed into the weekend and the new month.
This Friday Five episode covers the following studies published and announced over the past month:
- A new drug is shown to slow the rate of Alzheimer's disease
- The need for speed if you want to reduce your risk of dementia
- How to refreeze the north and south poles
- Ancient wisdom about Neti pots could pay off for Covid
- Two women, one man and a baby