Understanding the biology of a fatal disease
Damian* was 55 years old when he first noticed something was not right with his hands. His fingers had started betraying his commands, making it more and more difficult to button his shirt and tie his shoes. Despite being proud of his balance and fitness, he often stumbled over and fell straight on his face before his hands could block the fall. Weirdest of all were the fast palpitations, clinically called fasciculations, that would start out of nowhere in the area between his thumb and index finger and last several minutes. He thought maybe stress and too much coffee were to blame for these symptoms. Worst case, he thought they could be caused by some kind of hernia that is squeezing his nerves. He decided to mention it to his doctor during his annual checkup. Never did he think that it could be worse than a simple hernia until his doctor studied the muscle tone in his arms and legs and referred him to a neurologist right away. After several months of multiple tests and worsening symptoms, he was diagnosed with the worst of the worst. Its name was Amyotrophic Lateral Sclerosis.
Amyotrophic Lateral Sclerosis, ALS, is also known as Lou Gehrig’s disease after the famous New York Yankees player who was nicknamed the ‘iron horse’ of baseball for more consecutive games than any other player until his diagnosis at the young age of 36. Affecting over 30,000 patients in the US alone, ALS is the most frequent adult-onset paralytic disorder and the third most common neurodegenerative disease, after Alzheimer’s and Parkinson’s. The disease is found worldwide, with a prevalence of roughly 3–5 per 100,000 individuals. Onset of symptoms is usually in the fourth or fifth decade of life with about 10% of the cases beginning before the age of 40 and less than 5% before the age of 30. According to ALS CARE Database, 60% of patients are men and over 90% of them are Caucasian. However, to this day, no causal effects involving ethnic, racial or socioeconomic factors have been established with the disease.
Like in Damian’s case, common clinical features of the disease start with muscle weakness and wasting of voluntary muscles, such as the ones in hands, arms and legs, followed by problems with swallowing and speech, eventually leading to paralysis and respiratory failure. Even though the disease does not majorly affect the mental state and cognition, the muscles of the patient progressively shut down making patients feel like they are getting locked inside their bodies until their death within three to five years of diagnosis. To date, only a few approved treatments, such as mechanical ventilation and the drugs riluzole and Radicava (edaravone), prolong survival to some extent in ALS patients. However, the disease’s cause and mechanism by which it progresses remain largely a mystery to researchers. So, what do we already know about the biology of ALS and why is it so hard to stop, cure or prevent?
Pathologically, ALS is characterized by a loss of motor neurons that connect the brain and the spinal cord to muscles throughout the body resulting in the deterioration of muscles that no longer receive input from the brain. Specifically, the motor neurons undergo a so-called ‘die-back’ mechanism by which their neuromuscular junctions and nerve terminals connecting neurons to muscle die followed by their cell bodies. This is why by the time patients start noticing muscle weakness symptoms, most of the neuromuscular junctions are dead and it is too late in the disease progress to intervene and stop successfully.
Moreover, ALS is a heterogeneous disorder: researchers over the span of 20 years found more than a dozen genes causing the disease. Even though all of these genes have differing functions in the body, mutations in these genes result in the same disease process, making it very difficult to understand how the motor neurons die. ALS is mostly a sporadic disease where only about 5–10% of cases are hereditary. However, the same genetic mutations and disease mechanisms are involved in all these cases. Additionally, researchers have found that motor neurons die in multiple ways, ranging from defects in RNA metabolism and protein homeostasis to endoplasmic reticulum stress and mitochondrial dysfunction (resulting in defects in cells’ energy production), making it impossible to fight the disease through one target mechanism.
For the longest time, researchers focused their efforts on studying the disease on motor neurons themselves, since they were the main victims of ALS. However, studies about 10 years ago started to discover that cells neighboring the motor neurons in the brain and the spinal cord, such as astrocytes, that support and provide for neurons under healthy conditions, contribute to their demise during the disease process. Moreover, recent findings in the field show that even innate immune cells, the defense system of the body that the central nervous systems was thought devoid of, get involved in the disease. All of these biological aspects render the disease very complicated to fully understand and to cure.
However, several recent scientific advances are showing promise and reasons to be optimistic. These advances include finding biomarkers that can help detect the disease earlier, as well as creating new animal models that more accurately mimic the human disease. One such development is the antisense oligonucleotide (ASO) therapy. ASOs are short single-stranded DNA molecules, which once taken up by a cell, can target and degrade the messenger RNA of a gene-of-interest before it becomes a protein. Using this technology to eliminate the production of ALS-causing proteins in motor neurons, scientists were able to carry this therapy to clinical trials with very promising results. Similarly, recent advances made on human induced pluripotent stem cells (iPSCs), skin or blood-derived cells that are reprogrammed into an embryonic-like pluripotent state, from ALS patients enabled scientists to develop new models to study and understand the disease more efficiently. Together, these advances will unlock the mysteries of this horrible disease and will make the development of rapid and efficient therapies possible.
*Damian is a fictional character created to exemplify a common patient profile.