Transcript:
Amyotrophic Lateral Sclerosis (ALS) is a fatal, neurodegenerative illness that we must fight against as a society, stronger than we presently are. For a disease in which there is a new diagnosis every ninety minutes, a new death every ninety minutes, a life expectancy of only 3-5 years after onset, and a 0% chance of survival, we have not made nearly enough progress. The first gene associated with ALS was discovered about 20 years ago. Since then, all we have gathered is an assortment of potential causes, and that too coming nearly exclusively from studies on patients of European descent (ALS Association, NA). While it might be more exciting to look for a cure, the sequential next step is to attempt to establish a degree of correlation between ALS and particular genes in non-Caucasian populations.
Doing this will widen the field of potential causes/genes at play. If one of the genes from one of the many non-demographically diverse studies was discovered to be a legitimate cause, we would have known by now as many of these genes have been known by scientists for close to 20 years. Since this is not the case, it is time to think outside the box. It is known that ALS manifests differently in different demographic populations–Indian ALS patients are diagnosed with the disease at an earlier age and live longer with the disease compared to their European-descent counterparts (Sondhi et al. 2018). What if a novel gene discovered through tests on patients of non-Western demographics yields researchers their first definitive ALS-related gene correlation/causation. Taking this initiative is in the best interest of all patients since the disease is undeniably interlinked in all ALS patients; therefore, one breakthrough is all that is needed for the domino effect of research discoveries to begin. We must acknowledge that ALS is an illness that is lethal in 100% of cases and not as rare as some may think, and as such we must explore more avenues in searching for its cure. The aforementioned stark difference in manifestation of the illness in patients of differing demographics is primary evidence for why we must pursue this lead and uncover the genetic backbone of ALS in patients of this Indian demographic.
A recent study has been conducted by researchers at the All India Institute of Medical Sciences to address this gap in knowledge. To understand their methods, it’s first worth taking a closer look at the field of ALS research as a whole. A primary set of subtopics on ALS research is familial vs sporadic ALS. Unfortunately, many studies isolate these two, as some study only patients with sporadic ALS, while others look only at patients with familial ALS. Unfortunately, studies of this nature are focusing on the difference in pathology between these two branches of ALS instead of focusing on the similarities and common genes at play. It should be noted that both variations have a strong genetic basis (Narain et al. 2018). Another important set of sub-topics is limb onset vs bulbar onset. Limb onset means the first symptoms exhibit themselves in the limbs while bulbar onset means first symptoms are seen in effects on speech and swallowing. This study contains over 90% sporadic ALS cases, and single digit percentage familial cases, which is statistically representative of the true breakdown of the entire ALS population. The location of onset was mentioned in each individual patient’s profile but no overarching statement was made, which leads us to believe there was no intentional decision made here and that therefore, this too is statistically representative of the location of onset of all ALS patients. It should be noted that aside from the intentional focus on one particular demographic, this study is representative of the entire population of ALS patients in other pertinent manners.
As for ethical concerns regarding the field of ALS research, stem cells are the primary one. Stem cells are a primary method of studying ALS-affected motor neuron cells since isolating and studying these cells in a petri dish is much more effective and feasible than studying the cells in actual ALS patients. Additionally, stem cells offer great therapeutic promise as a potential treatment in themselves. However, a key ethical concern is that prototypical stem cells come from human embryos. To complicate matters, while there are ethical concerns to studying stem cells, there are even more ethical concerns to subjecting ALS patients to experimental test conditions just to be able to examine their motor neurons. As a result, the ALS research field as a whole faces a nuanced set of ethical concerns, which partly explains but is not an excusatory factor for the lack of progress, awareness, and funding in this field over the last 20 years. The study by Narain et al. did not have to deal with any of these aforementioned ethical concerns since this was a study focused on making advancement towards a cause, not a cure.
There is no hypothesis since while this was an experiment in which the scientists attempted to find the genetic basis of Indian ALS patients, they did not have any guess beforehand as to what these genes would be. The findings were 13 pathogenic variants in ALS-related genes in Indian ALS patients. Of these 13, 6 were already known from studies on European populations but 7 were novel/rare (Narain et al. 2018).
To get these results, it was genetic sequencing that the researchers conducted. First, they created an ALS gene panel using Illumina Design Studio. This panel included 25 genes with some level of prior association with ALS. They then took blood samples from the subjects, from which they took the DNA and isolated the aforementioned genes. They did this by breaking the DNA down to form shorter DNA molecules (formally called ‘oligonucleotides’) that each carried the targeted genes. Afterwards, they analyzed this sequencing data. It is a fairly straightforward method; the only potential places for contention are the software being used or the total number of genes included in the panel.
People who conducted this study were responding not to one particular previous study, but to the overall context that most previous studies looked only at European-descent populations. It is true that the majority of ALS patients are white, however, when minority demographics of ALS have been examined in the past, there have been unique gene discoveries. Additionally, there is no precedent for a study of this kind in an Indian population, so the people who conducted this study were trying to extrapolate the concept of discovering new gene affiliations when studying various ethnic groups to an unexplored group with a different phenotypic expression of the illness. The lack of a genetic database on Indian ALS patients led to the broad scope, undefined specific question, and lack of hypothesis in this study.
The study could be improved by following up or continuing the study and focusing on the 7 gene aberrations that are prevalent in Indian ALS patients that had not been discovered in European-descent ALS patients. The researchers also could have proposed a hypothesis and performed a more experimental, less information-gathering centered experiment since ultimately, it is the experiments about the application of the genetic information that are important to moving closer to a cure. However, given the aforementioned lack of an information database at all for Indian ALS patients, I understand and support the rationale for the type of experiment performed. It was a first step but a necessary first step–gathering a baseline of information to better equip future researchers in pursuit of finding a definitive cause(s). Additionally, I had no qualms with the specific methods used in this particular experiment. Those are all my own observations. As for flaws admitted by the researchers, the main two are the screening of a limited number of genes (I agree with this assessment) and the small sample size of 154 (an assessment I do not agree with, since ALS is an incredibly rare disease and putting together a large sample size is often not possible). The researchers do, however, start the very next sentence with the word “nonetheless”, followed by the fact that they are the first study to screen for novel genetic aberrations in Indian ALS patients, from which I infer that they viewed the study to be pioneering, and therefore a positive development.
The larger implication of this study is that the genetic blueprint for ALS in Indian patients is definitively different than their European-descent counterparts, and through prior secondary sources and statistics we can see this was what made for a very different course of progression of the illness. While this altered disease timeline does not bring about the necessity for a different treatment of symptoms since the terminal symptoms are the same in all patients and there are essentially still no legitimate treatments, it does provide a stimulus for more critical research questions in the search for the genetic and environmental causes of this illness, which thereafter would facilitate the search for a cure. A cure for an illness that, once again, the moment patients are handed their diagnosis is equivalent to a death sentence, with no appeal possible. Finally, in the context of the broad field of medical research, this study goes to show we must diversify pathological studies as a whole–especially in the case of rare diseases–since the different genetics of different demographics of people can lead to novel discoveries, which provide more critical information to the pursuit of a cure for all.
“My head. I can talk. I can kind of wiggle my fingers and stuff, I can’t lift my hands. I can move my legs but I can’t lift them. I can’t walk. Can’t feed myself.”
“For the last year he’s been practicing with the computer. His eye works as the cursor. A blink acts like the click of a mouse. Mike Brom is preparing for the day when he can no longer talk.”
It is vital to look at this study for what it is: a collection of individuals, individuals with lives, families, people and aspirations to live for—not merely statistics in a study.
“We don’t have a survivor. There’s not really a survivor of ALS. You’re living with ALS. There’s no remission. And that’s the difference, there are survivors of cancers, there’s remission of cancer.”
It is with this point of view that we as a society will cultivate the sense of urgency necessary to improve health outcomes and save lives.
Bibliography:
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Featured Image Citation:
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