Technological Advancements in ALS Research and Drug Development
Throughout the past few years, there has been a significant increase in the amount of attention and awareness relating to the disease ALS (Amyotrophic Lateral Sclerosis). ALS is recognized as one of the deadliest diseases that does not have a cure. Around 3 to 5 people for every 100,000 people present the total amount of cases that arise per year around the globe (Al-Chalabi 2017). As ALS paralyzes most of the human body, the body’s function and movement slowly deteriorates as the disease spreads and matures, initially targeting the brain and the spinal cord (Al-Chalabi 2017). ALS also damages the ability to talk as the disease worsens (Revell). As the paralysis spreads quickly around the body, the respiratory system begins to fail, and ALS patients have few years to live. Though there are two main drugs that the FDA has approved to weaken the advancement of the disease, there is no cure that currently exists for ALS (Hirschler). The epidemiologic causes of ALS have been linked to familial and sporadic features that differ through genetic and non-genetic inheritance as well as various environmental factors (Al-Chalabi 2017). Advancement in AI technology has progressively begun to find genetic causes of ALS and has helped within the development of drugs that help prevent and cure the disease (Hirschler). The eyes and the muscles that control the eyes are rarely effected by ALS and can connect to modern technology that is created to help people that suffer from ALS communicate with others. While no cure currently exists for ALS, advancement in research and evaluation of environmental and genetic factors have linked the disease to multiple genes that may cause ALS and have led to the evaluation and advancement of drugs and technological innovations that slow down the progression of ALS.
Amyotrophic Lateral Sclerosis, otherwise known as ALS or Lou Gehrig’s disease, is a crippling disorder that progressively attacks various parts of the body. ALS has many effects on the neurological functionality of the brain as it attacks the upper and lower neurons of the brain (Al-Chalabi 2017). While upper motor neurons of the brain begin to deteriorate, ALS patients usually experience stiffness and spasms in their muscles (Al-Chalabi 2017). While lower motor neurons of the brain are impacted, ALS patients experience twitches in their muscles (Al-Chalabi 2017). As ALS patients neurons are affected, their bodies slowly begin to fail as the paralysis from the loss of function of the lower and upper neurons spreads throughout the body. The name Amyotrophic Lateral Sclerosis originates from the “degeneration of the corticospinal axons…(sclerosis) of the lateral aspects of the spinal cord…[and]…as the brain stem and spinal motor neurons die, there is thinning of the ventral roots and denervational atrophy (amyotrophy) of the muscles of the tongue, oropharynx, and limbs” (Al-Chalabi 2017). Though most cases of ALS originate in the limbs of the body, one third of ALS cases occur in the bulbar region of the brain (Al-Chalabi 2017). While most cases of ALS begin in the limbs of the body, those that begin in the bulbar region affect the functions of the mouth such as swallowing, talking or eating (Al-Chalabi 2017). Though ALS initially affects the limbs and the bulbar, it has delayed affects on the movement of the eyes and the sphincter muscles (Al-Chalabi 2017). The internal ramification of ALS can be connected to the increased changes in behavior, which can lead to dementia, and the inability to walk due to the paralysis of the body (Al-Chalabi 2017). As ALS significantly deteriorates the human body, its cause can be linked to sporadic and familial origins.
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ALS can be categorized as sporadic or familial (Al-Chalabi 2017). About 90% of cases of ALS are sporadic, and thus randomly found in patients that develop the disease on their own (Al-Chalabi 2017). About 10% of cases of ALS are familial and inherited from mutations of family members that pass down the genes that cause ALS (Bennett 2018). While males are more susceptible to be affected by sporadic ALS, the ratio of familial ALS have the same chances between gender (Al-Chalabi 2017). Though ALS typically affects people in their 50s, familial ALS can originate in teens (Al-Chalabi 2017). Though sporadic and familial ALS affect various people throughout the world, both are deadly and can be commonly linked to various genes within the body.
While looking at sporadic and familial cases of ALS, both categorizations typically display the aggregation and delocalization of TAR DNA-binding protein 43 (TDP-43) while sporadic ALS commonly displays superoxide dismutase 1 (SOD1) as well as 45% of cases displaying C9ORF72 (Al-Chalabi 2017). Though these genes are usually linked to sporadic and familial ALS, there are various genes that lead to the onset of the disease, thus making it challenging for researchers to connect a specific gene towards the development of ALS. Specifically, over one hundred and twenty genetic variants have been connected to the development of ALS (Al-Chalabi 2017). Researchers typically categorize ALS genes into three distinct groups that relate to “protein homeostasis, RNA homeostasis and trafficking and cytoskeletal dynamics” (Al-Chalabi 2017). While researchers analyze the three groups, there are many distinct characteristics that fit within each categorization and push for varying analysis of each group. The most commonly experimented grouping relates to protein homeostasis as the collection of clustered proteins and deficiencies that cells experience can be tied to mutations in the SOD1 gene (Al-Chalabi 2017). A potential reason for the frequent analysis of genes that relate to protein homeostasis could be that the SOD1 gene was the first gene linked to ALS, thus allowing researchers to further experiment with the gene more often than other genes. The grouping of RNA homeostasis and trafficking is commonly linked to TDP-43 which was the first RNA binding protein to be discovered in the body, while the most typically mutated gene is C9ORF72 (Al-Chalabi 2017). Researchers have yet to conclude why RNA binding proteins cause ALS (Al-Chalabi 2017). While analyzing the grouping of genes relating to cytoskeletal dynamics, three genes named DCTN1, PFN1 and TUBA4A have been identified as ALS genes (Al-Chalabi 2017). While multiple genes are aggregated and grouped into different categories, sporadic ALS has also been found to relate to environmental factors that may cause the disease.
Due to the random onset of sporadic ALS, it is typically challenging to distinctly link sporadic ALS to certain environmental factors. Due to the high death rate of ALS patients, it is challenging to find somebody in the early stages of ALS and help define the environmental onset of the disease. Varying conclusions have tied service in the military, smoking and exposure to dangerous metals, electromagnetic fields and pesticides as risk factors that increase the chances of a patient developing ALS (Al-Chalabi 2017). Researchers have also tested various viruses in connection to ALS and have only identified one retrovirus, K, that may cause sporadic ALS (Al-Chalabi 2017). Trauma could also relate to ALS as researchers have analyzed various injuries, and fractures that could potentially cause the disease and have discovered a connection between concussions and the increased risk of developing ALS (Al-Chalabi 2017). These traumatic factors have also been tied with the RNA binding protein, TDP-43 (Al-Chalabi 2017). As sporadic ALS develops in the body, these various environmental factors typically affect the functionality of the body and the development of ALS. Though the disease is sporadic, humans can stay away from some of these risk factors and try to limit the amount of environmental exposure they have with various risks such as working with dangerous metals or electromagnetic fields so they maintain a lower chance of environmentally acquiring the disease. Though environmental and genetic causes of ALS tend to differ, the presence of TDP-43 in some ALS patients can link sporadic and familial ALS as well as environmental and genetic inheritance. Although all of these types of ALS and ways of acquiring the disease differ, the common presence of TDP-43 should be further investigated as it connects to each form of ALS and each cause of ALS. Though investigations involving the RNA binding protein TDP-43 are currently happening as researchers strive to find a concrete cause for the disease, various researchers are using AI technology to investigate the causes and cures for ALS.
As ALS has no specific cure, there are many scientists, AI systems and institutions doing research relating to finding a drug that cures the disease and studying how the disease develops, specifically genes that cause ALS. There are currently two drugs, Riluzole and Edaravone, that are approved by the FDA for ALS treatment, though the drugs do not completely help with survival from the disease and ALS patients still face a high risk of death while taking the drugs (Al-Chalabi 2017). There are currently no drugs in clinical trial that are able to defeat the disease and adeno-associated viruses as well as stem cell research have led to few conclusions that strictly find the single genetic cause of ALS, as the disease has been found to be caused by various genes in the body (Al-Chalabi 2017). Though there are no conclusions that explicitly target the cause and cure for ALS, AI research has sped up the process of finding the answers to these problems.
Richard Mead, an English researcher, has found that artificial intelligence (AI) research and machines have helped him speed up the process of finding the origination and a cure for ALS (Hirschler 2017). AI systems scan through various amounts of data, published research and various scientific databases in order to help find a cause and cure for the disease (Hirschler 2017). Though Mead has not found a specific gene that causes ALS or a cure for ALS, Mead has found one proposal from the AI systems that leads to potentially stopping the death of motor neurons and slowing down the beginning of the disease (Hirschler 2017). Though Mead has not identified a direct biological gene or cure for the disease, his findings could potentially halt the development of ALS. Other groups such as the Barrow Neurological Institute have identified various genes connected to the disorder through AI research.
Using IBM’s supercomputer Watson, researchers at the Barrow Neurological Institute were able to identify five genes that are connected to ALS (Hirschler 2017). Many mutated RNA binding proteins contribute towards the development of ALS (Argentinis 2018). As 11 RNA binding proteins have been identified as the cause of familial ALS and 6 more atypical forms of RNA binding proteins have been found in connection with ALS, the Barrow Neurological Institute was able to identify 5 RNA binding proteins that contribute towards the cause of ALS using Watson’s assistance (Argentinis 2018). Similarly to Mead’s research, Watson sifted through various scientific documents and published research to identify RNA binding proteins that caused ALS (Argentinis 2018). The researchers at Barrow identified the top ten RNA binding proteins that Watson found and tested the RNA binding proteins with ALS tissues and control tissues, thus leading to the discovery of 5 new undiscovered RNA binding proteins named hnRNPU, Syncrip, RBMS3, Caprin-1 and NUPL2 that showed atypical changes when tested with ALS tissue (Argentinis 2018). The Barrow Neurological Institute’s approach has significantly contributed towards research that focuses on the development of ALS and the specific genes it attacks. Watson was able to identify five undiscovered genes and Barrow’s use of Watson’s advanced research style significantly sped up the process of finding various genes that abnormally responded to ALS tissue and were changed when exposed to the ALS tissue. Barrow’s successful use of Watson’s research system can lead to the use of various AI systems that can quickly identify genes that have yet to be discovered by humans. Watson’s findings lead to the increased and proven use of AI technology that is validated and will be used to find the cause and cure of ALS in the future. While Watson was not able to identify a cure for ALS, human research has identified potential ways of slowing down the progression of ALS.
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Recently, human researchers conducted an experiment that tested the effects of adding regulatory T cells to patients with ALS. The researchers tested three patients that have sporadic ALS and were at different stages of the progression of their ALS (Appel 2018). The researchers took a sample of white blood cells from the three patients and added four doses of the regulatory T cells to the samples over two months during the early stages of the disease (Appel 2018). After adding the first four doses, the researchers added four doses of the regulatory T cells to the samples over four months during the more developed and ending stages of the disease and regulatory T cells were found to slow the advancement and development of ALS over time (Appel 2018). Though regulatory T cells were infused into patients’ blood and slowed down the progression of ALS, further research could be analyzed on a larger sample size over a longer period of time at different doses speeds in order to further validate this research (Appel 2018). Regulatory T cells can help advance research on the progression of ALS, though the T cells did not directly end the disease in the experiment. As the human researchers that tested the regulatory T cells move into more advanced trials, the researchers could potentially pinpoint a direct dosage and timing of the deliverance of T cells in order to slow down the growth of ALS. Though the infusion of T cells to the three patients tissue, human researchers have found specific T cells that can help progress the advancement of the treatment of ALS. As T cells help slow the progression of ALS, other proteins have helped contribute towards finding a treatment to ALS.
Recently, various human researchers have identified a therapeutic polymerase that helps attack TDP-43. As TDP-43 is one of the most common genes in sporadic and familial ALS, researchers strive to find something that blocks the growth of TDP-43 related disease and neurodegeneration. The researchers downregulated PAR, otherwise known as tankyrase, which is necessary for the collection and growth of TDP-43 stress granules (Bonini 2018). The “Stress granule localization initially protects TDP-43 from disease-associated phosphorylation, but upon long-term stress, stress granules resolve, leaving behind aggregates of phosphorylated TDP-43” (Bonini 2018). As the researchers hindered PAR, it helped stop the formation of TDP-43 and did not affect the gathering of stress granules (Bonini 2018). Through reducing the amount of PAR, researchers were able to stop the growth of TDP-43 and the related diseases it causes and neurodegeneration within the body (Bonini 2018). As researchers continue to evaluate PAR, decreasing the amount of PAR in the body could lead to the reduction and treatment of diseases associated with TDP-43. Though researchers attempt to cure ALS, modern treatment options are currently costly and are very challenging for people with ALS to acquire.
As no cure has been found for ALS, the economic ramifications of the disease significantly impact the ALS patient as well as their support system, for example their family, that pays for treatment from the disease. While ALS costs and treatment have been analyzed, ALS remains one of the most expensive diseases to treat and live with. Researchers have studied over twelve studies from eight countries between January 2001-2015 and have begun to estimate the total cost of ALS across each specific country. While converting costs from these studies to the value of the 2015 U.S. dollar, the U.S. was found to have an annual cost of $69,475 per patient (Gladman 2015). While looking at the national value of money dedicated towards ALS treatment and costs, the total estimated cost that was spent in the U.S. in 2015 war around $279-472 million (Gladman 2015). These economic ramifications affect various abilities to afford treatment and healthcare for patients. While it may be quite easy for someone that has the means to pay for ALS treatment, others are unable to afford such expensive treatment. Though some patients are unable to afford proper healthcare and treatment, the ALS Ice Bucket Challenge raised a ton of money dedicated towards research and treatment from the disease. Researchers are still figuring out how to properly spend the significant amount of funds while looking at the current costs of ALS treatment in the U.S. (Gladman 2015). Though the costs of treating ALS remain high, the economic ramifications of ALS have also led to the purchase of expensive technological innovations that use the eyes of ALS patients to help patients communicate with others.
While failure of the upper and lower neurons of the brain and the weakening of the limbs and the spinal cord have been analyzed, modern research has yet to connect the delayed affects of ALS on eye movement. Mice stand as one of the key subjects in ALS research as mice typically display the same paralytic response that humans display while suffering from ALS (Al-Chalabi 2017). Researchers tested mice that carried the SOD1 gene with G93A mutations and attempted to connect satellite cells and innervation to the delayed impact ALS has on the neurological movement of the eyes (Tjust 2017). While testing the impact of the presence of satellite cells on the limbs and eye movements, the effect of satellite cells on the limbs had a large range of activated satellite cells, while the amount of satellite cells that remained in the control and eyes of ALS patients gave very similar results (Tjust 2017). The researchers were unable to identify satellite cells role in the advancement of ALS due to the amount of satellite cells that remained constant between the control and sample of mice that were tested for ocular movement (Tjust 2017). The researchers concluded that ocular movements are intrinsically controlled and the delayed neurological effect on the movement of the eyes could not be connected to satellite cells (Tjust 2017). Further research should be undergone in order to track the reasoning of delayed movement in the extraocular muscles of ALS patients as the results did not find a distinct biological element that gives reasoning for ALS’ delayed impact on eye movement. While researchers are unable to discover the reasoning of the delayed impact ALS has on the extraocular muscles, the extraocular muscles help people that suffer from ALS communicate with others through new technological innovation.
As ALS damages an individual’s ability to speak, there are many human resources, technological resources and apps available to help people that suffer from ALS communicate with others. Current communication devices track the eye movements of ALS patients. Recently, Microsoft developed GazeSpeak, an app that uses AI to track eye movements and convert those traced eye movements into sentences and words. The app groups letters together and selects various letters, then grouping the letters into four common words that can be chosen and selected by the patient, as the patient winks or stares at the phone to approve a certain word (Revell). This app poses an efficient and alternative solution to human tracking that tracks various letters on a white board as humans track eye movements to form words that people with ALS are trying to communicate with others (Revell). GazeSpeak was tested to take an average of 78 seconds to complete a sentence while a human took around 123 seconds to complete one (Revell). Other devices use infrared cameras to track eye movement, but these cameras and the software that accompany them are very costly (Revell). As modern technology continues to advance, the delayed impact ALS has on extraocular muscle movements allows ALS patients that cannot speak to communicate with others. The rise of apps such as GazeSpeak will lead to the further development of other apps that intend to serve the same fuction or add to what GazeSpeak has already created/discovered. While the biological reasoning for the functional movement of the eyes on people that have ALS has still yet to be found, these devices take advantage of the delayed neurological response ALS has on the eyes and allows patients to easily communicate with others.
ALS is a deadly disease that continues to affect a significant amount of people around the world every day. As the upper and lower motor neurons of the brain are affected, paralysis, failure of the limbs and the bulbar are significantly weakened as motor neurons die within the body. Sporadic ALS makes up the majority of cases of ALS, as patients randomly develop the disease due to environmental factors and genetic factors, while familial ALS is inheritably passed down from preceding generational genes. Sporadic and familial ALS can possibly both contain the gene TDP-43, which affects RNA homeostasis and trafficking, though genes can be broken down into three categories. Though the FDA has approved of two drugs to help combat ALS, the drugs do not really weaken the disease which continually leads to depth. This pushes for further AI research that evaluates the genes that cause ALS and drugs that cure ALS, as AI speeds up the process of ALS research and has discovered new genes that cause ALS. Human research has found therapeutic PAR and T-Cells that help delay the progression of ALS. As ALS has a significant economic ramification and remains costly for patients, researchers are trying to find ways to allocate money that has been raised to contribute towards ALS research. Though ALS has a delayed impact on the neurological ocular movements within the eyes, researchers have not found a biological reasoning for the delay. Various technological developers are creating AI systems to help people with ALS communicate with others. As a significant amount of cases of ALS are discovered every year, AI and human researchers can eventually find a T Cell or polymerase that delays the onset of the disease and slows progression of the disease in the body. AI technology could also solve the biological question of how the eye muscles are one of the last affected muscles in a patient that has ALS. As AI and human research improves and ALS is evaluated, there will eventually be a cure for the deadly disease, though it may not be for a while. Recent discoveries push researchers to strive for a solution to one of the deadliest diseases in America that significantly deteriorates the body and has yet to be cured.
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