While the cause for Alzheimer’s is poorly understood, according to the National Institutes of Aging, studies have shown that there is a genetic risk factor involved in some cases of early onset of the disease, whereas lifestyle, genetic, and environmental triggers are associated with the late stages. Once the disease begins to progress, the subsequent neuronal loss and changes to the brain are irreversible. These changes result in cognitive dysfunction like memory loss, impairment in the ability to think, and executing simple tasks. Most symptoms of Alzheimer’s appear when someone is in their 60s, and in 2015, this disease was found to be the seventh leading cause of death worldwide. Understanding the cause of Alzheimer’s and the progressive loss of nerve cells associated with the disease is extremely important.

Most researchers believe that the buildup of amyloid-beta proteins and tau tangles inside the brains of those with Alzheimer’s is the primary cause of this disease and cell death. However, the researchers who subscribe to the pathogen hypothesis believe that pathogens cause the brain cells to produce the amyloid-beta proteins, or that nerve cells that have been infected produce these proteins as a result of an inflammatory response. Brian Balin, a co-author on the review and the director of the Center for Chronic Disorders of Aging at the Philadelphia College of Osteopathic Medicine, said in a statement to Scientific American, “We think the amyloid story does come into play, but it’s secondary to the initial inflammation.”

Furthermore, individuals with a variant to their APOE 4 gene, a known risk factor for Alzheimer’s, are vulnerable to common microbial infections such as HSV-1, chlamydia, and even the bacteria that cause pneumonia and Lyme disease. One hypothesis, published in The Lancet in 1997, is that the variant of the gene makes it easier for infections to specifically target the brain cells.

Given the consistent failure to develop effective drugs, Rudolph Tanzi told The Scientist in a statement that “Any hypothesis about Alzheimer’s disease must include amyloid plaques, tangles,  inflammation—and, I believe, infection.”

Like all science theories that are initially hypothesized, this has been met with its fair share of criticism. Judith Miklossy from the International Alzheimer’s Research Center recalled being dismissed and denied funding for pursuing the role of spirochetes as an important factor in Alzheimer’s disease. One reason for skepticism, as John Hardy from the University College London told The Scientist that there is a lack of convincing evidence that links the distribution of amyloid plaques with infection. He further believes that the pathogen hypothesis “doesn’t fit the epidemiology, the neuropathology, or the genetics.”

The often overlooked role of microbes and fungi played in the onset of Alzheimer’s has been noted to be implicated with neurological conditions in several scientific journals. In a recent study published in Cell, researchers found that gut microbiota regulates movement disorders in mice and that alterations to the human gut microbiome places individuals at a risk of developing Parkinson’s disease. In a review published in Nature, scientists implore other researchers to investigate the role of microbes in mental health and mood disorders such as depression and bipolar disorder.

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Tumour samples are obtained from patients when a part of the tumour is excised (typically a non-invasive surgery known as a biopsy) and then preserved in a fixative for future testing. These samples can be taken from patients at any point in time, which gives physicians the possibility of sampling the same tumour at different time points of its development. With the presence of ITH, this leaves us with a tissue sample that no longer shares the same genetic profile of the initial tumour, excised at a different time; because of this, a treatment that initially showed consistent improvements could fail to target this new mutation.

Why can’t samples be taken from patients at regular intervals? First, it remains unknown when specific cells within a tumour begin to diverge and form new tumours. Second, it remains a mystery if all cells within a tumour have the capacity to do so. Studies in animal models continue to indicate the presence of highly metastatic variants in the parent population of tumour cells. To further investigate ITH, researchers began to examine tumours in patients. A seminal study led by Charles Swanton showed that in samples obtained from patients diagnosed with renal cell carcinoma, there were significant differences in the molecular profiles of biopsies obtained from different sites of the primary tumour and its associated metastatic site. The samples were subjected to an array of molecular diagnostic procedures such as immuno-histochemical assays, mutation analysis and RNA sequence profiling. Their results suggested that some molecular abnormalities were seen to be present in most of the analyzed cells while another set of mutations where present in only primary or metastatic sites.

Prior to the Swanton findings, researchers began to think that one of the efficient ways to stop cancer growth was to identify the key molecular pathways critical for cancer cell survival, a sort of Achilles heel of cancer. The most prominent question put forth was if the gene responsible for developing a normal cell into a tumour cell (oncogene) is required for it to maintain its invasive or malignant form. While searching for answers to these questions, researchers realized that it was possible that some cell variants no longer depend on an oncogene and that administration of a single anti-cancer drug could lead to drug resistance in cancer.

If you combine this with the findings from the Swanton study, we now have a few more pressing questions: If a single anti-cancer drug can’t target the required mutations, could a combination of drugs do it ? And more importantly how do some cells within a tumour gain the capacity to form new tumours or express new mutations ? Sadly, the answer to the first question is already evident: with the presence of diverse range of mutations in different areas of a tumour, it makes it impossible to develop a combination of drugs that can target each abnormality effectively without compromising the wellbeing of the patient.

Many theories were postulated to understand the development of this ITH, one prominent question was: could this heterogeneity arise from cancer cells behaving like stem cells? In principle, yes. A cancer stem cell, as defined by the American Association of Cancer Research, is a cell within a tumour that has the capacity to self-renew and cause the various lineages of cancer cells that comprise a tumour. To assess if cells from a tumour have properties of a cancer stem cell, researchers biopsy a tumour and transplant it into a mouse whose immune system is compromised (to prevent removal via their immune system). To qualify as a cancer stem cell, the cell must fulfil two important criteria: first, they must possess self-renewal properties and second, they must possess potential to form tumours. Once the excised tissue begins to grow in the immunocompromised mouse, it is periodically checked to see if they form tumours (i.e. tumorigenic capacity). While this test helps distinguish between cancer stem cells and non-cancer stem cells, the results are interpreted with caution and scientists are looking for a more robust and precise way of identifying cancer stem cells.

How does the identification of cancer stem cells help in diagnosis or treatment of cancers? Finding the root cause of a specific cancer or deciding a course of treatment for cancer patients has never been easy for clinicians and researchers alike. When it was assumed that each type of cancer had specific groups of mutation to blame for its occurrence, the diagnosis and treatment was aimed at identifying those mutations. Now, with the likelihood of each tumour possessing cancer cells that are capable of forming different tumours, it becomes harder to identify the main mutation and the subsequent treatments for it. At the same time, it is possible that in some cancers the tumours can only contain a small population of cancer stem cells while the other cells have lost their self-renewal or tumorigenic properties. This would make it profoundly difficult in not only testing the cancer stem cell model, but also identifying treatments for both the cancer stem cells and the non-tumorigenic cells. This then raises the concern of knowing the extent to which tumorigenic cells populate a tumour. While many researchers do believe that the percentage of cancer stem cells in a tumour may be less, it still remains a crucial hypothesis that helps researchers and clinicians understand the variability seen in patients.

As most treatment courses are determined from the results obtained from a single biopsy, current cancer treatments are inadequate in treating the ITH observed in tumours. As Charles Swanton and his colleagues demonstrated, variations in genetic mutations are observed when different samples are obtained from a single tumour, leaving most tumours with the ability to develop resistance to anti-cancer treatments. For example, if an anticancer drug targets a subpopulation of cancerous cells in a tumour expressing a specific genetic mutation, the remaining cells that do not express the same mutation remain unaffected and continue to grow. Hence, it is important to determine if a tumour is housing cancer stem cells that can continue the growth of the tumour after treatment. Along with drug resistance, there are many other ways ITH affects cancer treatments.

So what can be done to ensure more effective treatments? First, multiple biopsies would need to be conducted from the same tumour to ascertain the presence of ITH. But the underlying problem still remains: until the etiology of ITH is understood, it will remain difficult to develop effective cancer treatments. Many challenges lay ahead to achieve this, such as geographical and timely intervention, accurate, and precise methods to analyse treatment response and most importantly, active patient participation and effective research and clinical collaboration. But in time, it will be possible to deliver comprehensive personalized treatment to cancer patients to combat the ITH seen in cancer.

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At the Musée des Augustins in Toulouse, France sits a haunting sculpture of a woman being tormented by a demon sitting on her, while she is asleep. Sculpted by Eugène Thivier in 1894, “Le Cauchemar”, which translates to “The Nightmare,” is this sculptor’s most noteworthy masterpiece. It is believed to be inspired by the famous Henry Fuseli painting “The Nightmare”,which was exhibited at the Royal Academy of London more than a century before the installation of this sculpture. With wide interpretations ranging from the depiction of heartbreak, loss and sexual desire to the visualization of dreams and nightmares, this painting has proven to be an inspiration for many artists and poets alike.

Following its exhibition, Erasmus Darwin, the famed poet and naturalist philosopher described an unsettling experience of feeling helpless, immobile but awake during sleep in his poem titled ‘The Lover of The Plants’ in 1792. He adeptly goes on to describe the state of paralysis and the vision of a demon-like creature upon the chest of a woman. Along with him, many great authors such as Charles Dickens, Edgar Allen Poe and Herman Melville have all written about such experiences in their books. However, it wasn’t until 1928 that a famous British neurologist, Kinnear Wilson first set out to describe these attacks precipitated by a terrifying dream as “sleep paralysis.”

Today, sleep paralysis is described as a phenomenon in which an individual experiences brief periods of immobility, inability to speak or react while falling asleep or awakening. Why has something so simple been described as a terrifying experience?

Imagine that you have had a long and productive day. You are tired and all you want to do is sleep on your comfortable bed. You fall asleep, but instead of dreaming, you are awake and confused. You see a shadow-like figure approaching you. You want to move to get a clearer view, but you can’t because you are paralyzed. This shadow-like creature is inching closer and closer to you. You want to scream for help but no words come out of your mouth. You now feel something heavy sitting on your chest and feel an unsettling presence in the room which you can’t shake off. You are locked in, helpless and terrified.

If this sounds familiar, you are not alone. According to a study conducted on over 36,533 people by researchers at the University of Pennsylvania, about seven per cent of the general U.S. population have experienced an episode of sleep paralysis. With erratic working hours, high amounts of stress and anxiety, it comes as no surprise that over 28.5 per cent of students have reported experiencing sleep paralysis. While sleep paralysis itself isn’t fatal, it is considered to be one of the most frightening experiences one can face. Many have wondered what separates sleep paralysis from a scary dream, the difference lies in the fact that during an episode of sleep paralysis, the sleeper is awake, paralyzed and begins to hallucinate. All this occurs in a sleep state known as the Rapid Eye Movement (REM) phase. While a scary dream or night terror occurs when the sleeper is in the non-REM state (NREM). The hallucinations that accompany the brief periods of immobility are described to be the terrifying aspects of sleep paralysis.

These frightening experiences have been cited in a number of ancient mythologies and folklore across various cultures, going on to show that these haunting episodes have provided for a common source of nighttime terror across the world. Interestingly, the majority of hallucinations experienced by people are influenced by folklore and stories from their culture. With various accounts of spiritual and supernatural explanations ranging from witchcraft to extra-terrestrial attacks the influence of cultural entities is remarkable in sleep paralysis. Further described in depth in the book Sleep Paralysis: Historical, Psychological, and Medical Perspectives written by Brian Sharpless and Karl Doghramj, the multitude of references that have been made to the phenomenon of sleep paralysis is clearly explained. But why does the brain create these episodes?

With erratic working hours, high amounts of stress and anxiety, it comes as no surprise that over 28.5 per cent of students have reported experiencing sleep paralysis.

There have been many theories put forth to try and explain the mechanisms of sleep paralysis. One of these stems from the understanding that the brain switches from one state of sleep to another far too quickly. Adrian R. Morrison in A Window on the Sleeping Brain describes the neurophysiology of sleep. When we sleep, our brain moves through five stages, of which one of the most prominent is the REM phase. During REM, the brain electrical activity is very similar to that of a person who is awake and the person begins to dream. The dreamer’s muscles are paralyzed to ensure that they don’t act out their dreams. To enable this paralysis, certain chemicals in the brain that activate the neurons responsible for motor function are inhibited. It is believed that as we cycle between phases of sleep, the body ensures that the required levels of these molecules are also maintained. However, in the event of improper regulation at an unexpected phase, the body can remain paralyzed when it is required to achieve a state of arousal. While the muscles are still paralyzed, the person can begin to wake up from slumber only to be unable to move. Thus the sleeper experiences the dream-like characteristics of REM accompanied with paralysis.

However, what was assumed to be a simple interplay between molecules has now been shown to be a very complex mechanism. A study focusing on the neural substrates responsible for sleep paralysis at the University of Toronto has indicated that the specific role of the inhibitory molecules and their ability to override the subsequent activation of the muscles is to be re-evaluated. With further work being done in their lab, they have found that no single mechanism is responsible for the REM sleep paralysis. They were able to investigate the role of an additional inhibitory neurotransmitters (endogenous chemicals allowing communication within the brain) such as GABA, and found that this, along with glycine, play a key role in regulating the state of paralysis during REM. What remains to be investigated is how these molecules regulate this paralysis.

Scientists are still searching for the root cause of the episodes themselves. Many studies have pointed toward a disrupted sleep cycle and anxiety as important triggers. Combined with tiredness and high levels of stress and mental health conditions, it is surprising that more research is not devoted to elucidating the mechanisms of sleep paralysis. Sam Kean, in his book The Tale of the Dueling Neurosurgeons, describes his encounter with sleep paralysis. He attributes sleeping in a supine position (on the back) to be a reason for his sleep paralysis episodes. In “The Nightmare,” a critically acclaimed documentary directed by Rodney Ascher, eight people chronicle their struggles with sleep paralysis. All of them have different prompts that provoke an episode of sleep paralysis, where each episode is more horrifying than their previous one. While the underlying causes of sleep paralysis are still unclear, what remains a mystery is how the brain conjures vivid and frightening life-like figures when it happens.

During episodes of sleep paralysis, hallucinations involve all the sensory regions of the brain thus enabling people to see, hear or sense the presence of an outsider in their room. Commonly viewed as a shadowy figure, this intruder usually has the characteristics of a human being – in terms of height and body shape. While in most cases, the shadow figure does not have facial features, most experiencers interpret this shadow-like figure as per their cultural ideas. Baland Jalal and V.S Ramachandran from the Centre of Brain and Cognition at University of California at San Diego postulated that when a person experiences sleep paralysis, they have a distorted sense of their body image. They go on to say that specific brain regions such as those in the right parietal region are altered, which may lead to an “alternative sense of self” that is able to feel movement in limbs despite being paralyzed. Interestingly, they hypothesize that this alternative viewpoint is a result of the “internal hard-wired body image.” For example, they say that should a person with an amputation or body image disorder like anorexia nervosa face an episode of sleep paralysis, there is a higher probability that they will hallucinate a “shadowman” mirroring their own internal body image. While this provides for an interesting albeit peculiar theory, we still wonder if there is a way to combat the shadow-people.

Many people who have experienced sleep paralysis have noted that keeping a sleep log and maintaining a sleep routine involving a regular sleep time and sufficient hours of sleep can help in minimizing the onset of sleep paralysis episodes. Baland Jalal, in his paper titled “How to Make the Ghosts in my Bedroom Disappear?” talks about using a focused-attention meditation in conjunction with muscle relaxation therapy as treatment options for sleep paralysis intervention. He shows that using four steps namely, understanding the meaning of the attack, using emotional and psychological approaches to distance from the attack, meditating while that involves inward focused attention, and finally, utilizing muscle relaxation could help alleviate the fear and anxiety associated with sleep paralysis.

In search for answers to this terrifying phenomenon, people around the world have begun to share their experiences. While still preliminary in their approach, scientists have begun to pay more focus and attention to what’s responsible for the “shadowman.” Sleep paralysis, though a terrifying experience, could pave way for examining the fascinating biology behind sleep and why we dream.

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