Cobbers on the Brain

A diagnosis of ALS is often accompanied by feelings of fear, frustration, sadness, and anger. Amyotropic lateral sclerosis (ALS) affects about 6,000 Americans every year and usually appears in midlife. In order to better cope with a diagnosis or help a loved one going through it, education is important. Understanding what we do know about the disease can be beneficial. The image below outlines some of the potential contributing factors to ALS.

ALS can be difficult to clinically diagnose because there is no test for it. It is diagnosed by ruling out other options such as: thyroidtoxicosis, cervical spondylosis, diabetes affecting brachial plexus, carpal tunnel syndrome or lesion on the elbow, neuropathy, chronic inflammation, myasthenia gravis, sclerosis, spastic paraplegia. Only about 10-15% of people have a false positive diagnosis.

After a diagnosis you visit the doctor every 3-6 months. At an ALS Association Certified Center of Excellence, your team typically consists of the neurologist, RN, speech pathologist, respiratory therapist, physical therapist, occupational therapist, dietician, rehab tech, and a social worker. You can participate in clinical trials for new drug treatments if you fit the criteria.

The current understanding of the pathology of the disease is limited and there are many factors affecting the onset of ALS. We know that oxidative stress causes changes in the cell that contribute to the death of motor neurons. As you can see in the drawing, in the presence of oxidative stress, stress granules form and remove TDP43 and FUS from the nucleus (information center) of the cell. TDP43 and FUS are critical to cell function, and when they are removed from the nucleus and clump up in the cell, it causes damaging effects seen in ALS patients.

Treatment of ALS is very difficult to find because of the complicated nature of the disease. Researchers have not been able to find the key target that would stop or reverse the effects of the disease. The current drug on the market Riluzole only prolongs life by 2-3 months and is an antiglutamate drug acts by reducing levels of excess glutamate found in the nervous system. Current clinical trials are in progress for trying to use stem cells to promote neuron survival and growth. Because 90-95% of cases are sporadic it is difficult to pin down a genetic sequence that is inherited to explain the cause of the disease. It also tends to be found in Caucasians and is more common in males than in females.

While this disease is scary, it needs to be talked about to raise awareness and help work toward finding a cure. In order to better cope, it is helpful to join a support group and learn as much as you can about the disease. It is recommended to maintain a good lifestyle, healthy eating, exercise and time with loved ones.

For more information see: http://www.alsa.org/

Just three weeks ago, I purchased A Brief History of Time, by Stephen Hawking, and less than two weeks ago, I finished the book. From what I hear, Stephen Hawking’s persona is equally linked to ALS (amyotrophic lateral sclerosis) as it is to black holes, quantum mechanics, and general relativity. The “pop culture” idea of the man is as the wheelchair-bound genius. Thus, I found it remarkably coincidental that the following Monday I was required to read a recent journal review of ALS for my neurochemistry course.

The review highlighted recent research regarding RNA dysregulation and oxidative stress as main culprits for the debilitating disease. It insisted that the two were inexplicably linked through the processes of two nuclear (i.e. pertaining to the nucleus of the cell) proteins, FUS and TDP43. The overarching theory was that oxidative stress would cause these proteins to leave the nucleus, and find their way to other parts of the cell where they would cause problems with RNA (think of it as the link between DNA and proteins). Basically, oxidative stress was destroying the cell’s ability to properly make proteins. This would in turn lead to more oxidative stress which would just start the cycle over again, eventually the cell (a motor neuron, the body’s way of telling muscles to move) would die, and thus we have ALS.
This is truly a remarkable theory, and certainly there is evidence to support it, but there is a competing theory: excitotoxicity of motor neurons. Excitotoxicity is a big word. It means that the cell is getting too much stimulation, and thus eventually dies. (Too much of anything is bad it may seem.) Indeed, the best pharmaceutical drug prescribed to ALS, riluzole, is a glutamatergic inhibitor (prevents excitotoxicity). However, even this drug is thought to extend the average life expectancy of a patient, which is only 2-3 years usually, by only a few extra months.

If the drug works at all, it must be targeting something that is causing the disease, so we can readily assume that excitotoxicity is a culprit. But the drug certainly does not cure ALS, so it cannot be giving us the full story. Perhaps the review I mentioned gives the other half of the story, though that is highly doubtful. In the end, we must agree that there is no single answer to solving this problem.
I then look back at Hawking, and his book, A Brief History of Time, and again notice a coincidence. Hawking argues that our knowledge of the universe is likewise incomplete, as there may indeed be no singular answer to the problem. He argues for more collaboration, and ultimately more research. If this is to be the case, however, I wonder if perhaps our research into the workings of the universe would be misplaced.

Let us imagine, for a second, what kind of world we would live in if instead of wasting hours on end mathematically modeling the trajectories of black holes spiraling into one another, we put our efforts into saving lives medically. We spend enormous amounts of time on understanding the maddeningly large, and the unthinkably small, that we forget about the in-between where lives may be saved. How is it that we can say how much slower time may progress for a relativistic traveler, but we cannot discover the causes of ALS? Could Hawking himself have, if not cured, perhaps contributed to his own disease’s salvation? Educated human beings place so much effort into things that will likely never save lives. And I constantly wonder if my own pursuit of mathematics will do “harm” to the world in the sense that I am not doing as much “good” as I could in chemistry.
Without a doubt, we (as a species) could have saved millions of lives from countless diseases if we had put our efforts into medical technology, instead of other pursuits. And yet we continue to do otherwise. Why? Indeed, there can only be one answer. Human lives cannot be quantified as “better” by the amount of time they exist. What I mean to say is, saving a life is not saving a life if one has instead thrown away one’s own life in the process. We are only here for a fleeting moment, and as such it is important for each of us to make the most of the fleeting moment. That may indeed consist of saving lives medically, but it may also consist of “saving lives” in other ways. Perhaps an article written by a journalist prompts a young boy to enter politics, wherein he pushes to allocate more money to NASA, who in turn create a nano-scale polymer to shed heat on rockets reentering the atmosphere, but indeed that nano-scale science is published and gives medical researchers the ability to create cancer-targeting drugs, wherein countless lives are saved. The journalist, perhaps dead for twenty years, has just saved lives, by doing what she loved best. A scenario like this, can be represented by the butterfly effect, which states that the smallest change in initial conditions can have unforeseeable consequences for the future.
In the end, then, we can at least agree that our actions, however we decide to make them, will certainly change, and possibly even save, lives. Stephen Hawking may likely still be bringing about his disease’s salvation, just in an obscure way. But at the same time, he is following his own path and immensely impacting the world for the better. It is not only our right, but our duty to pursue our own passions, even at the extent of others’ deaths.

Stephen Hawking’s life with ALS shows how much the disease varies, and how little we still know about it.
When Hawking came down with ALS in 1963, Cambridge University told him he had two years left to live.  More than fifty years later, the fate of a patient is the same.  We have developed only one drug for ALS, and that merely gives people three extra months.
Most people get ALS in old age and have a few years to live.  However, a small percentage of people, like Hawking, get ALS when they are young, and for some unknown reason these people can live ten years or more.  This makes some sense because young people are more resistant to disease in general, but Stephen Hawking has shocked the world by living to the age of 75.
The simple answer to Stephen Hawking’s survival is that he can still breathe and eat.  It is possible for someone to live without use of their arms and legs, but ALS gets really difficult when other more important muscles start to atrophy.  (The human heart is a special exception because it can beat without any communication from the brain.)  People with ALS usually die from suffocation or dehydration due to paralysis of the diaphragm or the swallowing muscles.  Stephen Hawking gets round-the-clock care, but he is known to have breathing difficulties, and he has been on a ventilator several times in recent years.
Why are the most important muscles in the body the last to break down?  It really comes down to the neurons that control these muscles.  For some unknown reason, the neurons that control voluntary muscles are more vulnerable to ALS than the neurons that control automatic bodily functions like digestion and bladder control.  It is possible that ALS causes some neurons to become overactive and poison themselves.  The only current treatment for ALS, Riluzole, is able to calm neurons down and make them live a little longer.
Other neurons are especially resistant to ALS.  Research has shown that the nerves going to the eyes are resistant to hyperactivity.  Stephen Hawking can still move his eyes, which is normal in the end stages of ALS.  He can still smile,  and he communicates via his electronic voice by twitching a muscle in his cheek.   Maybe his neurons are able to stay calm.
ALS is a highly variable disease.  We can describe several types of ALS, but not all cases fall into categories.  With his lifespan and incredible mind both untouched by ALS, Stephen Hawking’s case is like no other.
 

And by drug scheduling, I mean that of the United States Food and Drug Administration. And by that of the United States Food and Drug Administration, I mean listing drugs as schedule I (i.e. ‘no medical uses’).
This is not a political rant, for even prescription drugs (in the wrong hands) can be illegal, and there are good reasons for making substances illegal. But just because a substance should not be used recreationally, does not imply that it has no medical uses. We know this, of course, from the legal (yet recreationally abused) drugs such as hydrocodone, oxycontin, Adderall, etc.
Drugs, by their very nature, affect body chemistry to elicit a response. Whether this response is the elevated awareness after a cup of morning coffee, or the stark opposite of a late-night’s beer, drugs are meant to change the way we feel about the world. To label any drug as having ‘no medical uses’ is to change the definition of drugs. While I may digress into philosophy, the Hedonists of ancient Greece would support the claim that all drugs are medicines, and are we truly so knowledgeable as to say we know every possible use for a single substance?

Okay, I sound like a hippie. I apologize. This is not where I mean to lead. Instead, I am arguing for more research on drugs, even illegal drugs. While ‘no medical uses’ may be the FDA’s criterion for schedule I, I argue that the new criterion should be ‘no medical uses yet discovered’. This criterion emphasizes that many compounds, in the right context, may have the ability to change lives for the better. By scheduling some compounds as illegal, we frighten researchers into avoiding life-saving chemicals.
Perhaps the most apt example of this is the recent upsurgence of medical marijuana, and its active compounds THC and CBD, the latter of which provides no ‘high’, but can still medicate many ailments.
Even further, Anxiety and PTSD are extremely prevalent ailments to our nation, and the drugs used to treat them are not always effective. PTSD has been shown to be treated with MDMA, but its legal status renders it nearly impossible to study, let alone administer. And while no illegal drugs have been found to alleviate anxiety as a blanket disorder, there are of course subsets to anxiety disorders. One of these, most often found in advanced stage cancer patients, is the anxiety associated with a fear of death.

A recent 2011 study observed the effects of psilocybin, the active ingredient in psychedelic mushrooms, on anxiety levels of advanced cancer patients with a fear of death. The results showed a significant reduction in the patient’s anxiety over the evaluated period as shown by the STAI (an anxiety test), which was sustained over 6 months from only a single treatment.[1]

Along with that, in 2010 a population of twenty individuals suffering from medium-to-severe PTSD were half given a placebo, and half given MDMA (the pure form of ecstasy/molly), and then participated in psychotherapy sessions. The control group was later allowed to participate in the MDMA-assisted sessions two months after the set of initial trials. There was a greater than 30% decrease in CAPS scores (a PTSD test) for MDMA-assisted psychotherapy, and the few who had earlier not been able to work because of PTSD were able to work after the study had finished.[2]

Both of these drugs are serotonin agonists, which means they bind and activate receptors in the brain that serotonin would have normally bound to. As such, realizing that these are treatment options for anxiety-related disorders can tell us something about anxiety itself: that it may result from specific brain regions having low serotonin levels. It is well-known that other anti-anxiety drugs also include serotonin agonists, but regardless, we see the positive effects of schedule I drugs on patients as well as their effects on increasing our knowledge of psychological disorders. It is for just this reason that I argue to, at the very least, change the criterion for scheduling drugs, and allowing more research to be performed on them.
The fallacy by which I title this post is as follows: An illegal drug is illegal because it has no medical uses. Because the drug is illegal, it cannot be studied. Because it cannot be studied, we cannot know if it has any medical uses. Therefore, it should be illegal.
Circular reasoning. Good job FDA.
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[1] Grob, Danforth, Chopra, Hagerty, McKay, Halberstadt, Greer. Archives of General Psychiatric. 2011.
[2] Mithoefer, Wagner, Mithoefer, Jerome, & Doblin. Journal of Psychopharmacology. 2010.