CHEM 106

Last week’s topic of Prion disease was very interesting to me, especially everything that was yet unknown about it and why it occurs. A seemingly healthy person suddenly begins to exhibit strange symptoms that have no obvious cause. Even though science has made many leaps in the study of genetics, Prion disease reminds us that we do not know everything about the human body as evidenced by the seemingly spontaneous malformation of prions that lead to Prion disease.

We see similar instances of unknown illnesses, whose existence are sometimes only revealing themselves to us now. This brings into question what we expect of science and scientists, if they cannot give us the answers that we are looking for right away. It was also interesting to look at the disease at an anthropological level as a way to understand diseases and their occurrences outside of the human body.

First of all, cows can have best friends.

Research shows cows become stressed when they are separated from their favorite bovine companions. During an experiment lead by Northampton University, cattle were placed in a pen with either a familiar cow friend with whom they’d developed a relationship or a cow stranger. Researchers measured the test cow’s cortisol levels and heart rate in 15 second intervals and found when cows were placed with their preferred partner, their stress levels were reduced.

Head researcher and discoverer of the phenomena, Krista McLennan said

‘I’ve spoken to a number of farmers who have said they do notice bonds building among their cows and some spending a lot of time together.’

BAM: Cows have best friends.

Two: Why do we feed animals their kin? That’s just disturbing! And it obviously spreads disease. BSE, or Mad Cow Disease, doesn’t spread naturally from cow to cow. It’s suspected the disease is transmitted by feeding cows animal meal. Moreover, the disease can spread from goats and sheep to cows so even feeding them not cows is potentially dangerous.

We should just feed these animals what they’re intended to eat.

Grass. Leafy stuff. Hay.

I thought class last Tuesday was really interesting and helped situate us in the role of either a physician or an anthropologist. I thought about those two roles and how depending on the perspective, the problem can look totally different. These two roles reminded me a lot about the scientist and artist that we spent time talking about in the first few weeks of the semester.

I’m interested in how people first fall ill with prion disease. In the reading, it is explained as “spontaneous” and in the YouTube video, it is explained as genetic predisposition and susceptibility. I looked into this and found a very interesting article about the prion protein structure and the differences between PrP and PrPSc. The article discusses the susceptibility of different mammals ranging from humans to mice. Hamsters and mice seem to have higher susceptibility when compared to horses and dogs, for example.

The article can be found here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2993331/

This got me thinking about our in class activity and the fact that when the researchers tried testing on animals to see if they could understand the pathology of Kuru, they did not see any of the same effects on the mice and other laboratory animals that they saw on humans. Since humans have closely linked protein and body structures to primates, when scientists used three chimpanzees as their subjects, they then saw similar effects to those exhibited by infected humans. Similarly, Scrapie for sheep was transmittable to goats and other similar animals but not to humans in the same form. I’m interested about the similarities that allow certain diseases to be transmitted across some species but not others.

I really enjoyed our class last week! It was great to finally utilize the scientific method in our case analysis and interesting to see how much collaboration was required between two fields I had never really realized were that similar, namely Anthropology and Medicine.

As we learned in class, Prion is actually a naturally occurring protein that is found in all of us. Only when it gets ‘infected’ does it change form, and start infecting the other Prion proteins around it. I found an interesting article online that said that researchers at The Scripps Research Institute, in studying Prion disease were actually able to discover a killing mechanism that could underpin the range of most intractable neurodegenerative diseases such as Alzheimers, Parkinson’s and ALS.

In this study, scientists studied the misfolded form of the Prion disease protein (TPrP) and demonstrated that it induces neuronal death by depleting NAD+, a metabolite that is important in cellular energy production and homeostastis. Restoring NAD+ was thus critical to rescue the neurons subjected to TPrP injury. The loss of NAD+ is also indicative in other neurodegenerative diseases such as Alzheimers and Parkinsons.

However, this study was conducted on animals but does show that a treatment is in the works, even though these are just the early stages.

Link to the study: http://www.bovinevetonline.com/news/animal-health/scripps-scientists-discover-key-mechanism-prion-diseases

After learning about prion diseases in class and having heard of Mad Cow Disease before, but never truly understanding it, I decided to investigate further. Mad Cow Disease, otherwise known as Bovine spongiform encephalopathy, became an epidemic in the United Kingdom in the late 1980’s. It has many similarities to Scrapie and Kuru. All cause degeneration of the brain and lead to behavioral and neurological changes usually ending in death. Mad Cow Disease got its common name from the symptoms that develop in cows. Infected bovines had an increase in aggression and would react excessively to noise or touch. This caused farmers to believe that they had gone “mad.”

The true reason that Mad Cow Disease became such a worldwide phenomenon is that humans began to be infected and the disease was almost always fatal. The frenzy and fear associated with the disease led the European Union to ban the exportation of British Beef in 1996. This ban lasted for ten years. This ban may have saved thousands of lives because much of that beef may have been infected. Just like with Kuru and Scrapies, the disease was transmitted through the consumption of infected brain and spinal cord. Although cows are usually herbivores, the British cattle had been fed ground up cow remains from the slaughtering process. This is very similar to the spread of Scrapie among sheep and goats. The general public began to panic when the disease spread to humans. Slaughtering practices at the time allowed for some traces of nervous system tissue to be included in the mince and beef that was to be consumed by humans. When a human bought and consumed a beef product which contained this infected nervous system tissue, the misfolded cow prions were able to affect healthy human prions in the consumer’s brain. In humans, the disease is known as Variant Creutzfeldt Jakob disease. The only way to end the epidemic was to ban the exportation of British meat, exterminate nearly all British cattle that hadn’t already been slaughtered, and create new regulations for the feeding and slaughtering of cattle. Nearly 200 people died from contracting the disease, but new regulations have put Bovine spongiform encephalopathy to rest.

One of the the aspects of prion disease that interests me most is its long incubation period. An incubation period is the time between the moment a person is infected with a pathogen and the moment a person starts displaying symptoms of disease. In the case of prion diseases, incubation periods can last three years. Incubation periods are vital to understand the epidemiological structure of disease. How can you trace the spread of disease if you do not know when the infection was contracted?

The incubation period is distinct from the contagious period, in which disease can be spread from organism to organism. As someone that works with children, I was curious about the differences between incubation periods in young and old people. It turns out that children have shorter incubation periods than adults (because their bodies are worse at fighting the illness) but that they have longer contagious periods. This reason, along with others, is why children tend to get more sick than adults.

To connect back to our class activity, I was confused about why children were getting the neurodegenerative illness. Often neurological symptoms are common in older adults who suffer from MS, Alzheimer’s, Parkinson’s, and ALS, so it was disturbing to me that kids were getting it. Certainly a strange case. I wondered about early onset Alzheimer’s, which is on the rise, for reasons that doctors do not know. This seems to highlight the importance of epidemiologists and the hard work that they have to do.

Here is a chart I found about the incubation and contagious periods of common illnesses!

http://en.wikipedia.org/wiki/Incubation_period 
http://www.childrensoscillo.com/features/healthy-kids/http://www.childrenshealthnetwork.org/CRS/CRS/pa_incubate_hhg.htm
                        Incubation 
  Disease             Period (days)    Contagious Period 
---------------------------------------------------------------
---------------------------------------------------------------
SKIN INFECTIONS 

Chickenpox                10 to 21    5 days before rash
                                      until all sores have
                                      crusts (5-7 days)

Hand, foot, and mouth      3 to 6     Onset of mouth ulcers
  disease                             until fever is gone

Impetigo (strep or staph)  2 to 5     Onset of sores until
                                      24 hours on antibiotic

Measles                    8 to 12    4 days before until 5
                                      days after rash appears

Meningitis                 3 to 6     Onset of symptoms and for
                                      1 to 2 weeks

Rubella (German measles)  14 to 21    7 days before until
                                      5 days after rash appears

Shingles (contagious      14 to 16    Onset of rash until
  for chickenpox)                     all sores have crusts
                                      (7 days) (Note: No
                                      need to isolate if
                                      sores can be kept
                                      covered.)

---------------------------------------------------------------
RESPIRATORY INFECTIONS 

Bronchiolitis              4 to 6     Onset of cough until
                                      7 days

Colds                      2 to 5     Onset of runny nose
                                      until fever is gone

Cold sores (herpes)        2 to 12    See footnote B

Coughs (viral)             2 to 5     Onset of cough until
                                      fever is gone

Influenza (Seasonal)       1 to 3     Onset of symptoms until
                                      fever is gone over 24 hours

Influenza (H1N1)           4 to 6     Onset of symptoms until
                                      fever is gone over 24 hours 
Sore throat, strep         2 to 5     Onset of sore throat
                                      until 24 hours on
                                      antibiotic

Sore throat, viral         2 to 5     Onset of sore throat
                                      until fever is gone

After our class on Prion diseases, I was interested in finding out more about potential solutions for preventing or stopping chronic wasting disease. Because Prion proteins can manipulate normal proteins into changing their form to fit with the Prion, it is difficult to find a way to inhibit the stacking and changing of protein shape.

In a UC San Diego article that I read, scientists had found a loop in the protein, signifying a possible way to stop the conversion of normal proteins into prion proteins. They figured this out through testing elk prions (the chronic wasting disease also occurs in deer, aside from cows, sheep, goats, and humans) in a human-like scenario–on mice. Interestingly, though humans are susceptible to “mad cow” disease through the ingestion of sick cow brain, they are not susceptible to the equivalent in deer. The reasoning behind this is a “loop” in normal proteins, which cause human proteins and elk prions to be incompatible.

The researchers are excited about the prospect of finding a potential cure for chronic wasting diseases. Currently there are five forms of human CWD: Creutzfeldt-Jakob Disease (CJD), Variant Creutzfeldt-Jakob Disease (vCJD), Gerstmann-Straussler-Scheinker Syndrome, Fatal Familial Insomnia, and Kuru. Though these diseases are rare, they are 100% fatal and as a result deserve more research for prevention or antidote.

Our introduction to prion diseases this week, like the mad cow disease and scrapie, got me interested in reading more about prion diseases. Usually we classify diseases into four categories: genetic, degenerative, infectious or bacterial/viral. However, it was interesting to note that prion can be classified as sporadic, genetic and acquired. All differ with relation to signs, symptoms and duration of the disease.
There are two types of sporadic diseases (Creutzfeldt-Jakob Disease (sCJD) and Sporadic Fatal Insomnia (sFI)), which means that they occur in people without any known risk factors or gene mutations. The typical symptoms for sCJD include imbalance and incoordination, memory loss and impaired thinking, and psychiatric symptoms such as anxiety or depression. Once the symptoms do appear, CJD progresses very quickly and is usually fatal within a few months of symptom onset. sCJD typically affects people in their 60s and is rarely seen in people younger than 40 years old.
For the genetic strain of the disease, this is caused by inherited mutations in the prion protein gene (PRNP) which provides instructions to your cells regarding how to make prion protein. In the genetic form, the mutations cause the cells to form an abnormal prion protein instead of the normal one. This could be passed down through generations or could be a new mutation in the gene. The symptoms of this largely depend on the type of the mutation but include: balance & coordination problems, memory loss and impaired thinking.
Prion protein diseases can also be caused by exposure to prion, however, this is extremely rare and acquired diseases account for only 1% of the prion protein cases. This could be contracted through either exposure to these prion proteins in certain types of medical settings or the ingestion on beef or any other meat affected by this condition. In the early symptoms patients often present with personality changes and psychiatric symptoms such as depression or withdrawal. Physical symptoms start developing a little later such as falling, difficulty walking, stumbling etc. The estimated incubation period is 5-40 years and the durations of the illness is typically 12-24 months after signs and symptoms appear.
Therefore, even for this one specific disease, it is extremely interesting how there are many different ways of contracting it.

This week we learned about prion diseases, which are 100% fatal to all patients. I decided to look into some of the treatment options that might exist or are being developed for these diseases. The research that goes into treating these diseases is particularly interesting to me because it illustrates very well how scientists work.

The problem at hand is that prion proteins get altered into a different, maladaptive form, one which the body doesn’t reject on its own. This problem is complicated by the fact that symptoms don’t show immediately, and might not show until even 50 years after the initial infection. Many teams are researching how prion diseases are caused in great detail, and are working multiple angles of the process to find the most effective treatment method. For instance, some methods try to destroy the maladaptive form of the protein, while others try to prevent the conversion process, or simply destroy the regular prion proteins before they can be converted at all. I’ll go through some of the pros and cons of some potential treatment options below.

Drug therapy – Some think that we might be able to use drugs in order to delay the disease or cure it entirely. Several already-existing drugs, such as antimalarials and antipsychotics, are going through trials to see how effective they are. Some of the pros for this treatment are the fact that we already have these drugs available for use, and they seem to work well at getting rid of the disease in the limited environments of test tubes and petri dishes. Some work by preventing the conversion of the normal prion protein to the folded version, and others might target other molecules that are involved in the conversion process. A major con, though, is that they haven’t been shown to work effectively in humans. One of the issues with these treatments is that the drugs have to cross the blood-brain barrier (the tightly-packed walls of cells around blood vessels in the brain) to treat the infected areas of the brain. However, this requires small molecules, and some of the drug compounds just aren’t small enough to make it to the areas that need treatment. Surgery can be used to put pumps for the medication inside the brain, but the surgical complications are tough to deal with. At present some drugs have been shown to delay the patients’ death a bit, but none prevent it entirely. Research is ongoing to find new drugs and new ways of delivering those drugs to the brain that will give better results.

Immunotherapy – Another option with a lot of potential is immunotherapy, where antibodies are injected into the patient. Antibodies are proteins that bind to infective materials to remove them; the body produces many antibodies naturally, but they can also be synthesized by scientists. The pros here are that there are several types of antibody proteins created that have been shown to be effective at treating prion diseases in petri dishes and in mice. However, in humans they face the same challenge as the drugs discussed earlier. The major con for this treatment is that antibody proteins are just too big to cross the blood-brain barrier, so they can’t get to the parts of the human brain that are being infected in order to wipe out the disease. Further research is being done here as well in order to see if the current problems with this treatment can be resolved.

Gene therapy – One of the really interesting ideas for treating prion diseases is to cut off the disease at its source: if there are no prion proteins, then they can’t be converted to the maladaptive form, and the disease will go away. The prion protein gene translates its production messages using RNA, and in theory we could stick our own manufactured pieces of RNA/DNA to those RNA strands before they deliver the message to produce the protein. This effectively “turns off” the prion protein gene. A pro for this treatment is that the prion protein doesn’t appear to serve an essential purpose to humans, so if we could shut off its production there wouldn’t be any ill effects. This has been proven true in mice at the very least. However, there are two big cons to this method as well. The first is that the pieces of RNA or DNA that need to be administered are once again big molecules that can’t get across the blood-brain barrier, and need to be injected into the brain itself. The second is that even if they make it to one area of the brain, the treatment might not be effective unless they can be evenly distributed across the entire brain. Without any way of doing this, the disease might be stopped in one area only to develop in another.

Overall, none the present treatment methods are capable of effectively treating prion diseases. However, research continues in these areas and others, and there is hope that in the future an effective cure will be found.