Reviewing the big P…Prions!

Student guest post by Rajeshwari Nair

Discussion on consumption of meat products is a common occurrence in my household. Hailing from India, I have always relished meat dishes that my mom cooks up, hot and spicy! However, there is always a nagging guilt on eating animals. People have tried convincing me that we are all part of the food-chain in this ecosystem, so either eat or be eaten. However, in recent times one thought crosses my mind when I stuff that yummy piece of meat in my salivating mouth, will this karma get to me soon? Will my brain dissolve as I chew on the brain of this mute four-legged creature? All this began not very long after my first lecture on ‘Prion diseases’. I sit in class thinking, ‘Hey we are built of protein matter, we eat forms of protein daily, we digest proteins daily and look at what a tiny solitary protein can do to us.’

Prions (pronounced pree-ons) are an acronym for proteinacious infectious particles. A normal prion protein, designated as PrPc is produced by every cell in a human body. This protein is encrypted by a highly conserved gene PrP in the human genome (chromosome 20) [5]. Okay all this sounds just fine, so what about this protein? Well believe it or not, it has a life of its own. Yes, superior to viruses and bacteria and it does not need a DNA or RNA to survive or infect other living forms.
Prion protein has a beautiful structure made of alpha helix sheets. This protein can be digested by enzymes generally used to breakdown proteins. However, something goes awry and this awe-inspiring protein changes to a structure with several beta sheets. What transpires here is really not well understood. However, there have been several hypotheses, what we know better as educated guess! The protein gets misfolded (PrPsc) and leads to further misfolding of normal PrPc. Thus there is a school of thought that the ‘first misfolded prion protein’ may be the infectious agent [1]. However, propagation process does not stop at this. These misfolded proteins form plaques and thus begins the destruction of a thinking organ, the brain. Hey, but why did the first prion protein misfold. It could be due to something you inherited from your parents, something you ate at your favorite food joint, a mutation or just like that…research is ongoing!

Abnormal prion proteins cause a spectrum of diseases known as transmissible spongiform encephalopathy or TSE. Prion diseases are progressive, neurodegenerative disorders that affect animals as well as humans. The disease spectrum includes gory sounding conditions in humans such as true Cruetzfeld-Jakob Disease (CJD), Kuru (spread by ritualistic cannibalism), Fatal Familial Insomnia, and Gerstmann-Sträussler-Scheinker syndrome [4]. Remember the ‘Mad Cow disease’ which caused chaos in England way back in 1986. Farmers back then fed their cattle soybean. However soybean did not grow well, so these farmers found an alternative. They fed their cattle animal byproducts, brain, blood, bones from other cattle and sheep. Hmm…I am thinking ‘animal cannibalism’. Anyways, these infected cows found their way to markets in England, either as fuel (food) or fertilizer (manure). People who came in contact with these infected animals soon took ill, and contracted what is known as Variant form of CJD (vCJD). At least 157 people were infected and killed till 2004. United States has not been oblivious to this disease. Holman et al., reported an analysis of death certificates of US residents which estimated 6,917 deaths with CJD, 1979-2006. Most of these deaths were among people 65 years and older and mostly whites. At least three patients have died of vCJD since 2004 [2]. Occurrence of prion diseases could be familial (inheritance of mutated prion genes), just out of the blue with no known cause (sporadic), ingestion of infected material, and even through transplant of infected organs such as the brain, ocular tissue or human pituitary growth hormone [4]. Signs and symptoms depend on part of the brain infected and age at infection. Disease symptoms can be easily mistaken for other neurological conditions such as Alzheimer’s, Parkinson’s or even just depression. Prions can turn our brain into a complete mush which may not be diagnosed until an autopsy is performed. Something to ponder about may be…increase in mental health conditions such as Alzheimer’s, dementia and others. Ever speculate there may be a prion disease since above mentioned conditions are often clinically diagnosed.

It is time to further investigate this situation and fill in existing gaps in knowledge. Various forms of therapy are under investigation with focus on preventing structural changes to the normal prion, thus preventing disease. Drugs which can cross the blood brain barrier are being considered to combat prions. Some antimalarial drugs such as Mepacrine, an anti-tumoral drug Iododoxorubicin and even Tetracycline are being considered potential for anti-prion therapy. Some of these drugs have been tested on animal models and cell cultures, and have shown robust effects. Even a vaccine was being tested by clinical trial as a method to slow disease progression [3].

Even though all these facts sound alarming, one may be lead to think why should we care. There are hardly any cases occurring, there are several other battle to be fought. This one can be laid to rest for now. On the contrary, in today’s world with new emerging and re-emerging diseases prions could be a significant assault on living forms. Also, globalization and environmental interactions could act as fuel to this fire. We hear of diseases being transmitted from animals to human (zoonotic) and the reverse. Is there a chance that prion diseases could add to this list?

References:

1. Gains MJ, LeBlanc AC. (2007). Canadian Association of Neurosciences Review: Prion protein and prion diseases: The good and the bad. The Canadian Journal of Neurological Sciences, 34: 126-145.

2. Holman RC, Belay ED, Christensen KY, Maddox RA, Minino AM, Folkema AM, et al. Human prion diseases in the United States. PLoS ONE. 5;1:e8521.

3. Caramelli M, Ru G, Acutis P, Forloni G. Prion Diseases Current understanding of epidemiology and pathogenesis and therapeutic advances. CNS Drugs. 20;1:15-28.
4. Pedersen NS, Smith E. Prion diseases: Epidemiology in man. Acta Pathologica, Microbiologica et Immunologica Scandinavica. 110:14-22.

5. Glatzel M, Stoeck K, Seeger H, Lührs T, Aguzzi A. Human prion diseases:molecular and clinical aspects. Archives of Neurology. 2005;62:545-52.

Getting the whole story- attempting to make sense of disease through evolutionary medicine

Student guest post by Anne Dressler

The idea of evolutionary medicine is new to me and my understanding is quite shallow but it has piqued my interest. Currently, the book “Why We Get Sick” by Randolph M. Nesse and George C. Williams has been satisfying my curiosity during the 15 minutes of intellectual thought I have left at the end of the day while reading before bed. From what I’ve read, I’m finding how useful it can be to consider disease in light of evolution and I’m left wondering how I haven’t heard of it before. I’m guessing I’m not the only one interested, so let’s talk evolutionary medicine, starting with some of the basics and finishing with why I find this particularly interesting for the nexus between infectious and chronic disease.

If basic biology and traditional medicine make up the plot of our disease “stories”, evolutionary medicine would be somewhat like the moral. My roommate is a medical student and when asked, she can tell you how just about anything in the human body works and what is happening when things go wrong. When asked why things go wrong, her answer will refer to a proximate cause, such as certain foods leading to plaque build up which can lead to heart disease. If the question of why is rephrased, as in why does the disease even exist at all, then she’s stumped. This is the question considered by evolutionary medicine. Why aren’t our bodies able to repair clogged arteries? Why are we prone to infections? Why are our bodies so good at some things but so inept at others? At first I found theses questions strange- after studying epidemiology’s risk factors for the past year, I had started viewing them as the sole reason for the existence of disease. And that kind of makes sense…if you completely ignore evolution. Enter famous and ubiquitous Dobzhansky quote:

“Nothing in biology makes sense except in the light of evolution.”
-Theodosius Dobzhansky

It is through the perspective of evolution that one can consider why a disease exists beyond the obvious.

In their book, Nesse and Williams propose six categories for evolutionary explanations of disease: infection, novel environments, genes, design compromises, evolutionary legacies, and defenses. The basis for all these explanations is evolution through natural selection thus I think it is wise to keep in mind some key points. First, natural selection occurs when survival and reproduction are affected by genetic variation among individuals. Genes are only passed on by the organisms that survive to reproduce. Note, surviving to reproduce doesn’t necessarily have anything to do with health or survival later in life nor does it necessarily mean good health before reproduction either.

“If tendencies to anxiety, heart failure, nearsightedness, gout, and cancer are somehow associated with increased reproductive success, they will be selected for and we will suffer even as we ‘succeed,’ in the purely evolutionary sense.”
-Randolph M. Nesse and George C. Williams, Why We Get Sick

Also, think Richard Dawkins and “selfish genes”- selection doesn’t consider populations, but rather benefits genes. With this in mind, let’s go over one of the proposed categories for explaining disease- infection (even if it is just skimming the surface).

Infectious agents have long been a cause of human disease. As we have evolved means to avoid infection, pathogens have evolved means to counter us leaving us prone to infection. Due to their relatively rapid reproduction, pathogens can evolve much more quickly than we can. One way we attempt to make up for this deficiency is by using antibiotics. Interestingly, by using antibiotics we are essentially taking advantage of the evolutionary advantages of another organisms. Toxins produced by fungi and bacteria are a result of millions of years of selection to combat pathogens and competitors. Dangerously, many believed that with antibiotics we would finally be in control of infections. Unfortunately, that was an underestimation of evolutionary forces and while almost all staphylococcal strains were susceptible to penicillin in 1941, today nearly all are resistant. This pattern is standard for most newly introduced antibiotics

The concept seems simple enough, but it’s not the only thing we’ve misunderstood about the evolution of pathogens. A common misperception is that a pathogen will evolve from being virulent to being more and more benign in order for the host to live long enough for the pathogen to pass on offspring to new hosts. This makes sense, yet doesn’t fully take into account the need to pass on offspring. Being able to disperse offspring to new hosts may mean it is most beneficial to the pathogen for the host to be sneezing, coughing, or laying prostrate. Another force behind pathogens evolving increased virulence is within-host selection. Simply, if there is more than one strain of a pathogen within a host, the one that uses the host’s resources most effectively will be the one to disperse the most offspring.

So if infections are one evolutionary explanation for disease, what’s an example? I recently came across an interesting article about infection and it’s relation to premenstrual syndrome. In the article Premenstrual Syndrome: an evolutionary perspective on its causes and treatment, Doyle et al. propose premenstrual syndrome is due to an exacerbation of a set of infectious diseases during cyclic changes of immunosuppression by estrogen and progesterone. While genetics and non-infectious environmental influences have been examined and found largely unable to explain PMS, infectious causes have been overlooked. However, it is know how immune function varies throughout the menstrual cycle in such a way that there could be less effective control of fungi, viruses, and intracellular bacteria, so making the leap to a persistent infection contributing to PMS doesn’t seem too difficult. Supporting this hypothesis is a long list of chronic diseases with suspected infectious causes that are exacerbated premenstrually including Crohn’s disease with Mycobacterium avium and juvenile onset OCD with Streptococcus pyogenes.

I think the most important point to take from this article is that there may be many other chronic diseases we don’t yet fully understand that are caused by infectious agents.

Yet even while the who, what, when, and where of some diseases may already be understood, the why of a disease is usually ignored. With an evolutionary perspective, we can try to answer the question of why diseases arise and persist under the forces of selection. These insights could help answer some old questions, such as those regarding unknown causes of chronic diseases, and ask some new ones, such as how could PMS be treated if it’s cause really is infectious. Finally, while guiding health care practices to improve health is the ultimate goal, at the very least evolutionary medicine reminds us to keep thinking about things in new ways.

Sources:

Doyle, C., H. A. Ewald, and P. W. Ewald. “Premenstrual Syndrome: An Evolutionary Perspective on its Causes and Treatment.” Perspectives in biology and medicine 50.2 (2007): 181-202.

Gammelgaard, A. “Evolutionary Biology and the Concept of Disease.” Medicine, health care, and philosophy 3.2 (2000): 109-16.

Nesse, Randolph M., and George C. Williams. Why we Get Sick. New York: Vintage Books, 1994.

Nesse, R. M. “How is Darwinian Medicine Useful?” The Western journal of medicine 174.5 (2001): 358-60.

Stearns, S. C., and D. Ebert. “Evolution in Health and Disease: Work in Progress.” The Quarterly review of biology 76.4 (2001): 417-32.

Williams, G. C., and R. M. Nesse. “The Dawn of Darwinian Medicine.” The Quarterly review of biology 66.1 (1991): 1-22.

What is the Hygiene Hypothesis?

Guest post by Zainab Khan

In most western countries, germs have become synonymous with the idea of something bad that needs to be killed as quickly as possible. However, people have long been questioning the validity of these ideas; a few decades ago it was hypothesized that not enough exposure to germ can and does cause insufficient development of an individuals immune system. New studies have recently shown that this idea of getting rid of all germs, and keeping children exposure to them at an absolute minimum, may possibly cause more harm then good; over cleanliness is suspected to be one of the main reasons that there is such an increased number in asthma and allergy ridden people in western countries. Also, compared to just a generation or two ago, people today have an increased chance of having/developing allergies. Is this all due to society’s craze over germs?

It is important when talking about allergies to have some working knowledge on what happens when an individual has allergies or an allergic attack. Allergies are an extreme and inappropriate reaction by an individual’s immune system to what typically is a common harmless stimuli found in a normal environment; the body takes something such as hay, food, pollen, etc. and has a hypersensitivity reaction to it. The body ends up activating its white blood cells (these are the cells that defend the body against any foreign bad stimuli), which typically are what help humans ward of virus and bacteria, for example the flu or an infection, which results in an inflammatory response. This inflammatory response manifests itself in different ways: asthma, eczema, hives, runny nose or eyes, coughing etc.

The Hygiene Hypothesis

Over two decades ago, the idea that there is such a thing as too much cleanliness was first proposed by David P. Strachan in his Hygiene Hypothesis. The idea behind this theory is that a lack of early exposure to the types of germs and stimuli that people used to have is the cause of allergies. In developing nations and in earlier time periods families tended to be larger then today. It was uncommon to have just one or two children; the idea behind having more children is that the elder child exposes the younger children to more germs and in turn the children end up having to develop a stronger immune system because the immune system has been fully developed by all the early stimuli [1,2]. This idea of exposure to other children has also held true for children who attend daycare at an early age. Daycare children tend to develop fewer allergies then those who are never in such environments. Research has gone even farther to say that children who are exposed to hepatitis A or the measles are less likely to have certain types of allergies [3].

Arguments against the hygiene hypothesis emerged when statistics were followed about inter city African American children in the United States, who have very high numbers of asthma. A study was done that showed that many of these children had been sensitized to the common allergens found around them; however, they still developed asthma at the same rate as those kids who were not sensitized to the same allergens [4]. Also, it is a scientific fact that some allergies have a genetic component. A child who has two parents with allergies has a 75% chance of also developing allergies. There are genetic links that have been found between certain types of allergic responses which complicates the idea of how much immunity is inherited and how much can be developed [5].

Although the idea of germ exposure has been building momentum within the last few years, the debate and research behind it is certainly not complete. If the hygiene hypothesis is true, this opens up another type of debate on how much and what kinds of bacteria, exposure, and caution should be taken around children. What exactly are the “right” germs, and how many are too many? In a society obsessed with antibacterial hand soaps, disinfectants, and bottled water it is going to be quite a challenge trying to convince people that germs are not all that bad.

Works Cited

1. Am. J. Respir. Crit. Care Med., Volume 164, Number 7, October 2001. The Increase in Asthma Ca Be Ascribed to Cleanliness 1106-1107 Link.

2.Strachan David, Thorax. Family Size, Infection and Atopy: The first Decade of the ‘hygiene hypothesis’ Link.

3. Matricardi Paolo, Rosmini Franceso, Riondino Silvia, Fortini Michele, Ferrigno Luigina, Rapicetta Maria, Sergio Bonini, BMJ 2000;320 Exposure to foodborne and orofecal microbes versus airborne viruses in relation to atopy and allergic asthma: epidemiological study 412-417. Link

4. R. Call, T. Smith, E. Morris, M. Chapman, T. Platts-Mills, The Journal of Pediatrics, Volume 121, Issue 6 Risk factors for asthma in inner city children, 862-866. Link

5. Mackay, Rosen, Volume 344, January 2001. Allergy and Allergic Diseases 30-37
Link.

Why are the schools closing and other good H1N1 links…

Over at DailyKos, DemfromCT has an excellent post explaining why it may be beneficial for schools to close temporarily, even if they only have one confirmed case of swine influenza: H1N1: Why Do Schools Close, And When Do They Open?

DarkSyde also has one up on the basic biology and evolution of the flu.

Nick Kristof discusses our lack of attention to public health and what it means in the event of a pandemic in today’s NY Times.

[Updated: and via the comment theads, this post which further discusses what I mentioned here regarding testing–and how the confirmed cases are only the tip of the iceberg (complete with diagram!).

Swine flu–deja vu all over again?

Back in 2007, I wrote about an outbreak of swine influenza from an Ohio county fair. The peer-reviewed paper analyzing the swine influenza isolated from that outbreak has just recently come out. From the abstract:

The swine isolate, A/SW/OH/511445/2007 (OH07), was evaluated in an experimental challenge and transmission study reported here. Our results indicate that the OH07 virus was pathogenic in pigs, was transmissible among pigs, and failed to cross-react with many swine H1 anti-sera. Naturally exposed pigs shed virus as early as 3 days and as long as 7 days after contact with experimentally infected pigs. This suggests there was opportunity for exposure of people handling the pigs at the fair. The molecular analysis of the OH07 isolates demonstrated that the eight gene segments were similar to those of currently circulating triple reassortant swine influenza viruses. However, numerous nucleotide changes leading to amino acid changes were demonstrated in the HA gene and throughout the genome as compared to contemporary swine viruses in the same genetic cluster. It remains unknown if any of the amino acid changes were related to the ability of this virus to infect people. The characteristics of the OH07 virus in our pig experimental model as well as the documented human transmission warrant close monitoring of the spread of this virus in pig and human populations.

Meanwhile, I mentioned yesterday that gene sequences from the new H1N1 virus had been released. Sandy has taken a look at some of these, and compared them with H1N1 and H1N2 viruses from humans and pigs.

Yes, there is a point to the juxtaposition of these two points, and it’s big–after the jump…
Continue reading “Swine flu–deja vu all over again?”

How long does it take to sequence an influenza virus?

…asked Joe. Answer: only a few days to sequence, clean up the data, and submit to NCBI. Seven H1N1 swine flu sequences are up (H/T Jonathan Eisen). I’ve not had a chance to crack anything open yet, but I hope to see some analysis from more of the genomics geeks soon…However, one bummer is that they don’t have any from the Mexico cases available–and particularly, any sequence data from any of the fatal cases. These will be helpful to see if there are any point mutations that could possibly account for a virulence difference between the Mexican and US cases. (Unlikely, I’d guess, but it would be nice to check it out…)

Swine flu: a quick overview–and new New York and Kansas cases

Sorry for the radio silence–I’ve been working on grants and manuscripts like a fiend, and so have tried to limit as many distractions as possible (which, unfortunately, includes blogging). However, the swine flu news is right up my alley, so I do just want to say a few words about it, and point you to some excellent stories already up elsewhere.

First, in case you’ve not been paying attention to the news in the last few days, there have been 8 reported cases of swine influenza infections in humans (6 in California and 2 in Texas, with additional suspected cases) and reports from Mexico suggesting as many as 1000 ill and 68 dead from influenza in the past month or so. Of the Mexican cases, a dozen thus far have been confirmed to be the same strain as the US swine flu strain from California/Texas.

What does all this mean? Much more after the jump.
Continue reading “Swine flu: a quick overview–and new New York and Kansas cases”

MRSA ST398 in US swine

A little over a year ago I put a post up documenting research out of Canada which found methicillin-resistant Staphylococcus aureus (MRSA) in Canadian pigs. This had also been seen in Europe (with a lot of research coming out of the Netherlands). What I didn’t note at the time was that we were gearing up to start some sampling of our own on area swine farms. Some of you saw that we presented the results of that research last year at ICEID and ASM; now the paper is out describing our pilot project in PLoS ONE. (Note: the paper was available earlier, but now they seem to have removed it…keep an eye on that link).
Continue reading “MRSA ST398 in US swine”