Category Archives: biology

What’s the deal with prions?

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Image: Bovine spongiform encephalopathy (BSE) prion.

First of all: It’s usually pronounced “pree-on.” If you say “pry-on”, people will probably still know what you mean.

This is an exploratory post on what prions are, and how they work, and a lot of other things I found interesting about them.

Primer on protein folding

  • Proteins are strings of amino acids produced from blueprints in DNA. Proteins run your cells, catalyze reactions, and do just about every important thing in the body.
  • A protein’s function is determined from its amino acid composition, and then mostly from its shape. A protein’s shape determines what other kind of molecules it can interact with, how it’ll interact with them, and everything it can do. One of the main reasons amino acid composition is important is because it determines how proteins can fold.
  • One string of amino acids can be folded into different shapes, which will have different properties. (The particular shape of a specific string of amino acids is called an isoform.)
  • While strings of amino acids will fold themselves into some kind of shape as they’re being made, they may also be folded later – into different or more complex shapes – elsewhere in the cell.
  • One of the things that can refold proteins is other proteins.
  • A prion is a protein that folds other, similar proteins into copies of itself. These new copies are very stable and difficult to unfold.
  • These copies can then go on and fold more proteins into more copies.
CJD plaques in the brain surrounded by prion proteins

CJD’s impact in the brain – red clumps are amyloid plaques, surrounded by blue clumps of prion proteins. || Image is public domain by the CDC.

Some prion diseases

Prion diseases in animals appear to be mostly neurological. All known mammal prions are isoforms of a single nerve protein, PrP. They can both emerge on their own when the protein misfolds in the brain, or spread as an infectious agent.

Creutzfeldt-Jakob Disease affects one in one million people. (It’s also the most common modern prion disease. Prion diseases are very rare.) It comes in a variety of forms, but all have similar symptoms: depression, fatigue, dementia, hallucinations, loss of coordination, and other neurological symptoms, generally resulting in deaths a few months after symptoms start.

  • 84-90% of cases are sporadic, meaning that the protein misfolds on its own. This mostly occurs in people older than 60.
  • 10-15% of cases are familial, where a family carriers a gene that makes PrP likely to misfold.
  • >1% of cases are iatrogenic, meaning they occur as a result of hospital treatment. If medical care fucks up really badly, they might transplant organs from people with CJD, or inject people with growth hormone extracted from the pituitary glands of dead people, or even just use surgical tools once on CJD patients, and they catch it.

(The surgical tools one is really scary. Normal autoclaves – that operate well above the threshold needed to inactivate bacteria and viruses –  kill some but not all prions. And while it takes a large dose of ingested prions before you’re likely to get sick, it takes 100,000 times less when exposure is brain-to-brain. Cleaning with “benzene, alcohol and formaldehyde” still doesn’t kill prions. The World Health Organization issued prion-specific instrument cleaning procedures in 1999- towards the end of Britain’s brush with bovine spongiform encephalopathy- which include bleach or sodium hydroxide and longer autoclaving. I don’t know if these are still used outside of known epidemics.)

Mad cow disease, or bovine spongiform encephalopathy (BSE), is also a prion disease. It transmitted between cows when they were fed a feed that contained meat and bone meal, including brain matter from cows with the disease. The incubation period is between 5 and 40 years. The source molecule is essentially a cow-originated Creutzfeld-Jakob prion, and when the prion replicates in humans, it’s probably the cause of variant Creutzfeld-Jakob disease.

Between 1900 and 1960, the Fore people of New Guinea had an epidemic of an unknown neurodegenerative disease – mostly among women – that caused shaking, difficulty walking, loss of muscle coordination, outbursts of laughter and depression, neurological degeneration, and eventually death.

The Fore tribe practiced funerary cannibalism, and women both prepared and ate the dead, including the brains, and fed them to children and the elderly. This transmitted kuru, a prion disease with an incubation period of years. The last known sufferer of kuru died in 2005.

(The source of kuru was probably a single person with CJD. There are other tribes that practiced funerary cannibalism– I wonder if any of them also had prion epidemics from eating the brains of people who spontaneously developed CJD.)

Fatal familial insomnia is a genetic prion disease. Unlike CJD or BSE, fatal familial insomnia prions target the thalamus. If your family has it, and you inherit it, you live until about 30 – then lose the ability to sleep, hallucinate, and die within months. There is no cure. There are more painful and equally fatal diseases, but this must be one of the scariest.

Undulates really get the short end of the prion stick. Chronic wasting disease affects elk and deer and can run rampant in herds. Scrapie affects sheep and goats, and makes them scrape their fleece off and then die.

Prion evolution

Prions differ from their pathogenic, self-replicating brethren – the viruses, the bacteria, the parasites – in one major way: They don’t have DNA or RNA. They don’t even have a central means of storing information.

But studies show that prions can evolve. They can’t change their amino acid composition because they’re not involved in producing it, but do change their progeny’s folding.

This doesn’t seem surprising. The criteria for something to undergo Darwinian evolution don’t necessarily require DNA – just a self-replicator that has some level of random variation, and passes that variation down to its replicas.

Most brain prions don’t transmit, though, so it seems safe to say that the evolutionary lineages of most prions are very short – less than the lifespan of the host. Very contagious prions, like scrapies, presumably have jumped from host to host many times and have longer lineages.

Structure of death

All known mammal prions are variants of a single gene, PrP, and exist in the brain. Why?

Some hypotheses:

  • Brain proteins are more likely to misfold than other proteins
    • Why? Brain proteins replicate less than other proteins, and are really really central to the body’s function.
  • PrP is especially liable to turn into a self-replicator if misfolded.
    • Predictions: Other amyloid-based brain diseases are also PrP isoforms. Prions have a similar shape that makes replication happen. Maybe PrP itself self-replicates in the body under some circumstances.
  • The brain clears misfolded proteins less well than other body parts.
    • Predictions: Other waste product buildup happens in the brain. The rest of the body has some way of combating amyloids or prions.

We know of very few prions (we know that one non-mammal animal, the ostrich, may have them.) Except in fungi. Fungi have tons of prions. Fungi prions don’t come from the same gene either – if you click through to that last link, you’ll see that the misfolds came from a variety of initial proteins that don’t appear to be related at all. Presumably, they have widely different structures.

So why are these the two prion hotbeds? Here’s what I suspect.

We know that both fungi and mammal proteins have related structures – they’re amyloids, aggregating proteins with a distinctive architecture called a cross-β-sheet. (Amyloids in general are implicated in some other diseases, and are sometimes produced intentionally as well. Spider silk has amyloids.) Beta sheets are long, sticky amino acid chains that attach to each other, forming large, water-insoluble clumps that are difficult for the body to clear.

To take an ad hoc survey that could loosely be called a literature review, let’s take the Wikipedia page for amyloid-based diseases. Of those listed, four involve deposits in the brain, and four form deposits in the kidneys (runners-up include ones that deposit in a variety of organs, and ones that deposit in the eyes.

Why the kidney? Given its role as the body’s filter,  it makes sense: if a protein floats in the blood, it’ll end up in the kidney, and if multiple sticky proteins circulate, they’ll end congregate there. Wikipedia points out that people on long-term dialysis are also more likely to develop amyloidosis.

Why the brain?

The blood-brain barrier limits the reach of the immune system into the brain, where it could potentially deal with amyloids that it recognizes as foreign material. Sequestered beyond the reach of the immune system, the brain and nervous system clear loose gunk and proteins (including amyloids) via the glymphatic system, via channels in the brain called astrocytes. (The glymphatic system appears to do much of its work while you’re asleep.)

[Caution: Speculation.] I suspect that this system has a lower flow-through rate than the circulatory or lymphatic system, which are responsible for the same task on the other side of the blood-brain barrier. Fungi, including yeast, don’t seem to have robust waste-clearing systems. This might be the connection that explains how prions build up in each.

What about other multicellular organisms without circulatory systems- do prions exist for bacteria, plants, or larger fungi? I don’t think we know. I’m guessing that they exist in other animals or organisms, but since they’re made up of the same compounds as the rest of the body, it’s very difficult to find or test for a prion – if you’re not sure what you’re looking for. [/speculation]

Gathering blood from a sheep to test for scrapie.

Drawing blood to test a sheep for genetic resistance to scrapie. || Public domain, by USDA Agricultural Research Service.

Some notes on infectivity

  • Scrapie is transmitted between sheep by cuts and ingestion, and chronic wasting disease is often transmitted by ingestion, as when a sick deer dies on ground that grows grass, which is eaten by new herbivores. They can also be aerosolized (yikes).
  • CJD and kuru are still infectious, but less so- you have to ingest brain matter to get them.
  • Meanwhile, Alzheimer’s disease might be slightly infectious- if you take brain extracts from people who died of Alzheimer’s, and inject them into monkey’s brains, the monkeys develop spongy brain tissue that suggests that the prions are replicating. This technically suggests that the Alzheimer’s amyloids are infectious, even if that would never happen in nature.

What makes scrapie so much more transmissible than CJD, and CJD so much more transmissible than Alzheimer’s? I’m not sure. The shape of the prion might be relevant. Scrapie is just another mutation of PrP, so I’m not sure why no human prions have ever had the same effect (except that since scrapie is a better replicator, it would only need to have happened once in sheep.)

It might also be behavioral – sheep appear to shed scrapie in feces, and undulates have more indirect contact with their own feces than other animals (deer poop on grass, deer eat the grass, repeat.)

Fun Prion Facts

  • We can design synthetic prions. Current synthetic prions are also variations of the PrP protein in mammals.
  • Did I mention they can be airborne? They can also be airborne.
  • Even though they’re just different configurations of proteins that are already in your body, the immune system can distinguish prions from normal proteins. For a while we thought this was a problem because most immune cells can’t cross the blood-brain barrier, but it turns out some can.
  • The possibility of bloodborne prion transmission (of mad cow disease) is the reason why people who lived in Britain during certain years still can’t donate blood in the US.
  • Some fungi also appear to produce a molecule that degrades mammal prions.  Don’t take that at face value – as far as I could tell, the study didn’t compare non-prion PrP to prion PrP. That said, it has implications for, say, treating surgical instruments.
  • The zombie virus isn’t real, but if it were, it would definitely be a prion and not a virus.
  • Sometimes, if you’re infected with one prion, it’s more difficult for you to get infected with another. This is true sometimes but not always.
  • Build-up of amyloids or prions may sequester pathogens in the brain.
  • Finally, for most diseases, if we eliminated all of the extant disease-causing particles, the disease would go extinct- the same way that if we kill off of species X and don’t store its DNA, species X goes extinct forever and never comes back. Creutzfeldt-Jacob is an interesting case of an infectious self-replicator where that isn’t true. Even if all CJD prions were instantly destroyed, it would emerge naturally in the genetic or spontaneous cases where the brain itself misfolds proteins, and could spread iatrogenically or through ingestion.
Longtoothed bristlemouth

What’s the most common animal species?

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I tried to answer this question by doing some reading. Why should we care?

  • Most people don’t have a good sense of the scope and scale of biodiversity and common species on the planet. Whatever you think are the most common inhabitants of earth, you’re probably wrong.
  • When scientists think of “successful” organisms, they tend to think of ones with great diversity: beetles, for instance, or in terms of environments, rainforests. Looking at sheer numbers of individual species is another way of doing this.
  • “Okay,” you say, “Why animals, and not plants or bacteria? Those are way more common.” I study bacteriophage. I know. Two reasons: Animals have brains, which is one reason to focus on them- don’t you want to know who’s doing the majority of the world’s thinking? Secondly, it’s harder to find data on non-animals, but stay tuned.
  • Similarly, if you’re concerned about wild animal suffering, this may give you a sense of where best to focus your concern.

Mammals don’t come anywhere near the top, but sure, they’re furry and warm and cute and also you’re one, so let’s begin here. Humans aren’t actually a bad call as far as larger organisms- there are 7.5 billion (7,500,000,000) of us crawling around the planet, handily beating out other close competitors.

Rule 1: If you want to make an organism numerous, association with humans is a good start.

Large wild mammals are not especially common. Cows (1.4 billion) have the largest non-human large mammal population, and sheep, pigs, and goats (~1 billion each) beat out all other competitors. The curious will be interested to know that there are 50% more cats globally than dogs (600,000,000 vs 400,000,000).

What about birds? As of 1997, between 200 and 400 billion (brought to us by the excellently titled paper, How Many Birds Are There?) The most numerous wild bird is the red-billed quelea, which terrorizes African farmers in enormous flocks (1.5 billion). (The Smithsonian flagrantly claims it’s the house sparrow, but the population of those is maybe half a billion and dropping.) Again, association with human comes in- the most common bird is the chicken, at 19 billion (19,000,000,000) or 2.5 chickens per human.

Hundreds of roosters standing in a field

“Capons in Hainan” by Anna Frodesiak / CC0 1.0

So chickens are looking good so far. What about mice or rats? They’re tiny, reproduce voraciously, and also follow humans. Unfortunately, I couldn’t find good estimates on global mouse populations. Maybe there’s ten mice per human? Maybe there’s 75 billion mice. Sure. Fortunately, it doesn’t matter. Remember the grand rule of biomes:

Rule 2: Whatever’s happening in the ocean is much bigger and much wackier than anything on land.

You’ve probably never heard of the bristlemouth, genus Cyclothone, a three-inch-long deep-ocean fish with a big mouth and weird teeth. As it happens, most of the planet’s surface is deep ocean. Unspecified “icthyologists” found by the New York Times speculate a population in the hundreds of trillions (> 200,000,000,000,000).

Their sheer population has only recently come to light- they’re found many meters deep into the water column and don’t surface at night, and the extent of their dominion has only recently been discovered via trawling with fine nets and the dawn of deep-sea exploration. If these “ichthyologists” can be believed, the bristlemouth is probably the most common vertebrate on earth.

Maybe you’re confused as to how there could be so many bristlemouths, since they’re relatively large compared to, say, insects. I’m not actually convinced that the trillions number is correct, but nonetheless, consider: The oceans represent 75% of the planet’s surface, and while land animals are more or less limited to a flat surface, ocean animals can “stack” in three dimensions.

Finally, a fun fact: If a bristlemouth brain weighs as much as a goldfish brain, then:

7,500,000,000 human brains * 1,350 grams/human brain = 10,000,000,000 kg

200,000,000,000,000 bristlemouth brains * 0.097 grams/bristlemouth brain = 19,400,000,000 kg

Mass of human brains ≈ mass of bristlemouth brains

Draw your own conclusions.

Rule 3: Ant biologists need to get it together.

Ants feeding on a honey droplet

“Meat eater ants feeding on honey” by flagstaffotos / CC BY-NC

All the world’s ants are popularly said to weigh the same amount as all the world’s human beings. It takes 16 million ants to outweigh a human, and since your garden-variety ant colony has about 4,000 ants, that would be 40,000 ant colonies per person.

This sounds ridiculous, and a University of Sussex professor suggests that it is– that ants may have outweighed humans earlier in our existence, but we’ve spread too far too quickly for them to catch up. This article posits 100,000,000,000,000 (1×1014) ants.

But wait. A different article from BBC suggests 1,000,000,000,000,000,000,000,000 (1×1024).

What’s going on here? To our instinctive brains, both of those guesses occupy a similar conceptual space as “really large numbers”, but they’re not close. They’re ten orders of magnitude apart. One of these numbers is ten billion times larger than the other. There’s one quantity of ants, or there’s ten billion times that number of ants. What?!

I have no idea. Worse yet, they’re both from the same source. The BBC can’t be a reliable news source if they don’t have a standard journalistic value for “total number of ants” that’s rough to within oh, say, five orders of magnitude.

Fortunately, we can perform a sanity check. The earth has 1.5×1014 square meters of dry land.

1×1024 global ants / 1.5×1014 square meters = ~7,000,000,000 ants per square meter

Given that we’re not swimming in ants at every single moment, we can knock off a few zeroes and come down to 1×1019 (10,000,000,000,000,000,000 or ten billion billion ants, at 70 ants per square meter, which seems more reasonable.)

Even if the most common ant species is just 1% of all ants, where ants ranks depends drastically on which value the right value is. Bristlemouths might outnumber them, or they might not. Dear ant researchers: work on this, but at the least, stop telling people there are 1×1024 ants. That’s too many ants.

(While researching this, I also learned about the long and short scales– everyone uses the same “million”, but my “trillion” may not be the same as your “trillion”. While normally I try to avoid being prescriptivist about language, this is a terrible use of words and everybody should either use lots of zeroes or scientific notation from here on out. Ugh. Anyways.)

Antarctic krill

Antarctic krill by Uwe kils / CC BY-NC

The antarctic krill is the foundation of the antarctic ecosystem. It feeds whales, seals, squids, fish, and everything else. 500 million tons of it exist, and Wikipedia claims it’s probably the most abundant species on the planet. Using Wikipedia’s mass value of up to 2 grams (say, 1.5 grams on average), that’s 3×1014 (300,000,000,000,000) krill.

Rule 4: Maybe we just don’t know what’s going on.

Let’s talk about uncertainty. There are a couple other candidates. They may easily hold the title, but I don’t know because nobody has done the research. There are certainly plausible reasons to suspect any of them of holding the title, and we can use Fermi calculations for the sake of a guess, but I don’t expect these to be very accurate.

Most of the guesses above did come with specific numbers, but aren’t necessarily completely trustworthy. Articles written about ants, antarctic krill, nematodes, and copepods have all variously claimed to be the most common animal. It seems like this could happen because of the availability bias– if you’re a krill biologist, and someone asks you what the most common animal is, and you know that there are a whole lot of krill, you’re probably going to say krill.

Narrowing down a common species is also more difficult- I can attest (from work with tiny snails) that doing field identification via microscope is the worst. So presumably, most studies don’t do it, and focus on the broader picture.

Alternatively, invertebrate researchers have field-wide conspiracies in order to get more grant money. Invertebrate researchers are welcome to deny this in the comments.

Copepods

Tiny free-swimming ocean crustaceans, at the root of many food chains.

Some scientists say they form the largest animal biomass on earth.

[…]

Copepods almost certainly contribute far more to the secondary productivity of the world’s oceans, and to the global ocean carbon sink than krill, and perhaps more than all other groups of organisms together. – Wikipedia

Also, bristlemouths eat them. Oceanic food chains don’t always work the same way land food chain pyramids do- there’s not necessarily more biomass at the base of the chain than at the top– but as far as I know, it’s strong evidence for them having more biomass.

Frustratingly, as with the nematodes, nobody seems to know what the most common copepod is.

My probable candidate:

  • A small cosmopolitan mid-ocean-level copepod.

Copepod expert Geoff Boxshall on Plankton Safari estimates 1.3×1021 (1,300,000,000,000,000,000,000) copepods. If the most common species represents 1% of all copepods, that’s 1.3×1019 of a common copepod species out there.

But I think we can do better.One study found an average 20 zooplankton per cubic meter in the Atlantic ocean, with occasional high spikes and huge seasonal variation. If we assume that such a number is constant over all the oceans and throughout the euphotic zone (the top layer of the ocean that receives sunlight and supports photosynthesis), that adds up to at least 5.78×1017 plankton. Since we know copepods are quite common, let’s say that 50% of the zooplankton is copepods, and that the most common species represents 1% of all copepods. That’s:

5.78×1017 zooplankton worldwide x (50% copepods) x (1% of the most common species) = 2.89×1015 of the most common copepod.

Copepods

By Lennart Lennuk / CC BY-SA

Nematodes

They are ubiquitous in freshwater, marine, and terrestrial environments, where they often outnumber other animals in both individual and species counts, and are found in locations as diverse as mountains, deserts and oceanic trenches. – Wikipedia

Everyone (read: all scientists who have expressed an opinion on the matter) seems to think that nematodes are incredibly numerous. That said, Nematoda is a very broad umbrella- sort of like saying that there aren’t very many Chordates (the phylum that contains all vertebrates plus a handful of squishy sea creatures.) Bristlemouths, meanwhile, are narrowed down to a single genus of only a dozen species.

My guesses for a candidate Most Common Nematode are:

  • A small, free-living, deep ocean floor or mid-ocean-level species
  • A small parasitic nematode that inhabits cattle or bristlemouth guts.

(Why these two? My educated guess is that smaller animals tend to be more common, and that the smallest species are routinely parasites. Other small species tend to be among the more numerous free-living animals- think mice and Palegibacter ubique.)

My extrapolations (more details on those numbers) from a 2006 study of benthic microfauna – very small animals living on the ocean floor at various depths – suggest that there are maybe 9.03×1019 such critters in Earth’s oceans. These include nematodes, benthic copepods, and other species. As with copepods, let’s guess that half of these are nematodes, and that 0.1% of nematodes are in the most prolific species.

9.03×1019 microfauna on the ocean floor x (50% nematodes) x (0.1% of nematodes in the most common species) = 4.52×1016 of a common nematode species.

This aligns well with another, rougher back of the envelope calculation from a different source:

Roughly 2000 nematodes / square meter * (5.1×1014 meters on the ocean floor) * (1% of nematodes in most common species) = 1.02×1016 (1,020,000,000,000,000) of a common nematode species.

Conclusion: It’s a nematode world.

[Updated as of 4/14/2017.]