Unraveling the mystery behind dogs' floppy ears

Dogs' floppy ears may be part of why they and other domesticated animals love humans so much.

Unraveling the mystery behind dogs' floppy ears
Photo by Jamie Street on Unsplash
  • Nearly all domestic animals share several key traits in addition to friendliness to humans, traits such as floppy ears, a spotted coat, a shorter snout, and so on.
  • Researchers have been puzzled as to why these traits keep showing up in disparate species, even when they aren't being bred for those qualities. This is known as "domestication syndrome."
  • Now, researchers are pointing to a group of a cells called neural crest cells as the key to understanding domestication syndrome.

The grey wolf's sense of smell can detect prey nearly two miles away, and it can hear subtle sounds up to ten miles away. At night, it sees in the dark. When chasing prey, it can reach a speed of 35 mile per hour and deliver crushing bites with 1,500 pounds of pressure per square inch of jaw. Wolf packs have also been known to take down much larger prey, like moose or bison.

As for their distant cousins, the domesticated dog, I once had a dog who would fart himself awake at night and stare accusatorily at me.

Despite their differences, grey wolves are the closest living relative to the domesticated dog. They share an extinct, unknown ancestor, an apex predator that likely hunted ancient megafauna. But at some point, one of the descendants of that ancient ancestor learned how beneficial it was to hunt alongside humans. In tracking game, we became closer as hunters. Eventually, proto-dogs left the wildness behind and began to transform. Their ears became floppier, their coats grew lightly-colored patches. Their personality — perhaps after getting to know human children over centuries — became more playful and less fearful. The changes continued: their snout shortened, and their teeth and brain shrunk.

Just like that, Fenrir transformed into Scooby-Doo.

How did this change happen?

Photo by Michael LaRosa on Unsplash

The common logic says that the wolves' new environment, one spent in frequent contact with humans, put a pressure on them to become friendlier. Eventually, humans began breeding these dogs for certain desirable traits, such as a border collie's herding instinct or a pug's cute (and extremely unhealthy) squashed snout.

This is true to an extent. But upon observing other animals undergoing domestication, scientists noticed something strange. They all seemed to change in the exact same way.

Consider, for instance, the case of Dmitry Belyaev, a Soviet biologist who experimented with breeding wild foxes. The sole basis of his experiment was to take a generation of wild foxes and breed the ones friendliest to humans. The experiment is still ongoing today, nearly 60 years and many fox generations later. Now, the foxes are exceptionally friendly (though not quite ready to be pets). In addition, like domesticated dogs, their coats have splashes of lighter color, their tails curl, and their ears are floppy.

Similar changes have been observed in domesticated cats, horses, pigs, ferrets, camels… the list goes on. Somehow, selecting for friendliness towards humans in animals — domesticating them — causes a constellation of seemingly unrelated physiological changes. Researchers have given this mystery a name: Domestication syndrome.

Now, researchers have discovered a compelling reason why these changes are indeed related, and it has to do with something called neural crest cells.

Hijacking stem cells for a friendlier wolf

These dogs display the floppy ears, short snouts, and lighter pigment on their faces and chests common to domesticated animals. Photo by Anoir Chafik on Unsplash

Neural crest cells are a kind of stem cell, meaning that as an animal's body develops in the womb, these cells differentiate into more specialized cells that eventually become different parts of the body. Crucially, neural crest cells contribute to the development of the adrenal medulla, which is part of the adrenal gland in the brain.

This structure is responsible for releasing adrenaline and noradrenaline in response to stressful stimuli: essentially, it contributes to the flight-or-fight response, fear, and stress. Wild animals obviously need their neural medulla to be sensitive. For a grey wolf, the world is a dangerous place, not least because of humans. But if we want a wolf to be more like a dog, less inclined to fear humans and behave aggressively, then we would breed two relatively unafraid wolves together, selecting for a weaker neural medulla. If their adrenal medulla is less developed, then at some point the wolf's neural crest cells were somehow repressed during its development.

Over time, selecting for animals with fewer neural crest cells produces a friendlier critter. But these cells play a diverse role in the body: they're stem cells, so they become many different things. Among these, neural crest cells become melanocytes, which create darker colors in skin or fur. Because the development of neural crest cells is degraded in domesticated animals, these cells don't have the chance to spread uniformly throughout the body. Instead, distant regions in the body become splotchy, which is why many dogs have lighter patches of fur above their eyes or on their chest.

As the dog develops in the womb, its neural crest cells are located in the spot that will eventually become the base of the tail. Because these cells are repressed in domesticated dogs, they can't spread throughout the body. As a result, distant regions like the skull, brain, ears, and facial and chest fur are often affected.

Wilkins et al., 2014

Cartilage, too, is derived from neural crest cells, which is why domesticated animals tend to have floppy ears. The skull and brain are also dependent on these cells, which is why domesticated dogs have smaller brains than wolves, shorter snouts, and smaller teeth.

If you look at other animals besides dogs, these traits hold true. Domesticated horses have spotted pelts. Cats often have bands of color (although they rarely have floppy ears). Domesticated mice, foxes, ferrets, birds, and even fish all share some combination of these different traits.

A delicate balance

Human beings have bred these animals for friendliness, but as an unintended side effect, we have changed their physiology in drastic ways. While their appearance is drastically different, the changes in their genome can almost be considered subtle. There are many genes responsible for the production of neural crest cells. When any one of these genes is completely shut down, it's often fatal for the animal. Or, if these genes are downregulated too much, then we begin to see genetic disorders appear such as Waardenburg syndrome, Treacher Collins syndrome, or Mowat-Wilson syndrome (interestingly, one of the symptoms of Mowat-Wilson syndrome is excessive friendliness).

In domesticated animals, many of these genes are just ever-so-slightly downregulated to put the right limit on neural crest cell production during an animal's development. As a result, you get a healthy, friendly, floppy-eared dog instead of an apex predator fetching the paper for you in the morning.

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Credit: Getty Images
Surprising Science
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COVID and "gain of function" research: should we create monsters to prevent them?

Gain-of-function mutation research may help predict the next pandemic — or, critics argue, cause one.

Credit: Guillermo Legaria via Getty Images

This article was originally published on our sister site, Freethink.

"I was intrigued," says Ron Fouchier, in his rich, Dutch-accented English, "in how little things could kill large animals and humans."

It's late evening in Rotterdam as darkness slowly drapes our Skype conversation.

This fascination led the silver-haired virologist to venture into controversial gain-of-function mutation research — work by scientists that adds abilities to pathogens, including experiments that focus on SARS and MERS, the coronavirus cousins of the COVID-19 agent.

If we are to avoid another influenza pandemic, we will need to understand the kinds of flu viruses that could cause it. Gain-of-function mutation research can help us with that, says Fouchier, by telling us what kind of mutations might allow a virus to jump across species or evolve into more virulent strains. It could help us prepare and, in doing so, save lives.

Many of his scientific peers, however, disagree; they say his experiments are not worth the risks they pose to society.

A virus and a firestorm

The Dutch virologist, based at Erasmus Medical Center in Rotterdam, caused a firestorm of controversy about a decade ago, when he and Yoshihiro Kawaoka at the University of Wisconsin-Madison announced that they had successfully mutated H5N1, a strain of bird flu, to pass through the air between ferrets, in two separate experiments. Ferrets are considered the best flu models because their respiratory systems react to the flu much like humans.

The mutations that gave the virus its ability to be airborne transmissible are gain-of-function (GOF) mutations. GOF research is when scientists purposefully cause mutations that give viruses new abilities in an attempt to better understand the pathogen. In Fouchier's experiments, they wanted to see if it could be made airborne transmissible so that they could catch potentially dangerous strains early and develop new treatments and vaccines ahead of time.

The problem is: their mutated H5N1 could also cause a pandemic if it ever left the lab. In Science magazine, Fouchier himself called it "probably one of the most dangerous viruses you can make."

Just three special traits

Recreated 1918 influenza virionsCredit: Cynthia Goldsmith / CDC / Dr. Terrence Tumpey / Public domain via Wikipedia

For H5N1, Fouchier identified five mutations that could cause three special traits needed to trigger an avian flu to become airborne in mammals. Those traits are (1) the ability to attach to cells of the throat and nose, (2) the ability to survive the colder temperatures found in those places, and (3) the ability to survive in adverse environments.

A minimum of three mutations may be all that's needed for a virus in the wild to make the leap through the air in mammals. If it does, it could spread. Fast.

Fouchier calculates the odds of this happening to be fairly low, for any given virus. Each mutation has the potential to cripple the virus on its own. They need to be perfectly aligned for the flu to jump. But these mutations can — and do — happen.

"In 2013, a new virus popped up in China," says Fouchier. "H7N9."

H7N9 is another kind of avian flu, like H5N1. The CDC considers it the most likely flu strain to cause a pandemic. In the human outbreaks that occurred between 2013 and 2015, it killed a staggering 39% of known cases; if H7N9 were to have all five of the gain-of-function mutations Fouchier had identified in his work with H5N1, it could make COVID-19 look like a kitten in comparison.

H7N9 had three of those mutations in 2013.

Gain-of-function mutation: creating our fears to (possibly) prevent them

Flu viruses are basically eight pieces of RNA wrapped up in a ball. To create the gain-of-function mutations, the research used a DNA template for each piece, called a plasmid. Making a single mutation in the plasmid is easy, Fouchier says, and it's commonly done in genetics labs.

If you insert all eight plasmids into a mammalian cell, they hijack the cell's machinery to create flu virus RNA.

"Now you can start to assemble a new virus particle in that cell," Fouchier says.

One infected cell is enough to grow many new virus particles — from one to a thousand to a million; viruses are replication machines. And because they mutate so readily during their replication, the new viruses have to be checked to make sure it only has the mutations the lab caused.

The virus then goes into the ferrets, passing through them to generate new viruses until, on the 10th generation, it infected ferrets through the air. By analyzing the virus's genes in each generation, they can figure out what exact five mutations lead to H5N1 bird flu being airborne between ferrets.

And, potentially, people.

"This work should never have been done"

The potential for the modified H5N1 strain to cause a human pandemic if it ever slipped out of containment has sparked sharp criticism and no shortage of controversy. Rutgers molecular biologist Richard Ebright summed up the far end of the opposition when he told Science that the research "should never have been done."

"When I first heard about the experiments that make highly pathogenic avian influenza transmissible," says Philip Dormitzer, vice president and chief scientific officer of viral vaccines at Pfizer, "I was interested in the science but concerned about the risks of both the viruses themselves and of the consequences of the reaction to the experiments."

In 2014, in response to researchers' fears and some lab incidents, the federal government imposed a moratorium on all GOF research, freezing the work.

Some scientists believe gain-of-function mutation experiments could be extremely valuable in understanding the potential risks we face from wild influenza strains, but only if they are done right. Dormitzer says that a careful and thoughtful examination of the issue could lead to processes that make gain-of-function mutation research with viruses safer.

But in the meantime, the moratorium stifled some research into influenzas — and coronaviruses.

The National Academy of Science whipped up some new guidelines, and in December of 2017, the call went out: GOF studies could apply to be funded again. A panel formed by Health and Human Services (HHS) would review applications and make the decision of which studies to fund.

As of right now, only Kawaoka and Fouchier's studies have been approved, getting the green light last winter. They are resuming where they left off.

Pandora's locks: how to contain gain-of-function flu

Here's the thing: the work is indeed potentially dangerous. But there are layers upon layers of safety measures at both Fouchier's and Kawaoka's labs.

"You really need to think about it like an onion," says Rebecca Moritz of the University of Wisconsin-Madison. Moritz is the select agent responsible for Kawaoka's lab. Her job is to ensure that all safety standards are met and that protocols are created and drilled; basically, she's there to prevent viruses from escaping. And this virus has some extra-special considerations.

The specific H5N1 strain Kawaoka's lab uses is on a list called the Federal Select Agent Program. Pathogens on this list need to meet special safety considerations. The GOF experiments have even more stringent guidelines because the research is deemed "dual-use research of concern."

There was debate over whether Fouchier and Kawaoka's work should even be published.

"Dual-use research of concern is legitimate research that could potentially be used for nefarious purposes," Moritz says. At one time, there was debate over whether Fouchier and Kawaoka's work should even be published.

While the insights they found would help scientists, they could also be used to create bioweapons. The papers had to pass through a review by the U.S. National Science Board for Biosecurity, but they were eventually published.

Intentional biowarfare and terrorism aside, the gain-of-function mutation flu must be contained even from accidents. At Wisconsin, that begins with the building itself. The labs are specially designed to be able to contain pathogens (BSL-3 agricultural, for you Inside Baseball types).

They are essentially an airtight cement bunker, negatively pressurized so that air will only flow into the lab in case of any breach — keeping the viruses pushed in. And all air in and out of the lap passes through multiple HEPA filters.

Inside the lab, researchers wear special protective equipment, including respirators. Anyone coming or going into the lab must go through an intricate dance involving stripping and putting on various articles of clothing and passing through showers and decontamination.

And the most dangerous parts of the experiment are performed inside primary containment. For example, a biocontainment cabinet, which acts like an extra high-security box, inside the already highly-secure lab (kind of like the radiation glove box Homer Simpson is working in during the opening credits).

"Many people behind the institution are working to make sure this research can be done safely and securely." — REBECCA MORITZ

The Federal Select Agent program can come and inspect you at any time with no warning, Moritz says. At the bare minimum, the whole thing gets shaken down every three years.

There are numerous potential dangers — a vial of virus gets dropped; a needle prick; a ferret bite — but Moritz is confident that the safety measures and guidelines will prevent any catastrophe.

"The institution and many people behind the institution are working to make sure this research can be done safely and securely," Moritz says.

No human harm has come of the work yet, but the potential for it is real.

"Nature will continue to do this"

They were dead on the beaches.

In the spring of 2014, another type of bird flu, H10N7, swept through the harbor seal population of northern Europe. Starting in Sweden, the virus moved south and west, across Denmark, Germany, and the Netherlands. It is estimated that 10% of the entire seal population was killed.

The virus's evolution could be tracked through time and space, Fouchier says, as it progressed down the coast. Natural selection pushed through gain-of-function mutations in the seals, similarly to how H5N1 evolved to better jump between ferrets in his lab — his lab which, at the time, was shuttered.

"We did our work in the lab," Fouchier says, with a high level of safety and security. "But the same thing was happening on the beach here in the Netherlands. And so you can tell me to stop doing this research, but nature will continue to do this day in, day out."

Critics argue that the knowledge gained from the experiments is either non-existent or not worth the risk; Fouchier argues that GOF experiments are the only way to learn crucial information on what makes a flu virus a pandemic candidate.

"If these three traits could be caused by hundreds of combinations of five mutations, then that increases the risk of these things happening in nature immensely," Fouchier says.

"With something as crucial as flu, we need to investigate everything that we can," Fouchier says, hoping to find "a new Achilles' heel of the flu that we can use to stop the impact of it."

The misguided history of female anatomy

From "mutilated males" to "wandering wombs," dodgy science affects how we view the female body still today.

Credit: Hà Nguyễn via Unsplash
Sex & Relationships
  • The history of medicine and biology often has been embarrassingly wrong when it comes to female anatomy and was surprisingly resistant to progress.
  • Aristotle and the ancient Greeks are much to blame for the mistaken notion of women as cold, passive, and little more than a "mutilated man."
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