Sana, a petite 31-year-old French woman with curly brown hair, is strapped to a chair at the Clinical Center at the National Institutes of Health. In front of her, a desk. Surrounding her, 12 infrared cameras tracking her every move. The test is about to begin.

On the desk, a black cylinder stands upright. Its topped with a silvery plastic ball. Heres the challenge: Shes asked to touch her nose and then touch the ball in front of her. Easy. She touches her nose. She touches the ball.

Now comes the hard part.

A lab technician tells her to close her eyes. He places her finger on the ball, and then moves it back to her nose. He lets go and asks Sana to do it herself while keeping her eyes closed.

Suddenly, its like the location of the ball has been erased from her mind. She gropes around, swinging her arm widely to the left and the right. When she manages to touch the ball, it seems like an accident. She struggles to find her nose on her face, outright missing a few times.

Its like I am lost, she says, through an interpreter. When her eyes are closed, she doesnt know where her body is in space.

Try this task for yourself. Place a drinking glass in front of you. Touch the top of it a few times with your eyes open. Then try to find it with your eyes closed. Chances are you still can.

When we close our eyes, our sense of the world and our bodys place in it doesnt disappear. An invisible impression remains. This sense is called proprioception (pronounced pro-pree-o-ception); its an awareness of where our limbs are and how our bodies are positioned in space. And like the other senses vision, hearing, and so on it helps our brains navigate the world. Scientists sometimes refer to it as our sixth sense.

Proprioception is different from the others in a key way: It never turns off, except in very rare cases. We know what silence is when we cover our ears, we know what darkness is when we shut our eyes.

Sana is one of the few people in the entire world who knows what its like when the proprioceptive sense is turned off. Another is her older sister, Sawsen, 36, who was also undergoing the testing at the NIH, in August. She, too, has trouble finding her nose in the dark.

At home, Sawsen says, if the power goes out and shes standing up, I fall to the ground. The feeling is as hard to imagine as it is to describe. Its as if you had a blindfold and somebody turned you several times, and then youre asked to go in a direction. The first few seconds, you dont know what direction youre going in. Pure disorientation.

The sisters, whose last names Im not using for privacy reasons, also share another curiosity: They cant feel a lot of the things they touch. Even with my eyes open, when I touch the little ball, I dont feel it, Sawsen says.

Of all the senses, touch and proprioception are arguably the least understood. But in the past decade, neuroscientists have made huge breakthroughs that reveal how touch and proprioception work. That has led to hopeful insights that could yield better ways to treat pain and better prostheses for amputees. Its also given us a more complete understanding of what it means to be human and experience the world through a body.

Sana, Sawsen, and a handful of similar patients are ideal subjects for scientists who study touch and proprioception. Theres nothing unusual about their muscles or their brains. Theyre simply missing one tiny, but hugely consequential, thing: a molecule-sized receptor that acts as the doorway through which physical forces enter the nervous system and ascend into conscious awareness. The receptor is called piezo2, and it was discovered just 10 years ago.

The missing molecule essentially leaves them without the eyes of the proprioceptive system. It also leaves their skin unable to feel some specific sensations.

These patients are rare the NIH team and their colleagues around the world have identified only 18 cases, with the first two documented in the New England Journal of Medicine in 2016. They are the equivalent of identifying the first blind person, or the first deaf person, Alexander Chesler, a neuroscientist at the NIH who has been working with Sana, Sawsen, and the others, says. Here are people who, based on what we understood of the molecule at the time, would be touch-blind.

The effects of the condition can make it hard for people to control their bodies, particularly when their vision is occluded. And the symptoms of this rare genetic disorder are often misdiagnosed, or go undiagnosed for years.

By studying them, neuroscientists get to probe the essential functions of touch and the proprioceptive system, and also get to learn about the brains remarkable ability to adapt.

Carsten Bnnemann is a detective of neurological medical mysteries. When children have neurological conditions that are difficult to diagnose, he swoops in to try to crack the case. We look for the inexplicable, Bnnemann, a pediatric neurologist at the National Institute of Neurological Disorders and Stroke, says.

In 2015, one such mystery brought him to Calgary, Canada, to examine an 18-year-old woman with a strange disorder. She could walk she learned around age 7 but only when she looked at her feet. If she closed her eyes while standing, shed collapse to the floor. It was like her eyesight contained the power to turn on a secret switch and give her control over the body part she gazed upon. Out of sight, her body was beyond her control.

And when I examined her, I realized that she had no ... proprioception, Bnnemann says. When her eyes were closed, she had no sensation of her doctors gently moving her fingers up or down. But the absence of awareness wasnt just in her finger joints. She had no sense of movement in her elbows, her shoulders, her hips in any joint in her body.

Though it is often not in our conscious awareness, proprioception still serves a critical function. If you want to move in a coordinated fashion, you have to know where your body is at all moments, says Adam Hantman, a neuroscientist at the Howard Hughes Medical Institute who studies proprioception. You could look at your limbs, but that means you cant look at other things. Proprioception allows our eyes to pay attention to whats going on outside our bodies.

To make the diagnosis, Bnnemanns team sequenced the girls entire genome and found a mutation on genes that code for a touch receptor called piezo2. In 2015, piezo2 was still new to science.

Before that, scientists had known for a long time that all kinds of special nerves are devoted to sensing the outside world. If nerves are the wires that transmit information from the world to our brains, these receptors are the switches the first cog in the biological machine where the electrical signals originate.

The landmark discovery of piezo2 happened at the Scripps Research Institute, where researchers had spent years prodding cells with tiny glass probes. (When poked, the piezo receptor produces a small electrical current. Piezo is Greek for to press.) The researchers found two receptors piezo1 and piezo2. When cells that contain these receptors are stretched, the receptors open up, letting in ions and setting off an electrical pulse.

Piezo1 is implicated in our bodys built-in blood-pressure monitoring systems, as well as other internal systems that rely on pressure sensing. Piezo2, further research revealed, is a molecule critical for both touch and proprioception, a gateway through which mechanical forces begin their journey into our consciousness.

In 2015, scientists were just starting to figure out what piezo2 did in mice, let alone humans. Bnnemann had to study up, and he returned to the NIH in Bethesda, Maryland, and emailed Chesler, who was studying mice whose genes had been modified to lack piezo2. Bnnemann emailed him about the patient, as well as another an 8-year-old girl in San Diego they had identified as having the mutation.

And that made me basically fall out of my chair and run up to his office, Chesler says. Id never had the opportunity to ask my mice just to describe what their life was like, what their experience was like, ask them questions.

Sana and Sawsen, like Bnnemanns first patient, were born with a genetic mutation that makes their piezo2 genes non-functioning. And thats left them with lifelong impairments with their proprioception, touch, and movement. Both women can walk a bit on their own, but use electric wheelchairs to get around. Both live independently. Sana is a clinical psychologist, and Sawsen heads up a camp for children with disabilities.

They dont know life with proprioception, which makes it hard for them to even describe what they lack. I have no good comparisons, because Ive always been this way, Sana says.

Of the few cases of people without proprioception in the medical history literature, the most famous was of Ian Waterman, a British man whose neurons sensing touch and proprioception were damaged by an infection. It left him without any feeling or proprioception from the neck down, though he could still move his body. It was a limbless limbo, the neurologist Jonathan Cole wrote in a medical biography of Waterman.

Waterman clearly had nerve damage. But until about a year ago, Sana and Sawsen never really knew what was wrong with them. Then, they tested positive for a mutation on their piezo2 genes, and that led them to Bonneman and Cheslers ongoing research on how piezo2 functions in the human body. So far, the researchers have seen a dozen patients who have non-functional piezo2 receptors.

Touch is a very complicated sense, since there are so many forms of it, each relying on slightly different systems of nerves and receptors.

Just appreciating all the things we can feel can invoke a sense of awe. If one of us snuck up behind you and moved a single hair, you would immediately know it, Chesler says. This is one of the most amazing biological machines.

In many ways, the sensory information we get from our bodies is much more varied than the information we get from our eyes, ears, and mouths.

For instance, heat and cold sensation work on different nerves than light touch sensations, and use different receptors (some of which were also only recently discovered). Pain, itch, and pressure are distinct too. There are also some touch sensations that are dependent on context. Think of how the feeling of a light touch of a T-shirt on your body fades from your awareness the longer you wear it. Or how, during a sunburn, wearing that T-shirt suddenly becomes unbearable.

Without piezo2, the sisters cant feel light, gentle touch, particularly on their hands and fingers. Sawsen tells me that when she puts her hand into a pocketbook, I will take my hand out of the bag thinking Im holding something, and my hand is empty, she says. She cant feel the objects, and she doesnt know where her hand is. So a pocketbook might as well be a black hole when shes not directly looking into it.

But the sisters can feel heat and cold. They can feel pressure. And theyre not immune to pain. Particularly, they can feel sharp sensations.

Sawsen has taken up sharpshooting as a hobby (to relieve stress) and has outfitted the trigger of the weapon with a hard-edged rectangular piece. When she digs her finger into the edge, she can feel it.

That type of pinching pain must begin its journey into the nervous system by a receptor other than piezo2. So when youre pinched, that feeling, we dont understand at the molecular level whats going on to activate your neurons, Chesler says. Thats surprising. How the acute pain of stepping on a LEGO brick exactly enters our nervous system is still a scientific mystery in the year 2019.

They can feel that type of pain, but they cant feel another called tactile allodynia. Thats when light touch sensations, which are normally pleasant, become painful. (In the lab, researchers create tactile allodynia by rubbing skin with capsaicin the spicy chemical in hot peppers.)

Another mystery: The patients can feel when their skin with hair is stroked, like on their arms. But strangely, they cant seem to feel individual hair movements. We dont know how they do it, Chesler says. Which is to say: Neuroscience doesnt understand, completely, how this sensation is generated in the body.

Its these insights that could lead to some practical outcomes of this research: Namely, new ways to treat pain. Scientists hope by identifying the receptors that bring physical sensations into our bodies, they can learn to augment them, perhaps turning them off when theyre causing pain.

That is the dream of pain research, Chesler says. Can we get away from these really coarse ways of looking at pain, and understand it at a more mechanistic level? If you dont know the receptor responsible for sharp pain, for instance, you cant design a drug to turn it off.

Touch is complicated. Proprioception might be even more so. But in studying it, researchers may yield discoveries and applications that stretch far beyond the human body.

Deep in all our muscles are fibers called muscle spindles: This is a bundle of fibers and nerves that record muscle stretch. On the nerves endings of the muscle spindles, yes, youll find piezo2. When the muscles are stretched, others contract, and piezo2 then transmits all that information to your spinal cord to determine where your limbs are.

Whats amazing is how every muscle in your body is sending out this information all the time. Your nervous system somehow processes that massive amount of data without any conscious work on our part. How could it possibly be conscious? Youd go wild from information overload.

Just think of what it takes to sit up straight. All the muscles in your back have to relay the right information so you can keep all the bones of your spine in line. The piezo2-less patients dont have that. They have scoliotic posture because they dont have the muscles in their back telling their brains how to align their spine. (Many of these patients, Im told, are also malpositioned in the womb before birth, or are born with hip displacement thats how fundamental of a sense proprioception is.)

Lacking the primary input for proprioception, Sana and Sawsen have to concentrate hard to not feel disoriented. Sometimes, Sana says, just her hair getting in the way of her eyes will cause her to lose orientation of where her body is. The same can happen if someone gets too close to her face, blocking her peripheral vision. Which means she needs to concentrate extra hard if she wants to kiss someone.

Its still a deep mystery how the brain pulls together all the sources of proprioceptive information so effortlessly.

The most amazing this about it is how utterly flexible it is, says Adam Hantman, a neuroscientist at the Howard Hughes Medical Institute who studies proprioception. You can ask me to reach out for a cup, and say, Dont do it in any way youve ever done it before, and without practicing, I could snap my hand around upside down, put it behind my back and reach that cup. Ive never done that action before in my life, and I could do it without practice.

And there are so many beautiful complications in this research still not well understood by scientists.

Scientists generally regard touch and proprioception as different systems. But they can overlap to a certain extent, says Joriene De Nooij, a neurology researcher who studies proprioception at Columbia University. Receptors in the skin contribute to our understanding of where our limbs are. When youre walking theres all these pressure receptors in your feet that will be activated every time you take a step, she says. And that also gives our brains information about where the body is.

We have so, so many inputs into our sensory system that give us feedback and orient our minds to what our bodies are doing. Learning how the brain actually pulls this off what are the algorithms it uses to build these models and utilize them will help us make better machines, Hantman says.

Particularly, it may help researchers make better prosthetics that are directly controlled by an amputees nervous system. The machines are pretty good at taking a signal from the brain and making the prosthetics move, he says. But we really havent done that great a job closing the loop, getting sensory information back.

The brain also does another thing involving proprioception that researchers deeply want to understand: How it compensates in the face of loss, like in the cases of Sana and Sawsen.

The muscle spindles and other nerve endings explain how proprioception works in the body. But even stranger is how it manifests in our minds.

I keep thinking about what happens when I close my eyes and reach for something. Theres a glass out in front of me on my desk. I can still grab it with my eyes closed. Im trying to concentrate on the thought of where the glass is in space, and dissect it: What exactly am I experiencing in this moment?

Its like trying to describe a daydream. You know its there. It seems real. But it has no form. Its consciousness, says Ardem Patapoutian, a neuroscience researcher at Scripps, whose lab first discovered the piezo receptors. A physical aspect of consciousness, he says, is informed and shaped, in part, by proprioception.

In reporting this story, Ive come to think of the process by which the brain creates consciousness as a kind of wizard or conjurer stirring a potion. The wizard takes sensory inputs from our bodies: like touch, temperature, joint awareness, mixes it in with our thoughts, our emotions, and our memories, our predictions about the world, and throws it in the cauldron to generate our consciousness. A whole sense of self emerges from these disparate parts. Its greater than the sum of the parts, and singular.

But its not like if youre missing an ingredient, the potion goes bad. Sana and Sawsen are missing information from their piezo2 receptors, but their minds still use other ingredients to compensate. Theyre as conscious as anyone else.

Chesler believes the sisters brains still generate a map of their body. They just have to use other inputs, like their vision, or other sensations, like heat and cold, or painful touch.

Like a blind person with an attuned ear, they use their other senses to compensate for what they lack. When Sana was reaching out for the cylinder with her eyes closed, she says she was trying to feel a draft from a nearby air conditioning duct. She remembered it felt colder by the ball and was trying to find that cold spot.

Whats going on in their brains to construct their body image in the absence of information that we rely on so steadily? This question is one of the most important ones we could be asking about this sense, Chesler says, and one that Im hoping, in the next few years, my lab will actually start addressing.

But you dont need a study to see this is true: The human mind has remarkable resilience.

You get used to your own body, Sawsen says. You learn to cope with the materials you have access to.

Brian Resnick is a senior science reporter at Vox, covering psychology, space, medicine, the environment, and anything that makes you think, Whoa, thats cool.

Correction: An earlier version of this story misspelled the name Sawsen.

Link:
Proprioception is our silent sixth sense. Neuroscience is just beginning to understand it. - Vox.com