Caltech Chemists Solve Major Piece of Cellular Mystery

Team determines the architecture of a second subcomplex of the nuclear pore complex

Not just anything is allowed to enter the nucleus, the heart of eukaryotic cells where, among other things, genetic information is stored. A double membrane, called the nuclear envelope, serves as a wall, protecting the contents of the nucleus. Any molecules trying to enter or exit the nucleus must do so via a cellular gatekeeper known as the nuclear pore complex (NPC), or pore, that exists within the envelope.

How can the NPC be such an effective gatekeeper—preventing much from entering the nucleus while helping to shuttle certain molecules across the nuclear envelope? Scientists have been trying to figure that out for decades, at least in part because the NPC is targeted by a number of diseases, including some aggressive forms of leukemia and nervous system disorders such as a hereditary form of Lou Gehrig's disease. Now a team led by André Hoelz, assistant professor of biochemistry at Caltech, has solved a crucial piece of the puzzle.

In February of this year, Hoelz and his colleagues published a paper describing the atomic structure of the NPC's coat nucleoporin complex, a subcomplex that forms what they now call the outer rings (see illustration). Building on that work, the team has now solved the architecture of the pore's inner ring, a subcomplex that is central to the NPC's ability to serve as a barrier and transport facilitator. In order to the determine that architecture, which determines how the ring's proteins interact with each other, the biochemists built up the complex in a test tube and then systematically dissected it to understand the individual interactions between components. Then they validated that this is actually how it works in vivo, in a species of fungus.

For more than a decade, other researchers have suggested that the inner ring is highly flexible and expands to allow large macromolecules to pass through. "People have proposed some complicated models to explain how this might happen," says Hoelz. But now he and his colleagues have shown that these models are incorrect and that these dilations simply do not occur.

"Using an interdisciplinary approach, we solved the architecture of this subcomplex and showed that it cannot change shape significantly," says Hoelz. "It is a relatively rigid scaffold that is incorporated into the pore and basically just sits as a decoration, like pom-poms on a bicycle. It cannot dilate."

The new paper appears online ahead of print on August 27 in Science Express. The four co-lead authors on the paper are Caltech postdoctoral scholars Tobias Stuwe, Christopher J. Bley, and Karsten Thierbach, and graduate student Stefan Petrovic.


Crystal Structure of Fungal Channel Nucleoporin Complex
This video features a rotating three-dimensional crystal structure of the fungal channel nucleoporin complex bound to the adaptor nucleoporin Nic96. This interaction is the complex's sole site of attachment to the rest of the inner ring of the NPC. The channel nucleoporin complex borders the central transport channel and fills it with filamentous structures (phenylalanine-glycine repeats) that form a diffusion barrier and provide docking sites for proteins that ferry molecules across the nuclear envelope. Credit: Andre Hoelz/Caltech and Science

Together, the inner and outer rings make up the symmetric core of the NPC, a structure that includes 21 different proteins. The symmetric core is so named because of its radial symmetry (the two remaining subcomplexes of the NPC are specific to either the side that faces the cell's cytoplasm or the side that faces the nucleus and are therefore not symmetric). Having previously solved the structure of the coat nucleoporin complex and located it in the outer rings, the researchers knew that the remaining components that are not membrane anchored must make up the inner ring.

They started solving the architecture by focusing on the channel nucleoporin complex, or channel, which lines the central transport channel and is made up of three proteins, accounting for about half of the inner ring. This complex produces filamentous structures that serve as docking sites for specific proteins that ferry molecules across the nuclear envelope.

The biochemists employed bacteria to make the proteins associated with the inner ring in a test tube and mixed various combinations until they built the entire subcomplex. Once they had reconstituted the inner ring subcomplex, they were able to modify it to investigate how it is held together and which of its components are critical, and to determine how the channel is attached to the rest of the pore.

Hoelz and his team found that the channel is attached at only one site. This means that it cannot stretch significantly because such shape changes require multiple attachment points. Hoelz notes that a new electron microscopy study of the NPC published in 2013 by Martin Beck's group at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, indicated that the central channel is bigger than previously thought and wide enough to accommodate even the largest cargoes known to pass through the pore.

When the researchers introduced mutations that effectively eliminated the channel's single attachment, the complex could no longer be incorporated into the inner ring. After proving this in the test tube, they also showed this to be true in living cells.

"This whole complex is a very complicated machine to assemble. The cool thing here is that nature has found an elegant way to wait until the very end of the assembly of the nuclear pore to incorporate the channel," says Hoelz. "By incorporating the channel, you establish two things at once: you immediately form a barrier and you generate the ability for regulated transport to occur through the pore." Prior to the channel's incorporation, there is simply a hole through which macromolecules can freely pass.

Next, Hoelz and his colleagues used X-ray crystallography to determine the structure of the channel nucleoporin subcomplex bound to the adaptor nucleoporin Nic96, which is its only nuclear pore attachment site. X-ray crystallography involves shining X-rays on a crystallized sample and analyzing the pattern of rays reflected off the atoms in the crystal. Because the NPC is a large and complex molecular machine that also has many moving parts, they used an engineered antibody to essentially "superglue" many copies of the complex into place to form a nicely ordered crystalline sample. Then they analyzed hundreds of samples using Caltech's Molecular Observatory—a facility developed with support from the Gordon and Betty Moore Foundation that includes an automated X-ray beam line at the Stanford Synchrotron Radiation Laboratory that can be controlled remotely from Caltech—and the GM/CA beam line at the Advanced Photon Source at the Argonne National Laboratory. Eventually, they were able to determine the size, shape, and position of all the atoms of the channel nucleoporin subcomplex and its location within the full NPC.

"The crystal structure nailed it," Hoelz says. "There is no way that the channel is changing shape. All of that other work that, for more than 10 years, suggested it was dilating was wrong."

The researchers also solved a number of crystal structures from other parts of the NPC and determined how they interact with components of the inner ring. In doing so they demonstrated that one such interaction is critical for positioning the channel in the center of the inner ring. They found that exact positioning is needed for the proper export from the nucleus of mRNA and components of ribosomes, the cell's protein-making complexes, rendering it critical in the flow of genetic information from DNA to mRNA to protein.

Hoelz adds that now that the architectures of the inner and outer rings of the NPC are known, getting an atomic structure of the entire symmetric core is "a sprint to the summit."

"When I started at Caltech, I thought it might take another 10, 20 years to do this," he says. "In the end, we have really only been working on this for four and a half years, and the thing is basically tackled. I want to emphasize that this kind of work is not doable everywhere. The people who worked on this are truly special, talented, and smart; and they worked day and night on this for years."

Ultimately, Hoelz says he would like to understand how the NPC works in great detail so that he might be able to generate therapies for diseases associated with the dysfunction of the complex. He also dreams of building up an entire pore in the test tube so that he can fully study it and understand what happens as it is modified in various ways. "Just as they did previously when I said that I wanted to solve the atomic structure of the nuclear pore, people will say that I'm crazy for trying to do this," he says. "But if we don't do it, it is likely that nobody else will."

The paper, "Architecture of the fungal nuclear pore inner ring complex," had a number of additional Caltech authors: Sandra Schilbach (now of the Max Planck Institute of Biophysical Chemistry), Daniel J. Mayo, Thibaud Perriches, Emily J. Rundlet, Young E. Jeon, Leslie N. Collins, Ferdinand M. Huber, and Daniel H. Lin. Additional coauthors include Marcin Paduch, Akiko Koide, Vincent Lu, Shohei Koide, and Anthony A. Kossiakoff of the University of Chicago; and Jessica Fischer and Ed Hurt of Heidelberg University.

 

 

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NSF BRAIN Funding Awarded to Caltech Neuroscientist

On August 12, in support of President Obama's Brain Research through Advancing Innovative Neurotechnology—or BRAIN—Initiative, the National Science Foundation (NSF) announced 16 new grants for fundamental brain research. A cognitive neuroengineering project co-led by Richard Andersen, the James G. Boswell Professor of Neuroscience, was selected as a recipient for one of these grants.

Designed to bring together interdisciplinary teams of scientists and engineers from diverse fields, the grants represent two themes: neuroengineering and brain-inspired concepts and designs, and individuality and variation. Each grants provides up to $1 million in funding over two to four years.

Andersen, whose work falls under the first theme, plans to use his grant to improve the functionality of neural prosthetic devices—devices that, when implanted in the brain, can allow patients with amputations or paralysis to control the movement of a robotic limb. The work is a collaboration with Charles Y. Liu, of Keck Medicine of USC, and Kapil Katyal of Johns Hopkins University.

In a clinical trial earlier this year, Andersen showed that a neural prosthetic device implanted in the brain's center for intentions—the posterior parietal cortex—could allow a tetraplegic patient to control a robotic arm with only his thoughts. The new work will build on this idea, Andersen says. "We are developing a shared control system in which we can record the intent of a tetraplegic patient and immediately communicate that intent to a smart robotic limb that can handle the details of the movement. This enables more effortless control by the patients," he says.

The grants are funded by the NSF Integrative Strategies of Understanding Neural and Cognitive Systems program and the NSF Computer & Information Science & Engineering Directorate. The NSF Directorates for Engineering and for Education and Human Resources also support the grants.

Andersen, who also received a grant from the state-funded Cal-BRAIN program for work in improving neural prosthetics, joins six other Caltech projects associated with the BRAIN Initiative that were funded by the National Institutes of Health last fall.

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Mosquitoes Use Smell to See Their Hosts

On summer evenings, we try our best to avoid mosquito bites by dousing our skin with bug repellents and lighting citronella candles. These efforts may keep the mosquitoes at bay for a while, but no solution is perfect because the pests have evolved to use a triple threat of visual, olfactory, and thermal cues to home in on their human targets, a new Caltech study suggests.

The study, published by researchers in the laboratory of Michael Dickinson, the Esther M. and Abe M. Zarem Professor of Bioengineering, appears in the July 17 online version of the journal Current Biology.

When an adult female mosquito needs a blood meal to feed her young, she searches for a host—often a human. Many insects, mosquitoes included, are attracted by the odor of the carbon dioxide (CO2) gas that humans and other animals naturally exhale. However, mosquitoes can also pick up other cues that signal a human is nearby. They use their vision to spot a host and thermal sensory information to detect body heat.

But how do the mosquitoes combine this information to map out the path to their next meal?

To find out how and when the mosquitoes use each type of sensory information, the researchers released hungry, mated female mosquitoes into a wind tunnel in which different sensory cues could be independently controlled. In one set of experiments, a high-concentration CO2 plume was injected into the tunnel, mimicking the signal created by the breath of a human. In control experiments, the researchers introduced a plume consisting of background air with a low concentration of CO2. For each experiment, researchers released 20 mosquitoes into the wind tunnel and used video cameras and 3-D tracking software to follow their paths.

When a concentrated CO2 plume was present, the mosquitos followed it within the tunnel as expected, whereas they showed no interest in a control plume consisting of background air.

"In a previous experiment with fruit flies, we found that exposure to an attractive odor led the animals to be more attracted to visual features," says Floris van Breugel, a postdoctoral scholar in Dickinson's lab and first author of the study. "This was a new finding for flies, and we suspected that mosquitoes would exhibit a similar behavior. That is, we predicted that when the mosquitoes were exposed to CO2, which is an indicator of a nearby host, they would also spend a lot of time hovering near high-contrast objects, such as a black object on a neutral background."

To test this hypothesis, van Breugel and his colleagues did the same CO2 plume experiment, but this time they provided a dark object on the floor of the wind tunnel. They found that in the presence of the carbon dioxide plumes, the mosquitoes were attracted to the dark high-contrast object. In the wind tunnel with no CO2 plume, the insects ignored the dark object entirely.

While it was no surprise to see the mosquitoes tracking a CO2 plume, "the new part that we found is that the CO2 plume increases the likelihood that they'll fly toward an object. This is particularly interesting because there's no CO2 down near that object—it's about 10 centimeters away," van Breugel says. "That means that they smell the CO2, then they leave the plume, and several seconds later they continue flying toward this little object. So you could think of it as a type of memory or lasting effect."

Next, the researchers wanted to see how a mosquito factors thermal information into its flight path. It is difficult to test, van Breugel says. "Obviously, we know that if you have an object in the presence of a CO2 plume—warm or cold—they will fly toward it because they see it," he says. "So we had to find a way to separate the visual attraction from the thermal attraction."

To do this, the researchers constructed two glass objects that were coated with a clear chemical substance that made it possible to heat them to any desired temperature. They heated one object to 37 degrees Celsius (approximately human body temperature) and allowed one to remain at room temperature, and then placed them on the floor of the wind tunnel with and without CO2 plumes, and observed mosquito behavior. They found that mosquitoes showed a preference for the warm object. But contrary to the mosquitoes' visual attraction to objects, the preference for warmth was not dependent on the presence of CO2.

"These experiments show that the attraction to a visual feature and the attraction to a warm object are separate. They are independent, and they don't have to happen in order, but they do often happen in this particular order because of the spatial arrangement of the stimuli: a mosquito can see a visual feature from much further away, so that happens first. Only when the mosquito gets closer does it detect an object's thermal signature," van Breugel says.

Information gathered from all of these experiments enabled the researchers to create a model of how the mosquito finds its host over different distances. They hypothesize that from 10 to 50 meters away, a mosquito smells a host's CO2 plume. As it flies closer—to within 5 to 15 meters—it begins to see the host. Then, guided by visual cues that draw it even closer, the mosquito can sense the host's body heat. This occurs at a distance of less than a meter.

"Understanding how brains combine information from different senses to make appropriate decisions is one of the central challenges in neuroscience," says Dickinson, the principal investigator of the study. "Our experiments suggest that female mosquitoes do this in a rather elegant way when searching for food. They only pay attention to visual features after they detect an odor that indicates the presence of a host nearby. This helps ensure that they don't waste their time investigating false targets like rocks and vegetation. Our next challenge is to uncover the circuits in the brain that allow an odor to so profoundly change the way they respond to a visual image."

The work provides researchers with exciting new information about insect behavior and may even help companies design better mosquito traps in the future. But it also paints a bleak picture for those hoping to avoid mosquito bites.

"Even if it were possible to hold one's breath indefinitely," the authors note toward the end of the paper, "another human breathing nearby, or several meters upwind, would create a CO2 plume that could lead mosquitoes close enough to you that they may lock on to your visual signature. The strongest defense is therefore to become invisible, or at least visually camouflaged. Even in this case, however, mosquitoes could still locate you by tracking the heat signature of your body . . . The independent and iterative nature of the sensory-motor reflexes renders mosquitoes' host seeking strategy annoyingly robust."

These results were published in a paper titled "Mosquitoes use vision to associate odor plumes with thermal targets." In addition to Dickinson and van Breugel, the other authors are Jeff Riffell and Adrienne Fairhall from the University of Washington. The work was funded by a grant from the National Institutes of Health.

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Sniffing Out Answers: A Conversation with Markus Meister

Blindfolded and asked to distinguish between a rose and, say, smoke from a burning candle, most people would find the task easy. Even differentiating between two rose varieties can be a snap because the human olfactory system—made up of the nerve cells in our noses and everything that allows the brain to process smell—is quite adept. But just how sensitive is it to different smells?

In 2014, a team of scientists from the Rockefeller University published a paper in the journal Science, arguing that humans can discriminate at least 1 trillion odors. Now Markus Meister, the Anne P. and Benjamin F. Biaggini Professor of Biological Sciences at Caltech, has published a paper in the open-access journal eLife, in which he disputes the 2014 claim, saying that the science is not yet in a place where such a number can be determined.

We recently spoke with Meister about his new paper and what it says about the claim that we can distinguish a trillion smells.

 

What was the goal of the 2014 paper, and why do you take issue with it?

The overt question the authors asked was: How many different smells can humans distinguish? That is a naturally interesting question, in part because in other fields of sensory biology, similar questions have already been answered. People quibble about the exact numbers, but in general scientists agree that humans can distinguish about 1 to 2 million colors and something on the order of 100,000 pure tones.

But as interesting as the question is, I argue that we, as a field, are not yet prepared to address it. First we need to know how many dimensions span the perceptual space of odors. And by that I mean: how many olfactory variables are needed to fully describe all of the odors that humans can experience?

In the case of human vision, we say that the perceptual space for colors has three dimensions, which means that every physical light can be described by three numbers—how it activates the red, green, and blue cone photoreceptors in the retina.

As long as we don't know the dimensionality of odor space, we don't know how to even start interpreting measurements. Once we know the dimensionality, we can start probing the space systematically and ask how many different odors fit into it in the same way that we've looked at how many different colors fit into the three-dimensional space of colors.

The fundamental conceptual mistake that the authors of the Science paper made was to assume that the space of odor perception has 128 dimensions or more and then interpret the data as though that was the case . . . even though there is absolutely no evidence to suggest that the odor space has such high dimensionality.

 

What makes it so hard to determine the dimensionality of odor?

Well, there are a couple of things. First, there is no natural coordinate system in which olfactory stimuli exist. This stands in contrast with visual and auditory stimuli. For example, pure (monochromatic) lights or tones can be represented nicely as sinusoidal waves with just two variables, the frequency and the amplitude of the wave. We can easily control those two variables, and they correspond nicely to things we perceive. For pure tones, the amplitude of the sine wave corresponds to loudness and the frequency corresponds to perceived pitch. For a pure light, the frequency determines your perception of the color; if you change the intensity of the light, that alters your perception of the brightness. These simple physical parameters of the stimulus allow us to explore those spaces more easily.

In the case of odors, there are probably several hundred thousand substances that have a smell that can be perceived. But they all have different structures. There is no intuitive way to organize the stimuli. There has been some recent progress in this area, but in general we have not been successful in isolating a few physical variables that can account for a lot of what we smell.

Another aspect of olfaction that has complicated people's thinking is that humans have about 400 types of primary smell receptors. These are the actual neurons in the lining of the nasal cavity that detect odorants. So at the very input to the nervous system, every smell is characterized by the action it has on those 400 different sensors. Based on that, you might assume that smell lives in a much larger space than color vision—one with as many as 400 dimensions.

But can we perceive all of those 400 dimensions? Just because two odors cause a different pattern of activation of nerve cells in the nose doesn't mean you can actually tell them apart. Think about our sense of touch. Every one of our hairs has at its root several mechanoreceptors. If you run a comb through the hair on your head, you activate a hundred thousand mechanoreceptors in a particular pattern. If you repeat the action, you activate a different pattern of receptors, but you will be unable to perceive a difference. Similarly, I argue, there's no reason to think that we can perceive a difference between all the different patterns of activation of nerve cells in the nasal cavity. So the number of dimensions could, in fact, be much lower than 400. In fact, some recent studies have suggested that odor lives in a space with 10 or fewer perceptual dimensions.

 

In your work you describe a couple of basic experimental design failures of the 2014 paper. Can you walk us through those?

Basically, two scientific errors were made in the original study. They have to do with the concept of a positive-control experiment and the concept of testing alternative hypotheses.

In science, when we come up with a new way of analyzing things, we need to perform a test—called a positive control—that gives us confidence that the new analysis can find the right answer in a case where we already know what the answer is. So, for example, if you have devised a new way of weighing things, you will want to test it by weighing something whose weight you already know very well based on some accepted procedure. If the new procedure gives a different answer, we say it failed the positive control.

The 2014 paper did not include a positive-control test. In my paper, I provide two; applying the system that the authors propose to a very simple model microbe and to the human color-vision system. In both cases, the answers come out wrong by huge factors.

The other failure of the 2014 paper is a failure to consider alternate hypotheses. When scientists interpret the outcome of an experiment, we need to seriously analyze alternate hypotheses to the ones we believe are most likely and show why they are not reasonable explanations for what we are seeing.

In my paper, I show that an alternate model that is clearly absurd—that humans can only discriminate 10 odors—explains the data just as well as the very complicated explanation that the authors propose, which involves 400 dimensions and 1 trillion odor percepts. What this really means is that the experiment was poorly designed, in the sense that it didn't constrain the answer to the question.

By the way, there is an accompanying paper by Gerkin and Castro in the same issue of eLife that critiques the experimental design from an entirely different angle, regarding the use of statistics. I found this article very instructive, and have used it already in teaching.

 

How do you suggest scientists go about determining the dimensionality of the odor space?

One concrete idea is to try to figure out what the number of dimensions is in the vicinity of a particular point in that space. If you did that with color, you would arrive at the number three from the vast majority of points. So I suggest we start at some arbitrary point in odor space—say a 50 percent mixture of 30 different odors—and systematically go in each of the directions from there and ask: can humans actually distinguish the odor when you change the concentration a little bit up or down from there? If you do that in 30 different dimensions you might find that maybe only five of those dimensions contribute to changing the perceived odor and that along the other dimensions there is very little change. So let's figure out the dimensionality that comes out of a study like that. Is it two? Probably not. I would guess for something like 10 or 20.

Once we know that, we can start to ask how many odors fit into that space.

 

Why does all of this matter? Why do we need to know how many odors we can smell?

The question of how many smells we can discriminate has fascinated people for at least a century, and the whole industry of flavors and fragrances has been very interested in finding out whether there is a systematic set of rules by which one could mix together some small number of primary odors in order to produce any target smell.

In the field of color vision, that problem has been solved. As a result, we all use color monitors that only have three types of lights—red, green, and blue. And yet by mixing them together, they can make just about every color impression that you might care about. So there's a real technological incentive to figuring out how you can mix together primary stimuli to make any kind of perceived smell.

 

What is the big lesson you would like people to take away from this scientific exchange?

One lesson I try to convey to my students is the value of a simple simulation—to ask, "Could this idea work even in principle? Let's try it in the simplest case we can imagine." That sort of triage can often keep you from walking down an unproductive path.

On a more general note, people should remain skeptical of spectacular claims. This is particularly important when we referee for the high-glamour journals, where the editors have a predilection for unexpected results. As a community we should let things simmer a bit before allowing a spectacular claim to become the conventional wisdom. Maybe we all need to stop and smell the roses.

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Students in Bioengineering Course Take Inspiration from Nature

A new class in bioengineering debuted this term at Caltech: "Exploring Biological Principles Through Bio-Inspired Design" (BE 107). The class was the brainchild of Michael Dickinson, the Esther M. and Abe M. Zarem Professor of Bioengineering, and Richard Murray, the Thomas E. and Doris Everhart Professor of Control and Dynamical Systems and Bioengineering, who are hoping to make this a regular part of the curriculum at Caltech to create more opportunities for interdisciplinary work in biology.

"Design courses in which students actually build something are not uncommon in some academic disciplines—such as electrical engineering, mechanical engineering, industrial design, and so forth—but are quite rare in biology," Dickinson says. BE 107 was designed to redress this lack. In the course, students were required to either build a new instrument that could derive information from a biological system or create a hardware platform, such as a robot, that successfully mimics a given biological behavior.

On June 4, teams of two to three students presented their bioinspired creations to each other and to the professors, postdocs, and TAs who worked with them over the course of the term.

One student group pursued the first design option and developed a new instrument to track animal behavior—specifically, the rhythmic motions of jellyfish. The group's camera array and image processing and data analysis system observed jellyfish motion and output data that could then be analyzed and interpreted to reveal the frequency and size of jellyfish contractions, even in a tank with several jellyfish of different sizes and species.

Two other groups opted to create robots that mimicked an animal behavior. One such robot was designed to navigate through space via the "cast and surge" technique used by Drosophila, the common fruit fly, to detect and track an odor plume to its source, such as a tasty (to a fruit fly) piece of rotting fruit. The robot did not fly, nor did it smell, but it was engineered to roll along on four wheels in pursuit of a computer-generated spatial pattern that mimicked an odor plume.

The third team's robot was also a four-wheeled vehicle, but one designed to navigate through a lane marked out on a patch of campus concrete using patterns of polarized light in the sky created by the passage of sunlight and moonlight through the atmosphere. In nature, dung beetles, among other animals, use this type of navigation. The students tested their robot in the late afternoon, when the sun produces a polarization pattern that can be more easily tracked, and were able to get it to swing about in the sunshine in a not-quite-random dance.

Creating a bioinspired design is far from trivial. "Biological systems are much more complicated than engineered systems," Murray says, using a wide variety of sensory inputs to yield behavioral outputs. But this, says Dickinson, is one of the best aspects of the course: the opportunity "to make explicit comparisons between how nature constructs devices via evolution and how engineers design comparable machines."

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Injured Jellyfish Seek to Regain Symmetry

Self-repair is extremely important for living things. Get a cut on your finger and your skin can make new cells to heal the wound; lose your tail—if you are a particular kind of lizard—and tissue regeneration may produce a new one. Now, Caltech researchers have discovered a previously unknown self-repair mechanism—the reorganization of existing anatomy to regain symmetry—in a certain species of jellyfish.

The results are published in the June 15 online edition of the journal Proceedings of the National Academy of Sciences (PNAS).

Many marine animals, including some jellyfish, can rapidly regenerate tissues in response to injury, and this trait is important for survival. If a sea turtle takes a bite out of a jellyfish, the injured animal can quickly grow new cells to replace the lost tissue. In fact, a jellyfish-like animal called the hydra is a very commonly used model organism in studies of regeneration.

But Caltech assistant professor of biology Lea Goentoro, along with graduate student Michael Abrams and associate research technician Ty Basinger, were interested in another organism, the moon jellyfish (Aurelia aurita). Abrams, Basinger, and Goentoro, lead authors of the PNAS study, wanted to know if the moon jellyfish would respond to injuries in the same manner as an injured hydra. The team focused their study on the jellyfish's juvenile, or ephyra, stage, because the ephyra's simple body plan—a disk-shaped body with eight symmetrical arms—would make any tissue regeneration clearly visible.

To simulate injury—like that caused by a predator in the wild—the team performed amputations on anesthetized ephyra, producing animals with two, three, four, five, six, or seven arms, rather than the usual eight. They then returned the jellyfish to their habitat of artificial seawater, and monitored the tissue response.

Although wounds healed up as expected, with the tissue around the cut closing up in just a few hours, the researchers noticed something unexpected: the jellyfish were not regenerating tissues to replace the lost arms. Instead, within the first two days after the injury, the ephyra had reorganized its existing arms to be symmetrical and evenly spaced around the animal's disklike body. This so-called resymmetrization occurred whether the animal had as few as two limbs remaining or as many as seven, and the process was observed in three additional species of jellyfish ephyra.

"This is a different strategy of self-repair," says Goentoro. "Some animals just heal their wounds, other animals regenerate what is lost, but the moon jelly ephyrae don't regenerate their lost limbs. They heal the wound, but then they reorganize to regain symmetry."

There are several reasons why symmetry might be more important to the developing jellyfish than regenerating a lost limb. Jellyfish and many other marine animals such as sea urchins, sea stars, and sea anemones have what is known as radial symmetry. Although the bodies of these animals have a distinct top and bottom, they do not have distinguishable left and right sides—an arrangement, present in humans and other higher life forms, known as bilateral symmetry. And this radial symmetry is essential to how the jellyfish moves and eats, first author Abrams says.

"Jellyfish move by 'flapping' their arms; this allows for propulsion through the water, which also moves water—and food—past the mouth," he says. "As they are swimming, a boundary layer of viscous—that is, thick—fluid forms between their arms, creating a continuous paddling surface. And you can imagine how this paddling surface would be disturbed if you have a big gap between the arms."

Maintaining symmetry appears to be vital not just for propulsion and feeding, the researchers found. In the few cases when the injured animals do not symmetrize—only about 15 percent of the injured animals they studied—the unsymmetrical ephyra also cannot develop into normal adult jellyfish, called medusa.

The researchers next wanted to figure out how the new self-repair mechanism works. Cell proliferation and cell death are commonly involved in tissue regeneration and injury response, but, the team found, the amputee jellyfish were neither making new cells nor killing existing cells as they redistributed their existing arms around their bodies.

Instead, the mechanical forces created by the jellyfish's own muscle contractions were essential for symmetrization. In fact, when muscle relaxants were added to the seawater surrounding an injured jellyfish, slowing the animal's muscle contractions, the symmetrization of the intact arms also was slowed down. In contrast, a reduction in the amount of magnesium in the artificial seawater sped up the rate at which the jellyfish pulsed their muscles, and these faster muscle contractions increased the symmetrization rate.

"Symmetrization is a combination of the mechanical forces created by the muscle contractions and the viscoelastic jellyfish body material," Abrams says. "The cycle of contraction and the viscoelastic response from the jellyfish tissues leads to reorganization of the body. You can imagine that in the absence of symmetry, the mechanical forces are unbalanced, but over time, as the body and arms reorganize, the forces rebalance."

To test this idea, the team collaborated with coauthor Chin-Lin Guo, from Academia Sinica in Taiwan, to build a mathematical model, and succeeded in simulating the symmetrization process.

In addition to adding to our understanding about self-repair mechanisms, the discovery could help engineers design new biomaterials, Goentoro says. "Symmetrization may provide a new avenue for thinking about biomaterials that could be designed to 'heal' by regaining functional geometry rather than regenerating precise shapes," she says. "Other self-repair mechanisms require cell proliferation and cell death—biological processes that aren't easily translated to technology. But we can more easily apply mechanical forces to a material."

And the impact of mechanical forces on development is being increasingly studied in a variety of organisms, Goentoro says. "Recently, mechanical forces have been increasingly found to play a role in development and tissue regulation," she says. "So the symmetrization process in Aurelia, with its simple geometry, lends itself as a good model system where we can study how mechanical forces play a role in morphogenesis."

These results are published in a paper titled "Self-repairing symmetry in jellyfish through mechanically driven reorganization." In addition to Abrams, Basinger, Goentoro, and Guo, former SURF student William Yuan from the University of Oxford was also a coauthor. Jellyfish were provided by the Cabrillo Marine Aquarium and the Monterey Bay Aquarium. John Dabiri, professor of aeronautics and bioengineering, provided discussions and suggestions throughout the study. Abrams is funded by the Graduate Research Fellowship Program of the National Science Foundation.

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Urging Caution During a Genomic Revolution: A Conversation with David Baltimore

Earlier this year, an elite group of scientists and ethicists—including Nobel Laureate David Baltimore, president emeritus and Robert Andrews Millikan Professor of Biology at Caltech—convened in Napa, California, to discuss the scientific, medical, legal, and ethical implications of genome engineering technology.

Such technologies—chief among them a now-widespread genetic tool known as CRISPR-Cas9, known colloquially as "DNA scissors"—allow scientists to make precise edits to the genome, or the entire genetic script, of an organism. By essentially rewriting genomes, researchers can, in weeks rather than years, create animal strains that mimic human diseases to test new therapies; easily knock out genes in the cells of animals and humans to test their function; and even change DNA sequences to correct genetic defects. Such edits can be made in both body cells and in germ-line cells (sperm and eggs), to alter heritable genes.

We recently spoke with Baltimore about these new technologies and the issues they raise.

 

What was your motivation for participating in this conversation in January about the uses of genome engineering technology?

I was most concerned about the ability to carry out germ-line modifications of humans using this technology. Other issues came up—modification of the general biosphere, somatic gene therapy as opposed to heritable gene therapy—but I think those things are less concerning at the moment.

 

What is the big issue with human germ-line modification?

The big issue is how simple it is, at least conceptually, to modify cells—embryonic stem cells as well as somatic cells. The major concern is the potential for off-target effects: If you carry out the germ-line modification of a gene that you have identified as of concern, how do you know that, somewhere else in the genome, there hasn't been an alteration which you didn't plan to do but that has occurred anyway? Most of the genome is not coding—it doesn't code for anything. So you wouldn't necessarily see a protein change. But that change would become heritable generations into the future. You want to be pretty sure that that is not happening.

We know that people have put a lot of effort into minimizing such off-target effects. Whether they have been minimized enough is a very important safety consideration.

 

Are you and your colleagues concerned about the potential for using this technology to create "designer" babies?

I think the thing to do is to distinguish between the long-term concern about modifications that are heritable but made for reasons that are "cosmetic," and a situation in which a modification is made in order to ameliorate a serious human disease.

The example that I find most compelling is Huntington's disease. It involves a mutation in the genome that most people don't carry; the few people who do carry it suffer very serious deleterious consequences that only become apparent with age. Ridding the genome of that modified gene seems to me to be an unalloyed good. Therefore, the question becomes, do you need to use genome alteration technology to accomplish that end or is there some other way to accomplish that? But the end seems to me to be something almost everybody would agree is a good.

 

But there are situations that are not that clear-cut . . .

Exactly. You go from, on one side, Huntington's disease, and on the other side, the desire for a more intelligent child. One is easy, it can be fixed by changing a single gene. The other is much more complicated. Intelligence certainly isn't determined by a single gene. It is multigenic—the result of many genes. One is a pretty straightforward medical decision; the other is an issue which is very culturally bound. So those are the two poles, and then there is everything in between.

 

For the in-between situations, that is just a judgment call?

Yes, it is a judgment call.

 

Who makes the decisions in those cases?                                                                   

Society, in the end, will make those decisions. The problem that I think everybody has with it is that although society has the ability to make decisions like that, it is a big world. And you could imagine things being done in other jurisdictions, where we don't have control.

 

How do we manage that?

My personal thought is that the best we can do is to make absolutely unambiguous the consensus feeling of society. Because the scientific community is an international community, we do have the ability to at least provide moral guidelines.

Any kind of modification that involves something as elusive as intelligence is a long way off. We don't understand it well enough to make modifications today, and so to an extent we are trying to establish a framework that will serve the world well into the future. That is a big order, and whether an international meeting can grapple with anything as profound as that, we will see.

 

Where do you see this technology in 10 years? 100 years?

That is a good distinction—10 years versus 100 years. The latter is very hard to think about, because we have really no idea what scientific advances are going to be made in the next 100 years. About all we can be sure of is that they will be impressive and maybe revolutionary, and will present us with a very different technological landscape in which these questions will evolve.

In 10 years, we certainly are likely to know the outline of what we are likely to see, and it is not going to be a whole lot different from what we are seeing today. I would guess that in 10 years, we would understand multigenic traits better than we do now. I do suspect that people will be gratified that at this time we began the basic considerations, because the problems will get more difficult rather than easier.

 

Forty years ago, you were one of the organizers of the influential Asilomar Conference on Recombinant DNA, which laid out voluntary guidelines for the use of genetic engineering—the same type of guidelines you and your colleagues are advocating for now with genome engineering. What was the original inspiration for convening the Asilomar Conference?

It was the advent of recombinant DNA technology that drew our attention. We all worked in the biological sciences. We recognized that recombinant DNA technology was a game changer because it was going to allow scientific investigation of the questions that heretofore had been unavailable. In some ways, many of us had designed our careers around the inability to do this kind of work, and, suddenly, we were going to be able to do things that we had only previously dreamed about, if we had considered them at all.

But at the same time, there seemed to be potentially problematic aspects to it, in particular the ability to modify organisms, mainly microbial organisms, in ways that could have given the organisms the ability to be a danger to human health.

Actually, we simply did not know whether that was a realistic concern or not. As we talked to other people, we discovered that no one knew. So it seemed like a good idea to take a breather and to give consideration to these concerns of potential hazards in an international meeting that would be convened in the United States.

 

Was there some thought that if you tried to self-regulate you could avoid governmental regulation?

It wasn't a matter of avoiding governmental regulation. It was that we thought that we—the scientific community—were uniquely capable of putting in perspective these new capabilities. The answer might have been to have legislation. In fact, as our thinking progressed, we realized that the very best situation would be to avoid legislation because legislation is very hard to undo. We wanted to be sure we would have the flexibility to respond to inevitably changing scientific perspectives.

 

In retrospect, do you think Asilomar was a success?

It worked out very close to how we hoped it would. That is, as we learned more, we became more comfortable with the technology; as we investigated potential hazards, we saw less and less reason to be concerned; and we had a built-in flexibility in the system to allow it to evolve in the context of newer understanding.

 

Are you aware of any situations where scientists did not follow the rules?

To my knowledge, that has never happened.

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Yeast Protein Network Could Provide Insights into Human Obesity

A team of biologists and a mathematician have identified and characterized a network composed of 94 proteins that work together to regulate fat storage in yeast.

"Removal of any one of the proteins results in an increase in cellular fat content, which is analogous to obesity," says study coauthor Bader Al-Anzi, a research scientist at Caltech.

The findings, detailed in the May issue of the journal PLOS Computational Biology, suggest that yeast could serve as a valuable test organism for studying human obesity.

"Many of the proteins we identified have mammalian counterparts, but detailed examinations of their role in humans has been challenging," says Al-Anzi. "The obesity research field would benefit greatly if a single-cell model organism such as yeast could be used—one that can be analyzed using easy, fast, and affordable methods."

Using genetic tools, Al-Anzi and his research assistant Patrick Arpp screened a collection of about 5,000 different mutant yeast strains and identified 94 genes that, when removed, produced yeast with increases in fat content, as measured by quantitating fat bands on thin-layer chromatography plates. Other studies have shown that such "obese" yeast cells grow more slowly than normal, an indication that in yeast as in humans, too much fat accumulation is not a good thing. "A yeast cell that uses most of its energy to synthesize fat that is not needed does so at the expense of other critical functions, and that ultimately slows down its growth and reproduction," Al-Anzi says.

When the team looked at the protein products of the genes, they discovered that those proteins are physically bonded to one another to form an extensive, highly clustered network within the cell.

Such a configuration cannot be generated through a random process, say study coauthors Sherif Gerges, a bioinformatician at Princeton University, and Noah Olsman, a graduate student in Caltech's Division of Engineering and Applied Science, who independently evaluated the details of the network. Both concluded that the network must have formed as the result of evolutionary selection.

In human-scale networks, such as the Internet, power grids, and social networks, the most influential or critical nodes are often, but not always, those that are the most highly connected.

The team wondered whether the fat-storage network exhibits this feature, and, if not, whether some other characteristics of the nodes would determine which ones were most critical. Then, they could ask if removing the genes that encode the most critical nodes would have the largest effect on fat content.

To examine this hypothesis further, Al-Anzi sought out the help of a mathematician familiar with graph theory, the branch of mathematics that considers the structure of nodes connected by edges, or pathways. "When I realized I needed help, I closed my laptop and went across campus to the mathematics department at Caltech," Al-Anzi recalls. "I walked into the only office door that was open at the time, and introduced myself."

The mathematician that Al-Anzi found that day was Christopher Ormerod, a Taussky–Todd Instructor in Mathematics at Caltech. Al-Anzi's data piqued Ormerod's curiosity. "I was especially struck by the fact that connections between the proteins in the network didn't appear to be random," says Ormerod, who is also a coauthor on the study. "I suspected there was something mathematically interesting happening in this network."

With the help of Ormerod, the team created a computer model that suggested the yeast fat network exhibits what is known as the small-world property. This is akin to a social network that contains many different local clusters of people who are linked to each other by mutual acquaintances, so that any person within the cluster can be reached via another person through a small number of steps.

This pattern is also seen in a well-known network model in graph theory, called the Watts-Strogatz model. The model was originally devised to explain the clustering phenomenon often observed in real networks, but had not previously been applied to cellular networks.

Ormerod suggested that graph theory might be used to make predictions that could be experimentally proven. For example, graph theory says that the most important nodes in the network are not necessarily the ones with the most connections, but rather those that have the most high-quality connections. In particular, nodes having many distant or circuitous connections are less important than those with more direct connections to other nodes, and, especially, direct connections to other important nodes. In mathematical jargon, these important nodes are said to have a high "centrality score."

"In network analysis, the centrality of a node serves as an indicator of its importance to the overall network," Ormerod says.

"Our work predicts that changing the proteins with the highest centrality scores will have a bigger effect on network output than average," he adds. And indeed, the researchers found that the removal of proteins with the highest predicted centrality scores produced yeast cells with a larger fat band than in yeast whose less-important proteins had been removed.

The use of centrality scores to gauge the relative importance of a protein in a cellular network is a marked departure from how proteins traditionally have been viewed and studied—that is, as lone players, whose characteristics are individually assessed. "It was a very local view of how cells functioned," Al-Anzi says. "Now we're realizing that the majority of proteins are parts of signaling networks that perform specific tasks within the cell."

Moving forward, the researchers think their technique could be applicable to protein networks that control other cellular functions—such as abnormal cell division, which can lead to cancer.

"These kinds of methods might allow researchers to determine which proteins are most important to study in order to understand diseases that arise when these functions are disrupted," says Kai Zinn, a professor of biology at Caltech and the study's senior author. "For example, defects in the control of cell growth and division can lead to cancer, and one might be able to use centrality scores to identify key proteins that regulate these processes. These might be proteins that had been overlooked in the past, and they could represent new targets for drug development."

Funding support for the paper, "Experimental and Computational Analysis of a Large Protein Network That Controls Fat Storage Reveals the Design Principles of a Signaling Network," was provided by the National Institutes of Health.

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Doris Tsao Named Howard Hughes Medical Institute Investigator

The Howard Hughes Medical Institute (HHMI) has selected Caltech professor of biology Doris Tsao (BS '96) as one of 26 new HHMI investigators. Investigators represent some of the nation's top biomedical researchers and receive five years of funding to "move their research in creative new directions."

Tsao is a systems neuroscientist studying the neural mechanisms underlying primate vision. She and her group aim to discover how the brain "stitches together" individual pixels of light—the photons hitting our retinas—to create the visual experience of discrete and recognizable objects in space.

"The central problem I want to understand is how visual objects are represented in the brain, and how these representations are used to guide behavior," she says. "I feel inexpressibly lucky for the support from the HHMI that will allow us to dive deep into this program."

The group has used functional magnetic resonance imaging (fMRI) scanning to study neural responses to images and has identified discrete areas in the brain, called "face patches," that play important roles in detecting and identifying faces.

Tsao received her PhD in neuroscience from Harvard after completing her undergraduate studies in biology and mathematics at Caltech. She returned to Caltech as an assistant professor in 2008 and became a full professor in 2014. Her appointment brings the number of current Caltech HHMI investigators to eleven.

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Controlling a Robotic Arm with a Patient's Intentions

Neural prosthetic devices implanted in the brain's movement center, the motor cortex, can allow patients with amputations or paralysis to control the movement of a robotic limb—one that can be either connected to or separate from the patient's own limb. However, current neuroprosthetics produce motion that is delayed and jerky—not the smooth and seemingly automatic gestures associated with natural movement. Now, by implanting neuroprosthetics in a part of the brain that controls not the movement directly but rather our intent to move, Caltech researchers have developed a way to produce more natural and fluid motions.

In a clinical trial, the Caltech team and colleagues from Keck Medicine of USC have successfully implanted just such a device in a patient with quadriplegia, giving him the ability to perform a fluid hand-shaking gesture and even play "rock, paper, scissors" using a separate robotic arm.

The results of the trial, led by principal investigator Richard Andersen, the James G. Boswell Professor of Neuroscience, and including Caltech lab members Tyson Aflalo, Spencer Kellis, Christian Klaes, Brian Lee, Ying Shi and Kelsie Pejsa, are published in the May 22 edition of the journal Science.

"When you move your arm, you really don't think about which muscles to activate and the details of the movement—such as lift the arm, extend the arm, grasp the cup, close the hand around the cup, and so on. Instead, you think about the goal of the movement. For example, 'I want to pick up that cup of water,'" Andersen says. "So in this trial, we were successfully able to decode these actual intents, by asking the subject to simply imagine the movement as a whole, rather than breaking it down into myriad components."

For example, the process of seeing a person and then shaking his hand begins with a visual signal (for example, recognizing someone you know) that is first processed in the lower visual areas of the cerebral cortex. The signal then moves up to a high-level cognitive area known as the posterior parietal cortex (PPC). Here, the initial intent to make a movement is formed. These intentions are then transmitted to the motor cortex, through the spinal cord, and on to the arms and legs where the movement is executed.

High spinal cord injuries can cause quadriplegia in some patients because movement signals cannot get from the brain to the arms and legs. As a solution, earlier neuroprosthetic implants used tiny electrodes to detect and record movement signals at their last stop before reaching the spinal cord: the motor cortex.

The recorded signal is then carried via wire bundles from the patient's brain to a computer, where it is translated into an instruction for a robotic limb. However, because the motor cortex normally controls many muscles, the signals tend to be detailed and specific. The Caltech group wanted to see if the simpler intent to shake the hand could be used to control the prosthetic limb, instead of asking the subject to concentrate on each component of the handshake—a more painstaking and less natural approach.

Andersen and his colleagues wanted to improve the versatility of movement that a neuroprosthetic can offer by recording signals from a different brain region—the PPC. "The PPC is earlier in the pathway, so signals there are more related to movement planning—what you actually intend to do—rather than the details of the movement execution," he says. "We hoped that the signals from the PPC would be easier for the patients to use, ultimately making the movement process more intuitive. Our future studies will investigate ways to combine the detailed motor cortex signals with more cognitive PPC signals to take advantage of each area's specializations."

In the clinical trial, designed to test the safety and effectiveness of this new approach, the Caltech team collaborated with surgeons at Keck Medicine of USC and the rehabilitation team at Rancho Los Amigos National Rehabilitation Center. The surgeons implanted a pair of small electrode arrays in two parts of the PPC of a quadriplegic patient. Each array contains 96 active electrodes that, in turn, each record the activity of a single neuron in the PPC. The arrays were connected by a cable to a system of computers that processed the signals, decoded the intent of the subject, and controlled output devices that included a computer cursor and a robotic arm developed by collaborators at Johns Hopkins University.

After recovering from the surgery, the patient was trained to control the computer cursor and the robotic arm with his mind. Once training was complete, the researchers saw just what they were hoping for: intuitive movement of the robotic arm.

"For me, the most exciting moment of the trial was when the participant first moved the robotic limb with his thoughts. He had been paralyzed for over 10 years, and this was the first time since his injury that he could move a limb and reach out to someone. It was a thrilling moment for all of us," Andersen says.

"It was a big surprise that the patient was able to control the limb on day one—the very first day he tried," he adds. "This attests to how intuitive the control is when using PPC activity."

The patient, Erik G. Sorto, was also thrilled with the quick results: "I was surprised at how easy it was," he says. "I remember just having this out-of-body experience, and I wanted to just run around and high-five everybody."

Over time, Sorto continued to refine his control of his robotic arm, thus providing the researchers with more information about how the PPC works. For example, "we learned that if he thought, 'I should move my hand over toward to the object in a certain way'—trying to control the limb—that didn't work," Andersen says. "The thought actually needed to be more cognitive. But if he just thought, 'I want to grasp the object,' it was much easier. And that is exactly what we would expect from this area of the brain."

This better understanding of the PPC will help the researchers improve neuroprosthetic devices of the future, Andersen says. "What we have here is a unique window into the workings of a complex high-level brain area as we work collaboratively with our subject to perfect his skill in controlling external devices."

"The primary mission of the USC Neurorestoration Center is to take advantage of resources from our clinical programs to create unique opportunities to translate scientific discoveries, such as those of the Andersen Lab at Caltech, to human patients, ultimately turning transformative discoveries into effective therapies," says center director Charles Y. Liu, professor of neurological surgery, neurology, and biomedical engineering at USC, who led the surgical implant procedure and the USC/Rancho Los Amigos team in the collaboration.

"In taking care of patients with neurological injuries and diseases—and knowing the significant limitations of current treatment strategies—it is clear that completely new approaches are necessary to restore function to paralyzed patients. Direct brain control of robots and computers has the potential to dramatically change the lives of many people," Liu adds.

Dr. Mindy Aisen, the chief medical officer at Rancho Los Amigos who led the study's rehabilitation team, says that advancements in prosthetics like these hold promise for the future of patient rehabilitation. "We at Rancho are dedicated to advancing rehabilitation through new assistive technologies, such as robotics and brain-machine interfaces. We have created a unique environment that can seamlessly bring together rehabilitation, medicine, and science as exemplified in this study," she says.

Although tasks like shaking hands and playing "rock, paper, scissors" are important to demonstrate the capability of these devices, the hope is that neuroprosthetics will eventually enable patients to perform more practical tasks that will allow them to regain some of their independence.

"This study has been very meaningful to me. As much as the project needed me, I needed the project. The project has made a huge difference in my life. It gives me great pleasure to be part of the solution for improving paralyzed patients' lives," Sorto says. "I joke around with the guys that I want to be able to drink my own beer—to be able to take a drink at my own pace, when I want to take a sip out of my beer and to not have to ask somebody to give it to me. I really miss that independence. I think that if it was safe enough, I would really enjoy grooming myself—shaving, brushing my own teeth. That would be fantastic." 

To that end, Andersen and his colleagues are already working on a strategy that could enable patients to perform these finer motor skills. The key is to be able to provide particular types of sensory feedback from the robotic arm to the brain.

Although Sorto's implant allowed him to control larger movements with visual feedback, "to really do fine dexterous control, you also need feedback from touch," Andersen says. "Without it, it's like going to the dentist and having your mouth numbed. It's very hard to speak without somatosensory feedback." The newest devices under development by Andersen and his colleagues feature a mechanism to relay signals from the robotic arm back into the part of the brain that gives the perception of touch.

"The reason we are developing these devices is that normally a quadriplegic patient couldn't, say, pick up a glass of water to sip it, or feed themselves. They can't even do anything if their nose itches. Seemingly trivial things like this are very frustrating for the patients," Andersen says. "This trial is an important step toward improving their quality of life."

The results of the trial were published in a paper titled, "Decoding Motor Imagery from the Posterior Parietal Cortex of a Tetraplegic Human." The implanted device and signal processors used in the Caltech-led clinical trial were the NeuroPort Array and NeuroPort Bio-potential Signal Processors developed by Blackrock Microsystems in Salt Lake City, Utah. The robotic arm used in the trial was the Modular Prosthetic Limb, developed at the Applied Physics Laboratory at Johns Hopkins. Sorto was recruited to the trial by collaborators at Rancho Los Amigos National Rehabilitation Center and at Keck Medicine of USC. This trial was funded by National Institutes of Health, the Boswell Foundation, the Department of Defense, and the USC Neurorestoration Center.

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