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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Do Fruit Flies Have Emotions?

A fruit fly starts buzzing around food at a picnic, so you wave your hand over the insect and shoo it away. But when the insect flees the scene, is it doing so because it is actually afraid? Using fruit flies to study the basic components of emotion, a new Caltech study reports that a fly's response to a shadowy overhead stimulus might be analogous to a negative emotional state such as fear—a finding that could one day help us understand the neural circuitry involved in human emotion.

The study, which was done in the laboratory of David Anderson, Seymour Benzer Professor of Biology and an investigator with the Howard Hughes Medical Institute, was published online May 14 in the journal Current Biology.

Insects are an important model for the study of emotion; although mice are closer to humans on the evolutionary family tree, the fruit fly has a much simpler neurological system that is easier to study. However, studying emotions in insects or any other animal can also be tricky. Because researchers know the experience of human emotion, they might anthropomorphize those of an insect—just as you might assume that the shooed-away fly left your plate because it was afraid of your hand. But there are several problems with such an assumption, says postdoctoral scholar William T. Gibson, first author of the paper.

"There are two difficulties with taking your own experiences and then saying that maybe these are happening in a fly. First, a fly's brain is very different from yours, and second, a fly's evolutionary history is so different from yours that even if you could prove beyond any doubt that flies have emotions, those emotions probably wouldn't be the same ones that you have," he says. "For these reasons, in our study, we wanted to take an objective approach."

Anderson and Gibson and their colleagues did this by deconstructing the idea of an emotion into basic building blocks—so-called emotion primitives, a concept previously developed by Anderson and Ralph Adolphs, Bren Professor of Psychology and Neuroscience and professor of biology.

"There has been ongoing debate for decades about what 'emotion' means, and there is no generally accepted definition. In an article that Ralph Adolphs and I recently wrote, we put forth the view that emotions are a type of internal brain state with certain general properties that can exist independently of subjective, conscious feelings, which can only be studied in humans," Anderson says. "That means we can study such brain states in animal models like flies or mice without worrying about whether they have 'feelings' or not. We use the behaviors that express those states as a readout."

Gibson explains by analogy that emotions can be broken down into these emotion primitives much as a secondary color, such as orange, can be separated into two primary colors, yellow and red. "And if we can show that fruit flies display all of these separate but necessary primitives, we then may be able to make the argument that they also have an emotion, like fear."

The emotion primitives analyzed in the fly study can be understood in the context of a stimulus associated with human fear: the sound of a gunshot. If you hear a gun fire, the sound may trigger a negative feeling. This feeling, a primitive called valence, will probably cause you to behave differently for several minutes afterward. This is a primitive called persistence. Repeated exposure to the stimulus should also produce a greater emotional response—a primitive called scalability; for example, the sound of 10 gunshots would make you more afraid than the sound of one shot.

Gibson says that another primitive of fear is that it is generalized to different contexts, meaning that if you were eating lunch or were otherwise occupied when the gun fired, the fear would take over, distracting you from your lunch. Trans-situationality is another primitive that could cause you to produce the same fearful reaction in response to an unrelated stimulus—such as the sound of a car backfiring.

The researchers chose to study these five primitives by observing the insects in the presence of a fear-inducing stimulus. Because defensive behavioral responses to overhead visual threats are common in many animals, the researchers created an apparatus that would pass a dark paddle over the flies' habitat. The flies' movements were then tracked using a software program created in collaboration with Pietro Perona, the Allen E. Puckett Professor of Electrical Engineering.

The researchers analyzed the flies' responses to the stimulus and found that the insects displayed all of these emotion primitives. For example, responses were scalable: when the paddle passed overhead, the flies would either freeze, or jump away from the stimulus, or enter a state of elevated arousal, and each response increased with the number of times the stimulus was delivered. And when hungry flies were gathered around food, the stimulus would cause them to leave the food for several seconds and run around the arena until their state of elevated arousal decayed and they returned to the food—exhibiting the primitives of context generalization and persistence.

"These experiments provide objective evidence that visual stimuli designed to mimic an overhead predator can induce a persistent and scalable internal state of defensive arousal in flies, which can influence their subsequent behavior for minutes after the threat has passed," Anderson says. "For us, that's a big step beyond just casually intuiting that a fly fleeing a visual threat must be 'afraid,' based on our anthropomorphic assumptions. It suggests that the flies' response to the threat is richer and more complicated than a robotic-like avoidance reflex."

In the future, the researchers say that they plan to combine the new technique with genetically based techniques and imaging of brain activity to identify the neural circuitry that underlies these defensive behaviors. Their end goal is to identify specific populations of neurons in the fruit fly brain that are necessary for emotion primitives—and whether these functions are conserved in higher organisms, such as mice or even humans.

Although the presence of these primitives suggests that the flies might be reacting to the stimulus based on some kind of emotion, the researchers are quick to point out that this new information does not prove—nor did it set out to establish—that flies can experience fear, or happiness, or anger, or any other feelings.

"Our work can get at questions about mechanism and questions about the functional properties of emotion states, but we cannot get at the question of whether or not flies have feelings," Gibson says.

The study, titled "Behavioral Responses to a Repetitive Stimulus Express a Persistent State of Defensive Arousal in Drosophila," was published in the journal Current Biology. In addition to Gibson, Anderson, and Perona, Caltech coauthors include graduate student Carlos Gonzalez, undergraduate Rebecca Du, former research assistants Conchi Fernandez and Panna Felsen (BS '09, MS '10), and former postdoctoral scholar Michael Maire. Coauthors Lakshminarayanan Ramasamy and Tanya Tabachnik are from the Janelia Research Campus of the Howard Hughes Medical Institute (HHMI). The work was funded by the National Institutes of Health, HHMI, and the Gordon and Betty Moore Foundation.

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Andersen Wins Inaugural Cal-BRAIN Funding

Richard Andersen, James G. Boswell Professor of Neuroscience, has been selected as a recipient of one of the first grants from the California Blueprint for Research to Advance Innovations in Neuroscience (Cal-BRAIN) program.

Cal-BRAIN, a joint initiative led by UC San Diego and the Lawrence Berkeley National Laboratory, is the California complement to President Obama's federal BRAIN Initiative. Scientists from all California nonprofit research institutions were eligible to apply for the state initiative's first round of $120,000 seed grants; Andersen from Caltech and the 15 other inaugural winners from Stanford, USC, Lawrence Berkeley National Laboratory, and 10 UC campuses were selected from a pool of 126 applicants.

The initiative's goal is for funded projects to use an interdisciplinary approach to advance the diagnosis and treatment of all brain disorders as well as develop better neural prosthetic devices that would allow paralyzed patients to move a robotic limb using signals from the patient's own brain. By supporting this research specifically, Cal-BRAIN aims to position California as a leader in the growing neurotechnology sector—a possible future source of economic growth and job creation in the state.

Andersen's Cal-BRAIN–funded project, titled "Engineering Artificial Sensation," will focus on artificially replicating the sensation of touch in patients with paralysis accompanied by loss of touch perception; such replication would improve the dexterity of neural prosthetic devices. This capability, when combined with a traditional neural prosthetic device and robotic arm, would enable patients to manipulate their environment and would provide feedback allowing them to recognize, for example, that they had used too much or too little force when grasping an object. The project is being done in collaboration with physicians Charles Liu, Brian Lee, and Christi Heck at the Keck School of Medicine of USC and the USC Neurorestoration Center. 

A full list of the Cal-BRAIN funded institutions, researchers, and projects can be viewed here: http://cal-brain.org/content/cal-brain-awards-2015.

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“Freezing a Bullet” to Find Clues to Ribosome Assembly Process

Researchers Figure Out How Protein-Synthesizing Cellular Machines Are Built in Stepwise Fashion

Ribosomes are vital to the function of all living cells. Using the genetic information from RNA, these large molecular complexes build proteins by linking amino acids together in a specific order. Scientists have known for more than half a century that these cellular machines are themselves made up of about 80 different proteins, called ribosomal proteins, along with several RNA molecules and that these components are added in a particular sequence to construct new ribosomes, but no one has known the mechanism that controls that process.

Now researchers from Caltech and Heidelberg University have combined their expertise to track a ribosomal protein in yeast all the way from its synthesis in the cytoplasm, the cellular compartment surrounding the nucleus of a cell, to its incorporation into a developing ribosome within the nucleus. In so doing, they have identified a new chaperone protein, known as Acl4, that ushers a specific ribosomal protein through the construction process and a new regulatory mechanism that likely occurs in all eukaryotic cells.

The results, described in a paper that appears online in the journal Molecular Cell, also suggest an approach for making new antifungal agents.

The work was completed in the labs of André Hoelz, assistant professor of chemistry at Caltech, and Ed Hurt, director of the Heidelberg University Biochemistry Center (BZH).

 

 

"We now understand how this chaperone, Acl4, works with its ribosomal protein with great precision," says Hoelz. "Seeing that is kind of like being able to freeze a bullet whizzing through the air and turn it around and analyze it in all dimensions to see exactly what it looks like."

That is because the entire ribosome assembly process—including the synthesis of new ribosomal proteins by ribosomes in the cytoplasm, the transfer of those proteins into the nucleus, their incorporation into a developing ribosome, and the completed ribosome's export back out of the nucleus into the cytoplasm—happens in the tens of minutes timescale. So quickly that more than a million ribosomes are produced per day in mammalian cells to allow for turnover and cell division. Therefore, being able to follow a ribosomal protein through that process is not a simple task.

Hurt and his team in Germany have developed a new technique to capture the state of a ribosomal protein shortly after it is synthesized. When they "stopped" this particular flying bullet, an important ribosomal protein known as L4, they found that its was bound to Acl4.

Hoelz's group at Caltech then used X-ray crystallography to obtain an atomic snapshot of Acl4 and further biochemical interaction studies to establish how Acl4 recognizes and protects L4. They found that Acl4 attaches to L4 (having a high affinity for only that ribosomal protein) as it emerges from the ribosome that produced it, akin to a hand gripping a baseball. Thereby the chaperone ensures that the ribosomal protein is protected from machinery in the cell that would otherwise destroy it and ushers the L4 molecule through the sole gateway between the nucleus and cytoplasm, called the nuclear pore complex, to the site in the nucleus where new ribosomes are constructed.

"The ribosomal protein together with its chaperone basically travel through the nucleus and screen their surroundings until they find an assembling ribosome that is at exactly the right stage for the ribosomal protein to be incorporated," explains Ferdinand Huber, a graduate student in Hoelz's group and one of the first authors on the paper. "Once found, the chaperone lets the ribosomal protein go and gets recycled to go pick up another protein."

The researchers say that Acl4 is just one example from a whole family of chaperone proteins that likely work in this same fashion.

Hoelz adds that if this process does not work properly, ribosomes and proteins cannot be made. Some diseases (including aggressive leukemia subtypes) are associated with malfunctions in this process.

"It is likely that human cells also contain a dedicated assembly chaperone for L4. However, we are certain that it has a distinct atomic structure, which might allow us to develop new antifungal agents," Hoelz says. "By preventing the chaperone from interacting with its partner, you could keep the cell from making new ribosomes. You could potentially weaken the organism to the point where the immune system could then clear the infection. This is a completely new approach."

Co-first authors on the paper, "Coordinated Ribosomal L4 Protein Assembly into the Pre-Ribosome Is Regulated by Its Eukaryote-Specific Extension," are Huber and Philipp Stelter of Heidelberg University. Additional authors include Ruth Kunze and Dirk Flemming also from Heidelberg University. The work was supported by the Boehringer Ingelheim Fonds, the V Foundation for Cancer Research, the Edward Mallinckrodt, Jr. Foundation, the Sidney Kimmel Foundation for Cancer Research, and the German Research Foundation (DFG).

 

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Tuesday, May 19, 2015
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