Four Caltech Professors Elected to National Academy of Inventors

Caltech professors Frances Arnold, David Baltimore, Carver Mead, and Axel Scherer have been named fellows of the National Academy of Inventors (NAI).

Election as an NAI fellow is an honor bestowed upon academic innovators and inventors who have "demonstrated a prolific spirit of innovation in creating or facilitating outstanding inventions and innovations that have made a tangible impact on quality of life, economic development, and the welfare of society." Fellows are named inventors on U.S. patents and were each nominated by their peers for their contributions to innovation.

According to its website, the NAI "was founded in 2010 to recognize and encourage inventors with patents issued from the U.S. Patent and Trademark Office, enhance the visibility of academic technology and innovation, encourage the disclosure of intellectual property, educate and mentor innovative students, and translate the inventions of its members to benefit society."

Frances Arnold is the Dick and Barbara Dickinson Professor of Chemical Engineering, Bioengineering and Biochemistry, and director of the Donna and Benjamin M. Rosen Bioengineering Center at Caltech. Her group has pioneered methods of "directed evolution" to engineer new proteins in the lab. The method is now widely used to create catalysts for use in industrial processes, including the production of fuels and chemicals from renewable resources. The Arnold group also uses the results of laboratory evolution experiments to elucidate principles of biological design. Arnold is a coinventor on more than 40 U.S. patents. She was inducted into the National Inventors Hall of Fame in 2014 and received the National Medal of Technology and Innovation in 2013.

David Baltimore is the Robert Andrews Millikan Professor of Biology, and President Emeritus of Caltech. His research group focuses on two major areas: investigation of the development and functioning of the mammalian immune system, and translational studies of the viral transfer of genes into immune cells to increase their ability to fight disease and resist cancer. He was awarded the Nobel Prize in Physiology or Medicine in 1975.

Carver Mead (BS '56, MS '57, PhD '60) is the Gordon and Betty Moore Professor of Engineering and Applied Science, Emeritus, in computation and neural systems. Mead has significantly advanced the technology of integrated circuits by developing a method called very-large-scale integration (VSLI) that allows engineers to combine thousands of transistors onto a single microchip, thus exponentially expanding computer processing power. He received the National Medal of Technology and Innovation in 2002.

Axel Scherer is the Bernard Neches Professor of Electrical Engineering, Medical Engineering, Applied Physics and Physics, and the director of the Caltech Global Health Initiative. Holding more than 100 patents in the area of nanofabrication and device design, Scherer has most recently developed ways to integrate optics, electronics, and fluidics into sensor systems. Much of his work is currently focused on systems for medical diagnosis and health monitoring through molecular pathology and wireless implants. Over the past decades, technology from his group has been commercialized through several start-up ventures in telecommunications and health care devices.

Arnold, Baltimore, Mead, and Scherer will join Vice Provost Morteza Gharib, the Hans W. Liepmann Professor of Aeronautics and Bioinspired Engineering, and Robert H. Grubbs, the Victor and Elizabeth Atkins Professor of Chemistry, as Caltech's Fellows of the NAI. They will be inducted during the fourth annual conference of the National Academy of Inventors, which will be held at Caltech on March 20, 2015.

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SKIES App Aids Learning in Caltech Classrooms

When you first walk into Bruce Hay's genetics class, it looks like any other 21st-century college lecture hall: the professor, backed by his PowerPoint slides, faces a room full of students with iPads. However, as Hay delivers a lecture about the mechanisms that inhibit gene expression, a rectangular yellow bubble suddenly pops up on the screen below his lecture slide. It's from a student, asking a question about RNA interference. Soon another bubble pops up, this one with a link to a video that explains how microRNAs can affect the color pattern of flower petals. Other bubbles branch off from each other, and hands rise into the air.

Suddenly, you realize you're in the classroom of the future.

Those pop-up bubbles are a key component of a new interactive lecture format made possible by an app developed by two Caltech alums and brought to campus by Caltech's Center for Teaching, Learning, and Outreach (CTLO). The iPad app—produced by Su-Kam Intelligent Education Systems, or SKIES, named after cofounders Julius Su (BS '98, BS '99, PhD '07) and Victor Kam (PhD '08)—is now being used in several classes on campus.

"It's been known for a long time that lecturing—just a professor teaching and the students passively listening—is not an optimal way for students to learn. You always want to have students doing some thinking, some processing, and some recall during the lecture," says Su, who is a CTLO program manager in addition to being one of the cofounders of SKIES.

With this in mind, Su and his colleagues at CTLO have been experimenting with ways to change the traditional Caltech classroom. The SKIES app is based on one such approach—active learning, which gets students participating in a variety of ways, and is supported by a great deal of evidence indicating its effectiveness.

The wiki-like app facilitates this kind of active learning by allowing students to directly interact with lecture materials both inside and outside the classroom. The app compiles and connects notes, links, videos, and other materials—contributed by students, teaching assistants, and the professor—into a branching tree of collective knowledge stemming from an initial seed of slides or other multimedia material.

This concept of students and teachers interacting to create knowledge together is what drew Professor of Biology Bruce Hay to become one of the first users of the SKIES app in 2012.

Students can ask questions during Hay's lecture in the SKIES app. The questions or comments pop up below the lecture slide in real time.

"The big struggle that I have—and that lots of people have—is just getting students to ask questions; getting people to turn the class into more of a discussion rather than just the lecturer speaking," Hay says. "I knew that Julius and Victor were developing this prototype, and I thought, I've been teaching this same course for 15 years now and maybe this would be a good idea, to just try something new that might make it a little more interactive."

In the three years Hay has used the app in his genetics class, he says the app has done just what he'd hoped it would: provided an alternative channel by which students can participate. During class, Hay says students often add cards to his lecture slides as a form of public note-taking; for example, in one lecture, a student added a card to a particular slide, saying, "Professor Hay says this would be an excellent exam question." After class is over, he says, students often post cards with questions about the day's materials; these can then be addressed by Hay or the class's teaching assistants, either directly in class or through another branch of cards in the app.

Hay says that the app lets him monitor what students are contributing—and it allows him to promote and highlight information he considers particularly helpful and relevant to understanding the lecture material. Conversely, the app also allows students to rate how well they understand his lecture slides, as well as the cards added by TAs and other students.

"After class, I take a look at the reviews to see how well the students understood what we talked about in class that day," Hay says. "If I see that a slide is rated green [the app's version of a thumb's up], I can assume that it was pretty straightforward and understandable. But if the students have rated it red, I can add extra material to the slide, like additional text or figures. Then, in the next class, I can go back and say, 'It looks like this part was a little bit difficult. Let's just go back and review it again before we go on to the new stuff.'"

Although these continuous double checks require a bit more effort on the part of the professor and the students, they seem to be paying off: Hay says the average grades in his class went up by almost a full grade point after his first year using the app. The improvement was so noticeable, he says, "it was actually almost frightening. That was probably the biggest indication this was making a difference in terms of learning, instead of just making it fun for me and them."

In the SKIES app, students create dialogue by adding 'cards' that branch off of the professor's lecture slides.

Hay says the added content from students in the SKIES app over the past three years has enabled his course "tree" to grow and improve each term. "I'm not just repeating all the same slides every year. Many of the slides stay the same, but now I add new things, based on what the students found helpful in terms of explanations, quiz questions, and examples. So everyone is involved in making the course better," he notes.

After hearing about some of the app's early successes, other instructors across campus began using SKIES in their courses. This includes Bill Goddard, Charles and Mary Ferkel Professor of Chemistry, Materials Science, and Applied Physics, who has used SKIES to teach lectures and manage group projects in his computational and theoretical chemistry classes; Jeff Mendez, lecturer in chemistry, who has used SKIES to teach the lecture portion of his freshman solar chemistry lab; and Yaser Abu-Mostafa, professor of electrical engineering and computer science, who has used SKIES to promote and manage discussions in the in-class portion of his well-regarded Learning From Data MOOC, which has attracted over 200,000 students within and outside Caltech since its inception.

The app is also being used by many Caltech outreach programs, such as the Summer Research Connection, the Community Science Academy, and Harry Gray's Solar Army, to broaden the impact of university initiatives at the K–12 level; and is being used to teach several classes at Pasadena City College, as well as in several local middle schools and high schools.

SKIES is currently only available on iPad and iPhone, and as the app's popularity has grown, support from the Provost's Innovation in Education Fund and the Bechtel Foundation fund has allowed CTLO to expand the use of SKIES on campus through the purchase of more iPads. In the future, Su hopes that the app's reach will grow even further, both on iPads and eventually by expanding the app to work on other operating systems.

Aside from those few comments on the hardware limitations, Su says the feedback he and his colleagues at the CTLO have received from professors and students who have been using SKIES has been overwhelmingly positive.

"CTLO is continually providing Caltech faculty and TAs with evidence about what helps students learn more effectively. Active and collaborative approaches tend to work well," he says. "This app is just one way to foster more active and collaborative learning, but I think we can already see that it's providing new ways for professors to make classes even more lively and engaging for students at Caltech."

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An App for the Teacher
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Tuesday, December 2, 2014
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New Center Supports Data-Driven Research

With the advanced capabilities of today's computer technologies, researchers can now collect vast amounts of information with unprecedented speed. However, gathering information is only one half of a scientific discovery, as the data also need to be analyzed and interpreted. A new center on campus aims to hasten such data-driven discoveries by making expertise and advanced computational tools available to Caltech researchers in many disciplines within the sciences and the humanities.

The new Center for Data-Driven Discovery (CD3), which became operational this fall, is a hub for researchers to apply advanced data exploration and analysis tools to their work in fields such as biology, environmental science, physics, astronomy, chemistry, engineering, and the humanities.

The Caltech center will also complement the resources available at JPL's Center for Data Science and Technology, says director of CD3 and professor of astronomy George Djorgovski.

"Bringing together the research, technical expertise, and respective disciplines of the two centers to form this joint initiative creates a wonderful synergy that will allow us opportunities to explore and innovate new capabilities in data-driven science for many of our sponsors," adds Daniel Crichton, director of the Center for Data Science and Technology at JPL.

At the core of the Caltech center are staff members who specialize in both computational methodology and various domains of science, such as biology, chemistry, and physics. Faculty-led research groups from each of Caltech's six divisions and JPL will be able to collaborate with center staff to find new ways to get the most from their research data. Resources at CD3 will range from data storage and cataloguing that meet the highest "housekeeping" standards, to custom data-analysis methods that combine statistics with machine learning—the development of algorithms that can "learn" from data. The staff will also help develop new research projects that could benefit from large amounts of existing data.

"The volume, quality, and complexity of data are growing such that the tools that we used to use—on our desktops or even on serious computing machines—10 years ago are no longer adequate. These are not problems that can be solved by just buying a bigger computer or better software; we need to actually invent new methods that allow us to make discoveries from these data sets," says Djorgovski.

Rather than turning to off-the-shelf data-analysis methods, Caltech researchers can now collaborate with CD3 staff to develop new customized computational methods and tools that are specialized for their unique goals. For example, astronomers like Djorgovski can use data-driven computing in the development of new ways to quickly scan large digital sky surveys for rare or interesting targets, such as distant quasars or new kinds of supernova explosions—targets that can be examined more closely with telescopes, such as those at the W. M. Keck Observatory, he says.

Mary Kennedy, the Allen and Lenabelle Davis Professor of Biology and a coleader of CD3, says that the center will serve as a bridge between the laboratory-science and computer-science communities at Caltech. In addition to matching up Caltech faculty members with the expertise they will need to analyze their data, the center will also minimize the gap between those communities by providing educational opportunities for undergraduate and graduate students.

"Scientific development has moved so quickly that the education of most experimental scientists has not included the techniques one needs to synthesize or mine large data sets efficiently," Kennedy says. "Another way to say this is that 'domain' sciences—biology, engineering, astronomy, geology, chemistry, sociology, etc.—have developed in isolation from theoretical computer science and mathematics aimed at analysis of high-dimensional data. The goal of the new center is to provide a link between the two."

Work in Kennedy's laboratory focuses on understanding what takes place at the molecular level in the brain when neuronal synapses are altered to store information during learning. She says that methods and tools developed at the new center will assist her group in creating computer simulations that can help them understand how synapses are regulated by enzymes during learning.

"The ability to simulate molecular mechanisms in detail and then test predictions of the simulations with experiments will revolutionize our understanding of highly interconnected control mechanisms in cells," she says. "To some, this seems like science fiction, but it won't stay fictional for long. Caltech needs to lead in these endeavors."

Assistant Professor of Biology Mitchell Guttman says that the center will also be an asset to groups like his that are trying to make sense out of big sets of genomic data. "Biology is becoming a big-data science—genome sequences are available at an unprecedented pace. Whereas it took more than $1 billion to sequence the first genome, it now costs less than $1,000," he says. "Making sense of all this data is a challenge, but it is the future of biomedical research."

In his own work, Guttman studies the genetic code of lncRNAs, a new class of gene that he discovered, largely through computational methods like those available at the new center. "I am excited about the new CD3 center because it represents an opportunity to leverage the best ideas and approaches across disciplines to solve a major challenge in our own research," he says.

But the most valuable findings from the center could be those that stem not from a single project, but from the multidisciplinary collaborations that CD3 will enable, Djorgovski says. "To me, the most interesting outcome is to have successful methodology transfers between different fields—for example, to see if a solution developed in astronomy can be used in biology," he says.

In fact, one such crossover method has already been identified, says Matthew Graham, a computational scientist at the center. "One of the challenges in data-rich science is dealing with very heterogeneous data—data of different types from different instruments," says Graham. "Using the experience and the methods we developed in astronomy for the Virtual Observatory, I worked with biologists to develop a smart data-management system for a collection of expression and gene-integration data for genetic lines in zebrafish. We are now starting a project along similar methodology transfer lines with Professor Barbara Wold's group on RNA genomics."

And, through the discovery of more tools and methods like these, "the center could really develop new projects that bridge the boundaries between different traditional fields through new collaborations," Djorgovski says.

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Wednesday, October 29, 2014
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Wednesday, October 29, 2014
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Improving The View Through Tissues and Organs

On Saturday, October 18, hundreds of undergraduate students will share the results of their projects during SURF Seminar Day. The event, which is open to the public, is an opportunity for students to discuss and explain their research to individuals with a wide-range of expertise and interests.

This summer, several undergraduate students at Caltech had the opportunity to help optimize a promising technique that can make tissues and organs—even entire organisms—transparent for study. As part of the Summer Undergraduate Research Fellowship (SURF) program, these students worked in the lab of Assistant Professor of Biology Viviana Gradinaru, where researchers are developing such so-called clearing techniques that make it possible to peer straight through normally opaque tissues rather than seeing them only as thinly sectioned slices that have been pieced back together.

Gradinaru's group recently published a paper in the journal Cell describing a new approach to tissue clearing. The method they have created builds on a technique called CLARITY that Gradinaru helped develop while she was a research associate at Stanford. CLARITY allowed researchers to, for the first time, create a transparent whole-brain specimen that could then be imaged with its structural and genetic information intact.

CLARITY was specifically developed for studying the brain. But the new approach developed in Gradinaru's lab, which the team has dubbed PARS (perfusion-assisted agent release in situ), can also clear other organs, such as the kidney, as well as tissue samples, such as tumor biopsies. It can even be applied to entire organisms.

Like CLARITY, PARS involves removing the light-scattering lipids in the tissue to make samples transparent without losing the structural integrity that lipids typically provide. First the sample is infused with acrylamide monomers that are then polymerized into a hydrogel that provides structural support. Next, this tissue–hydrogel hybrid is immersed in a detergent that removes the lipids. Then the sample can be stained, often with antibodies that specifically mark cells of interest, and then immersed in RIMS (refractive index matching solution) for imaging using various optical techniques such as confocal or lightsheet microscopy.

Over the summer, Sam Wie, a junior biology major at Caltech, spent 10 weeks in the Gradinaru lab working to find a polymer that would perform better than acrylamide, which has been used in the CLARITY hydrogel. "One of the limitations of CLARITY is that when you put the hydrogel tissue into the detergent, the higher solute concentration in the tissue causes liquid to rush into the cell. That causes the sample to swell, which could potentially damage the structure of the tissue," Wie explains. "So I tried different polymers to try to limit that swelling."

Wie was able to identify a polymer that produces, over a similar amount of time, about one-sixth of the swelling in the tissue.

"The SURF experience has been very rewarding," Wie says. "I've learned a lot of new techniques, and it's really exciting to be part of, and to try to improve, CLARITY, a method that will probably change the way that we image tissues from now on."

At another bench in Gradinaru's lab, sophomore bioengineering major Andy Kim spent the summer focusing on a different aspect of the PARS technique. While antibodies have been the most common markers used to tag cells of interest within cleared tissues, they are too large for some studies—for example, those that aim to image deeper parts of the brain, requiring them to cross the blood–brain barrier. Kim's project involved identifying smaller proteins, such as nanobodies, which target and bind to specific parts of proteins in tissues.

"While PARS is a huge improvement over CLARITY, using antibodies to stain is very expensive," Kim says. "However, some of these nanobodies can be produced easily, so if we can get them to work, it would not only help image the interior of the brain, it would also be a lot less costly."

During his SURF, Kim worked with others in the lab to identify about 30 of these smaller candidate binding proteins and tested them on PARS-cleared samples.

While Wie and Kim worked on improving the PARS technique itself, Donghun Ryu, a third SURFer in Gradinaru's lab, investigated different methods for imaging the cleared samples. Ryu is a senior electrical engineering and computer science major at the Gwangju Institute of Science and Technology (GIST) in the Republic of Korea.

Last summer Ryu completed a SURF as part of the Caltech–GIST Summer Undergraduate Research Exchange Program in the lab of Changhuei Yang, professor of electrical engineering, bioengineering, and medical engineering at Caltech. While completing that project, Ryu became interested in optogenetics, the use of light to control genes. Since optogenetics is one of Gradinaru's specialties, Yang suggested that he try a SURF in Gradinaru's lab.

This summer, Ryu was able to work with both Yang and Gradinaru, investigating a technique called Talbot microscopy to see whether it would be better for imaging thick, cleared tissues than more common techniques. Ryu was able to work on the optical system in Yang's lab while testing the samples cleared in Gradinaru's lab.

"It was a wonderful experience," Ryu says. "It was special to have the opportunity to work for two labs this summer. I remember one day when I had a meeting with both Professor Yang and Professor Gradinaru; it was really amazing to get to meet with two Caltech professors."

Gradinaru says that the SURF projects provided a learning opportunity not only for the participating students but also for her lab. "For example," she says, "Ryu strengthened the collaboration that we have with the Yang group for the BRAIN Initiative. And my lab members benefited from the chance to serve as mentors—to see what works and what can be improved when transferring scientific knowledge. These are very important skills in addition to the experimental know-how that they master."  

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Friday, October 17, 2014
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Caltech Researchers Receive NIH BRAIN Funding

On September 30, the National Institutes of Health (NIH) announced its first round of funding in furtherance of President Obama's "Brain Research through Advancing Innovative Neurotechnology"—or BRAIN—Initiative. Included among the 58 funded projects—all of which, according to the NIH, are geared toward the development of "new tools and technologies to understand neural circuit function and capture a dynamic view of the brain in action"—are six projects either led or co-led by Caltech researchers.

The Caltech projects are:

"Dissecting human brain circuits in vivo using ultrasonic neuromodulation"

Doris Tsao, assistant professor of biology
Mikhail Shapiro, assistant professor of chemical engineering

Tsao and Shapiro are teaming up to develop a new technology that both uses ultrasound to map and determine the function of interconnected brain networks and, ultimately, to change neural activity deep within the brain. "This would open new horizons for understanding human brain function and connectivity, and create completely new options for the noninvasive treatment of brain diseases such as intractable epilepsy, depression, and Parkinson's disease," Tsao says. "The key," Shapiro adds, "is to gain a precise understanding of the various mechanisms by which sound waves interact with neurons in the brain so we can use ultrasound to produce very specific neurological effects. We will be able to do this across the full spectrum, from molecules up to large model organisms."

"Modular nanophotonic probes for dense neural recording at single-cell resolution"

Michael Roukes, Robert M. Abbey Professor of Physics, Applied Physics, and Bioengineering
Thanos Siapas, professor of computation and neural systems

Roukes, Siapas, and their colleagues at Columbia University and Baylor College of Medicine propose to build ultra-dense arrays of miniature light-emitting and light-sensing probes using advanced silicon "chip" technology that permits their production en masse. These probes open the new field of integrated neurophotonics, Roukes says, and will permit simultaneous recording of the electrical activity of hundreds of thousands to, ultimately, millions of neurons, with single-cell resolution, in any given region of the brain. "The instrumentation we'll develop will enable us to observe the trafficking of information, in vivo, in brain circuits on an unprecedented scale, and to correlate this activity with behavior," he says.

"Time-Reversal Optical Focusing for Noninvasive Optogenetics"

Changhuei Yang, professor of electrical engineering, bioengineering, and medical engineering
Viviana Gradinaru, assistant professor of biology

Deep-brain stimulation has been used successfully for nearly two decades for the treatment of epilepsy, Parkinson's disease, chronic pain, depression, and other disorders. Current systems rely on electrodes implanted deep within the brain to modify the firing pattern of specific clusters of neurons, bringing them back into a more normal pattern. Yang and Gradinaru are working together on a method that would use only light waves to noninvasively activate light-sensitive molecules and precisely guide the firing of nerves. Biological tissues are opaque due to the scattering of light waves, and that scattering makes it impossible to finely focus a laser beam deep into brain tissue. The researchers hope to use an optical "time-reversal" trick previously developed by Yang to counteract the scattering, allowing light beams to be targeted to specific locations within the brain. "The technology to be developed in this project has the potential for wide-ranging applications, including noninvasive deep brain stimulation and precise incisionless laser surgery," he says.

"Integrative Functional Mapping of Sensory-Motor Pathways"

Michael H. Dickinson, Esther M. and Abe M. Zarem Professor of Bioengineering

As in other animals, locomotion in the fruit fly is a complicated process involving the interplay of sensory systems and motor circuits in the brain. Dickinson and his colleagues hope to decipher just how the brain uses sensory information to guide movements by developing a system to record the activity of large numbers of individual neurons from across the brains of fruit flies, as the flies fly in flight simulator or walk on a treadmill and are simultaneously exposed to various sights and sounds. Understanding sensory–motor integration, he says, should lead to a better understanding of human disorders, including Parkinson's disease, stroke, and spinal cord injury, and aid in the design and optimization of robotic prosthetic limbs and prosthetic devices that restore sight and other senses.

"Establishing a Comprehensive and Standardized Cell Type Characterization Platform"

David J. Anderson, Seymour Benzer Professor of Biology; Investigator, Howard Hughes Medical Institute (co-PI)

In collaboration with Hongkui Zeng and colleagues at the Allen Institute for Brain Science in Seattle, Anderson will help to develop a detailed, publicly available database characterizing the genetic, physiological, and morphological features of the various cell types in the brain that are involved in circuits controlling sensations and emotions. Understanding the cellular building blocks of brain circuits, the researchers say, is crucial for figuring out how those circuits can malfunction in disease. In particular, Anderson's lab will focus on the cells of the brain's hypothalamus and amygdala—structures that are vital to emotions and behavior, and involved in human psychiatric disorders such as post-traumatic stress disorder, anxiety, and depression. "This project will serve as a model for hub-and-spoke collaborations between academic laboratories and the Allen Institute, permitting access to their valuable resources and technologies while advancing the field more broadly," Anderson says.

"Vertically integrated approach to visual neuroscience: microcircuits to behavior"

Markus Meister, Lawrence A. Hanson, Jr. Professor of Biology (co-PI)

This project, led by Hyunjune Sebastian Seung of Princeton University, will use genetic, electrophysiological, and imaging tools to identify and map the neural connections of the retina, the light-sensing tissue in the eye, and determine their roles in visual perception and behavior. "Here we are shooting for a vertically integrated understanding of a neural system," Meister says. "The retina offers such a fantastic degree of experimental access that one can hope to bridge all scales of organization, from molecules to cells to microcircuits to behavior. We hope that success here can eventually serve as a blueprint for understanding other parts of the brain." Knowing the neural mechanisms for vision can also influence technological applications, such as new algorithms for computer vision, or the development of retinal prostheses for the treatment of blindness.

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