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MIT Colloquium on the Brain and Cognition

Anne Trafton |

SPEAKER: Xiaoqin Wang, PhD
AFFILIATION: Professor of Biomedical Engineering and Neuroscience, Department of Biomedical Engineering, Johns Hopkins University School of Medicine
Director of Tsinghua-Johns Hopkins Joint Center for Biomedical Engineering Research
DATE + TIME: Thursday, April 10, 2014 @ 4:00 PM
LOCATION: MIT Bldg 46-3002 (Singleton Auditorium)
HOST: Guoping Feng, McGovern Institute

ABSTRACT:
Properly chosen animal models are pivotal in understanding brain mechanisms for behaviors. Research on the primate auditory system has been hampered for the lack of appropriate animal models with adequate vocal behaviors in laboratory conditions. We have developed a new model system to study neural basis of audition and vocal communication using the common marmoset (Callithrix jacchus), a highly vocal New World primate species. Marmosets have a rich repertoire of communication calls and remain highly vocal in captivity. Anatomically, marmosets have a smooth brain that provides easy access to many regions of the cerebral cortex for electrophysiological and optical recordings. They are easily bred and have a high reproductive rate, making it feasible to conduct developmental and transgenic studies. Using this unique model system, we have identified non-linear transformations of time-varying signals in auditory cortex and revealed harmonic organizations of this cortical region. We also showed that cortical representations of self-produced vocalizations are shaped by auditory feedback and vocal control signals during vocal communication. These findings have important implications for understanding how the brain processes speech and music and how it operates during speaking. They also demonstrate the potential of this non-human primate species in studying the neural basis of social interactions.

Remembering Pat McGovern: A Photo Montage

Anne Trafton |

A photo montage of McGovern Institute co-founder Patrick J. McGovern. Pat McGovern passed away on March 19, 2014.

Photos: AP Images, Corbis, Donna Coveney, Robert Desimone, Jason Grow, IDG, Justin Knight, MIT News Office, MIT Sloan School of Management, MIT Yearbook, Dominick Reuter, Bethany Versoy.

MRI reveals genetic activity

Anne Trafton |

Doctors commonly use magnetic resonance imaging (MRI) to diagnose tumors, damage from stroke, and many other medical conditions. Neuroscientists also rely on it as a research tool for identifying parts of the brain that carry out different cognitive functions.

Now, a team of biological engineers at MIT is trying to adapt MRI to a much smaller scale, allowing researchers to visualize gene activity inside the brains of living animals. Tracking these genes with MRI would enable scientists to learn more about how the genes control processes such as forming memories and learning new skills, says Alan Jasanoff, an MIT associate professor of biological engineering and leader of the research team.

“The dream of molecular imaging is to provide information about the biology of intact organisms, at the molecule level,” says Jasanoff, who is also an associate member of MIT’s McGovern Institute for Brain Research. “The goal is to not have to chop up the brain, but instead to actually see things that are happening inside.”

To help reach that goal, Jasanoff and colleagues have developed a new way to image a “reporter gene” — an artificial gene that turns on or off to signal events in the body, much like an indicator light on a car’s dashboard. In the new study, the reporter gene encodes an enzyme that interacts with a magnetic contrast agent injected into the brain, making the agent visible with MRI. This approach, described in a recent issue of the journal Chemical Biology, allows researchers to determine when and where that reporter gene is turned on.

An on/off switch

MRI uses magnetic fields and radio waves that interact with protons in the body to produce detailed images of the body’s interior. In brain studies, neuroscientists commonly use functional MRI to measure blood flow, which reveals which parts of the brain are active during a particular task. When scanning other organs, doctors sometimes use magnetic “contrast agents” to boost the visibility of certain tissues.

The new MIT approach includes a contrast agent called a manganese porphyrin and the new reporter gene, which codes for a genetically engineered enzyme that alters the electric charge on the contrast agent. Jasanoff and colleagues designed the contrast agent so that it is soluble in water and readily eliminated from the body, making it difficult to detect by MRI. However, when the engineered enzyme, known as SEAP, slices phosphate molecules from the manganese porphyrin, the contrast agent becomes insoluble and starts to accumulate in brain tissues, allowing it to be seen.

The natural version of SEAP is found in the placenta, but not in other tissues. By injecting a virus carrying the SEAP gene into the brain cells of mice, the researchers were able to incorporate the gene into the cells’ own genome. Brain cells then started producing the SEAP protein, which is secreted from the cells and can be anchored to their outer surfaces. That’s important, Jasanoff says, because it means that the contrast agent doesn’t have to penetrate the cells to interact with the enzyme.

Researchers can then find out where SEAP is active by injecting the MRI contrast agent, which spreads throughout the brain but accumulates only near cells producing the SEAP protein.

Exploring brain function

In this study, which was designed to test this general approach, the detection system revealed only whether the SEAP gene had been successfully incorporated into brain cells. However, in future studies, the researchers intend to engineer the SEAP gene so it is only active when a particular gene of interest is turned on.

Jasanoff first plans to link the SEAP gene with so-called “early immediate genes,” which are necessary for brain plasticity — the weakening and strengthening of connections between neurons, which is essential to learning and memory.

“As people who are interested in brain function, the top questions we want to address are about how brain function changes patterns of gene expression in the brain,” Jasanoff says. “We also imagine a future where we might turn the reporter enzyme on and off when it binds to neurotransmitters, so we can detect changes in neurotransmitter levels as well.”

Assaf Gilad, an assistant professor of radiology at Johns Hopkins University, says the MIT team has taken a “very creative approach” to developing noninvasive, real-time imaging of gene activity. “These kinds of genetically engineered reporters have the potential to revolutionize our understanding of many biological processes,” says Gilad, who was not involved in the study.

The research was funded by the Raymond and Beverly Sackler Foundation, the National Institutes of Health, and an MIT-Germany Seed Fund grant. The paper’s lead author is former MIT postdoc Gil Westmeyer; other authors are former MIT technical assistant Yelena Emer and Jutta Lintelmann of the German Research Center for Environmental Health.

Patrick J. McGovern, 1937-2014

Anne Trafton |

Patrick McGovern was born in 1937 in Queens, New York, and grew up in New York and Philadelphia. He became interested in the brain as a teenager, when he came across a book titled “Giant Brains, or Machines that Think” in the Philadelphia public library. As he recalled in an interview some 50 years later, “It was the first book that talked about computers and their role as an amplifier of the human mind,” and it sparked a lifelong interest in science and technology. In 1955 Pat was admitted to MIT, where he majored in biophysics. He studied neurophysiology, and recalls using a glass electrode to study electrical activity in tadpoles. He also became involved in student newspapers, and after graduating from MIT in the class of 1959, he was hired as an assistant editor for a new magazine, “Computers and Automation,” founded by Ed Berkeley, the author of the book that had so intrigued him ten years earlier.

After four years as a magazine editor, Pat left to found his own company, now known as International Data Group (IDG), which under his leadership grew to become the world’s foremost publisher of computer-related news, information and research. IDG today is a multi-billion-dollar business, with 2013 revenues of over $3.5 billion. The story of Pat’s career at IDG has been often told, and his business accomplishments have been recognized with many honors, including lifetime achievement awards from American Business Media and from the Magazine Publishers of America. Yet despite his success and his imposing physical presence, Pat retained a modest demeanor and never cultivated the trappings of great wealth. Instead, he focused his energies on leadership of the company (of which he remained chairman until the time of his death) and increasingly in his later years, on his philanthropic priorities.

His career and fortune were made in computer technology, but never lost sight of his early dream to understand the brain, which he often described as the world’s most complex computer. When he studied neurophysiology at MIT in the 1950s, the tools were not adequate to the enormous challenge of understanding how the human brain works, but by the 1990s, technological progress had been so dramatic that the field had been transformed almost beyond recognition. A scientific understanding of the brain, while still a daunting challenge, was no longer within the realm of science fiction, but was a real prospect for the future.

Pat’s dream was shared by his wife Lore Harp McGovern, a Silicon Valley entrepreneur whose interests included healthcare, education and hi-tech. In the late 1990s they decided that the time was right to establish a new institute for brain research, and after consultations with many leading scientists and universities, they decided that the new institute would be at MIT.

Pat and Lore had both been longstanding MIT supporters; Pat was a member of the MIT Corporation, and Lore was chair of the Board of Associates at the affiliated Whitehead Institute. But they always emphasized that their choice of MIT was not simply a matter of loyalty to Pat’s alma mater. They felt that MIT was the right choice because of its alignment with their vision of a multidisciplinary, outward-looking institute that would engage the widest possible range of scientific talents in support of its mission to understand the brain. One goal was to understand the basis of brain disorders and to lay the foundation for new treatments for conditions such as psychiatric and neurodegenerative diseases – a goal that Pat and Lore considered vitally important, given the enormous suffering and economic costs that are inflicted by these disorders. But their vision was not confined to disease research; they also understood the brain to be the source of our humanity, our creative achievements and our conflicts, and they saw the possibility that understanding these things in scientific terms could transform the world for the better.

The McGovern Institute for Brain Research was formally established in 2000, with a commitment of $350 million from Pat and Lore, one of the largest philanthropic gifts in the history of higher education. Nobel laureate and Institute Professor Phillip A. Sharp, was named founding director, and Robert Desimone succeeded Sharp as director in 2004. In the fall of 2005, the McGovern Institute moved into spacious facilities in MIT’s Brain and Cognitive Sciences Complex, one of the most distinctive landmarks on the MIT campus and among the largest neuroscience research buildings in the world.

The McGovern Institute has continued to thrive since it moved to its new home, expanding in size and scope as it has hired new faculty and built new laboratories. Most importantly, it has produced a steady stream of discoveries about the working of the brain, in areas ranging from the genetic control of brain development to the neural basis of human thought and emotion. This progress was deeply gratifying to Pat and Lore, who visited regularly to attend the institute’s board meetings and scientific events, mingling with faculty and researchers and engaging deeply in discussions of their new findings. Throughout his life, Pat retained an extraordinary ability to absorb new information, and researchers were frequently impressed at his ability to cite detailed facts and figures about the brain. He was a tireless advocate for the institute and its mission, hosting many visits and tours, and inspiring others to follow his philanthropic example. He was, and Lore remains, an enormous source of inspiration and encouragement to the researchers at the institute.

Throughout Pat’s business career, his vision was global, and he took great pride in the fact that IDG was one of the first Western companies to establish a business presence in China after the end of the Cultural Revolution. It is thus fitting that Pat and Lore’s philanthropic vision also extended to China; since 2011, three new IDG/McGovern Institutes have been established in Beijing, at Tsinghua University, Peking (“Beida”) University and Beijing Normal University.

Like the McGovern Institute at MIT, the new institutes in China are focused on fundamental research in neuroscience as well as translational work on disease applications. Pat always saw brain disorders as global problems that required global solutions, and one of his greatest hopes was that the new institutes would help accelerate the international cooperation that he saw as essential to the ultimate goal of understanding the human brain in health and disease.

Pat’s wife Lore has been a full partner throughout the McGovern Institute’s 14-year history, serving on the governing board of the institute along with Pat and his daughter Elizabeth McGovern. All of us at the institute offer our deepest condolences to Lore, to their four children, and to all of Pat’s family members and friends. He will be greatly missed.

See below for a photo gallery of Pat McGovern.

Photos: Justin Knight

Fear, Trauma and Memory: A Panel Discussion

Anne Trafton |

How accurate are our memories after a traumatic event? Does chronic stress make us more vulnerable to trauma? Will scientists one day succeed in preventing PTSD?

We invite you to join the discussion with a distinguished group of experts who will explore new lines of research and treatment strategies for stress disorders and traumatic memory. On Monday, April 7th, McGovern Institute director Bob Desimone will moderate a panel of experts and will engage the audience in a Q&A session. This event is free and open to the public, but registration is required. We hope you will join us!

 

REGISTER NOW

 

 

Fear, Trauma and Memory: A Panel Discussion

DATE: Monday April 7, 2014
TIME: 5:30 reception | 6:30 panel discussion
LOCATION: McGovern Institute for Brain Research at MIT (MIT Bldg 46-3189)
QUESTIONS? ldargus@mit.edu or 617.324.2077

 

MODERATOR

Robert DesimoneRobert Desimone is the director of the McGovern Institute and the Doris and Don Berkey Professor of Neuroscience in MIT’s Department of Brain and Cognitive Sciences. Prior to joining the McGovern Institute in 2004, he was director of the Intramural Research Program at the National Institutes of Mental Health. He is a member of the National Academy of Sciences and the American Academy of Arts and Sciences and a recipient of numerous awards, including the Troland Prize of the National Academy of Sciences.

 

 

PANELISTS

uniform photoMichael Ball is originally from Boston and is a graduate of Boston Latin Academy High School. He enlisted in the United States Marine Corps upon graduation from high school and was stationed out of Camp Lejeune, North Carolina. Ball was deployed twice to Afghanistan with the 2nd Battalion 6th Marine Regiment, and subsequently diagnosed with both post traumatic stress disorder and traumatic brain injury after receiving multiple concussions from IED blasts in southern Helmand Province. Now out of the Marine Corps for one year, Michael now volunteers to help veterans in need and spread awareness of the struggles veterans face upon separation from the military.

 

122x122-gabrieliBWJohn Gabrieli is the director of the Athinoula A. Martinos Imaging Center at the McGovern Institute. He is an Investigator at the Institute, with faculty appointments in the Department of Brain and Cognitive Sciences and the Institute for Medical Engineering at MIT. Gabrieli’s major research focus is combining brain imaging with behavioral analysis to understand the organization of memory, thought, and emotion in the human brain. A central theme of Gabrieli’s research is memory in its different forms: the short-term recall that allows us to dial a phone number, our long-term memory of events and places, and the emotional associations that often color our factual memories. These different types of memory are mediated by different brain systems, and Gabrieli seeks to tease these systems apart and understand how they interact to shape our overall sense of the past.

Prior joining MIT, Gabrieli spent 14 years at Stanford University in the Department of Psychology and Neurosciences Program. Since 1990, he has served as Visiting Professor, Department of Neurological Sciences, Rush-Presbyterian-St. Luke’s Hospital and Rush Medical College. He earned a PhD in Behavioral Neuroscience in the MIT Department of Brain and Cognitive Sciences in 1987 and BA in English from Yale University in 1978.


122x122-kigoosensBWKi Ann Goosens is a Principal Investigator at the McGovern Institute and Assistant Professor in the MIT Department of Brain and Cognitive Sciences. Goosens is currently dedicated to studying the relationship between fear, anxiety, and stress. In 2013, Goosens published new findings demonstrating that the hormone ghrelin, a stomach hormone whose production is dramatically enhanced in times of stress, makes the brain more vulnerable to traumatic events and may predispose people to post-traumatic stress disorder. Goosens hopes that a better understanding of the brain’s response to stress will lead to new therapeutic strategies for anxiety and stress disorders, depression, and other psychiatric diseases.

Prior to joining the McGovern Institute, Goosens was a postdoctoral fellow with Dr. Robert Sapolsky at Stanford University. She earned a PhD in Biopsychology from the University of Michigan, Ann Arbor, in 2002 and, prior to that, a BA with Distinction in Cognitive Science with a Concentration in Neuroscience from the University of Virginia.


Dr. Mireya Nadal-Vicens is a staff psychiatrist at Massachusetts General Hospital, where she specializes in treating individuals with stress- and trauma-related disorders. She conducts research in the Center for Anxiety and Traumatic Stress Disorder and Center for Addiction Medicine at Mass. General Hospital, and is an Instructor of Psychiatry at Harvard Medical School. Nadal-Vicens is rigorously trained in basic laboratory science in the field of brain development. Her research and training plan relates to establishing a new model for depression and social defeat, and in this work she draws from several disciplines and departments at MGH/Harvard, including psychiatry, neuroscience, pharmacology, and genetics.

Nadal-Vicens earned a BA from Harvard College, an MS in Neuroscience from Stanford University, and an MD/PhD in the Department of Neuroscience at Harvard Medical School. During her PhD thesis work, she studied the molecular signaling cascade responsible for the generation of neurons and glial cells during early brain development, working with newly discovered neural stem cells.

 

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McGovern Institute to honor neurogenetics researcher Huda Zoghbi

Anne Trafton |

The McGovern Institute for Brain Research at MIT announced today that Huda Y. Zoghbi, of Baylor College of Medicine and Texas Children’s Hospital, is the winner of the 2014 Edward M. Scolnick Prize in Neuroscience. The Prize is awarded annually by the McGovern Institute to recognize outstanding advances in the field of neuroscience.

“Huda Zoghbi has been a pioneer in the study of human genetic disease,” says Robert Desimone, director of the McGovern Institute and chair of the selection committee. “Her work has provided fundamental insights into the mechanisms of hereditary neurodegenerative and neuropsychiatric diseases, and has pointed the way to new treatments for these disorders.”

Zoghbi studied medicine in her native Lebanon and later in the US, where she specialized in pediatric neurology. Following her residency she trained as a molecular geneticist with Arthur Beaudet at Baylor College of Medicine, where she became a faculty member in 1988. She is currently an investigator with the Howard Hughes Medical Institute.

Zoghbi’s first major scientific contribution was the identification in 1993 of the gene responsible for spinocerebellar ataxia type 1 (SCA1), a progressive neurodegenerative disease with an unusual pattern of inheritance. In collaboration with Harry Orr at the University of Minnesota, Zoghbi showed that SCA1, like Huntington’s disease, is caused by a pathological expansion of a repeated three-nucleotide sequence. The more times this is repeated, the earlier the onset of disease and the more severe the symptoms. The number of repeats can increase from one generation to the next, meaning that children are often more severely affected than the parent. Zoghbi continues to study SCA1, and her recent work has focused on identifying genetic factors that slow the progression of the disease, a strategy that she hopes will also be applicable to other neurodegenerative disorders.

Zoghbi is perhaps best known for her pioneering work on Rett syndrome, a genetic neurological disease that affects young girls (males with the condition usually die in infancy). Girls born with the disease develop normally for one or two years, but then begin to show progressive loss of motor skills, speech, and other cognitive abilities.

Zoghbi first encountered children with Rett syndrome during her residency, and decided to search for its genetic cause. This was a challenging task; the disease was not widely recognized at the time and was often misdiagnosed, and family studies were difficult because the majority of cases were caused by isolated sporadic mutations. Zoghbi persisted despite these challenges, and after a 16-year search, she succeeded in identifying the Rett gene in 1999. This discovery provided a definitive genetic diagnosis for the condition, and also opened the door to a biological understanding and a search for treatment. Zoghbi demonstrated that Rett syndrome is caused by deficiency in a protein called MeCP2, which binds methylated DNA and regulates the expression of many other genes. The gene lies on the X chromosome, and in females one of the two X chromosomes is randomly inactivated in each cell; thus each patient with the Rett mutation has a different pattern of healthy and mutant cells, explaining some of the variability of Rett symptoms.

Identification of the Rett gene allowed researchers to make equivalent mutations in mouse models, which develop progressive neurological symptoms strikingly similar to those of human patients. This in turn laid the groundwork for further studies by Zoghbi and many other labs, and to the development of new therapeutic strategies that are now undergoing clinical trials.

The implications of this work extend beyond Rett syndrome (a relatively rare condition). Many Rett patients show symptoms of autism, and one hope is that understanding these symptoms may lead to new treatments that will be effective not only for people with Rett syndrome but also for other more common cases of autism. Zoghbi’s recent work has focused on identifying the cell types and brain circuits that are responsible for the autistic-like behaviors of the mouse Rett model, which may represent promising targets for future therapeutic intervention.

In addition to running her own laboratory, Zoghbi is the founding director of the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital. She has received numerous awards and honors for her work, including election to both the Institute of Medicine and the National Academy of Sciences.
The McGovern Institute will award the Scolnick Prize to Dr. Zoghbi on Wednesday April 30, 2014. At 4:00 pm she will deliver a lecture entitled “A neural tipping point: MeCP2 and neuropsychiatric disorders,” to be followed by a reception, at the McGovern Institute in the Brain and Cognitive Sciences Complex, 43 Vassar Street (building 46, room 3002) in Cambridge. The event is free and open to the public.

About the Edward M. Scolnick Prize in Neuroscience:
The Scolnick Prize, awarded annually by the McGovern Institute, is named in honor of Dr. Edward M. Scolnick, who stepped down as President of Merck Research Laboratories in December 2002 after holding Merck’s top research post for 17 years. Dr. Scolnick is now a core member of the Broad Institute, where he is chief scientist at the Stanley Center for Psychiatric Research. He also serves as a member of the McGovern Institute’s governing board. The prize, which is endowed through a gift from Merck to the McGovern Institute, consists of a $100,000 award, plus an inscribed gift. Previous winners are Thomas Jessell (Columbia University), Roger Nicoll (University of California, San Francisco), Bruce McEwen (Rockefeller University), Lily and Yuh-Nung Jan (University of California, San Francisco), Jeremy Nathans (Johns Hopkins University), Michael Davis (Emory University), David Julius (University of California, San Francisco), Michael Greenberg (Harvard Medical School), Judith Rapoport (National Institute of Mental Health) and Mark Konishi (California Institute of Technology).

Broad, MIT researchers reveal structure of key CRISPR complex

Anne Trafton |

Researchers from the Broad Institute and MIT have teamed up with colleagues from the University of Tokyo to form the first high definition picture of the Cas9 complex – a key part of the CRISPR-Cas system used by scientists as a genome-editing tool to silence genes and probe the biology of cells. Their findings, which are reported this week in Cell, are expected to help researchers refine and further engineer the tool to accelerate genomic research and bring the technology closer to use in the treatment of human genetic disease.

First discovered in bacteria in 1987, CRISPRs (Clustered Regularly Interspaced Short Palindromic Repeats) have recently been harnessed as so-called genome editing tools. These tools allow researchers to home in on “typos” within the three-billion-letter sequence of the human genome, and cut out and even alter the problematic sequence. The Cas9 complex, which includes the CRISPR “cleaving” enzyme Cas9 and an RNA “guide” that leads the enzyme to its DNA target, is key to this process.

“We’ve come to view the Cas9 complex as the ultimate guided missile that we can use to target precise sites in the genome,” said co-senior author Feng Zhang, a core member of the Broad Institute, an investigator at the McGovern Institute for Brain Research, and an assistant professor at MIT. “This study provides a schematic of the entire system – it shows the missile (the Cas9 protein), the programming instructions (the guide RNA) that send it to the right location, and the target DNA. It also reveals the secret of how these pieces function together to make the whole system work.”

To deconstruct this system, Zhang approached the paper’s co-senior author Osamu Nureki at the University of Tokyo. Together, they assembled a team to work out the complicated structure.

“Cas9-based genome editing technologies are proving to be revolutionary in a wide range of life sciences, enabling many new experimental techniques, so my colleagues and I were excited to work with Feng’s lab on this important research,” said first author Hiroshi Nishimasu, an assistant professor of biophysics and biochemistry who works in Nureki’s lab at the University of Tokyo.

The two teams worked closely to reveal the structural details of the Cas9 complex and to test their functional significance. Their efforts revealed a division of labor within the Cas9 complex. The researchers determined that the Cas9 protein consists of two lobes: one lobe is involved in the recognition of the RNA and DNA elements, while the other lobe is responsible for cleaving the target DNA, causing what is known as a “double strand break” that disables the targeted gene. The team also found that key structures on Cas9 interface with the guide RNA, allowing Cas9 to organize itself around the RNA and the target DNA as it prepares to cut the strands.

Identifying the key features of the Cas9 complex should enable researchers to improve the genome-editing tool to better suit their needs.

“Up until now, it has been very difficult to rationally engineer Cas9. Now that we have this structural information, we can take a principled approach to engineering the protein to make it more effective,” said Zhang, who is also a co-founder of Editas Medicine, a company that was started last year to develop Cas9 and other genome editing technologies into a novel class of human therapeutics.

Currently, Cas9 is used in experiments to silence genes in mammalian cells – sometimes at multiple sites across the genome – and large libraries of RNA sequences have been created to guide Cas9 to genes of interest. However, the system can only target specific types of sites. Some studies have also shown that the RNA could lead Cas9 “off-target,” potentially causing unexpected problems within the cellular machinery.

The researchers plan to use this new, detailed picture of the Cas9 complex to address these concerns.

“Understanding this structure may help us engineer around the current limitations of the Cas9 complex,” said study author F. Ann Ran, a graduate student in Zhang’s lab. “In the future, it could allow us to design versions of these editing tools that are more specific to our research needs. We may even be able to alter the type of nucleic acid sequences that Cas9 can target.”

Such technological improvements will be needed if the CRISPR-Cas system is to evolve into a therapeutic tool for the treatment of genetic disease.

The study was supported by the National Institute of Mental Health (NIMH); an NIH Director’s Pioneer Award; the Japan Science and Technology Agency; the Japan Society for the Promotion of Science; the Keck, McKnight, Poitras, Merkin, Vallee, Damon Runyon, Searle Scholars, Klingenstein, and Simons Foundations; as well as Bob Metcalfe and Jane Pauley.

Other researchers who worked on the study include Patrick D. Hsu, Silvana Konermann, Soraya Shehata, Naoshi Dohmae, and Ryuichiro Ishitani.

Written by Veronica Meade-Kelly, Broad Institute

Paper cited:

Nishimasu H et al. “Crystal structure of Cas9 in complex with guide RNA and target DNA.” Cell DOI: 10.1016/j.cell.2014.02.001

About the Broad Institute of Harvard and MIT
The Eli and Edythe L. Broad Institute of Harvard and MIT was launched in 2004 to empower this generation of creative scientists to transform medicine. The Broad Institute seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods and data openly to the entire scientific community.

Founded by MIT, Harvard and its affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to http://www.broadinstitute.org.

About the McGovern Institute for Brain Research at MIT
The McGovern Institute for Brain Research at MIT is led by a team of world-renowned neuroscientists committed to meeting two great challenges of modern science: understanding how the brain works and discovering new ways to prevent or treat brain disorders. The McGovern Institute was established in 2000 by Patrick J. McGovern and Lore Harp McGovern, who are committed to improving human welfare, communication and understanding through their support for neuroscience research. The director is Robert Desimone, formerly the head of intramural research at the National Institute of Mental Health.

Optogenetic toolkit goes multicolor

Anne Trafton |

Optogenetics is a technique that allows scientists to control neurons’ electrical activity with light by engineering them to express light-sensitive proteins. Within the past decade, it has become a very powerful tool for discovering the functions of different types of cells in the brain.

Most of these light-sensitive proteins, known as opsins, respond to light in the blue-green range. Now, a team led by MIT has discovered an opsin that is sensitive to red light, which allows researchers to independently control the activity of two populations of neurons at once, enabling much more complex studies of brain function.

“If you want to see how two different sets of cells interact, or how two populations of the same cell compete against each other, you need to be able to activate those populations independently,” says Ed Boyden, a member of the McGovern Institute for Brain Research at MIT and a senior author of the new study.

The new opsin is one of about 60 light-sensitive proteins found in a screen of 120 species of algae. The study, which appears in the Feb. 9 online edition of Nature Methods, also yielded the fastest opsin, enabling researchers to study neuron activity patterns with millisecond timescale precision.

Boyden and Gane Ka-Shu Wong, a professor of medicine and biological sciences at the University of Alberta, are the paper’s senior authors, and the lead author is MIT postdoc Nathan Klapoetke. Researchers from the Howard Hughes Medical Institute’s Janelia Farm Research Campus, the University of Pennsylvania, the University of Cologne, and the Beijing Genomics Institute also contributed to the study.

In living color

Opsins occur naturally in many algae and bacteria, which use the light-sensitive proteins to help them respond to their environment and generate energy.

To achieve optical control of neurons, scientists engineer brain cells to express the gene for an opsin, which transports ions across the cell’s membrane to alter its voltage. Depending on the opsin used, shining light on the cell either lowers the voltage and silences neuron firing, or boosts voltage and provokes the cell to generate an electrical impulse. This effect is nearly instantaneous and easily reversible.

Using this approach, researchers can selectively turn a population of cells on or off and observe what happens in the brain. However, until now, they could activate only one population at a time, because the only opsins that responded to red light also responded to blue light, so they couldn’t be paired with other opsins to control two different cell populations.

To seek additional useful opsins, the MIT researchers worked with Wong’s team at the University of Alberta, which is sequencing the transcriptomes of 1,000 plants, including some algae. (The transcriptome is similar to the genome but includes only the genes that are expressed by a cell, not the entirety of its genetic material.)

Once the team obtained genetic sequences that appeared to code for opsins, Klapoetke tested their light-responsiveness in mammalian brain tissue, working with Martha Constantine-Paton, a professor of brain and cognitive sciences and of biology, a member of the McGovern Institute for Brain Research at MIT, and also an author of the paper. The red-light-sensitive opsin, which the researchers named Chrimson, can mediate neural activity in response to light with a 735-nanometer
wavelength.

The researchers also discovered a blue-light-driven opsin that has two highly desirable traits: It operates at high speed, and it is sensitive to very dim light. This opsin, called Chronos, can be stimulated with levels of blue light that are too weak to activate Chrimson.

“You can use short pulses of dim blue light to drive the blue one, and you can use strong red light to drive Chrimson, and that allows you to do true two-color, zero-cross-talk activation in intact brain tissue,” says Boyden, who is a member of MIT’s Media Lab and an associate professor of biological engineering and brain and cognitive sciences at MIT.

Researchers had previously tried to modify naturally occurring opsins to make them respond faster and react to dimmer light, but trying to optimize one feature often made other features worse.

“It was apparent that when trying to engineer traits like color, light sensitivity, and kinetics, there are always tradeoffs,” Klapoetke says. “We’re very lucky that something natural actually was more than several times faster and also five or six times more light-sensitive than anything else.”

Selective control

These new opsins lend themselves to several types of studies that were not possible before, Boyden says. For one, scientists could not only manipulate activity of a cell population of interest, but also control upstream cells that influence the target population by secreting neurotransmitters.

Pairing Chrimson and Chronos could also allow scientists to study the functions of different types of cells in the same microcircuit within the brain. Such cells are usually located very close together, but with the new opsins they can be controlled independently with two different colors of light.

“I think the tools described in this excellent paper represent a major advance for both basic and translational neuroscience,” says Botond Roska, a senior group leader at the Friedrich Miescher Institute for Biomedical Research in Switzerland, who was not part of the research team. “Optogenetic tools that are shifted towards the infrared range, such as Chrimson described in this paper, are much better than the more blue-shifted variants since these are less toxic, activate less the pupillary reflex, and activate less the remaining photoreceptors of patients.”

Most optogenetic studies thus far have been done in mice, but Chrimson could be used for optogenetic studies of fruit flies, a commonly used experimental organism. Researchers have had trouble using blue-light-sensitive opsins in fruit flies because the light can get into the flies’ eyes and startle them, interfering with the behavior being studied.

Vivek Jayaraman, a research group leader at Janelia Farms and an author of the paper, was able to show that this startle response does not occur when red light is used to stimulate Chrimson in fruit flies.

Because red light is less damaging to tissue than blue light, Chrimson also holds potential for eventual therapeutic use in humans, Boyden says. Animal studies with other opsins have shown promise in helping to restore vision after the loss of photoreceptor cells in the retina.

The researchers are now trying to modify Chrimson to respond to light in the infrared range. They are also working on making both Chrimson and Chronos faster and more light sensitive.

MIT’s portion of the project was funded by the National Institutes of Health, the MIT Media Lab, the National Science Foundation, the Wallace H. Coulter Foundation, the Alfred P. Sloan Foundation, a NARSAD Young Investigator Grant, the Human Frontiers Science Program, an NYSCF Robertson Neuroscience Investigator Award, the IET A.F. Harvey Prize, Janet and Sheldon Razin ’59, and the Skolkovo Institute of Science and Technology.