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The Neurogenetics of Language – Patricia Kuhl

Larry H. Bernstein, MD, FCAP, Curator

Leaders in Pharmaceutical Innovation

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WordCloud Image Produced by Adam Tubman

Series E. 2; 5.7

2015 George A. Miller Award

In neuroimaging studies using structural (diffusion weighted magnetic resonance imaging or DW-MRI) and functional (magnetoencephalography or MEG) imaging, my laboratory has produced data on the neural connectivity that underlies language processing, as well as electrophysiological measures of language functioning during various levels of language processing (e.g., phonemic, lexical, or sentential). Taken early in development, electrophysiological measures or “biomarkers” have been shown to predict future language performance in neurotypical children as well as children with autism spectrum disorders (ASD). Work in my laboratory is now combining these neuroimaging approaches with genetic sequencing, allowing us to understand the genetic contributions to language learning.

http://www.youtube.com/watch%3Fv%3DG2XBIkHW954

http://www.youtube.com/watch%3Fv%3DM-ymanHajN8

Patricia Kuhl shares astonishing findings about how babies learn one language over another — by listening to the humans around them

Kuhl Constructs: How Babies Form Foundations for Language

MAY 3, 2013

by Sarah Andrews Roehrich, M.S., CCC-SLP

Years ago, I was captivated by an adorable baby on the front cover of a book, The Scientist in the Crib: What Early Learning Tells Us About the Mind, written by a trio of research scientists including Alison Gopknik, PhDAndrew Meltzoff, PhD, and Patricia Kuhl, PhD.

At the time, I was simply interested in how babies learn about their worlds, how they conduct experiments, and how this learning could impact early brain development.  I did not realize the extent to which interactions with family, caretakers, society, and culture could shape the direction of a young child’s future.

Now, as a speech-language pathologist in Early Intervention in Massachusetts, more cognizant of the myriad of factors that shape a child’s cognitive, social-emotional, language, and literacy development, I have been absolutely delighted to discover more of the work of Dr. Kuhl, a distinguished speech-and-language pathologist at The University of Washington.  So, last spring, when I read that Dr. Kuhl was going to present “Babies’ Language Skills” as one part of a 2-part seminar series sponsored by the Mind, Brain, and Behavior Annual Distinguished Lecture Series at Harvard University1, I was thrilled to have the opportunity to attend. Below are some highlights from that experience and the questions it has since sparked for me:

Lip ‘Reading’ Babies
According to a study by Dr. Patricia Kuhl and Dr. Andrew Meltzoff, “Bimodal Perception of Speech in Infancy” (Science, 1982), cited in the 2005 Seattle Times article, “Infant Science: How do Babies Learn to Talk?” by Paula Bock, Drs. Patricia Kuhl and Andrew Meltzoff showed that babies as young as 18 weeks of age could listen to “Ah ah ah” or “Ee ee ee” vowel sounds and gaze at the correct, corresponding lip shape on a video monitor.
This image from Kuhl’s 2011 TED talk shows how a baby is trained to turn his head in response to a change in such vowel sounds, and is immediately rewarded by watching a black box light up while a panda bear inside pounds a drum.  Images provided courtesy of Dr. Patricia Kuhl’s Lab at the University of Washington.

Who is Dr. Patricia Kuhl and how has her work re-shaped our knowledge about how babies learn language?

Dr. Kuhl, who is co-director of the Institute for Learning and Brain Sciences at The University of Washington, has been internationally recognized for her research on early language and brain development, and for her studies on how young children learn.  In her most recent research experiments, she’s been using magnetoencephalography (MEG)–a relatively new neuroscience technology that measures magnetic fields generated by the activity of brain cells–to investigate how, where, and with what frequency babies from around the world process speech sounds in the brain when they are listening to adults speak in their native and non-native languages.

A 6-month-old baby sits in a magnetoencephalography machine, which maps brain activity, while listening to various languages in earphones and playing with a toy. Image originally printed in “Brain Mechanisms in Early Language Acquisition” (Neuron review, Cell Press, 2010) and provided courtesy of Dr. Patricia Kuhl’s Lab at the University of Washington.

Not only does Kuhl’s research point us in the direction of how babies learn to process phonemes, the sound units upon which many languages are built, but it is part of a larger body of studies looking at infants across languages and cultures that has revolutionized our understanding of language development over the last half of the 20th century—leading to, as Kuhl puts it, “a new view of language acquisition, that accounts for both the initial state of linguistic knowledge in infants, and infants’ extraordinary ability to learn simply by listening to their native language.”2

What is neuroplasticity and how does it underlie child development?

Babies are born with 100 billion neurons, about the same as the number of stars in the Milky Way.3 In The Whole Brain Child,Daniel Siegel, MD and Tina Payne Bryson, PhD explain that when we undergo an experience, these brain cells respond through changes in patterns of electrical activity—in other words, they “fire” electrical signals called “action potentials.”4

In a child’s first years of life, the brain exhibits extraordinary neuroplasticity, refining its circuits in response to environmental experiences. Synapses—the sites of communication between neurons—are built, strengthened, weakened and pruned away as needed. Two short videos from the Center on the Developing Child at Harvard, “Experiences Build Brain Architecture” and “Serve and Return Interaction Shapes Brain Circuitry”, nicely depict how some of this early brain development happens.5

Since brain circuits organize and reorganize themselves in response to an infant’s interactions with his or her environment, exposing babies to a variety of positive experiences (such as talking, cuddling, reading, singing, and playing in different environments) not only helps tune babies in to the language of their culture, but it also builds a foundation for developing the attention, cognition, memory, social-emotional, language and literacy, and sensory and motor skills that will help them reach their potential later on.

When and how do babies become “language-bound” listeners?

In her 2011 TED talk, “The Linguistic Genius of Babies,” Dr. Kuhl discusses how babies under 8 months of age from different cultures can detect sounds in any language from around the world, but adults cannot do this. 6   So when exactly do babies go from being “citizens of the world”, as Kuhl puts it, to becoming “language-bound” listeners, specifically focused on the language of their culture?”

Between 8-10 months of age, when babies are trying to master the sounds used in their native language, they enter a critical period for sound development.1  Kuhl explains that in one set of experiments, she compared a group of babies in America learning to differentiate the sounds “/Ra/” and “/La/,” with a group of babies in Japan.  Between 6-8 months, the babies in both cultures recognized these sounds with the same frequency.  However, by 10-12 months, after multiple training sessions, the babies in Seattle, Washington, were much better at detecting the “/Ra/-/La/” shift than were the Japanese babies.

Kuhl explains these results by suggesting that babies “take statistics” on how frequently they hear sounds in their native and non-native languages.  Because “/Ra/” and “/La/” occur more frequently in the English language, the American babies recognized these sounds far more frequently in their native language than the Japanese babies.  Kuhl believes that the results in this study indicate a shift in brain development, during which babies from each culture are preparing for their own languages and becoming “language-bound” listeners.

In what ways are nurturing interactions with caregivers more valuable to babies’ early language development than interfacing with technology?

If parents, caretakers, and other children can help mold babies’ language development simply by talking to them, it is tempting to ask whether young babies can learn language by listening to the radio, watching television, or playing on their parents’ mobile devices. I mean, what could be more engaging than the brightly-colored screens of the latest and greatest smart phones, iPads, iPods, and computers? They’re perfect for entertaining babies.  In fact, some babies and toddlers can operate their parents’ devices before even having learned how to talk.

However, based on her research, Kuhl states that young babies cannot learn language from television and it is necessary for babies to have lots of face-to-face interaction to learn how to talk.1  In one interesting study, Kuhl’s team exposed 9 month old American babies to Mandarin in various forms–in person interactions with native Mandarin speakers vs. audiovisual or audio recordings of these speakers–and then looked at the impact of this exposure on the babies’ ability to make Mandarin phonetic contrasts (not found in English) at 10-12 months of age. Strikingly, twelve laboratory visits featuring in person interactions with the native Mandarin speakers were sufficient to teach the American babies how to distinguish the Mandarin sounds as well as Taiwanese babies of the same age. However, the same number of lab visits featuring the audiovisual or audio recordings made no impact. American babies exposed to Mandarin through these technologies performed the same as a control group of American babies exposed to native English speakers during their lab visits.

This diagram depicts the results of a Kuhl study on American infants exposed to Mandarin in various forms–in person interactions with native speakers versus television or audio recordings of these speakers. As the top blue triangle shows, the American infants exposed in person to native Mandarin speakers performed just as well on a Mandarin phoneme distinction task as age-matched Taiwanese counterparts. However, those American infants exposed to television or audio recordings of the Mandarin speakers performed the same as a control group of American babies exposed to native English speakers during their lab visits. Diagram displayed in Kuhl’s TED TAlk 6, provided courtesy of Dr. Patricia Kuhl’s Lab at the University of Washington.

Kuhl believes that this is primarily because a baby’s interactions with others engages the social brain, a critical element for helping children learn to communicate in their native and non-native languages. 6  In other words, learning language is not simply a technical skill that can be learned by listening to a recording or watching a show on a screen.  Instead, it is a special gift that is handed down from one generation to the next.

Language is learned through talking, singing, storytelling, reading, and many other nurturing experiences shared between caretaker and child.  Babies are naturally curious; they watch every movement and listen to every sound they hear around them.  When parents talk, babies look up and watch their mouth movements with intense wonder.  Parents respond in turn, speaking in “motherese,” a special variant of language designed to bathe babies in the sound patterns and speech sounds of their native language. Motherese helps babies hear the “edges” of sound, the very thing that is difficult for babies who exhibit symptoms of dyslexia and auditory processing issues later on.

Over time, by listening to and engaging with the speakers around them, babies build sound maps which set the stage for them to be able to say words and learn to read later on.  In fact, based on years of research, Kuhl has discovered that babies’ abilities to discriminate phonemes at 7 months-old is a predictor of future reading skills for that child at age 5.7

I believe that educating families about brain development, nurturing interactions, and the benefits and limits of technology is absolutely critical to helping families focus on what is most important in developing their children’s communication skills.  I also believe that Kuhl’s work is invaluable in this regard.  Not only has it focused my attention on how babies form foundations for language, but it has illuminated my understanding of how caretaker-child interactions help set the stage for babies to become language-bound learners.

Sources

(1) Kuhl, P. (April 3, 2012.) Talk on “Babies’ Language Skills.” Mind, Brain, and Behavior Annual Distinguished Lecture Series, Harvard University.

(2) Kuhl, P. (2000). “A New View of Language Acquisition.” This paper was presented at the National Academy of Sciences colloquium “Auditory Neuroscience: Development, Transduction, and Integration,” held May 19–21, 2000, at the Arnold and Mabel Beckman Center in Irvine, CA. Published by the National Academy of Sciences.

(3) Bock, P. (2005.)  “The Baby Brain.  Infant Science: How do Babies Learn to Talk?” Pacific Northwest: The Seattle Times Magazine.

(4) Siegel, D., Bryson, T. (2011.)  The Whole-Brain Child: 12 Revolutionary Strategies to Nurture Your Child’s Developing Mind. New York, NY:  Delacorte Press, a division of Random House, Inc.

(5) Center on the Developing Child at Harvard University. “Experiences Build Brain Architecture” and “Serve and Return Interaction Shapes Brain Circuitry” videos, two parts in the three-part series, “Three Core Concepts in Early Development.

http://developingchild.harvard.edu/resources/multimedia/videos

(6) Kuhl, P.  (February 18, 2011.) “The Linguistic Genius of Babies,” video talk on TED.com, a TEDxRainier event.

www.ted.com/talks/patricia_kuhl_the_linguistic_genius_of_babies.html

(7) Lerer, J. (2012.) “Professor Discusses Babies’ Language Skills.”  The Harvard Crimson.

Andrew Meltzoff & Patricia Kuhl: Joint attention to mind

Sarah DeWeerdt  11 Feb 2013

Power couple: In addition to a dizzying array of peer-reviewed publications, Andrew Meltzoff and Patricia Kuhl have written a popular book on brain development, given TED talks and lobbied political leaders.

Andrew Meltzoff shares many things with his wife — research dollars, authorship, a keen interest in the young brain — but he does not keep his wife’s schedule.

“It’s one of the agreements we have,” he says, laying out the rule with a twinkle in his eye that conveys both the delights and the complications of working with one’s spouse.

Meltzoff, professor of psychology at the University of Washington in Seattle, and his wife, speech and hearing sciences professor Patricia Kuhl, are co-directors of the university’s Institute for Learning and Brain Sciences, which focuses on the development of the brain and mind during the first five years of life.

Between them, they have shown that learning is a fundamentally social process, and that babies begin this social learning when they are just weeks or even days old.

You could say the couple is attached at the cerebral cortex, but not at the hip: They take equal roles in running the institute, but they each have their own daily rhythms and distinct, if overlapping, scientific interests.

Kuhl studies how infants “crack the language code,” as she puts it — how they figure out sounds and meanings and eventually learn to produce speech. Meltzoff’s work focuses on social building blocks such as imitation and joint attention, or a shared focus on an object or activity. Meltzoff says these basic behaviors help children develop theory of mind, a sophisticated awareness and understanding of others’ thoughts and feelings.

All of these abilities are impaired in children with autism. Most of the couple’s studies have focused on typically developing infants, because, they say, it’s essential to understand typical development in order to appreciate the irregularities in autism.

Both also study autism, which can in turn help explain typical development.

In addition to a dizzying array of peer-reviewed publications, the duo have written a popular book on developmental psychiatry, The Scientist in the Crib, and promote their ideas through TED talks and by lobbying political leaders.

Geraldine Dawson, chief science officer of the autism science and advocacy organization Autism Speaks and a longtime collaborator, calls Meltzoff and Kuhl “the dynamic duo.” “They’re sort of bigger-than-life type people, who fill the room when they walk into it,” she says.

Making a match:

Meltzoff and Kuhl’s story began with a scientific twist on a standard rom-com meet cute.

It was the early 1980s, and Kuhl, who had recently joined the faculty at the University of Washington, wanted to understand how infants hear and see vowels. But she was having trouble designing an effective experiment.

“I kept running into Andy’s office,” which was near hers, to talk it through, Kuhl recalls.

Meltzoff had done some research on how babies integrate what they see with what they touch, a process called cross-modal matching1. Soon he and Kuhl realized that they could adapt his experimental design to her question, and decided to collaborate.

They showed babies two video screens, each featuring a person mouthing a different vowel sound – “ahhh” or “eeee.” A speaker placed between the two screens played one of those two vowel sounds.

They found that babies as young as 18 to 20 weeks look longer at the face that matches the sound they hear, integrating faces with voices2.

But that wasn’t the only significant result from those experiments.

“Speaking only for myself, I will say I became very interested in the very attractive, smart blonde that I was collaborating with,” Meltzoff says. “Criticizing each other’s scientific writing at the same time the relationship was building was… interesting.”

And effective: Their paper appeared in Science in 1982, and the couple married three years later.

Listening to Meltzoff tell that story, it’s easy to understand why some colleagues say he is funny but they can’t quite explain why. His humor is subtle and wry. More obvious is his passion, not just for science, but for working out the theory underlying empirical results. Even his wife describes his personality as “cerebral.”

“He just has this laser vision for homing in on what is the heart of the issue,” says Rechele Brooks, research assistant professor of psychiatry and behavioral sciences at the University of Washington, who collaborates with Meltzoff on studies of gaze.

For example, in one of his earliest papers, Meltzoff wanted to investigate how babies learn to imitate. He found that infants just 12 to 21 days old can imitate both facial expressions and hand gestures, much earlier than previously thought3.

“It really turned the scientific community on its head,” Brooks says.

Early insights:

Face to face: Meltzoff and Kuhl are developing a method to simultaneously record the brain activity of two people as they interact.

Meltzoff continued to study infants, tracing back the components of theory of mind to their earliest developmental source. That sparked the interest of Dawson, who had gotten to know Meltzoff as a student at the University of Washington in the 1970s, and became the first director of the university’s autism center in 1996.

Meltzoff and Dawson together applied his techniques to study young, often nonverbal, children with autism. In one study, they found that children with autism have more trouble imitating others than do either typically developing children or those with Down syndrome4.

In another study, they found that children with autism are less interested in social sounds such as clapping or hearing their name called than are their typically developing peers5.  They also found that how children with autism imitate and play with toys when they are 3 or 4 years old predicts their communication skills two years later6.

Most previous studies of autism had focused on older children, Dawson says, and this work helped paint a picture of the disorder earlier in childhood.

Kuhl began her career with studies showing that monkeys7 and even chinchillas8 can distinguish the difference between speech sounds, or phonemes, such as “ba” and “pa,” just as human infants can.

“The bottom line was that animals were sharing this aspect of perception,” Kuhl says.

So why are people so much better than animals at learning language? Kuhl has been trying to answer that question ever since, first through behavioral studies and then by measuring brain activity using imaging techniques.

Kuhl is soft-spoken, but a listener wants to lean in to catch every word. Scientists who have worked with her describe her as poised and perfectly put together, a master of gentle yet effective diplomacy.

“She has her sort of magnetic power to pull people together,” says Yang Zhang, associate professor of speech-language-hearing sciences at the University of Minnesota in Rochester, who was a graduate student and postdoctoral researcher in Kuhl’s lab beginning in the late 1990s.

Listen and learn:

At one point, Kuhl turned her considerable powers of persuasion on a famously smooth negotiator, then-President Bill Clinton.

Kuhl had shown that newborns hear virtually all speech sounds, but by 6 months of age they lose the ability to distinguish sounds that aren’t part of their native language9.

At the White House Conference on Early Childhood Development and Learning in 1997, she described how infants learn by listening, long before they can speak.

Clinton, ever the policy wonk, asked her how much babies need to hear in order to learn. Kuhl said she didn’t know — but if Clinton gave her the funds, she would find out. “Even the president could see that research on the effects of language input on the young brain had impact on society,” she says.

Kuhl used the funds Clinton gave her to design a study in which 9-month-old babies in the U.S. received 12 short Mandarin Chinese ‘lessons.’ The babies quickly learned to distinguish speech sounds in the second language, her team found — but only if the speaker was live, not in a video10.

Those results contributed to Kuhl’s ‘social gating’ hypothesis, which holds that social interaction is necessary for picking up on the sounds and patterns of language. “We’re saying that social interaction is a kind of gate to an interest in learning, the kind that humans are completely masters of,” she says.

Her results also suggest that the language problems in children with autism may be the result of their social deficits.

“Children with autism will have a very difficult time acquiring language if language requires the social gate to be open,” she says.

Over the years, Kuhl and Meltzoff have had largely independent research programs, but her recent focus on the social roots of language dovetails with his long-time focus on social interaction.

These days, they are trying to develop ‘face-to-face neuroscience,’ which involves simultaneously recording brain activity from two people as they interact with each other.

This approach would allow researchers to observe, for example, what happens in an infant’s brain when she hears her mother’s voice, and what happens in the mother’s brain as she sees her infant respond to her. “It’s going to be very special to do,” Meltzoff says enthusiastically, even though the effort is more directly related to Kuhl’s work than to his own.

It’s clear that this fervor for each other’s work goes both ways.

“That’s one of the great things about being married to a scientist,” Meltzoff says. “When you come home and think, ‘God, I really nailed this methodologically,’ your wife, instead of yawning, leans forward and says, ‘You did? Tell me about the method, that’s so exciting.’”

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

References:

1: Meltzoff A.N. and R.W. Borton Nature 282, 403-404 (1979) PubMed

2: Kuhl P.K. and A.N. Meltzoff Science 218, 1138-1141 (1982) PubMed

3: Meltzoff A.N. and M.K. Moore Science 198, 75-78 (1977) PubMed

4: Dawson G. et al. Child Dev. 69, 1276-1285 (1998) PubMed

5: Dawson G. et al. J. Autism Dev. Disord. 28, 479-485 (1998) PubMed

6: Toth K. et al. J. Autism Dev. Disord. 36, 993-1005 (2006) PubMed

7: Kuhl P.K. and D.M. Padden Percept. Psychophys. 32, 542-550 (1982) PubMed

8: Kuhl P.K. and J.D. Miller Science 190, 69-72 (1975) PubMed

9: Kuhl P.K. et al. Science 255, 606-608 (1992) PubMed

10: Kuhl P.K. et al. Proc. Natl. Acad. Sci. U.S.A. 100, 9096-9101 (2003) PubMed

Using genetic data in cognitive neuroscience: from growing pains to genuine insights

Adam E. Green, Marcus R. Munafò, Colin G. DeYoung, John A. Fossella, Jin Fan & Jeremy R. Gray
Nature Reviews Neuroscience 2008 Sep; 9, 710-720
http://dx.doi.org:/10.1038/nrn2461

Research that combines genetic and cognitive neuroscience data aims to elucidate the mechanisms that underlie human behaviour and experience by way of ‘intermediate phenotypes’: variations in brain function. Using neuroimaging and other methods, this approach is poised to make the transition from health-focused investigations to inquiries into cognitive, affective and social functions, including ones that do not readily lend themselves to animal models. The growing pains of this emerging field are evident, yet there are also reasons for a measured optimism.

NSF – Cognitive Neuroscience Award

The cross-disciplinary integration and exploitation of new techniques in cognitive neuroscience has generated a rapid growth in significant scientific advances. Research topics have included sensory processes (including olfaction, thirst, multi-sensory integration), higher perceptual processes (for faces, music, etc.), higher cognitive functions (e.g., decision-making, reasoning, mathematics, mental imagery, awareness), language (e.g., syntax, multi-lingualism, discourse), sleep, affect, social processes, learning, memory, attention, motor, and executive functions. Cognitive neuroscientists further clarify their findings by examining developmental and transformational aspects of such phenomena across the span of life, from infancy to late adulthood, and through time.

New frontiers in cognitive neuroscience research have emerged from investigations that integrate data from a variety of techniques. One very useful technique has been neuroimaging, including positron emission tomography (PET), functional magnetic resonance imaging (fMRI), magnetoencephalography (MEG), optical imaging (near infrared spectroscopy or NIRS), anatomical MRI, and diffusion tensor imaging (DTI). A second class of techniques includes physiological recording such as subdural and deep brain electrode recording, electroencephalography (EEG), event-related electrical potentials (ERPs), and galvanic skin responses (GSRs). In addition, stimulation methods have been employed, including transcranial magnetic stimulation (TMS), subdural and deep brain electrode stimulation, and drug stimulation. A fourth approach involves cognitive and behavioral methods, such as lesion-deficit neuropsychology and experimental psychology. Other techniques have included genetic analysis, molecular modeling, and computational modeling. The foregoing variety of methods is used with individuals in healthy, neurological, psychiatric, and cognitively-impaired conditions. The data from such varied sources can be further clarified by comparison with invasive neurophysiological recordings in non-human primates and other mammals.

Findings from cognitive neuroscience can elucidate functional brain organization, such as the operations performed by a particular brain area and the system of distributed, discrete neural areas supporting a specific cognitive, perceptual, motor, or affective operation or representation. Moreover, these findings can reveal the effect on brain organization of individual differences (including genetic variation), plasticity, and recovery of function following damage to the nervous system.

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Role of the basal ganglia

Larry H Bernstein, MD, FCAP, Curator

Leaders in Pharmaceutical Intelligence

Article ID #181: Role of the basal ganglia. Published on 9/6/2015

WordCloud Image Produced by Adam Tubman

 

Series E. 2; 5.8

 

Ann Graybiel
Investigator, McGovern Institute
Professor, Department of Brain and Cognitive Science

Ann Martin Graybiel (born 1942) is an Institute Professor and a faculty member in the Department of Brain and Cognitive Sciences at the Massachusetts Institute of Technology. She is also an investigator at the McGovern Institute for Brain Research. She is an expert on the basal ganglia and the neurophysiology of habit formation, and her work is relevant to Parkinson’s disease, Huntington’s disease, obsessive–compulsive disorder, substance abuse and other disorders that affect the basal ganglia.

Graybiel’s work is uncovering neural deficits related to these disorders, as well as the role the basal ganglia play in guiding normal behavior.

Graybiel receives the Medal of Science

For much of her career, Graybiel has focused on the physiology of the striatum, a basal ganglia structure implicated in the control of movement, cognition, habit formation, and decision-making. In the late 1970s, Graybiel discovered that while striatal neurons appeared to be an amorphous mass, they were in fact organized into chemical compartments, which she termed striosomes.[1] Later research revealed links between striosomal abnormalities and neurological disorders, such as mood dysfunction in Huntingdon’s disease[2] and depletion of dopamine in Parkinson’s disease.[3]

Graybiel’s subsequent research demonstrated how modular organization of the striatum relates to cognition, learning, and habit formation. She found that neurons project from areas in the sensory and motor cortices governing the same body part and cluster together in the striatum, forming matrisomes.[4] Graybiel went on to show that matrisomes exist for each body part and were organized into loops connecting the neocortex, a region responsible for cognition, perception and motor control, to the brain stem, a region coordinating movement.[5]Studies of rodents and primates revealed that matrisomes were crucial to habit formation.[6][7]

In later work, Graybiel demonstrated, first in the striatum and later in the infralimbic cortex, that a task-bracket or “chunking” pattern of neuronal activity emerges when a habit is formed, wherein neurons activate when a habitual task is initiated, show little activity during the task, and reactivate when the task is completed.[7][8]

In more recent work, Graybiel has focused on identifying specific pathways underlying aspects of behavior such as habit formation, learning and cognition, and decision-making, including being the first to analyze the effect of dopamine depletion on the activity of neurons affected by Parkinson’s disease during behavioral tasks.[9][10]

Beyond movement

The basal ganglia are best known for their control of movement. Parkinson’s disease, for example, results from the degeneration of neurons that release the neurotransmitter dopamine within the striatum, the largest part of the basal ganglia. It is becoming clear, however, that the basal ganglia do more than just control movement. These structures have been implicated in psychiatric diseases and addiction, and damage to the basal ganglia can affect not only movement but also mood and cognition. Graybiel believes that this broad range of functions reflects the capacity of the basal ganglia to influence how we select actions–motor actions as well as actions of thought.

Career

Graybiel majored in biology and chemistry at Harvard University, receiving her bachelor’s degree in 1964.[11] After receiving an MA in biology from Tufts University in 1966, she began doctoral study in psychology and brain science at MIT under the direction of Hans-Lukas Teuber and Walle Nauta.[11] She received her PhD in 1971 and joined the MIT faculty in 1973.[12]

In 1994, she was named the Walter A. Rosenblith Professor Neuroscience in the Department of Brain and Cognitive Science and was named an Investigator at the MIT McGovern Institute for Brain research in 2001.[12] She was named Institute Professor in 2008.[13]

In 2001, Graybiel was awarded the President’s National Medal of Science for “her pioneering contributions to the understanding of the anatomy and physiology of the brain, including the structure, chemistry, and function of the pathways subserving thought and movement.”[14] In 2012, she was awarded the Kavli Prize in Neuroscience, along with Cornelia Bargmann and Winfried Denk, “for elucidating basic neuronal mechanisms underlying perception and decision.” [15]

She is a member of the US National Academy of Sciences, the American Academy of Arts and Sciences, and the Institute of Medicine.[12]

References[edit]

Wikimedia Commons has media related to Ann Graybiel.
  1. Jump up^ Graybiel, AM; Ragsdale, Jr., CW (November 1978). “Histochemically distinct compartments in the striatum of human, monkey, and cat demonstrated by acetylthiocholinesterase staining”. Proc Natl Acad Sci U S A (1978) 75 (11): 5723–26. doi:10.1073/pnas.75.11.5723. PMID 103101. Retrieved 23 October 2014.
  2. Jump up^ Tippet, LJ; Waldvogel, HJ; Thomas, SJ; Hogg, VM; van Roon-Mom, W; Synek, BJ; Graybiel, AM; Faull, RL (Jan 2007). “Striosomes and mood dysfunction in Huntington’s disease”.Brain 130 (1): 206–21. doi:10.1093/brain/awl243. PMID 17040921. Retrieved 23 October 2014.
  3. Jump up^ Roffler-Tarlov, S; Graybiel, AM (5 Jan 1984). “Weaver mutation has differential effects on the dopamine-containing innervation of the limbic and nonlimbic striatum”. Nature 307: 62–66. doi:10.1038/307062a0. Retrieved23 October 2014.
  4. Jump up^ Flaherty, AW; Graybiel, AM (1991). “Corticostriatal transformations in the primate somatosensory system. Projections from physiologically mapped body-part representations.”. J Neurophysiol 66: 1249–63. Retrieved 23 October2014.
  5. Jump up^ Graybiel, AM; Toshihiko, A; Flaherty, AW; Kimura, M (1994). “The basal ganglia and adaptive motor control”. Science 265 (5180): 1826–31. doi:10.1126/science.8091209. JSTOR 2884650.
  6. Jump up^ Illing, R.-B.; Graybiel, AM (1994). “Pattern formation in the developing superior colliculus: Ontogeny of the periodic architecture in the intermediate layers”. Journal of Comparative Neurology 340 (3): 311–27.doi:10.1002/cne.903400303. Retrieved 23 October 2014.
  7. ^ Jump up to:a b Graybiel, AM (1998). “The Basal Gangila and Chunking of Action Repertoires”. Neurobiology of Learning and Memory 340 (3): 119–36. doi:10.1006/nlme.1998.3843. PMID 9753592. Retrieved 23 October 2014.
  8. Jump up^ Smith, KS; Graybiel, AM (July 2013). “A dual operator view of habitual behavior reflecting cortical and striatal dynamics”. Neuron 79 (2): 361–74. doi:10.1016/j.neuron.2013.05.038. Retrieved 23 October 2014.
  9. Jump up^ Hernandez, LF; Kubota, Y; Hu, D; Howe, MW; Lemaire, N; Graybiel, AM (2013). “Selective effects of dopamine depletion and L-DOPA therapy on learning-related firing dynamics of striatal neurons”. Journal of Neuroscience 33(11): 4782–95. doi:10.1523/JNEUROSCI.3746-12.2013. Retrieved 23 October 2014.
  10. Jump up^ Trafton, Anne (12 March 2013). “MIT News”. Breaking down the Parkinson’s pathway. Retrieved 23 October 2014.
  11. ^ Jump up to:a b “Neuroscience Laureate Biographies”. The Kavli Foundation. Retrieved 23 October 2014.
  12. ^ Jump up to:a b c “Ann Graybiel”. McGovern Institute for Brain Research at MIT. Retrieved 23 October 2014.
  13. Jump up^ Ann Graybiel named Institute Professor – MIT News Office. Web.mit.edu (2008-11-03). Retrieved on 2012-06-25.
  14. Jump up^ US NSF – The President’s National Medal of Science: Recipient Details. Nsf.gov. Retrieved on 2012-06-25.
  15. Jump up^ The Kavli Prize. Kavliprize.no. Retrieved on 2012-06-25.

Ann Graybiel: McGovern Institute Investigator

https://www.youtube.com/user/mittechtv

http://www.youtube.com/watch%3Fv%3D0Qi0B_jAMmw

 

https://www.youtube.com/playlist%3Flist%3DPL6D9E1BD5963BBF0C

 

Why We Do What We Do

http://www.technologyreview.com/article/522521/why-we-do-what-we-do/

Institute Professor Ann Graybiel, PhD ’71, has transformed our understanding of a “primitive” area of the brain.

Institute Professor Ann Graybiel, PhD ’71, is at the forefront of this research, having devoted much of a career now in its fifth decade to understanding a seemingly humble set of brain structures called the basal ganglia. Once known only for helping to control movement, this region deep within the brain is now believed to play fundamental roles in how we learn, process emotions, make decisions, and adopt habits. And that shift in thinking is due in no small part to the research done in Graybiel’s lab.

Her work has already yielded insights into patterns of brain activity associated with movement disorders and psychiatric diseases. Recent studies using light to control individual brain cells, for instance, show how shutting off some of this activity can control habit formation or pessimistic decision-­making. Although this technique, known as optogenetics, is still just a research tool, she is convinced that such technological advances hold therapeutic promise—and that learning about these deep patterns in the brain will also be important for everyone who wonders: What makes me do what I do?

http://www.scientificamerican.com/author/ann-m-graybiel/

 

QnAs with Ann M. Graybiel

Nicholette ZeliadtScience Writer

PNAS Oct 2013; 110(43).17166, http://dx.doi.org:/10.1073/pnas.1315012110

Ann M. Graybiel, a neuroscientist at the Massachusetts Institute of Technology and a National Academy of Sciences member, uncovers the neurobiological basis of how habits form and provides clues as to how habits can be changed.

PNAS: What is a habit?

Graybiel: A habit is something that we do routinely, that seems almost automatic, and that is fairly repetitive under certain circumstances. There are also extreme habits—such as addictions—and it’s an unresolved issue in the field whether the mechanisms underlying these are similar to those of our normal habits. Psychologists define habits as the kinds of behavior that a person does when acting as though no longer mindful of the outcome of the behavior. If we get to the point in a behavior at which it doesn’t matter whether the outcome is good or bad, then the behavior is almost automatic, not outcome-determined. We are using this outcome-sensitivity index to try to help us “define” a habit in our experiments.

 

PNAS: Many of your studies have involved recording the electrical activity in the striatum (a region of the basal ganglia) in rodents as they learn to navigate a maze to reach a reward and eventually develop a habit. What have you learned from these experiments?

Graybiel: We recorded in the part of the striatum that is active during motor behaviors and found that as animals learn to run mazes habitually, the neurons in this part of the striatum at first are active pretty much all during the runs; but then, as the animals become more automatic, the striatal neurons are mainly active at the beginning and end of the maze runs. It’s as though that entire habitual behavior becomes packaged in the neural representation, as though these beginning and end signals form a bracketing code for the learned behavior. And that reminded me of a very famous analogy that the psychologist George Miller made years ago. He said that it’s hard for us to remember long sequences of letters or numbers—for example, a really long phone number—and so what we do is “chunk” all those numbers together, and then all we have to do is remember the package. We think that the task-bracketing pattern we see might be a sign that once the behavior becomes habitual, it becomes chunked by the sensorimotor part of the striatum.

When we then recorded neural activity in the part of the striatum that former researchers had found to function in relation to being mindful of outcome, we didn’t find that bracketing pattern. Instead, what Katy Thorn in the laboratory found was that the strongest activity occurred when the animals had to make a decision about which way to turn in the maze. So we gradually built up the idea that there are different striatum-based neural circuits; some of them take care of one control feature, like forming the chunking pattern, at the same time that another circuit is encoding the deliberative part. Most interesting, these functional assignments actually have signatures in the spike patterns of the neurons. We hope that we are beginning to be able to link global population activation patterns to behaviors, and that this could turn out to be quite important when we face the issue of how to modify habits.

PNAS :In a 2012 PNAS paper, you disrupted the activity in one of these circuits. What did you find?

Graybiel: Kyle Smith and I recorded in two regions of the brain that are known to be habit-related: one was in the striatum, in its sensorimotor part where we had found that task-bracketing pattern, and the other one was in the prefrontal cortex. We found the same task-bracketing pattern in the sensorimotor striatum that we’ve now found over and over. However, in the prefrontal cortex we found that a bracketing pattern only formed very late in the learning process, when the behavioral habit became engrained. This made us think that the final settling of the bracketing pattern in the cortex might be necessary for the behavior to get set as a habit. So we tried to inhibit that small cortical zone to see whether the animals still would have a habit. We found they didn’t. Then, when we allowed the animal to develop a new habit, and we again inhibited that piece of cortex, the animal reverted to the original habit—it wasn’t gone after all! What the paper shows is that even though a behavior seems to be automatic, there is a bit of brain—in the case of our paper, it’s in the medial prefrontal cortex—that is monitoring things online. So, in fact, a behavior that seems automatic isn’t really automatic, because there’s a piece of brain that cannot only monitor the habit but also can veto the performance of the habit.

PNAS: How does understanding the neurobiology of the habit system advance our understanding of neurologic and psychiatric disorders?

Graybiel: In a number of neuropsychiatric conditions—for example, obsessive-compulsive disorder, Tourette syndrome, many forms of autism, schizophrenia—patients can develop repetitive behaviors, and these stereotyped behaviors are classic features of these disorders. These are behaviors that are repeated, semiautomatically, and they are under very poor volitional, deliberative, attentional control. These repetitive, overly focused behaviors may not rely on exactly the same circuits as “normal” habits, but the fundamental operation of the involved circuits may be similar. This is something we are intensely interested in.

 

2012 Neuroscience Laureate Biographies – CI Bargmann

Cornelia Isabella Bargmann was born in 1961 in Virginia and raised in Athens, Georgia, where she attended the University of Georgia. She then went north to study cancer-signalling genes and cloned the oncogene HER2, a key factor in breast cancer, in the laboratory of Robert Weinberg at the Whitehead Institute, Massachusetts Institute of Technology.

After receiving her Ph.D. in 1987, Professor Bargmann transferred to the laboratory of H. Robert Horvitz, at MIT, where she became acquainted with the tiny worm C. elegans. Professor Horvitz had already made major contributions to understanding neural development using C. elegans as a simple model organism. For this he shared the 2002 Nobel Prize in Physiology or Medicine with Sydney Brenner and John Sulston “for their discoveries concerning genetic regulation of organ development and programmed cell death”. Professor Bargmann then embarked upon what was to become a lifetime mission to define how genes and the environment influence behavior by dissecting the neural circuitry of C. elegans and the genes, receptors and signaling molecules involved in such behaviour as feeding and responses to odours.

In 1995 California beckoned, and Cornelia Bargmann took up an appointment as assistant professor at the University of California, San Francisco. In 1998, she was promoted to Professor, and in 1999 was named vice chair of the Department of Anatomy. In 2004 she returned to the east coast to take up the position of head of the Lulu and Anthony Wang Laboratory of Neural Circuits and Behaviour at Rockefeller University, New York, where she is now Torsten N. Weasel Professor and a Howard Hughes Medical Investigator. Rockefeller University president Paul Nurse welcomed her arrival saying, “Cori Bargmann typifies the Rockefeller scientist: she is bold and highly original in her thinking and her approach to studying the brain and other components of the nervous system”.

Professor Bargmann has received numerous awards, including the Charles Judson Herrick Award for comparative neurology in 2000, the Dargut and Milena Kemali International Prize for Research in the Field of Basic and Clinical Neurosciences in 2004, and the Richard Lounsbery Award from the US and French National Academies of Sciences in 2009. She is a member of the National Academy of Sciences and the American Academy of Arts and Sciences, and the European Molecular Biology Organisation.

Professor Bargmann has trained many students and postdocs in cutting-edge techniques and encouraged them to share her enthusiasm for research. She is as renowned for the quality of her presentations and breadth of knowledge as for her research.

 

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Proteins that control neurotransmitter release

Author & Curator: Larry H. Bernstein, MD, FCAP

Richard H. Scheller, PhD

The sec6/8 Complex Is Located at Neurite Outgrowth and Axonal Synapse-Assembly Domains

Christopher D. Hazuka, Davide L. Foletti, Shu-Chan Hsu, Yun Kee, F. Woodward Hopf, and Richard H. Scheller
Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305-5428

The Journal of Neuroscience, February 15, 1999, 19(4):1324–1334   http://www.jneurosci.org/content/19/4/1324.full.pdf

The molecules that specify domains on the neuronal plasma membrane for the delivery and accumulation of vesicles during neurite outgrowth and synapse formation are unknown. We investigated the role of the sec6/8 complex, a set of proteins that specifies vesicle targeting sites in yeast and epithelial cells, in neuronal membrane trafficking. This complex was found in layers of developing rat brain undergoing synaptogenesis. In cultured hippocampal neurons, the sec6/8 complex was present in regions of ongoing membrane addition: the tips of growing neurites, filopodia, and growth cones. In young axons, the sec6/8 complex was also confined to periodic domains of the plasma membrane. The distribution of synaptotagmin, synapsin1, sec6, and FM1–43 labeling in cultured neurons suggested that the plasma membrane localization of the sec6/8 complex preceded the arrival of synaptic markers and was downregulated in mature synapses. We propose that the sec6/8 complex specifies sites for targeting vesicles at domains of neurite outgrowth and potential active zones during synaptogenesis. Key words: synaptogenesis; neurotransmission; secretion; exocytosis; synaptic vesicle; vesicle targeting

Targeting of vesicles to synaptic sites during development may use similar mechanisms as those involved in vesicle fusion underlying membrane outgrowth. Before contact with a postsynaptic target, axons possess mobile vesicle clusters bearing synaptotagmin, which fuse with the plasma membrane after stimulation (Matteoli et al., 1992; Kraszewski et al., 1995; Dai and Peng, 1996). Thus, growing axons must contain the molecular machinery required for constitutive exocytosis, endocytosis, and activitydependent vesicle release. However, it is unclear how vesicles become clustered at synapses. Although vesicle fusion in axons might occur anywhere along the plasma membrane, there must be membrane targets that signal the clustering of vesicles for synapse formation. Furthermore, it is unclear how sites of vesicle exocytosis are modified as the neuron forms stable contacts with postsynaptic partners.

Identification of a Novel Rab11/25 Binding Domain Present in Eferin and Rip Proteins

Rytis Prekeris*, Jason M. Davies*, and Richard H. Scheller#
JBC Papers in Press. Published on July 31, 2001 as Manuscript M106133200
http://www.jbc.org/content/early/2001/07/31/jbc.M106133200.full.pdf

Rab11, a low molecular weight GTP binding protein, has been shown to play a key role in a variety of cellular processes, including endosomal recycling, phagocytosis, and transport of secretory proteins from the TGN. In this study we describe a novel Rab11 effector, EF hands containing Rab11 interacting protein (eferin). In addition, we identify a 20 amino acid domain that is present at the C-terminus of eferin and other Rab11/25 interacting proteins, such as Rip11 and nRip11. Using biochemical techniques we demonstrate that this domain is necessary and sufficient for Rab11 binding in vitro and that it is required for localization of Rab11 effector proteins in vivo. The data suggest that various Rab effectors compete with each other for the binding to Rab11/25 possibly accounting for the diversity of Rab11 functions.

Members of the Rab/Ypt GTPase family have emerged as important regulators of vesicular trafficking (1). Rab proteins have been proposed to mediate a variety of functions, including vesicle translocation and docking at a specific fusion sites. Like all small GTPases, Rabs cycle between active (GTP bound) and inactive (GDP bound) conformations (2). In the GTP bound state, Rab proteins can bind a variety of downstream effector proteins, while GTP hydrolysis leads to a conformational change in the “switch” region that renders the Rab GTPase unrecognizable to its effector proteins (3,4). A key question in understanding the interactions between Rabs and their effectors concerns the mechanisms by which Rab GTPases specifically bind a diverse spectrum of effectors and how this is regulated by the common structural motif used as a GTP switch. Biochemical and genetic studies have identified several hypervariable regions that might be involved in determining Rab specificity, including N- and C-termini, as well as α3/β5 by guest on September 6, 2015 http://www.jbc.org/ Downloaded from loop (5,6). Indeed, the recently reported structure of Rab3a bound to a putative effector, rabphillin-3a, revealed that Rab3a/rabphillin-3a complex interacts through two main regions (7). The first consists of conformationally sensitive “switch” regions of Rab3a bound to the a1 helix and the C-terminal part of rabphillin-3a. The second involves the SGAWFF domain of rabphillin-3a which fits into a pocket formed by the three hypervariable complementary determining regions (CDRs) of Rab3a, corresponding to the N- and C-termini and α3/β5 loop. Thus, it appears that the hypervariable RabCDR are involved in determining the specificity of effector binding, while the conserved “switch” regions impart GTP dependency and binding. It remains to be determined, however, whether this paradigm also applies to other Rab/effector complexes. Rab11a, -11b, and -25 are closely related members of Rab GTPase family that have been implicated in regulating a variety of different post-Golgi trafficking pathways, such as protein recycling (8), phagocytosis (9), insulin-stimulated Glut4 insertion in the plasma membrane (10), and membrane trafficking from early endosomes to the transGolgi network (11). During the last few years several Rab11/25 interacting proteins have been identified, including Rab11BP/Rabphilin-11, Rip11, nRip11, and myosin Vb (12- 15). However, the mechanisms of their function, as well as molecular aspects of their interactions with Rab11, remain to be fully understood. In the present study, we report the identification of EF-hands containing Rab11/25 interacting protein (eferin). Furthermore, we characterized a Rab binding domain (RBD11) which is present at the Cterminus of eferin as well as other Rab11/25 binding proteins, such as Rip11 and nRip11. Using biochemical techniques we demonstrated that RBD11 is the region which encodes the specificity for Rab11/25, but is distinct from the region interacting with Rab “switch” domain, since its interactions with the Rab11/25 are not GTP-dependent.

The functional significance of the differences in Rip and eferin interactions with Rab11/25 remains to be determined. One possibility is that additional cellular factors can regulate the affinity of Rab11/25 binding to its effectors. Indeed, the recombinant full length Rip11 binds poorly to Rab11a in pull down and yeast-two hybrid assays as compared to full length endogenous Rip11 from cellular TX-100 extracts (data not shown). Furthermore, it has been previously shown that Rip11 can also interact with γSNAP and cytoskeleton (13,24). Thus, the interactions of Rips and eferin with different factors could be used as a means of differentially regulating Rab11/25 binding. Alternatively, the Rab11/25 binding motif in eferin and Rip11 might be conformationlly hidden and require activation before binding to Rab11/25. We have previously demonstrated that phosphorylation of Rip11 plays an important role in its trafficking (13). Thus, differential phosphorylation on Rab11/25 binding motifs could also play a role in regulating the binding of Rip11 and eferin to Rab GTPases. Despite to recent progress in understanding the roles of Rabs and their effectors in regulating membrane trafficking, we are only beginning to unravel the structural determinants of their function. Identification and characterization of the Rab11/25 binding regions in Rip and Eferin proteins will be of a crucial importance in understanding the molecular mechanisms involved in differential regulation of the variety of Rab11-dependent trafficking pathways.

J. Immunol. Methods
J Immunol Methods 2008 Mar 14;332(1-2):41-52. Epub 2008 Jan 14.
Genentech Inc., 1DNA Way, South San Francisco, California, 94080, United States. jagath@gene.com
Cysteines with reactive thiol groups are attractive tools for site-specific labeling of proteins. Engineering a reactive cysteine residue into proteins with multiple disulfide bonds is often a challenging task as it may interfere with structural and functional properties of the protein. Here we developed a phage display-based biochemical assay, PHESELECTOR (Phage ELISA for Selection of Reactive Thiols) to rapidly screen reactive thiol groups on antibody fragments without interfering with their antigen binding, using trastuzumab-Fab (hu4D5Fab) as a model system

Antibody-drug conjugates enhance the antitumor effects of antibodies and reduce adverse systemic effects of potent cytotoxic drugs. However, conventional drug conjugation strategies yield heterogenous conjugates with relatively narrow therapeutic index (maximum tolerated dose/curative dose). Using leads from our previously described phage display-based method to predict suitable conjugation sites, we engineered cysteine substitutions at positions on light and heavy chains that provide reactive thiol groups and do not perturb immunoglobulin folding and assembly, or alter antigen binding.

Neuron
Neuron 2008 Nov;60(3):400-1

Antibody drug conjugates (ADCs) combine the ideal properties of both antibodies and cytotoxic drugs by targeting potent drugs to the antigen-expressing tumor cells, thereby enhancing their antitumor activity. Successful ADC development for a given target antigen depends on optimization of antibody selection, linker stability, cytotoxic drug potency, and mode of linker-drug conjugation to the antibody. Here, we systematically examined the in vitro potency as well as in vivo preclinical efficacy and safety profiles of a heterogeneous preparation of conventional trastuzumab-mcc-DM1 (TMAb-mcc-DM1) ADC with that of a homogeneous engineered thio-trastuzumab-mpeo-DM1 (thioTMAb-mpeo-DM1) conjugate.

Sensory and signaling pathways are exquisitely organized in primary cilia. Bardet-Biedl syndrome (BBS) patients have compromised cilia and signaling. BBS proteins form the BBSome, which binds Rabin8, a guanine nucleotide exchange factor (GEF) activating the Rab8 GTPase, required for ciliary assembly.

The reactive thiol in cysteine is used for coupling maleimide linkers in the generation of antibody conjugates. To assess the impact of the conjugation site, we engineered cysteines into a therapeutic HER2/neu antibody at three sites differing in solvent accessibility and local charge. The highly solvent-accessible site rapidly lost conjugated thiol-reactive linkers in plasma owing to maleimide exchange with reactive thiols in albumin, free cysteine or glutathione.

The intracellular pathogenic bacterium Salmonella enterica serovar typhimurium (Salmonella) relies on acidification of the Salmonella-containing vacuole (SCV) for survival inside host cells. The transport and fusion of membrane-bound compartments in a cell is regulated by small GTPases, including Rac and members of the Rab GTPase family, and their effector proteins. However, the role of these components in survival of intracellular pathogens is not completely understood.

Nat. Med.
Nat Med 2013 Oct;19(10):1232-5
Genentech Research and Early Development, 1 DNA Way, San Francisco, California, USA.
MAbs
MAbs 2014 Jan-Feb;6(1):95-107
Multi-transmembrane proteins are especially difficult targets for antibody generation largely due to the challenge of producing a protein that maintains its native conformation in the absence of a stabilizing membrane. Here, we describe an immunization strategy that successfully resulted in the identification of monoclonal antibodies that bind specifically to extracellular epitopes of a 12 transmembrane protein, multi-drug resistant protein 4 (MRP4). These monoclonal antibodies were developed following hydrodynamic tail vein immunization with a cytomegalovirus (CMV) promoter-based plasmid expressing MRP4 cDNA and were characterized by flow cytometry.

Antibody-drug conjugates (ADCs) have a significant impact toward the treatment of cancer, as evidenced by the clinical activity of the recently approved ADCs, brentuximab vedotin for Hodgkin lymphoma and ado-trastuzumab emtansine (trastuzumab-MCC-DM1) for metastatic HER2+ breast cancer. DM1 is an analog of the natural product maytansine, a microtubule inhibitor that by itself has limited clinical activity and high systemic toxicity. However, by conjugation of DM1 to trastuzumab, the safety was improved and clinical activity was demonstrated.

Richard H Scheller, PhD

Published on 16 Sep 2014

The Keck School of Medicine of USC is the first medical school in the nation to host the Lasker Lectures, featuring recipients of the prestigious 2013 Albert Lasker Basic Medical Research Award. In this installment, Richard H. Scheller, PhD, executive vice president of Genentech research and early development, discusses breakthoughs in drug development that are turning the tide in the war against cancer.

https://www.youtube.com/watch?v=Fx54EVJMcxM

Kavli Prize 2015

Xenon Pharmaceuticals Appoints Dr. Richard H. Scheller to Its Board of Directors

Biopharmaceutical company Xenon Pharmaceuticals (NasdaqGM:XENE) reported on Monday the addition of Richard H. Scheller, PhD to its board of directors.

Most recently, Dr Scheller has served as chief science officer and head of Therapeutics at 23andMe.

Previously Dr Scheller was the executive vice president at Genentech Research and Early Development & a member of the Roche Corporate Executive Committee; chief scientific officer, executive vice president of Research and senior vice president of Research at Genentech; as well as a professor of Molecular and Cellular Physiology and of Biological Sciences at Stanford University Medical Center and an investigator of the Howard Hughes Medical Institute.

Dr Scheller is currently an adjunct professor in the Department of Biochemistry and Biophysics, School of Medicine at the University of California, San Francisco.

He has been a Director at Xenon Pharmaceuticals Inc. since March 16, 2015 and Medrio, Inc. since November 2012. He serves as a Member of the Medical and Scientific Review Board of Evotec (US), Inc. (Renovis Inc.). In 2014, he was named a trustee of Caltech. He served as a Member of Scientific Advisory Board of Intra-Cellular Therapies, Inc. and Rinat Neuroscience Corporation.

He served on numerous advisory boards including the National Advisory Mental Health Council of the National Institutes of Health. Dr. Scheller served as chairman of the Genentech Foundation’s board of directors. He is a globally recognized leader in biomedical research.

He has published over 200 papers in scientific journals, and worked in cell biology. He has received several additional awards for his work elucidating the molecular mechanisms governing neurotransmitter release, including the 2013 Albert Lasker Basic Medical Research Award, the 2014 California Institute of Technology’s Caltech Distinguished Alumni Award, the 2010 Kavli Prize in Neuroscience, and the 1997 U.S. National Academy of Sciences Award in Molecular Biology. He is a Fellow of the American Academy of Arts and Sciences. Dr. Scheller holds a Doctorate in Chemistry from the California Institute of Technology in 1980, where he was also a Postdoctoral Fellow, Division of Biology. He was also a Postdoctoral Fellow at Columbia University, College of Physicians & Surgeons. He has Bachelor’s Degree in Biochemistry in 1975 at the University of Wisconsin, Madison.

Education: 1971-1975 University of Wisconsin-Madison B.S. – Biochemistry with Honors 1975-1980 California Institute of Technology Ph.D. – Chemistry – Advisor: Eric H. Davidson 1980-1981 California Institute of Technology Postdoctoral Fellow-Division of Biology Advisor: Eric H. Davidson 1981-1982 Columbia University-College of Physicians & Surgeons Postdoctoral Fellow-Molecular Neurobiology Advisors: Richard Axel and Eric R. Kandel Industry Positions: 2001-2003 Senior Vice President – Research Genentech, Inc. 2003-2009 Executive Vice President – Research Genentech, Inc. 2008-2009 Chief Scientific Officer and Executive Vice President – Research Genentech, Inc. 2009- Executive Vice President – Genentech Research and Early Development (gRED) and Member of the Enlarged Roche Corporate Executive Committee Academic Appointments: 1982-1987 Assistant Professor, Department of Biological Sciences, Stanford University 1987-1990 Associate Professor, Department of Biological Sciences, Stanford University 1990-1993 Associate Professor, Department of Molecular and Cellular Physiology, Stanford University Associate Professor (by courtesy), Department of Biological Sciences, Stanford University

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