Brain Disorder: Autism Spectrum Disorder

Alumnus gives MIT $4.5 million to study effects of cannabis on the brain

by MIT School of Science |

The following news is adapted from a press release issued in conjunction with Harvard Medical School.

Charles R. Broderick, an alumnus of MIT and Harvard University, has made gifts to both alma maters to support fundamental research into the effects of cannabis on the brain and behavior.

The gifts, totaling $9 million, represent the largest donation to date to support independent research on the science of cannabinoids. The donation will allow experts in the fields of neuroscience and biomedicine at MIT and Harvard Medical School to conduct research that may ultimately help unravel the biology of cannabinoids, illuminate their effects on the human brain, catalyze treatments, and inform evidence-based clinical guidelines, societal policies, and regulation of cannabis.

Lagging behind legislation

With the increasing use of cannabis both for medicinal and recreational purposes, there is a growing concern about critical gaps in knowledge.

In 2017, the National Academies of Sciences, Engineering, and Medicine issued a report calling upon philanthropic organizations, private companies, public agencies and others to develop a “comprehensive evidence base” on the short- and long-term health effects — both beneficial and harmful — of cannabis use.

“Our desire is to fill the research void that currently exists in the science of cannabis,” says Broderick, who was an early investor in Canada’s medical marijuana market.

Broderick is the founder of Uji Capital LLC, a family office focused on quantitative opportunities in global equity capital markets. Identifying the growth of the Canadian legal cannabis market as a strategic investment opportunity, Broderick took equity positions in Tweed Marijuana Inc. and Aphria Inc., which have since grown into two of North America’s most successful cannabis companies. Subsequently, Broderick made a private investment in and served as a board member for Tokyo Smoke, a cannabis brand portfolio, which merged in 2017 to create Hiku Brands, where he served as chairman. Hiku Brands was acquired by Canopy Growth Corp. in 2018.

Through the Broderick gifts to Harvard Medical School and MIT’s School of Science through the Picower Institute for Learning and Memory and the McGovern Institute for Brain Research, the Broderick funds will support independent studies of the neurobiology of cannabis; its effects on brain development, various organ systems and overall health, including treatment and therapeutic contexts; and cognitive, behavioral and social ramifications.

“I want to destigmatize the conversation around cannabis — and, in part, that means providing facts to the medical community, as well as the general public,” says Broderick, who argues that independent research needs to form the basis for policy discussions, regardless of whether it is good for business. “Then we’re all working from the same information. We need to replace rhetoric with research.”

MIT: Focused on brain health and function

The gift to MIT from Broderick will provide $4.5 million over three years to support independent research for four scientists at the McGovern and Picower institutes.

Two of these researchers — John Gabrieli, the Grover Hermann Professor of Health Sciences and Technology, a professor of brain and cognitive sciences, and a member of MIT’s McGovern Institute for Brain Research; and Myriam Heiman, the Latham Family Associate Professor of Neuroscience at the Picower Institute — will separately explore the relationship between cannabis and schizophrenia.

Gabrieli, who directs the Martinos Imaging Center at MIT, will monitor any potential therapeutic value of cannabis for adults with schizophrenia using fMRI scans and behavioral studies.

“The ultimate goal is to improve brain health and wellbeing,” says Gabrieli. “And we have to make informed decisions on the way to this goal, wherever the science leads us. We need more data.”

Heiman, who is a molecular neuroscientist, will study how chronic exposure to phytocannabinoid molecules THC and CBD may alter the developmental molecular trajectories of cell types implicated in schizophrenia.

“Our lab’s research may provide insight into why several emerging lines of evidence suggest that adolescent cannabis use can be associated with adverse outcomes not seen in adults,” says Heiman.

In addition to these studies, Gabrieli also hopes to investigate whether cannabis can have therapeutic value for autism spectrum disorders, and Heiman plans to look at whether cannabis can have therapeutic value for Huntington’s disease.

MIT Institute Professor Ann Graybiel has proposed to study the cannabinoid 1 (CB1) receptor, which mediates many of the effects of cannabinoids. Her team recently found that CB1 receptors are tightly linked to dopamine — a neurotransmitter that affects both mood and motivation. Graybiel, who is also a member of the McGovern Institute, will examine how CB1 receptors in the striatum, a deep brain structure implicated in learning and habit formation, may influence dopamine release in the brain. These findings will be important for understanding the effects of cannabis on casual users, as well as its relationship to addictive states and neuropsychiatric disorders.

Earl Miller, Picower Professor of Neuroscience at the Picower Institute, will study effects of cannabinoids on both attention and working memory. His lab has recently formulated a model of working memory and unlocked how anesthetics reduce consciousness, showing in both cases a key role in the brain’s frontal cortex for brain rhythms, or the synchronous firing of neurons. He will observe how these rhythms may be affected by cannabis use — findings that may be able to shed light on tasks like driving where maintenance of attention is especially crucial.

Harvard Medical School: Mobilizing basic scientists and clinicians to solve an acute biomedical challenge 

The Broderick gift provides $4.5 million to establish the Charles R. Broderick Phytocannabinoid Research Initiative at Harvard Medical School, funding basic, translational and clinical research across the HMS community to generate fundamental insights about the effects of cannabinoids on brain function, various organ systems, and overall health.

The research initiative will span basic science and clinical disciplines, ranging from neurobiology and immunology to psychiatry and neurology, taking advantage of the combined expertise of some 30 basic scientists and clinicians across the school and its affiliated hospitals.

The epicenter of these research efforts will be the Department of Neurobiology under the leadership of Bruce Bean and Wade Regehr.

“I am excited by Bob’s commitment to cannabinoid science,” says Regehr, professor of neurobiology in the Blavatnik Institute at Harvard Medical School. “The research efforts enabled by Bob’s vision set the stage for unraveling some of the most confounding mysteries of cannabinoids and their effects on the brain and various organ systems.”

Bean, Regehr, and fellow neurobiologists Rachel Wilson and Bernardo Sabatini, for example, focus on understanding the basic biology of the cannabinoid system, which includes hundreds of plant and synthetic compounds as well as naturally occurring cannabinoids made in the brain.

Cannabinoid compounds activate a variety of brain receptors, and the downstream biological effects of this activation are astoundingly complex, varying by age and sex, and complicated by a person’s physiologic condition and overall health. This complexity and high degree of variability in individual biology has hampered scientific understanding of the positive and negative effects of cannabis on the human body. Bean, Regehr, and colleagues have already made critical insights showing how cannabinoids influence cell-to-cell communication in the brain.

“Even though cannabis products are now widely available, and some used clinically, we still understand remarkably little about how they influence brain function and neuronal circuits in the brain,” says Bean, the Robert Winthrop Professor of Neurobiology in the Blavatnik Institute at HMS. “This gift will allow us to conduct critical research into the neurobiology of cannabinoids, which may ultimately inform new approaches for the treatment of pain, epilepsy, sleep and mood disorders, and more.”

To propel research findings from lab to clinic, basic scientists from HMS will partner with clinicians from Harvard-affiliated hospitals, bringing together clinicians and scientists from disciplines including cardiology, vascular medicine, neurology, and immunology in an effort to glean a deeper and more nuanced understanding of cannabinoids’ effects on various organ systems and the body as a whole, rather than just on isolated organs.

For example, Bean and colleague Gary Yellen, who are studying the mechanisms of action of antiepileptic drugs, have become interested in the effects of cannabinoids on epilepsy, an interest they share with Elizabeth Thiele, director of the pediatric epilepsy program at Massachusetts General Hospital. Thiele is a pioneer in the use of cannabidiol for the treatment of drug-resistant forms of epilepsy. Despite proven clinical efficacy and recent FDA approval for rare childhood epilepsies, researchers still do not know exactly how cannabidiol quiets the misfiring brain cells of patients with the seizure disorder. Understanding its mechanism of action could help in developing new agents for treating other forms of epilepsy and other neurologic disorders.

Scientists engineer new CRISPR platform for DNA targeting

by The Broad Institute |

A team that includes the scientist who first harnessed the revolutionary CRISPR-Cas9 and other systems for genome editing of eukaryotic organisms, including animals and plants, has engineered another CRISPR system, called Cas12b. The new system offers improved capabilities and options when compared to CRISPR-Cas9 systems.

In a study published today in Nature Communications, Feng Zhang and colleagues at the Broad Institute of MIT and Harvard and the McGovern Institute for Brain Research at MIT, with co-author Eugene Koonin at the National Institutes of Health, demonstrate that the new enzyme can be engineered to target and precisely nick or edit the genomes of human cells. The high target specificity and small size of Cas12b from Bacillus hisashii (BhCas12b) as compared to Cas9 (SpCas9), makes this new system suitable for in vivo applications. The team is now making CRISPR-Cas12b widely available for research.

The team previously identified Cas12b (then known as C2c1) as one of three promising new CRISPR enzymes in 2015, but faced a hurdle: Because Cas12b comes from thermophilic bacteria — which live in hot environments such as geysers, hot springs, volcanoes, and deep sea hydrothermal vents — the enzyme naturally only works at temperatures higher than human body temperature.

“We searched for inspirations from nature,” Zhang said. “We wanted to create a version of Cas12b that could operate at lower temperatures, so we scanned thousands of bacterial genetic sequences, looking in bacteria that could thrive in the lower temperatures of mammalian environments.”

Through a combination of exploration of natural diversity and rational engineering of promising candidate enzymes, they generated a version of Cas12b capable of efficiently editing genomes in primary human T cells, an important initial step for therapeutics that target or leverage the immune system.

“This is further evidence that there are many useful CRISPR systems waiting to be discovered,” said Jonathan Strecker, a postdoctoral fellow in the Zhang Lab, a Human Frontiers Science program fellow, and the study’s first author.

The field is moving quickly: Since the Cas12b family of enzymes was first described in 2015 and demonstrated to be RNA-guided DNA endonucleases, several groups have have been exploring this family of enzymes. In 2017 a team from Jennifer Doudna’s lab at UC Berkeley reported that Cas12b from Alicyclobacillus acidoterrestris can mediate non-specific collateral cleavage of DNA in vitro. More recently, a team from the Chinese Academy of Sciences in Beijing reported that another Cas12b, from Alicyclobacillus acidiphilus, was used to edit mammalian cells.

The Broad Institute and MIT are sharing the Cas12b system widely. As with earlier genome editing tools, these groups will make the technology freely available for academic research via the Zhang lab’s page on the plasmid-sharing website Addgene, through which the Zhang lab has already shared reagents more than 52,000 times with researchers at nearly 2,400 labs in 62 countries to accelerate research.

Zhang is a core institute member of the Broad Institute of MIT and Harvard, as well as an investigator at the McGovern Institute for Brain Research at MIT, the James and Patricia Poitras Professor of Neuroscience at MIT, and an associate professor at MIT, with joint appointments in the departments of Brain and Cognitive Sciences and Biological Engineering.

Support for this study was provided by the Poitras Center for Psychiatric Disorders Research, the Hock E. Tan and K. Lisa Yang Center for Autism Research, the National Human Genome Research Institute, the National Institute of Mental Health, the National Heart, Lung, and Blood Institute, and other sources. Feng Zhang is an Investigator with the Howard Hughes Medical Institute.

References:

Strecker J, et al. Engineering of CRISPR-Cas12b for human genome editing. Nature Communications. Online January 22, 2019. DOI: 10.1038/s41467-018-08224-4.

Rebecca Saxe

Mind Reading

Rebecca Saxe studies human social cognition, using a combination of behavioral testing and brain imaging technologies. She is best known for her work on brain regions specialized for abstract concepts such as “theory of mind” tasks that involve understanding the mental states of other people. While it was previously known that humans and animals have brain regions that are specialized for basic functions such as visual recognition and motor control, this was the first example of a brain region specialized for constructing abstract thoughts. Saxe continues to study this region and has found that it is involved when we make moral judgements about other people. She is also exploring its possible role in autism, where the ability to understand other people’s beliefs and motivations is often impaired. A major area of her work involves looking at how and when these specialized brain regions form in children.

Virtual Tour of Saxe Lab

Feng Zhang

Molecular Engineering

Feng Zhang develops tools that are broadly applicable to studying genetic diseases and developing diagnostics and therapeutics. These molecular engineering tools are useful for understanding nervous system function and diseases with genetic links such as autism spectrum disorder. Zhang pioneered the development of CRISPR-cas9 as a genome editing tool and its use in eukaryotic cells –including human cells– from a natural CRISPR immune system found in prokaryotes. He has substantially expanded this toolbox through discovery and harnessing of new CRISPRs. These new tools not only include DNA-targeting CRISPR systems, but also CRISPR systems that can target RNA. Through rational engineering he is improving specificity of CRISPR systems, and is expanding their window of opportunity. He has now engineered systems that can cleave within a specific, targeted nucleic acid sequence, and others that are designed to edit specific bases on the DNA or RNA target, and yet others that make epigenetic modifications. These tools, which he has made widely available, are accelerating research, particularly biomedical research, around the world.

Guoping Feng

Listening to Synapses

Guoping Feng studies the development and function of synapses – the interconnections between neurons – and their disruption in brain disorders. He uses molecular genetics combined with behavioral and electrophysiological methods to study the molecular components of the synapse and to understand how disruptions in these components can lead to neurodevelopmental and psychiatric disease. By understanding the molecular, cellular, and circuit changes underlying brain disorders, the Feng lab hopes one day to help develop new and effective treatments for brain disorders.

Virtual Tour of Feng Lab

Nancy Kanwisher

Elements of Perception

Nancy Kanwisher’s group studies the functional organization of the human brain as a window into the architecture of the mind. Over the last 20 years her lab has played a central role in the identification of several dozen regions of the cortex in humans that are engaged in particular components of perception and cognition. Many of these regions are very specifically engaged in a single mental function, such as perceiving faces, places, bodies, or words, or understanding the meanings of sentences or the mental states of others. Other regions bring together unexpected combinations of functions that may ultimately provide the strongest constraints on the computations conducted in those regions. Each of these regions is present in approximately the same location in virtually every normal person. 

Virtual Tour of Kanwisher Lab

Ann Graybiel

Probing the Deep Brain

Ann Graybiel studies the basal ganglia, forebrain structures that are profoundly important for normal brain function. Dysfunction in these regions is implicated in neurologic and neuropsychiatric disorders ranging from Parkinson’s disease and Huntington’s disease to obsessive-compulsive disorder, anxiety and depression, and addiction. Graybiel’s laboratory is uncovering circuits underlying both the neural deficits related to these disorders, as well as the role that the basal ganglia play in guiding normal learning, motivation, and behavior.

John Gabrieli

Images of Mind

John Gabrieli’s goal is to understand the organization of memory, thought, and emotion in the human brain, and to use that understanding to help people live happier, more productive lives. By combining brain imaging with behavioral tests, he studies the neural basis of these abilities in human subjects. One important research theme is to understand the neural basis of learning in children and to identify ways that neuroscience could help to improve learning in the classroom. In collaboration with clinical colleagues, Gabrieli also seeks to use brain imaging to better understand, diagnose, and select treatments for neurological and psychiatric diseases.

What is CRISPR?

by The Brain |

CRISPR (which stands for Clustered Regularly Interspaced Short Palindromic Repeats) is not actually a single entity, but shorthand for a set of bacterial systems that are found with a hallmarked arrangement in the bacterial genome.

When CRISPR is mentioned, most people are likely thinking of CRISPR-Cas9, now widely known for its capacity to be re-deployed to target sequences of interest in eukaryotic cells, including human cells. Cas9 can be programmed to target specific stretches of DNA, but other enzymes have since been discovered that are able to edit DNA, including Cpf1 and Cas12b. Other CRISPR enzymes, Cas13 family members, can be programmed to target RNA and even edit and change its sequence.

The common theme that makes CRISPR enzymes so powerful, is that scientists can supply them with a guide RNA for a chosen sequence. Since the guide RNA can pair very specifically with DNA, or for Cas13 family members, RNA, researchers can basically provide a given CRISPR enzyme with a way of homing in on any sequence of interest. Once a CRISPR protein finds its target, it can be used to edit that sequence, perhaps removing a disease-associated mutation.

In addition, CRISPR proteins have been engineered to modulate gene expression and even signal the presence of particular sequences, as in the case of the Cas13-based diagnostic, SHERLOCK.

Do you have a question for The Brain? Ask it here.

Charting the cerebellum

Anne Trafton |

Small and tucked away under the cerebral hemispheres toward the back of the brain, the human cerebellum is still immediately obvious due to its distinct structure. From Galen’s second century anatomical description to Cajal’s systematic analysis of its projections, the cerebellum has long drawn the eyes of researchers studying the brain.  Two parallel studies from MIT’s McGovern institute have recently converged to support an unexpectedly complex level of non-motor cerebellar organization, that would not have been predicted from known motor representation regions.

Historically the cerebellum has primarily been considered to impact motor control and coordination. Think of this view as the cerebellum being the chain on a bicycle, registering what is happening up front in the cortex, and relaying the information so that the back wheel moves at a coordinated pace. This simple view has been questioned as cerebellar circuits have been traced to the basal ganglia and to neocortical regions via the thalamus. This new view suggests the cerebellum is a hub in a complex network, with potentially higher and non-motor functions including cognition and reward-based learning.

A collaboration between the labs of John Gabrieli, Investigator at the McGovern Institute for Brain Research and Jeremy Schmahmann, of the Ataxia Unit at Massachusetts General Hospital and Harvard Medical School, has now used functional brain imaging to give new insight into the cerebellar organization of non-motor roles, including working memory, language, and, social and emotional processing. In a complementary paper, a collaboration between Sheeba Anteraper of MIT’s Martinos Imaging Center and Gagan Joshi of the Alan and Lorraine Bressler Clinical and Research Program at Massachusetts General Hospital, has found changes in connectivity that occur in the cerebellum in autism spectrum disorder (ASD).

A more complex map of the cerebellum

Published in NeuroImage, and featured on the cover, the first study was led by author Xavier Guell, a postdoc in the Gabrieli and Schmahmann labs. The authors used fMRI data from the Human Connectome Project to examine activity in different regions of the cerebellum during specific tasks and at rest. The tasks used extended beyond motor activity to functions recently linked to the cerebellum, including working memory, language, and social and emotional processing. As expected, the authors saw that two regions assigned by other methods to motor activity were clearly modulated during motor tasks.

“Neuroscientists in the 1940s and 1950s described a double representation of motor function in the cerebellum, meaning that two regions in each hemisphere of the cerebellum are engaged in motor control,” explains Guell. “That there are two areas of motor representation in the cerebellum remains one of the most well-established facts of cerebellar macroscale physiology.”

When it came to assigning non-motor tasks, to their surprise, the authors identified three representations that localized to different regions of the cerebellum, pointing to an unexpectedly complex level of organization.

Guell explains the implications further. “Our study supports the intriguing idea that while two parts of the cerebellum are simultaneously engaged in motor tasks, three other parts of the cerebellum are simultaneously engaged in non-motor tasks. Our predecessors coined the term “double motor representation,” and we may now have to add “triple non-motor representation” to the dictionary of cerebellar neuroscience.”

A serendipitous discussion

What happened next, over a discussion of data between Xavier Guell and Sheeba Arnold Anteraper of the McGovern Institute for Brain Research that culminated in a paper led by Anteraper, illustrates how independent strands can meet and reinforce to give a fuller scientific picture.

The findings by Guell and colleagues made the cover of NeuroImage.
The findings by Guell and colleagues made the cover of NeuroImage.

Anteraper and colleagues examined brain images from high-functioning ASD patients, and looked for statistically-significant patterns, letting the data speak rather than focusing on specific ‘candidate’ regions of the brain. To her surprise, networks related to language were highlighted, as well as the cerebellum, regions that had not been linked to ASD, and that seemed at first sight not to be relevant. Scientists interested in language processing, immediately pointed her to Guell.

“When I went to meet him,” says Anteraper, “I saw immediately that he had the same research paper that I’d been reading on his desk. As soon as I showed him my results, the data fell into place and made sense.”

After talking with Guell, they realized that the same non-motor cerebellar representations he had seen, were independently being highlighted by the ASD study.

“When we study brain function in neurological or psychiatric diseases we sometimes have a very clear notion of what parts of the brain we should study” explained Guell, ”We instead asked which parts of the brain have the most abnormal patterns of functional connectivity to other brain areas? This analysis gave us a simple, powerful result. Only the cerebellum survived our strict statistical thresholds.”

The authors found decreased connectivity within the cerebellum in the ASD group, but also decreased strength in connectivity between the cerebellum and the social, emotional and language processing regions in the cerebral cortex.

“Our analysis showed that regions of disrupted functional connectivity mapped to each of the three areas of non-motor representation in the cerebellum. It thus seems that the notion of two motor and three non-motor areas of representation in the cerebellum is not only important for understanding how the cerebellum works, but also important for understanding how the cerebellum becomes dysfunctional in neurology and psychiatry.”

Guell says that many questions remain to be answered. Are these abnormalities in the cerebellum reproducible in other datasets of patients diagnosed with ASD? Why is cerebellar function (and dysfunction) organized in a pattern of multiple representations? What is different between each of these representations, and what is their distinct contribution to diseases such as ASD? Future work is now aimed at unraveling these questions.