Rosbash, Hall & Young Awarded Nobel Prize

Michael Rosbash, Nobel Laureate

Brandeis researchers Michael Rosbash, the Peter Gruber Endowed Chair in Neuroscience, and Professor Emeritus of Biology Jeffrey C. Hall have received this year’s Nobel Prize in Physiology or Medicine, together with Michael Young from The Rockefeller University,  for their pioneering work on the molecular mechanisms controlling circadian rhythm.

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Rodal lab find surprising new link between inflammation and Lowe Syndrome

Could a disease with symptoms in the brain, eyes, and kidneys actually be caused by problems with immune cells? A team of scientists from the Rodal Lab, co-first authored by Steven Del Signore and Sarah Biber and including three Brandeis undergraduates (Katy Lehmann ‘16, Stephanie Heimler ‘17, and Ben Rosenfeld ’18), think this just might be the case with Lowe Syndrome, in a new paper published Oct 13th in PLOS Genetics.

Patients with Lowe Syndrome suffer from kidney failure, congenital cataracts, and several neurological problems including intellectual disability and seizures. Scientists have known for some time that the disease is caused by mutations in a gene called OCRL, but remain unsure how its loss causes such a diverse array of symptoms. A big problem has been that OCRL appears to do many different jobs inside cells, including controlling how they divide, how they sense their surroundings, and how they store and transport materials inside small packages called endosomes.

Fly immune cells showing the tracks of moving endosomes. Single tracks represent the path of individual endosomes over time.

To try to solve this mystery, a team of researchers from the Rodal lab used the fruit fly, which has its own version of the OCRL gene and allowed the investigators to perform powerful genetic experiments to figure out precisely what OCRL is doing, and where. To do this, the group created a fly missing its OCRL gene. They were surprised to find that, rather than eye or neurological defects, loss of OCRL hyper-activated cells of the innate immune system. The innate immune system is the first line of defense against infection in humans (and the only defense in fruit flies), when cells release inflammatory signals that mobilize specialized cells to attack invading pathogens.

The team determined that OCRL is required in one of these specialized immune cells in the fly, and that the immune-cell activation was caused by problems in a particular step of intracellular transport. Every cell of the body has its own postal service, which is used to pack and ship signals that tell the cell or its neighbors to grow, divide, or jump into action (see movie here to watch endosomes moving inside living fly immune cells). The OCRL mutant immune cells had a problem in a key step that controls whether signals get thrown in the trash or shipped outside the cell, and this caused the immune activation.

How do these findings relate to Lowe Syndrome? The authors think these results suggest a possible cause for the seizures that patients experience. When similar immune-like cells in the brain release excessive inflammatory signals, it can cause several forms of epilepsy. Further, OCRL has been linked to at least one mouse model of epilepsy. Going forward, the researchers will try to identify which immune signals are responsible, and how these findings translate to human cells.

Del Signore SJ (*), Biber SA (*), Lehmann KS, Heimler SR, Rosenfeld BH, Eskin TL, Sweeney ST, Rodal AA. dOCRL maintains immune cell quiescence by regulating endosomal traffic. Plos Genet. 2017;13(10):e1007052.



James Collins to receive the 2017 Gabbay Award on Oct. 18

James Collins

On Wednesday, October 18, 2017, the 2017 Jacob and Louise Gabbay Award in Biotechnology and Medicine will be given to James J. Collins from MIT. Professor Collins will be delivering his lecture entitled Synthetic Biology: Life Redesigned at 4:00pm at Brandeis in Gerstenzang 121.

Professor Collins is receiving the award “for his inventive work in synthetic biology that created a new area of research, enabling multiple biomedical applications and launching a new sector of the biotechnology industry”. He is the Termeer Professor of Medical Engineering and Science and Professor of Biological Engineering at MIT, also Core Founding Faculty at the Wyss Institute (Harvard University) and an Institute Member of the Broad Institute.

The Gabbay Award was created in 1998 by the Jacob and Louise Gabbay Foundation in order to recognize scientists working in academia, medicine or industry for their outstanding achievements developing scientific content and significant results in the biomedical sciences.


Ivanovic Receives 2017 NIH Director’s New Innovator Award

photo: Mike Lovett

Assistant Professor of Biochemistry Tijana Ivanovic has received a 2017 NIH Director’s New Innovator Award. This award is part of the NIH’s High-Risk, High-Reward Research program, designed to fund early career investigators who propose innovative and potentially transformative projects. Ivanovic will receive $1,500,000 in direct costs over five years to spearhead a research program aimed at comprehensively characterizing molecular changes in the viral cell-entry protein hemagglutinin (HA) that define pandemic influenza viruses. With the generated insights, Ivanovic hopes to ultimately be in a position to predict the pandemic potential of influenza viruses circulating in nature.

HA densely covers the influenza virion surface, where it allows the virus to both recognize and penetrate (fuse with) the cells of its host. HA is also a key target of neutralizing antibodies that protect us from influenza infection. An influenza pandemic is characterized by the adaptation of a new HA subtype to cell entry into human cells (of what was originally an avian virus). Without the pre-existing immunity to protect us, the virus quickly spreads around the globe. During pandemic adaptation, both HA functions in target-cell recognition and membrane fusion undergo key molecular changes. Ivanovic will use a custom-built Total Internal Reflection Fluorescence Microscope (TIRFM) to visualize, in real time, individual virus particles as they engage and fuse with target cell membranes. This system will allow her to obtain large-scale quantitative information about distinct HA functions at an unprecedented level of detail. She will compare avian viruses with their evolutionary offspring that infected humans, including past pandemic strains. She hopes to develop models for predicting which viruses will lead to a major flu outbreak.

Ivanovic obtained a PhD in virology from Harvard University and carried out postdoctoral research with Stephen Harrison in molecular biophysics. She integrates these diverse backgrounds in her laboratory, where members are trained across these two and other synergistic areas (such as laser microscope optics, and analytical and computational modeling). The funds from the New Innovator award have created new opportunities for hiring, and the lab is actively recruiting postdocs, PhD students (from the Biochemistry and Biophysics, Molecular and Cell Biology, and Physics graduate programs) and undergraduate researchers to undertake this ambitious program.

CaMKII: some basics to remember

The theme of Thursday’s Volen Center for Complex Systems annual retreat will be Breakthroughs in understanding the role of CaMKII in synaptic function and memory and honors the pioneering work of John Lisman. To help bring non-experts up to speed, we asked Neuroscience Ph.D. students Stephen D. Alkins and Johanna G. Flyer-Adams from the Griffith lab at Brandeis for a quick primer on CaMKII.

What’s a protein kinase? 

Protein kinases are enzymes that act by adding phosphate groups to other proteins – a process called phosphorylation. Phosphorylation of a protein usually initiates a cascade of downstream effects such as changes in the protein’s 3D shape,  changes in its interactions with other proteins, changes in its activity and changes in its localization. In causing these types of changes, kinases facilitate some of the most essential cellular and molecular processes required for survival and proper functionality.

Aren’t there lots of protein kinases? What makes CaMKII special? 

Among the roughly 500+ genes in the human genome encoding protein kinases, a kinase known as calcium (Ca2+)/calmodulin-dependent protein kinase II (CaMKII) phosphorylates serine or threonine residues in a broad array of target proteins.  Though found in many different tissues (skeletal muscle, cardiac muscle, spleen, etc.), there is a lot of CaMKII in the brain– about 1% of total forebrain protein and 2% of total hippocampal protein (in rats). Previous research, including pivotal contributions from the Lisman Lab at Brandeis University working in mammalian brain, has identified CaMKII as a cellular and molecular correlate of learning and memory through its multiple roles governing normal neuronal structure, synaptic strength, plasticity, and homeostasis. The Griffith Lab has been instrumental in demonstrating that these roles of the kinase are conserved in invertebrates.

Why do we think CaMKII might play a role in memory?

a) Location!

As previously mentioned, CaMKII accounts for up to 2% of all proteins in memory-important brain regions like the hippocampus. It’s also highly abundant at neuronal synapses, where neurons communicate with each other.

b) Function!

Memory is thought to require a process called long term potentiation (LTP) where two neurons, in response to environmental changes, will change the strength of the synaptic connections by which they communicate with each other—these changes will last even after the environmental input has disappeared. We know that CaMKII is required for LTP. We also know that the increases in neuronal calcium levels that accompany neuronal activation and cause LTP also allow CaMKII to phosphorylate itself. This autophosphorylation of CaMKII changes its kinase activity so that CaMKII can stay active well past the window of neuronal activation, essentially ‘storing’ the memory of previous neuronal activity—much like LTP!

c) Structure!

Ultimately, the issue with ‘molecular memory’ is that all proteins degrade over time, causing one to ask how we can remember things for so long when the original proteins that stored that memory no longer exist. CaMKII is such an exciting candidate for molecular memory because it is mostly found as a dodecameric holoenzyme—this means that CaMKII likes to exist as a big assembly of twelve identical CaMKII subunits. However, each CaMKII subunit retains its kinase activity even when all twelve are assembled. What’s interesting is that the autophosphorylation and activation of one CaMKII subunit (which happens when neurons are activated and intracellular calcium levels rise) actually makes it easier for the other CaMKII subunits in the twelve-unit holoenzyme to become autophosphorylated and activated. This means that maybe when an activated subunit is old and get degraded, another new CaMKII subunit could take its place among the twelve-unit holoenzyme—and become activated just like the old subunit, allowing for the ‘molecular memory’ to last beyond when proteins degrade!

CaMKII phosphorylation and activationCaMKII in more detail…

Calcium binds to the small protein calmodulin and forms (Ca2+/CaM), which acts as a ‘second messenger’ that increases in concentration when neurons are activated. CaMKII relies on calcium/calmodulin (Ca2+/CaM) binding to activate an individual domain containing a regulatory segment.  In conditions of low calcium, elements within the CaMKII regulatory segment will have less affinity for (Ca2+/CaM) binding, keeping CaMKII in an autoinhibited state.  In conditions of high calcium, (Ca2+/CaM) binding initiates phosphorylation at three threonine residue sites, including Thr286 which prevents rebinding of the regulatory segment, thus keeping CaMKII constitutively active even when calcium levels fall.  In this activated state CaMKII can autophosphorylate inactivated intra-kinase domains, and will undergo subunit exchange with neighboring inactivated CaMKII holoenzymes. Furthermore, mutation of CaMKII residues or binding sites in target proteins, such as postsynaptic glutamate (AMPA) receptors, disrupts establishment of long-term potentiation (LTP) in neurons.  Together, CaMKII’s role as molecular switch that bidirectionally, and autonomously regulates activity in neurons has earned it the illustrious title of a “memory molecule.”

What amino-acid manipulations might I hear about?

a) T286A:

Changing a threonine in a phosphorylation site to an alanine prevents phosphorylation at that site. Blocking Thr286 phosphorylation with a T286A mutation prevents CaMKII generation of autonomous activity that disrupts neuronal activity and results in learning deficits.

b) T286D:

Changing a threonine to an aspartate puts a negative charge at the site, often making it act like it’s always phosphorylated. In the case of CaMKII, a T286D mutation renders the kinase constitutively active, which can interrupt normal LTP induction and normal memory storage and acquisition.

To learn more:

Titia de Lange to receive 47th Rosenstiel Award

Professor Titia de Lange

The 47th Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Research has been awarded to Professor Titia de Lange of Rockefeller University for her studies on the protection of chromosome ends (telomeres) from degradation and rearrangement. Professor de Lange will receive the award on April 12, 2018 at Brandeis University where de Lange will present a public lecture.

Dr. de Lange’s laboratory identified and characterized the roles of proteins that compose the shelterin complex, which binds specifically to the special telomeric DNA sequences and maintains the stability of these ends.  Dr. de Lange’s work has shown that the shelterin complex and the unusual telomere-loop structure of telomere DNA prevent these ends from being detected as broken chromosome ends and thus protect telomeres from being degraded and rearranged as are the ends at chromosome breaks.  De Lange’s work has further shown that disabling different components of shelterin triggers different cellular alarms designed to detect broken and degraded DNA ends and leads to lethal chromosome rearrangements such as the fusion of chromosomes.  In addition, her lab has gained critical insights into the mechanisms of cellular response to the presence of DNA damage and recently has defined processes that lead to massive chromosome rearrangements (chromothripsis) associated with many human cancers.

She is the Leon Hess Professor and director of the Anderson Center for Cancer Research at Rockefeller University, as well as an American Cancer Society Research Professor.  Her honors include: the Life Sciences Breakthrough Prize, the Rosalind E. Franklin Award from the National Cancer Institute, the Vilcek Prize in Biomedical Sciences, election as a foreign member of the US National Academy of Sciences and as Fellow of the American Academy of Arts and Sciences.

The Rosenstiel Award has had a distinguished record of identifying and honoring pioneering scientists who subsequently have been honored with the Lasker and Nobel Prizes.  Professor de Lange joins a long list of past awardees.

Stanley Deser’s Influence on the 2017 Nobel Prize for Physics

Written by Albion Lawrence

Deser, Arnowitt, & Miser

Bornholm 1959
From the left, Richard Arnowitt, Charles Misner and Stanley Deser

Today’s Physics Nobel Prize to Rai Weiss, Kip Thorne, and Barry Barish for the detection by the LIGO experiment of gravitational waves is a well-deserved recognition of a remarkable achievement through perseverance. However, it is the nature of prizes such as the Nobel that they obscure the important efforts and insights of many scientists across space and time that lead to the result in question.

Stanley DeserThe extraction of a gravitational wave signal from the output of the LIGO detector requires understanding in advance what signals can be produced; these are based on numerical simulations of astrophysical events which provide templates that a signal must match.

This is possible due to the seminal work of Brandeis emeritus faculty Stanley Deser, with his colleagues Richard Arnowitt and Charles Misner, who developed the mathematical framework known as the ADM formalism, to treat general relativity as a Hamiltonian system; with this, the evolution in time of the gravitational field can be computed from initial conditions.

In addition, Stanley was instrumental in the LIGO experiment being funded in the first place. The story is best told by him in his inimitable style (here quoted from an email, and lightly expurgated):

“Marcel Bardon, then [director] of NSF physics, made me an offer I’d better not refuse. I was nominated to some advisory committee in order to plead for LIGO in front of my betters, who would then go to Congress, if convinced. Those were dark days for waves, experimentally; we (ADM) of course knew the Lord was not evil, but 3 suns’ worth we did not expect!….It worked quite well, and was duly made a line item.”

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