Category Archives: Cell Biology

Cell Biology

Chemists Discovered the Structure of a Key Influenza Protein Breakthrough Could Lead to Flu Treatment – SciTechDaily

This digitally-colorized transmission electron microscopic image depicts the ultrastructural details of an influenza virus particle. Credit: CDC, Frederick Murphy

A team of MIT chemists has discovered the structure of a key influenza protein, a finding that could help researchers design drugs that block the protein and prevent the virus from spreading.

The protein, known as BM2, is a proton channel that controls acidity within the virus, helping it to release its genetic material inside infected cells.

If you can block this proton channel, you have a way to inhibit influenza infection, says Mei Hong, an MIT professor of chemistry and senior author of the study. Having the atomic-resolution structure for this protein is exactly what medicinal chemists and pharmaceutical scientists need to start designing small molecules that can block it.

MIT graduate student Venkata Mandala is the lead author of the paper, which was published on February 3, 2020, in Nature Structural and Molecular Biology. Other authors include graduate students Alexander Loftis and Alexander Shcherbakov and associate professor of chemistry Bradley Pentelute.

There are three classes of influenza virus A, B, and C and each of them produces a different version of the M2 protein. M2 is an ion channel that carries protons through the viruss outer membrane, known as the lipid envelope. These protons usually flow into the virus, making the interior more acidic. This acidity helps the virus to merge its lipid envelope with the membrane of a cellular compartment called an endosome, allowing it to release its DNA into the infected cell.

Until now, most structural studies of the M2 protein have focused on the version of M2 found in influenza A, which is usually the most common form, especially earlier in the flu season. In this study, the researchers focused on the version of M2 found in influenza B viruses, which usually dominate in March and April. However, in contrast to previous patterns of seasonal flu infections, this winter, influenza B has been unusually dominant, accounting for 67 percent of all flu cases reported to the U.S. Centers for Disease Control since last September.

The A and B versions of M2 vary significantly in their amino acid sequences, so Hong and her colleagues set out to study what structural differences these proteins might have, and how those differences influence their functions. One key difference is that the BM2 channel can allow protons to flow in either direction, whereas the AM2 channel only allows protons to flow into the viral envelope.

To investigate the structure of BM2, the researchers embedded it into a lipid bilayer, similar to a cell membrane, and then used nuclear magnetic resonance (NMR) spectroscopy to analyze the structure with atomic-scale resolution. Very few ion channels have been studied at such high resolution because of the difficulty of studying proteins embedded within membranes. However, Hong has previously developed several NMR techniques that allow her to obtain accurate structural information from membrane-embedded proteins, including their orientation and the distances between atoms of the protein.

The M2 channel is made of four helices that run parallel to each other through the membrane, and Hong found that the alignment of these helices changes slightly depending on the pH of the environment outside the viral envelope. When the pH is high, the helices are tilted by about 14 degrees, and the channel is closed. When the pH goes down, the helices increase their tilt to about 20 degrees, opening up like a pair of scissors. This scissoring motion creates more space between the helices and allows more water to get into the channel.

Previous studies have found that as water flows into the M2 channel, the amino acid histidine grabs protons from the water in the top half of the channel and passes them to water molecules in the lower half of the channel, which then deliver the excess protons into the virion.

Unlike the AM2 channel, the BM2 channel has an extra histidine at the virion-facing end of the channel, which the MIT team believes to explain why protons can flow in either direction through the channel. More study is needed to determine what kind of advantage this may provide for influenza B viruses, the researchers say.

Now that chemists know the structure of both the open and closed states of the BM2 channel at atomic resolution, they can try to come up with ways to block it. There is precedent for this type of drug development: Amantadine and rimantadine, both used to treat influenza A, work by wedging themselves into the AM2 channel pore and cutting off the flow of protons. However, these drugs do not affect the BM2 channel.

Hongs research group is now investigating another one of BM2s functions, which is generating curvature in lipid membranes in order to allow progeny viruses to be released from cells. Preliminary studies suggest that a portion of the protein that sticks out from the membrane forms a structure called a beta sheet that plays a role in inducing the membrane to curve inward.

Reference: Atomic structures of closed and open influenza B M2 proton channel reveal the conduction mechanism by Venkata S. Mandala, Alexander R. Loftis, Alexander A. Shcherbakov, Bradley L. Pentelute and Mei Hong, 3 February 2020, Nature Structural and Molecular Biology.DOI: 10.1038/s41594-019-0371-2

The research was funded by the National Institutes of Health.

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Chemists Discovered the Structure of a Key Influenza Protein Breakthrough Could Lead to Flu Treatment - SciTechDaily

Cell Biology

If cancer were easy, every cell would do it – Newswise

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Newswise A new Scientific Reports paper puts an evolutionary twist on a classic question. Instead of asking why we get cancer, Leonardo Oa of Osnabrck University and Michael Lachmann of the Santa Fe Institute use signaling theory to explore how our bodies have evolved to keep us from getting more cancer.

It isnt obvious why, when any cancer arises, it doesnt very quickly learn to take advantage of the bodys own signaling mechanisms for quick growth. After all, unlike an infection, cancers can easily use the bodys own chemical language. Any signal that the body uses, an infection has to evolve to make, says Lachmann. If a thief wants to unlock your house, they have to figure out how to pick the lock on the door. But cancer cells have the keys to your house. How do you protect against that? How do you protect against an intruder who knows everything you know, and has all the tools and keys you have? Their answer: You make the keys very costly to use.

Oa and Lachmanns evolutionary model reveals two factors in our cellular architecture that thwart cancer: the expense of manufacturing growth factors (keys) and the range of benefits delivered to cells nearby. Individual cancer cells are kept in check when theres a high energetic cost for creating growth factors that signal cell growth. To understand the evolutionary dynamics in the model, the authors emphasize the importance of thinking about the competition between a mutant cancerous cell and surrounding cells. When a mutant cell arises and puts out a signal for growth, that signal also provides resources to adjacent, non-mutated cells. Thus, when the benefits are distributed to a radius around the signaling cell, the mutant cells have a hard time out-competing their neighbors and cant get established. The cancer loses the ability to give the signal.

The work represents a novel application of evolutionary biology toward a big-picture understanding of cancer. Oa and Lachmann draw from the late biologist Amotz Zahavis handicap principle, which explains how evolutionary systems are stabilized against cheaters when dishonest signals are costlier to produce than the benefit they provide. The male peacocks elaborate tail is the classic example of a costly signal an unhealthy bird would not have the energetic resources to grow an elaborate tail, and thus could not fake a signal of their evolutionary fitness. By the handicap principle, a cancer cell would be analogous to the unhealthy peacock that cant afford to signal for attention.

So how do some cancer cells overcome these evolutionary constraints? The authors point out that their model only addresses the scenario of an individual cancer trying to invade a healthy population. Once cancer has overcome the odds of extinction and reached a certain critical size, other dynamics prevail.

Many mechanisms seem to have evolved to prevent cancer from immune system control, cell death, limits on cell proliferation, to tissue architecture, the authors write. Our model only studies the reduced chance for invasion.

Cancer is incredibly complex, Lachmann says, and our model is relatively simple. Still, we believe its an important step toward understanding cancer and cancer prevention in evolutionary terms.

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If cancer were easy, every cell would do it - Newswise

Cell Biology

Study uncovers more pieces of the autism puzzle – News-Medical.net

A major international study from the Autism Sequencing Consortium with participation of researchers from the Danish iPSYCH psychiatry project, has recently mapped 102 new autism genes. The new findings provide a new understanding of the biology behind autism, which could in the future be utilised to provide an earlier and more precise diagnosis and better treatment options.

Ever since the first autism diagnosis was made in 1938, researchers have been trying to clarify where the disorder originates. There have been many suggestions - along with many disagreements. But one thing has been clear for a while: Genetics play a major role with a heritability of up to eighty per cent.

The largest study so far of rare genetic variants has now identified 102 new so-called risk genes for autism. The results have just been published in the international journal Cell.

"Broadly speaking, there are two types of genetic variants which play a role in autism. There are uncommon genetic variants that few people have, although these may have a big effect, and then there are frequent variants which we all carry some of, and which each contribute in a very small way to the risk," says Associate Professor Jakob Grove from Aarhus University, who is one of the driving forces behind the Danish contribution and a member of the iPSYCH research project.

In the study, the researchers mapped the DNA building blocks in the genes of 35,584 individuals, of whom 11,986 had autism. The researchers then determined how many times each gene is affected by variants with "protein disrupting consequences", as the researcher puts it. "If a gene is more often hit by these mutations among people with autism than among people without it, this indicates that the gene is involved in the processes that lead to autism, and is thus designated as a risk gene," explains Jakob Grove. The majority of the identified gene-destroying mutations are new mutations that are only found in the person with autism and not in their parents.

The genetic findings provide an entirely new insight into the biological processes that are involved in the development of autism. Some of the genes identified alter early development broadly, while others appear to be more specific to autism. Most of the genes help determine how neurones communicate with each other or they regulate the expression of other genes.

This new knowledge could provide a better basis for understanding autism. For example, it may help us to make a diagnosis earlier, which we already know makes life easier for people with autism and their relatives. It's also conceivable it could contribute to the development of personalized medicine for those who may want this."

Jakob Grove, Associate Professor, Aarhus University

In other words, the results of the study may turn out to be crucial for the treatment of psychiatric disorders in the future.

However, he also emphasizes that the new findings can only explain a few cases of autism as these genetic variants are only present in few individuals. "For this reason, iPSYCH continues to study both rare and more frequent genetic variants," he says.

The research has been carried out in collaboration with the Autism Sequencing Consortium (ASC) and the project is anchored at Mount Sinai in New York. In addition to researchers from Aarhus University, the Broad Institute in Boston, UCSF in San Francisco and Carnegie Mellon University in Pittsburgh have also participated along with researchers from altogether more than 50 sites.

Source:

Journal reference:

Satterstrom, F.K., et al. (2020) Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism. Cell. doi.org/10.1016/j.cell.2019.12.036.

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Study uncovers more pieces of the autism puzzle - News-Medical.net

Cell Biology

Unveiling the structure of the influenza virus – News-Medical.net

The flu season is coming, and the frigid temperatures make it worse. The influenza B virus is the causative agent of the common flu, but over the past years, it has become more potent in causing disease. Now, a team of MIT scientists has found and unveiled the structure of the virus, particularly the key influenza protein, in the hopes to develop new drugs to combat influenza.

The Centers for Disease Control and Prevention (CDC) reports that the overall hospitalizations related to influenza this season increased to 29.7 percent per 100,000, which is similar to what happened over the past seasons. Further, a total of 68 children had died due to influenza this season, with 14 deaths occurring during the 2019-2020 season. Overall, pneumonia and influenza mortality have been low while CDC estimates that for this season, there had been 19 million flu illnesses, 180,000 hospitalizations, and 10,000 deaths from flu.

This digitally-colorized transmission electron microscopic image depicts the ultrastructural details of an influenza virus particle. Image: CDC, Frederick Murphy

Known as BM2, the protein is a proton channel that regulates the acidity in the virus to aid in releasing its genetic material in infected cells.

The researchers believe that blocking the proton channel can help combat infection and block the effects of the virus. Knowing the structure of the protein, particularly its atomic-resolution structure, can help doctors, medicinal chemists, and pharmaceutical scientists to develop compounds and drugs to block its function.

Published in the journal Nature Structural and Molecular Biology, the study sheds light on the structure of the influenza B protein to help in the development of compounds to block its effect on the infected cell.

The three types of influenza virus influenza A, B, and C, produce a different kind of the M2 protein, which is an ion channel carrying protons through the outer membrane of the virus, known as the lipid envelope. The proteins go inside the virus and will create the internal environment more acidic. If the interior of the virus becomes acidic, it helps the virus release its DNA into the infected cell.

The M2 proteins are very interesting focuses for scientists, in the hopes of finding a cure for flu or treatment modalities to prevent further deaths. There had been many studies about the structure of the M2 protein, but most focused on the type A of the virus.

In the study, however, the team focused on the influenza B M2 protein, which usually dominates the March to April flu season, which accounts for about 67 percent of all flu cases reported by the CDC since September 2019.

The researchers aimed to study what structural differences in the proteins of A and B influenza viruses have. They found that one key difference between the two is that the BM2 channel allows the protons to flow in either direction, while the AM2 only allows the protons to flow into the envelope of the virus.

To land to their findings, the researchers studied BM2s structure by embedding it into a lipid bilayer, which is akin to a cell membrane. They used nuclear magnetic resonance (NMR) spectroscopy to investigate the structure with atomic-scale resolution.

They discovered that the M2 channel is made of four helices, wherein the alignment chances depending on how acidic or alkaline the environment outside the viral envelope is. If the pH is high, the helices begin to tilt by approximately 14 degrees, and if it decreases, the tilt increases to about 20 degrees. With the motion of the helices, mimicking a pair of scissors, it allows water to enter the channel.

They found that the BM2, unlike the AM2, has an extra histidine at the virion-facing end of the channel. The scientists believe that this explains why the protons can flow in both directions through the channel.

These results indicate that asymmetric proton conduction requires a backbone hinge motion, whereas bidirectional conduction is achieved by a symmetric scissor motion. The proton-selective histidine and gating tryptophan in the open BM2 reorient on the microsecond timescale, similar to AM2, indicating that side-chain dynamics are the essential driver of proton shuttling, the researchers concluded.

Funded by the National Institutes of Health, the study has revealed the structure of BM2 in its open and closed state, paving the way for finding a compound to finally block it.

Source:

Journal reference:

Mandala, V.S., Loftis, A.R., Shcherbakov, A.A. et al. Atomic structures of closed and open influenza B M2 proton channel reveal the conduction mechanism. Nat Struct Mol Biol (2020). https://doi.org/10.1038/s41594-019-0371-2

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Unveiling the structure of the influenza virus - News-Medical.net

Cell Biology

Aparna Bhaduri – The Conversation US

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Aparna Bhaduri earned a B.S in Biochemistry and Cell Biology and a B.A in Political Science from Rice University in 2010. She completed her doctoral studies at Stanford University in Cancer Biology in 2016, where she focused on epithelial tissue differentiation and neoplasms She is currently a postdoctoral scholar at the University of California San Francisco in the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, in the lab of Dr. Arnold Kriegstein. As a postdoctoral scholar, she has used single-cell RNA sequencing to characterize cell types in the developing cortex across cortical areas, in human and non-human primates, and in glioblastoma. Because experimental manipulations of the developing human cortex will require in vitro models, she has been using similar approaches to compare cells types in organoid models and primary tissues. Her long term interests are in understanding how stem cells during cortical development give rise to the human brain, and how aspects of these developmental programs can be hijacked in cancers such as glioblastoma. In order to explore these questions, Aparna uses single-cell genomics, informatic analysis, and organoid models.

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Aparna Bhaduri - The Conversation US

Cell Biology

Arranta Bio announces key leadership additions of Chief Operations Officer and SVP of Business Development as it commits to a $100M investment in…

WATERTOWN, Mass., Jan. 30, 2020 /PRNewswire/ -- Arranta Bio ("Arranta"), the leading microbiome contract development and manufacturing organization (CDMO), announced today the strengthening of its senior leadership team with the addition of David Stevens as Chief Operations Officer and Jason Rahal as Senior Vice President of Business Development. Arranta has committed $100M to build end-to-end capacity as the first dedicated microbiome CDMO.

As Chief Operations Officer, Dave will be responsible for driving the continued growth of Arranta's operations, including the ongoing expansion of the company's Microbiome process development center of excellence in Gainesville, FL as well as operationalizing Arranta's new best-in-class GMP facility in Watertown, MA. He is an accomplished business leader with a demonstrated track record of success within the contract development and manufacturing services industry.

Dave brings over 20 years of broad operational and commercial experience in the CRO and CDMO sectors. Most recently, Dave served as the Senior Vice President & Head of AMRI's Drug Product business unit where he had responsibility for sales and operations. During his tenure, he led the division through a period of significant growth and capacity expansion. Prior to that, Dave held roles of increasing responsibility at Aptuit and Charles River Laboratories in the UK, Italy and USA. Dave holds an MBA in strategy, finance and marketing from the University of Edinburgh and an undergraduate degree in Business.

Jason Rahal has over 25 years of experience in biotechnology. Prior to joining Arranta as SVP of Business Development, Jason was a member of the senior management team at Cobra Biologics, a CDMO providing ATMP services including Live Biotherapeutic Products (LBPs) with facilities in the United Kingdom and Sweden. Jason initially joined Cobra as VP Business Development in 2002, as the first US based employee to establish the company's presence in North America, he was promoted to SVP Business Development in 2006.

Prior to Cobra, Jason worked at Excell Biotech, a biologics CDMO based in Edinburgh, Scotland and Stratagene Cloning Systems based in La Jolla, CA in various business development and sales positions. Jason has a strong background in molecular and cell biology, beginning his career at Northwestern University in Evanston, IL managing a molecular endocrinology laboratory with several peer reviewed publications. Jason holds a BA in Biology and Studio Art from Knox College.

"I am delighted to have two experienced leaders join Arranta Bio's senior team as we continue to build out our organization and invest in facilities as the leading end-to-end dedicated CDMO supporting microbiome pioneers with our services" said Mark Bamforth, President & CEO of Arranta.

Almost 200 companies are actively exploring the linkage between diseases and the microbiome millions of bacteria, fungi, protozoa and viruses that live inside and on the human body in order to identify therapeutic targets. Scientists have called it the second genome, and in fact, the number of genes in the microbes making up one person's microbiome is estimated to be at least 200 times the number in the human genome.

Over the last decade, there has been rapid acceleration in scientific understanding of the composition and functions of the gut microbiota. Arranta is proud to be the leading CDMO focused on supporting the supply needs of these innovators.

About Arranta BioFounded in 2019, Arranta Bio is a contract development and manufacturing organization (CDMO) specifically established to focus on serving companies seeking to develop and commercialize therapies targeting the human microbiome. Arranta Bio acquired CaptozymeTM the leader in process development and clinical contract manufacturing for microbiome pioneers whose experienced team has worked with and developed processes for over 125 different species spanning 80 different genera of live biotherapeutics since 2009. Headed by a management team and technical experts with a proven track record in both process development and contract manufacturing through fermentation to lyophilization and encapsulation of live biopharmaceuticals, Arranta offers the knowledge and resources necessary to help clients develop and manufacture promising new microbiome therapies to meet the needs of patients. Additional information about Arranta is available at http://www.arrantabio.com. Enquiries can be sent to info@arrantabio.com

About Ampersand Capital PartnersFounded in 1988, Ampersand is a middle market private equity firm dedicated to growth-oriented investments in the healthcare sector. With offices in Boston, MA and Amsterdam, Netherlands, Ampersand leverages a unique blend of private equity and operating experience to build value and drive superior long-term performance alongside its portfolio company management teams. Ampersand has helped build numerous market-leading companies across each of its core healthcare sectors, including Avista Pharma Solutions, Brammer Bio, Confluent Medical, Genewiz, Genoptix, Talecris Biotherapeutics, and Viracor-IBT Laboratories. Additional information about Ampersand is available at http://www.ampersandcapital.com

Arranta Bio Media contact: Guy TieneThat's Nice LLCT: +1 212 366 4455E: guy@thatsnice.com

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Cell Biology

Cancer cure: Collaboration between Ervaxx and Cardiff University to develop T-cell immunotherapy treatment – EconoTimes

The coronavirus has everyone on high alert, but scientists have not forgotten about the existing diseases that have yet to have a cure, such as cancer. A new partnership between Cardiff University and biotechnology company Ervaxx was announced in order to develop the T-cell immunotherapy treatment further.

As announced on the Ervaxx site, the two institutions will collaborate in the development of a potential cure in the form of utilizing Dark Antigens to which the company is known for, in order to develop T-cell receptor-based immunotherapy treatments for cancer. Ervaxx will be funding the program. The partnership between the two groups will help bring forward the findings Professor Andrew Sewell and his team have documented.

They were able to identify a T-cell clone that can target and kill many types of cancer cells while keeping the healthy cells intact. This T-cell clone targets an MHC class-1-related protein named MR1, which is a cancer-specific ligand. This breakthrough may provide a universal cancer cure and change the game into the concept of immunotherapy as a treatment for the disease.

As part of the collaboration, Ervaxx will have exclusive access to the patents at Cardiff University that claim T-cells and T-cell receptors reacting to cancer-specific antigens. On the universitys side, Professor Sewell said, This collaboration will use our world-class expertise in T-cell biology to identify T-cells and TCRs reactive to those targets and pave the way for a new wave of treatments in cancer and potentially other areas,

Although this type of treatment for cancer has already been discovered years back, what makes this significant is that this method is slowly becoming accessible to more parts of the world. As pharmaceutical giants, while they may offer this type of treatment, the accessibility is very limited. Therapies like TCR-T and CAR-T, which also make use of a patients T-cells, which are genetically modified to kill the cancerous cells and re-introduced into the body are already existing. However, the disadvantage of these treatments is that it targets certain types of blood cancer and has not been successful when it comes to tumors.

Professor Sewell stated regarding their discovery, Not only would the treatment work for most types of cancer, but the same approach could be applied in all patients.

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Cancer cure: Collaboration between Ervaxx and Cardiff University to develop T-cell immunotherapy treatment - EconoTimes

Cell Biology

Talented Teacher – HSC Newsbeat

Angela Wandinger-Ness, PhD, professor in The University of New Mexico Department of Pathology, is being honored by the American Association for the Advancement of Science (AAAS) with its 2020 Lifetime Mentor Award.

She will receive the award, which recognizes her for mentoring some 270 scientists over her 29-year teaching career, at the associations annual meeting in Seattle on February 15.

Wandinger-Ness is both the associate director for education, training and mentoring and the Victor and Ruby Hansen Surface Endowed Professor in Cancer Cell Biology and Clinical Translation at the UNM Comprehensive Cancer Center.

I am deeply humbled by being nominated and receiving this award, she said, adding that she is especially moved to know that she was nominated for the award by people she trained and mentored who are now respected scientists in their own right.

Dr. Wandinger-Ness was an incredible mentor to me, providing personal and professional guidance throughout my time in her laboratory and beyond, wrote Mary-Pat Stein, professor of biology at California State University, Northridge, in a nominating letter to the AAAS.

The AAAS Mentor Award honors individuals who during their careers demonstrate extraordinary leadership to increase the participation of underrepresented groups in science and engineering fields and careers. These groups include women of all racial or ethnic groups African American, Native American and Hispanic men and people with disabilities.

Wandinger-Ness has twice been singled out by her colleagues at UNM for the annual Excellence in Research Award. In nominating her for the Teaching and Learning category in 2019, Cancer Center CEO Cheryl Willman, MD, hailed her unwavering commitment to scholarship in teaching and mentoring trainees at all levels of learning.

Willman added, Dr. Wandinger-Ness is a devoted and compassionate research mentor who invests her time to nurture and develop a more diverse scientific community and scientific leaders for our future.

Wandinger-Ness was elected a fellow of the AAAS in 2012. Her research has focused on GTPases, a family of enzymes that operate as molecular switches in many different cellular functions. She currently is looking for way to translate her work into potential therapies for ovarian cancer.

Wandinger-Ness joined the UNM faculty in 1998 after seven years at Northwestern University. Through the years, she mentored dozens of minority trainees, including 15 bachelors and masters students who went on to earn doctorate degrees, 26 PhD students and 53 postdoctoral fellows.

She was recruited to UNM by Mary Lipscomb, MD, then-chair of the Department of Pathology. She was an absolute 200% advocate for me, Wandinger-Ness says. She thought I walked on water, which I knew I didnt . . . that was the first time I felt that I understood what it meant to have somebody who gets you.

Wandinger-Ness, whose parents emigrated to the U.S. following World War II, recalls growing up feeling the animosity many people still held toward Germans.

I was assimilated, she says. Thats not true for a lot of people who come as immigrants. For me, it is deeply personal to train diverse trainees of every stripe to see that they should be welcome and part of this diverse community.

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Cell Biology

Neuroscientist John Ngai named director of NIH BRAIN Initiative – UC Berkeley

The National Institutes of Health (NIH) has picked long-time UC Berkeley neuroscientist John Ngai to head its BRAIN Initiative, a multibillion-dollar federal research push to develop new tools that will help scientists understand how the brain works and lead to new treatments for brain dysfunction.

The BRAIN Initiative aims to revolutionize our understanding of the brain and brain disorders, said NIH director Francis Collins today (Wednesday, Jan. 29) in announcing the appointment. We welcome Dr. Ngais leadership in steering this groundbreaking 21st century project.

As director of what formally is the NIH Brain Research through Advancing Innovative Neurotechnologies Initiative, Ngai will help steer about $500 million in research dollars this year to the most promising projects around the country. From 2014, when the first awards were given, through 2019, the initiative distributed $1.3 billion, and it is expected to disperse $5.2 billion by 2025.

In the first five years of the BRAIN Initiative, we have seen some remarkable advances in technologies for monitoring, as well as for perturbing activity in the brain, some of which have led to new innovations in treating patients with devices such as deep brain stimulators in the areas of epilepsy and Parkinsons disease, Ngai said. By continuing to develop new tools for understanding how the brain works, we hope to provide the basis for future clinical treatments.

Dr. Ngais appointment comes at a propitious time as the BRAIN Initiative enters a new and important phase, said Walter Koroshetz, director of NIHs National Institute of Neurological Disorders and Stroke (NINDS). Dr. Ngai will provide the initiative the clear vision the project needs to navigate through this critical period.

Ngai, the Coates Family Professor of Neuroscience at UC Berkeley, was a guest of the White House in 2013 when the initiative was first announced and together with nine Berkeley colleagues received one of the first NIH BRAIN Initiative grants to help classify cells in the brain. Over the past five years, the initiative has funded hundreds of research projects nationwide that have led to several breakthroughs, including the creation of systems for studying the circuits involved in generating behavior in animal models, the development of a computer program that can mimic natural speech from peoples brain signals and the construction of a brain cell parts list.

Most of the money comes from the annual budgets of 10 NIH institutes led by the NINDS and the National Institute of Mental Health (NIMH). Congress has appropriated additional funds each year since the passage of the 21st Century Cures Act in 2013.

Ngai will begin his new position in mid-March, overseeing the long-term strategy and day-to-day operations of the initiative with oversight by the directors of the 10 institutes participating in the BRAIN Initiative. He will retire from UC Berkeley as an emeritus professor and move his lab to new quarters in Bethesda, Maryland, home of the NIH.

Ngai first joined the UC Berkeley Department of Molecular and Cell Biology in 1993, after earning his Ph.D. in biology in 1987 from the California Institute of Technology and working as a postdoctoral fellow at Columbia University College of Physicians and Surgeons from 1988 until 1992. It was at Columbia, in the lab of future Nobel Laureate Richard Axel, that he initiated his studies of the bodys olfactory system: our sense of smell. At the time, it was one of the last of the five senses to be thoroughly studied, Ngai said, and he applied his training in molecular biology to unearthing the genes involved in receiving and processing information.

Neuroscientist John Ngai was appointed director of the NIH BRAIN Initiative. (UC Berkeley photo by Brittany Hosea-Small)

As new tools came along, he probed deeper and has in recent years employed the latest technology, single cell sequencing, to discover all the genes expressed in specific neurons. His latest interest is how the olfactory system repairs itself. As director of the Helen Wills Neuroscience Institute from 2011 to 2013, Ngai helped bring engineers and physical scientists into the institute to join biologists.

This was the vision that (former UC Berkeley professors) Corey Goodman and Carla Shatz had when they founded the institute in 1999, with the encouragement of then-Executive Vice Chancellor and Provost Carol Christ, now UC Berkeleys chancellor, Ngai said. To drive and accelerate the future of neuroscience requires the development of new tools and the incorporation of ideas from fields outside of biology. The BRAIN Initiative has enabled us to realize that vision in a grand way.

John has helped put UC Berkeley in the vanguard of the technology-centered approach that is the focus of the BRAIN Initiative, said Paul Alivisatos, UC Berkeleys vice chancellor and provost and one of the scientists who helped catalyze early discussions that laid the foundation for the initiative. This foresight to incorporate our unparalleled strengths in the physical and engineering sciences with our preeminence in neurobiology prepared Berkeley to leverage these new technologies five years ago to accelerate discovery and treatments in the neurosciences. That approach will continue to drive our research in the future.

Ngai also is director of the Functional Genomics Laboratory in the California Institute for Quantitative Biosciences, or QB3, a multi-campus initiative that fosters the development of biology as a quantitative, predictive science, with applications in health, energy and the environment. On the national level, Ngai has provided extensive service on NIH study sections, councils and steering groups, including as co-chair of the NIH BRAIN Initiative Cell Census Consortium Steering Group.

Ngai was born in New York City to Chinese immigrants who came to this country in 1947 to complete their medical training. He grew up with his two older sisters just outside of New York City in Teaneck, New Jersey. Science and medicine were the usual topics of conversation over dinner, as his parents were both faculty members at Columbia University College of Physicians and Surgeons, where his father a neuroscientist himself was professor and chair of anesthesiology and his mother a professor of pharmacology. He attended Pomona College in Claremont, California, and graduated with a bachelors degree in chemistry and zoology in 1980. His many honors include awards from the Sloan Foundation, Pew Charitable Trusts and McKnight Endowment Fund for Neuroscience.

Ngai said he will miss UC Berkeley, but is thrilled by the chance to head up one of the nations top biomedical priorities.

For the past 27 years, it has been such an amazing privilege for me to draw inspiration from the brilliant students, colleagues and staff at the worlds greatest public university, he said. I will take the lessons I learned here at Berkeley to my new role in enabling BRAIN Initiative investigators to unlock the secrets of the brain and lay new foundations for treating human brain disorders. The skys the limit.

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Cell Biology

The Future of Antivenom May Involve Mini Lab-Grown Snake Glands – Smithsonian.com

For the first time, scientists have grown miniature, venom-producing glands in the lab using coral snake embryos, according to a news study published in the journal Cell. Why might researchers want to create artificial venom glands, you ask?

The project was initially aimed to establish proof-of-concept more than anything else. Three graduate students at the Hubrecht Institute in the Netherlands had wondered: If lab-grown organs could be made that acted like mouse and human tissues, would it work for other animals, like reptiles?

Luckily, they were working in molecular geneticist Hans Clevers lab. Clevers is a prominent expert in stem cell research who pioneered research on the lab-grown organ imitationscalled organoidsa decade ago. Since then, researchers have created miniature human kidneys, livers, and brains in petri dishes.

On Fridays, members of the Clevers Lab are allowed to work on unstructured projects. To put their question to the test, Clevers students Yorick Post, Jens Puschhof, and Joep Beumer, would need a source of reptilian stem cells. As it happened, one of the researchers knew a guy: a snake breeder who could supply them with fertilized eggs, as STAT News Andrew Joseph reports.

They started with the egg of a Cape coral snake, removing the embryos venom glands and placing them in a dish. Then, they followed nearly the same protocol as they did with human cells, giving the cells ample supply of growth-inducing chemicals and storing them at a comfortable temperatureabout 89 degrees Fahrenheit, about ten degrees lower than the temperature used for human cells.

Soon, the plates held one-millimeter-long white blobs producing dangerous venom. With the organoids alive and well, the researchers told Clevers what theyd done, Leslie Nemo at Discover reports. If theyd told him beforehand, he would have told them it probably wouldnt work, Clevers tells the Atlantics Ed Yong. The chemicals they used were designed for human stem cells, and very little was known about stem cells in snakes. Still, the researchers were able to grow organoids from nine species of snakes.

Its a breakthrough, University of Costa Rica snake venom toxicologist Jos Mara Gutirrez, who was not involved in the study, tells Erin Malsbury at Science magazine. This work opens the possibilities for studying the cellular biology of venom-secreting cells at a very fine level, which has not been possible in the past, Malsbury says.

By looking closely at the organoids, Clevers team gained new insight into how multiple kinds of cells work together to produce the specific mixture of toxins and proteins that results in fully-developed venom.

Venomous snake bites kill between 81,000 and 138,000 people every year, according to the World Health Organization, and cause three times as many amputations and disabilities. The antidote to a snakebite is an antivenom, but each of thousands of venomous snakes have a different biteeach requiring a unique treatment. Even snakes of the same species can produce a slightly different venoms if they live in different regions.

Right now, antivenoms are produced using much the same process as was invented in the 19th century: a live snake is milked for its venom, that venom is injected into a horse. Horses have been used for antivenom production for years because of their docile nature and big veins, as Douglas Main wrote for Popular Mechanics in 2016. They are first injected with adjuvant, which stimulates their immune system to produce enough antibodies to neutralize the venom. Then, researchers take a sample of their blood and separate the antivenom from other component of blood, like plasma, in a centrifuge.

Clevers now hopes to create a bank of dozensand eventually thousandsof organoids from dangerous snakes and other reptiles that could aid in the effort to manufacture effective antivenoms.

"We could just sample one tissue once, and we have a source of [that snakes] venom for eternity," Clevers tells Discover.

Clevers is working with the Dutch biologist Freek Vonk, who he calls the Dutch Steve Irwin, to get samples of the snake species he hopes to include in the venom gland biobank. (Vonk works at Naturalis Biodiversity Center in Leiden and also has some excellent Dutch science tunes available on Spotify.)

With venom from organoids more easily available, the hope is to skip the horse in the antitoxin-production process. Researchers could instead use the organoid-produced venom to test an array of molecules for neutralizing abilities.

It will be interesting to see how the cost of producing venom using this system compares to the cost of purchasing venom milked from live snakes, since cost of antivenom is a key impediment to its wider use in countries where snakebite is a huge issue, like India and Nigeria, as Bangor University molecular zoologist Anita Malhotra tells the Atlantic.

Antivenoms made from lab-grown venom glands are likely years away, but the organoids could also be a big step for studying toxin production in more detail than previously possible. With the cells isolated from the rest of the snake, researchers might be able to look at how they can produce toxic chemicals without damaging themselves, for example.

Clevers tells Discover, We do the most interesting work when we dont have a proposal and just try things.

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