From Salk: “Protein turnover could be clue to living longer”

Salk Institute for Biological Studies

August 30, 2017

Overactive protein synthesis found in premature aging disease may also play role in normal aging.

Scientists at the Salk Institute found that protein synthesis is overactive in people with progeria. The work, described in Nature Communications on August 30, 2017, adds to a growing body of evidence that reducing protein synthesis can extend lifespan—and thus may offer a useful therapeutic target to counter both premature and normal aging.

“The production of proteins is an extremely energy-intensive process for cells,” says Martin Hetzer, vice president and chief science officer of the Salk Institute and senior author of the paper. “When a cell devotes valuable resources to producing protein, other important functions may be neglected. Our work suggests that one driver of both abnormal and normal aging could be accelerated protein turnover.”

Nucleoli in the cell nucleus, stained bright magenta and cyan against the purple backdrop of the nucleus, are enlarged in the progeria cell (right) compared to the normal cell (left). Credit: Salk Institute

Hutchinson-Gilford progeria is a very rare genetic disease causing people to age 8 to 10 times faster than the rest of us and leading to an early death. The rare mutation occurs in one of the structural proteins in the cell nucleus, lamin A, but it has been unclear how a single defective protein in the nucleus causes the myriad rapid-aging features seen in the disease.

Initially, Salk Staff Scientist Abigail Buchwalter, first author of the paper, was interested in whether the mutation was making the lamin A protein less stable and shorter lived. After measuring protein turnover in cultured cells from skin biopsies of both progeria sufferers and healthy people, she found that it wasn’t just lamin A that was affected in the disease.

“We analyzed all the proteins of the nucleus and instead of seeing rapid turnover in just mutant lamin A and maybe a few proteins associated with it, we saw a really broad shift in overall protein stability in the progeria cells,” says Buchwalter. “This indicated a change in protein metabolism that we hadn’t expected.”

Along with the rapid turnover of proteins, the team found that the nucleolus, which makes protein-assembling structures called ribosomes, was enlarged in the prematurely aging cells compared to healthy cells.

Even more intriguing, the team found that nucleolus size increased with age in the healthy cells, suggesting that the size of the nucleolus could not only be a useful biomarker of aging, but potentially a target of therapies to counter both premature and normal aging.

The work supports other research that appears in the same issue showing that decreasing protein synthesis extends lifespan in roundworms and mice. The Hetzer lab plans to continue studying how nucleolus size may serve as a reliable biomarker for aging.

“We always assume that aging is a linear process, but we don’t know that for sure,” says Hetzer, who also holds the Jesse and Caryl Philips Foundation Chair. “A biomarker such as this that tracks aging would be very useful, and could open up new ways of studying and understanding aging in humans.”

The work was funded by the National Institutes of Health, the Nomis Foundation, and the Glenn Center for Aging Research.

See the full article here .

Please help promote STEM in your local schools.

Stem Education Coalition

Every cure has a starting point. Like Dr. Jonas Salk when he conquered polio, Salk scientists are dedicated to innovative biological research. Exploring the molecular basis of diseases makes curing them more likely. In an outstanding and unique environment we gather the foremost scientific minds in the world and give them the freedom to work collaboratively and think creatively. For over 50 years this wide-ranging scientific inquiry has yielded life-changing discoveries impacting human health. We are home to Nobel Laureates and members of the National Academy of Sciences who train and mentor the next generation of international scientists. We lead biological research. We prize discovery. Salk is where cures begin.

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From Salk: “New method to rapidly map the “social networks” of proteins”

Salk Institute for Biological Studies

June 26, 2017
Office of Communications
Tel: (858) 453-4100
press@salk.edu

Salk scientists improved upon a classic approach to mapping the interactions between proteins.

A new mapping method let researchers discover new links (gray lines) between two groups of plant proteins (yellow and blue) that have a common structure (the BBX domain), suggesting many different combinations of interactions, rather than a few, are involved in coordinating cellular programs like flowering time and circadian rhythm. Credit: Salk Institute.

Salk scientists have developed a new high-throughput technique to determine which proteins in a cell interact with each other. Mapping this network of interactions, or “interactome,” has been slow going in the past because the number of interactions that could be tested at once was limited. The new approach, published June 26 in Nature Methods, lets researchers test millions of relationships between thousands of proteins in a single experiment.

“The power of this new approach is in the ability we now have to scale it up,” says senior author Joseph Ecker, professor and director of Salk’s Genomic Analysis Laboratory and investigator of the Howard Hughes Medical Institute. “This assay has the potential to begin to address questions about fundamental biological interactions that we haven’t been able to address before.”

The interactome of a cell, like a map of social networks, lets scientists see who’s working with who in the world of proteins. This helps them figure out the roles of different proteins and piece together the different players in molecular pathways and processes. If a newly discovered protein interacts with lots of other proteins involved in cellular metabolism, for instance, researchers can deduce that’s a likely role for the new protein and potentially target it for treatments related to metabolic dysfunction.

Until now, researchers have typically relied on standard high-throughput yeast two-hybrid (Y2H) assays to determine the interactions between proteins. The system requires using a single known protein—known as the “bait”—to screen against a pool of “prey” proteins. But finding all the interactions between, for instance, 1,000 proteins, would require 1000 separate experiments to screen once for each bait’s interaction partners.

“Current technologies essentially require that interactions detected in primary screening get retested individually,” says Shelly Trigg, an NSF Graduate Research Fellow at the University of California, San Diego, in the Ecker lab, and first author of the new paper. “That may no longer be necessary with the screening depth this approach achieves.”

In their new method, Ecker, Trigg and their colleagues added a twist to the standard Y2H assay for a much more effective way of measuring the interactome. The genes for two proteins, each on their own circle of DNA, are added to the same cell. If the proteins of interest interact inside the cell, a gene called Cre is activated. When turned on, Cre physically splices the two individual circles of DNA together, thus pairing the genes of interacting proteins together so the team can easily find them through sequencing. The team can generate a massive library of yeast cells—each containing different pairs of proteins by introducing random combinations of genes on circular DNA called plasmids. When cells are positive for a protein interaction, the researchers can use genetic sequencing to figure out what the two proteins interacting are, using new high-throughput DNA sequencing technologies similar to those used for human genome sequencing. This way, they’re no longer limited to testing one “bait” protein at a time, but could test the interactions between all the proteins in a library at once.

Joseph Ecker (courtesy of Salk Institute) and Shelly Trigg (courtesy of Austin Trigg)

Ecker’s group tested the new method, dubbed CrY2H-seq, on all the transcription factors—a large class of proteins—in the plant Arabidopsis.

“When you take 1,800 proteins and test the interactions among them, that’s nearly 4 million combinations,” says Ecker. “We did that ten times in a matter of a month.”

They revealed more than 8,000 interactions among those proteins tested, giving them new insight into which Arabidopsis transcription factors interact with each other. The data, they say, helps answer longstanding questions about whether certain groups of transcription factors have set functions. Some of the poorly understood transcription factors, they found, interact with more well-understood factors that regulate the plant’s response to auxin, a hormone involved in coordinating plant growth.

In the future, the method could be scaled up to test larger sets of proteins—human cells, for instance, contain about 20,000 different proteins. This easier and faster method to determine the entire interactome of a cell also opens up the possibility of studying how the interactome changes under different conditions—an experiment that’s never been possible in the past.

Other researchers on the study were Renee Garza, Andrew MacWilliams, Joseph Nery, Anna Bartlett, Rosa Castanon, Adeline Goubil, Joseph Feeney, Ronan O’Malley, Shao-shan Carol Huang, Zhuzhu Zhang, and Mary Galli of the Salk Institute.

See the full article here .

Please help promote STEM in your local schools.

Stem Education Coalition

Every cure has a starting point. Like Dr. Jonas Salk when he conquered polio, Salk scientists are dedicated to innovative biological research. Exploring the molecular basis of diseases makes curing them more likely. In an outstanding and unique environment we gather the foremost scientific minds in the world and give them the freedom to work collaboratively and think creatively. For over 50 years this wide-ranging scientific inquiry has yielded life-changing discoveries impacting human health. We are home to Nobel Laureates and members of the National Academy of Sciences who train and mentor the next generation of international scientists. We lead biological research. We prize discovery. Salk is where cures begin.

From U Washington: “Feedback from 1000s of designs could transform protein engineering”

University of Washington

07.12.2017
Leila Gray
206.685.0381
leilag@uw.edu

A model of a computationally designed mini-protein from a large-scale study to test structural stability. Institute for Protein Design.

The stage is set for a new era of data-driven protein molecular engineering as advances in DNA synthesis technology merge with improvements in computational design of new proteins.

This week’s Science reports the largest-scale testing of folding stability for computationally designed proteins, made possible by a new high-throughput approach.

The scientists are from the UW Medicine Institute for Protein Design at the University of Washington in Seattle and the University of Toronto in Ontario.

The lead author of the paper is Gabriel Rocklin, a postdoctoral fellow in biochemistry at the University of Washington School of Medicine. The senior authors are Cheryl Arrowsmith, of the Princess Margaret Cancer Center, the Structural Genomics Consortium and the Department of Medical Biophysics at the University of Toronto, and David Baker, UW professor of biochemistry and a Howard Hughes Medical Institute investigator.

Proteins are biological workhorses. Researchers want to build new molecules, not found naturally, that can perform tasks in preventing or treating disease, in industrial applications, in energy production, and in environmental cleanups.

“However, computationally designed proteins often fail to form the folded structures that they were designed to have when they are actually tested in the lab,” Rocklin said.

In the latest study, the researchers tested more than 15,000 newly designed mini-proteins that do not exist in nature to see whether they form folded structures. Even major protein design studies in the past few years have generally examined only 50 to 100 designs.

“We learned a huge amount at this new scale, but the taste has given us an even larger appetite,” said Rocklin. “We’re eager to test hundreds of thousands of designs in the next few years.”

The most recent testing led to the design of 2,788 stable protein structures and could have many bioengineering and synthetic biology applications. Their small size may be advantageous for treating diseases when the drug needs to reach the inside of a cell.

Design model structures from a comprehensive mutational analysis of stability in natural and designed proteins. UW Institute for Protein Design.

Proteins are made of amino acid chains with specific sequences, and natural protein sequences are encoded in cellular DNA. These chains fold into 3-dimensional conformations. The sequence of the amino acids in the chain guide where it will bend and twist, and how parts will interact to hold the structure together.

For decades, researchers have studied these interactions by examining the structures of naturally occurring proteins. However, natural protein structures are typically large and complex, with thousands of interactions that collectively hold the protein in its folded shape. Measuring the contribution of each interaction becomes very difficult.

The scientists addressed this problem by computationally designing their own, much simpler proteins. These simpler proteins made it easier to analyze the different types of interactions that hold all proteins in their folded structures.

“Still, even simple proteins are so complicated that it was important to study thousands of them to learn why they fold,” Rocklin said. “This had been impossible until recently, due to the cost of DNA. Each designed protein requires its own customized piece of DNA so that it can be made inside a cell. This has limited previous studies to testing only tens of designs.”

To encode their designs of short proteins in this project, the researchers used what is called DNA oligo library synthesis technology. It was originally developed for other laboratory protocols, such as large gene assembly. One of the companies that provided their DNA is CustomArray in Bothell, Wash. They also used DNA libraries made by Agilent in Santa Clara, Calif., and Twist Bioscience in San Francisco.

By repeating the cycle of computation and experimental testing over several iterations, the researchers learned from their design failures and progressively improved their modeling. Their design success rate rose from 6 percent to 47 percent. They also produced stable proteins in shapes where all of their first designs failed.

Their large set of stable and unstable mini-proteins enabled them to quantitatively analyze which protein features correlated with folding. They also compared the stability of their designed proteins to similarly sized, naturally occurring proteins.

The most stable natural protein the researchers identified was a much-studied protein from the bacteria Bacillus stearothermophilus.

The researchers compared the stability of some of their designed proteins to a natural protein found in a bacteria that withstands the high temperatures of hot springs like those in Yellowstone. Alice C. Gray.

This organism basks in high temperatures, like those in hot springs and ocean thermal vents. Most proteins lose their folded structures under such high temperature conditions. Organisms that thrive there have evolved highly stable proteins that stay folded even when hot.

“A total of 774 designed proteins had higher stability scores than this most protease-resistant monomeric protein,” the researchers noted. Proteases are enzymes that break down proteins, and were essential tools the researchers used to measure stability for their thousands of proteins.

The researchers predict that, as DNA synthesis technology continues to improve, high-throughput protein design will become possible for larger, more complex protein structures.

“We are moving away from the old style of protein design, which was a mix of computer modeling, human intuition, and small bits of evidence about what worked before.” Rocklin said. “Protein designers were like master craftsmen who used their experience to hand-sculpt each piece in their workshop. Sometimes things worked, but when they failed it was hard to say why. Our new approach lets us collect an enormous amount of data on what makes proteins stable. This data can now drive the design process.”

Their study was supported by the Howard Hughes Medical Institute and the Natural Sciences and Research Council of Canada. Rocklin is a Merck Fellow of the Life Sciences Research Foundation. Arrowsmith holds a Canadian Research Chair in Structural Genomics.

This work was facilitated by the Hyak supercomputer at the University of Washington and by donations of computing time from Rosetta@home participants.

Rosetta@home project, a project running on BOINC software from UC Berkeley

Dr. David Baker, Baker Lab, U Washington

Hyak supercomputer at the University of Washington

See the full article here .

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The University of Washington is one of the world’s preeminent public universities. Our impact on individuals, on our region, and on the world is profound — whether we are launching young people into a boundless future or confronting the grand challenges of our time through undaunted research and scholarship. Ranked number 10 in the world in Shanghai Jiao Tong University rankings and educating more than 54,000 students annually, our students and faculty work together to turn ideas into impact and in the process transform lives and our world. For more about our impact on the world, every day.
So what defines us —the students, faculty and community members at the University of Washington? Above all, it’s our belief in possibility and our unshakable optimism. It’s a connection to others, both near and far. It’s a hunger that pushes us to tackle challenges and pursue progress. It’s the conviction that together we can create a world of good. Join us on the journey.

From CSIRO: “Data visualisation isn’t just for communication, it’s also a research tool”

Commonwealth Scientific and Industrial Research Organisation

27th June 2017
Seán I. O’Donoghue
James B. Procter

A collage of biological data visualisations. Image from C. Stolte, B.F. Baldi, S.I. O’Donoghue, C. Hammang, D.K.G. Ma, and G.T. Johnson, CC BY.

At the heart of the scientific method lies the ability to make sense from data.

However, this is a challenge in the fast-moving field of biotechnology, where new experimental methods are creating huge amounts of complex data. These data promise to revolutionise healthcare, food and agriculture, but it can be difficult to extract answers to specific research questions from these sets of numbers.

Data visualisation can help. Our eyes deliver information very rapidly to our brains, and then sophisticated pattern recognition abilities take over. Well-designed visualisation tools can reveal discoveries that would otherwise remain buried.

Below we highlight three data visualisation tools we have developed to help life scientists find relevant and useful information among the noise. The visualisation principles used in these tools are general and help in many complex data challenges.

Managing large data sets

Proteins and other molecules in our bodies exist as complex 3D structures that constantly change shape and interact with each other. Mapping out the many possible ways that proteins can be structured helps scientists understand how biological processes work, and may inform drug development and treating diseases such as cancer.

Thanks to decades of research worldwide, we now have reliable, evidence-based 3D structures for tens of thousands of proteins, plus more than 100 million models of protein structures.

These models are useful for learning about life’s molecular processes – such as how RNA and proteins are made – however, the large number of models can make it difficult for scientists to pin down which specific models can help answer a particular research question.

To address this difficulty, one of us (Seán O’Donoghue) and colleagues developed Aquaria, a tool using the visualisation principle of “overview first, details on demand”. By using a technique called “clustering”, Aquaria creates a concise visual overview of all structural models available for any specific protein.

An overview of all 3D structural models available for p53, a protein that protects against cancer. Image created using Aquaria. S.I. O’Donoghue and C. Stolte, Author provided.

The image above shows this overview for p53, a protein that protects against cancer. Each cluster of related 3D models can be interactively expanded and explored (bottom of the image), helping scientists find the most useful models suited to address a specific research question.

Once a suitable model is found it is shown (top of the image), with dark colouring used to indicate regions where the structure of the model is less certain. In addition, yellow, blue and green are used to highlight different shapes within the structure, which helps scientists understand how the protein is arranged in three dimensions.

Viewing connections between different datasets

Sometimes, we need to look at data from multiple viewpoints. This is particularly true for a field of research known as sequencing. Sequencing involves determining the precise order of the chemical building blocks that make up DNA, RNA and protein. Knowing these sequences and comparing how they vary between individuals can tell us about mutations that cause disease and reveal how we evolved.

One of the most widely used tools for visualising sequences is Jalview, co-developed by one of us (James Procter), which brings together the huge amounts of data that are created through sequencing.

Jalview employs two principles – “linking and brushing” and “multiple coordinated views” – to bring together different types of information. Jalview also allows other tools to be connected, enabling scientists to navigate through complex, interrelated datasets.

The example below shows a family of proteins known as Aquaporins, which are molecular channels important for water balance and nutrient transport in cells. Aligning these protein’s sequences (close up on right) allows them to be clustered into a tree (shown top-left, with birds-eye view of the protein alignment next door). DNA mutations are mapped onto the protein alignment (shown in red), and these colours also locate the mutations in protein structure (bottom left).

Linked brushing and multiple data visualisations allow potential disease mutations to be identified at the core of Aquaporin, a protein important for water balance and nutrient transport. Image created using Jalview linked with UCSF Chimera. J.B. Procter, Author provided.

Visualising networks that change over time

Scientists are aiming to unravel diseases – such as obesity – by studying small changes that take place within our cells.

For example, food that we eat triggers the release of insulin into our blood stream, which then tells fat cells to store rather than release energy. This process ultimately influences our body weight.

Cells are tiny, but they are hives of activity. Thanks to recent advances in techniques such as mass spectrometry, we can now map the tens of thousands of events that are happening within each of our cells in response to hormones such as insulin.

The difficulty for scientists is to try to view this huge amount of information in an accurate and simple way, and one that reflects the chain of events in a cell that matter to our overall health.

One of us (Seán O’Donoghue) and colleagues developed Minardo, an approach that creates a sort of timeline of events that happen inside a cell. Minardo uses the principle that position on a viewing screen is the most effective visualisation strategy. The resulting visualisation helps scientists identify exactly what is going on inside a healthy cell, and what might be different in a diseased cell.

The image here shows (beginning top left, then clockwise) the sequence of events that take place after insulin (in pink) binds to the surface of a fat cell. The consequences of insulin binding include switching off the release of energy stores from the cell (around 1 minute after insulin binds), and switching on energy storage (around 5 minutes after insulin binds).

The sequence of key events within a human fat cell following insulin binding to its receptor (top left, pink). Image created using Minardo. D.K.G. Ma, C. Stolte, J.R. Krycer, D.E. James, and S.I. O’Donoghue, Author provided.

VIZBI, an international visualisation community

In building these tools, we aim to visualise data as clearly as possible, so the viewer can focus on the science.

Aquaria, Jalview and Minardo are freely accessible and used by tens of thousands of scientists and students worldwide – an accomplishment that we are proud of.

However, our tools address only three specific research questions – biology has thousands more. Tailored visualisations of this kind need an interdisciplinary team, take months to prototype and require years to develop into robust and usable tools.

Realising this, in 2010, we created an international initiative called VIZBI to connect tool-builders and raise the standard of data visualisation in biology. In June 2017, VIZBI and associated events came to the Asia-Pacific region for the first time.

The overwhelming complexity of biological data, substantial time and effort is required to create effective visualisation tools not just for communication but also for research itself.

Seán I. O’Donoghue, Senior Faculty Member at the Garvan Institute, Conjoint Professor at UNSW, and Senior Principal Research Scientist, CSIRO and James B. Procter, Jalview Coordinator, Bioinformatician and Open Source Software Developer, University of Dundee

See the full article here .

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CSIRO, the Commonwealth Scientific and Industrial Research Organisation, is Australia’s national science agency and one of the largest and most diverse research agencies in the world.

From Salk: “New method to rapidly map the ‘social networks’ of proteins”

Salk Institute for Biological Studies

June 26, 2017

Salk scientists improved upon a classic approach to mapping the interactions between proteins.

A new mapping method let researchers discover new links (gray lines) between two groups of plant proteins (yellow and blue) that have a common structure (the BBX domain), suggesting many different combinations of interactions, rather than a few, are involved in coordinating cellular programs like flowering time and circadian rhythm. Credit: Salk Institute

Salk scientists have developed a new high-throughput technique to determine which proteins in a cell interact with each other. Mapping this network of interactions, or “interactome,” has been slow going in the past because the number of interactions that could be tested at once was limited. The new approach, published June 26 in Nature Methods, lets researchers test millions of relationships between thousands of proteins in a single experiment.

“The power of this new approach is in the ability we now have to scale it up,” says senior author Joseph Ecker, professor and director of Salk’s Genomic Analysis Laboratory and investigator of the Howard Hughes Medical Institute. “This assay has the potential to begin to address questions about fundamental biological interactions that we haven’t been able to address before.”

The interactome of a cell, like a map of social networks, lets scientists see who’s working with who in the world of proteins. This helps them figure out the roles of different proteins and piece together the different players in molecular pathways and processes. If a newly discovered protein interacts with lots of other proteins involved in cellular metabolism, for instance, researchers can deduce that’s a likely role for the new protein and potentially target it for treatments related to metabolic dysfunction.

Until now, researchers have typically relied on standard high-throughput yeast two-hybrid (Y2H) assays to determine the interactions between proteins. The system requires using a single known protein—known as the “bait”—to screen against a pool of “prey” proteins. But finding all the interactions between, for instance, 1,000 proteins, would require 1000 separate experiments to screen once for each bait’s interaction partners.

“Current technologies essentially require that interactions detected in primary screening get retested individually,” says Shelly Trigg, an NSF Graduate Research Fellow at the University of California, San Diego, in the Ecker lab, and first author of the new paper. “That may no longer be necessary with the screening depth this approach achieves.”

In their new method, Ecker, Trigg and their colleagues added a twist to the standard Y2H assay for a much more effective way of measuring the interactome. The genes for two proteins, each on their own circle of DNA, are added to the same cell. If the proteins of interest interact inside the cell, a gene called Cre is activated. When turned on, Cre physically splices the two individual circles of DNA together, thus pairing the genes of interacting proteins together so the team can easily find them through sequencing. The team can generate a massive library of yeast cells—each containing different pairs of proteins by introducing random combinations of genes on circular DNA called plasmids. When cells are positive for a protein interaction, the researchers can use genetic sequencing to figure out what the two proteins interacting are, using new high-throughput DNA sequencing technologies similar to those used for human genome sequencing. This way, they’re no longer limited to testing one “bait” protein at a time, but could test the interactions between all the proteins in a library at once.

Joseph Ecker (courtesy of Salk Institute) and Shelly Trigg (courtesy of Austin Trigg)

Ecker’s group tested the new method, dubbed CrY2H-seq, on all the transcription factors—a large class of proteins—in the plant Arabidopsis.

“When you take 1,800 proteins and test the interactions among them, that’s nearly 4 million combinations,” says Ecker. “We did that ten times in a matter of a month.”

They revealed more than 8,000 interactions among those proteins tested, giving them new insight into which Arabidopsis transcription factors interact with each other. The data, they say, helps answer longstanding questions about whether certain groups of transcription factors have set functions. Some of the poorly understood transcription factors, they found, interact with more well-understood factors that regulate the plant’s response to auxin, a hormone involved in coordinating plant growth.

In the future, the method could be scaled up to test larger sets of proteins—human cells, for instance, contain about 20,000 different proteins. This easier and faster method to determine the entire interactome of a cell also opens up the possibility of studying how the interactome changes under different conditions—an experiment that’s never been possible in the past.

Other researchers on the study were Renee Garza, Andrew MacWilliams, Joseph Nery, Anna Bartlett, Rosa Castanon, Adeline Goubil, Joseph Feeney, Ronan O’Malley, Shao-shan Carol Huang, Zhuzhu Zhang, and Mary Galli of the Salk Institute.

The work and the researchers involved were supported by grants from the U.S. Department of Energy, National Science Foundation Graduate Research Fellowship Program, Howard Hughes Medical Institute, and Mary K. Chapman Foundation.

See the full article here .

Please help promote STEM in your local schools.

Stem Education Coalition

Every cure has a starting point. Like Dr. Jonas Salk when he conquered polio, Salk scientists are dedicated to innovative biological research. Exploring the molecular basis of diseases makes curing them more likely. In an outstanding and unique environment we gather the foremost scientific minds in the world and give them the freedom to work collaboratively and think creatively. For over 50 years this wide-ranging scientific inquiry has yielded life-changing discoveries impacting human health. We are home to Nobel Laureates and members of the National Academy of Sciences who train and mentor the next generation of international scientists. We lead biological research. We prize discovery. Salk is where cures begin.

From PNNL: “Tackling infectious disease — one protein at a time”

PNNL Lab

June 08, 2017
Tom Rickey
tom.rickey@pnnl.gov
(509) 375-3732

The structure of a protein named thioredoxin. Garry Buchko and colleagues used NMR to solve the structure of the protein, which is found in an infection often conveyed by ticks. Credit: SSGCID

A protein in the pathogen that causes cryptosporidiosis. The microbe can cause mild to severe diarrhea in people who accidentally swallow a mouthful of contaminated water. Credit: SSGCID

Buchko and colleagues solved this structure of a protein found in the organism that causes malaria. Credit: SSGCID

A protein in the microbe that causes melioidosis, which occurs most often in people who live in tropical climates. Infection often starts in the lungs when contaminated dust or soil is inhaled. Credit: SSGCID

A protein in the micro-organism that causes giardiasis, which translates to nausea, abdominal pain, fatigue and other symptoms in hundreds of millions of people worldwide each year. Credit: SSGCID

Garry Buchko and his colleagues are at the front line battling some of the most fearsome enemies that humanity has ever known: Tuberculosis. Pneumonia. Ebola. Plague. Botulism.

But he is not in a hospital or field tent, taking vital signs or administering medications. Instead, Buchko the biochemist is in the laboratory, where the front line is the world of proteins — the molecular workhorses that keep all organisms functioning properly and make life possible. Using some of the highest-tech approaches available, he works with scientists in the Pacific Northwest to uncover crucial information needed to develop better treatments or vaccines against a host of nasty agents that can cause body aches, nausea, fatigue, food poisoning, diarrhea, ulcers, difficulty breathing, and death.

Buchko does such work as part of the Seattle Structural Genomics Center for Infectious Disease, one of two centers funded by the National Institute of Allergy and Infectious Diseases tasked with solving the structure of proteins that enable pathogens to live, thrive, and infect people. Scientists from four institutions partner in the effort: The Center for Infectious Disease Research, Beryllium Discovery Corp., the University of Washington, and the Department of Energy’s Pacific Northwest National Laboratory, where Buchko does his research.

This week the team reached a milestone, announcing that its scientists have solved the 3-D structure of the 1,000th protein from more than 70 organisms that cause infectious disease in people. The proteins the team has studied come from microbes that cause several serious diseases, including tuberculosis, Listeria, Giardia, Ebola, anthrax, Clostridium difficile (C. diff) infection, Legionella, Lyme, chlamydia and the flu.

While the proteins isolated for study are not pathogenic, the structural information provides scientists the opportunity to design molecules that will knock out an essential process in such microbes.

It is challenging work. Protein shapes are very complex — many look a lot like convoluted roller coasters with multiple twists, turns, and loops, all squeezed into a tiny space just one ten-thousandth the width of a human hair. The arrangement and lengths of these features give each protein its specific biochemical properties — what other molecules they will interact with and precisely what they will do in the body. Knowing the precise shape of proteins provides a blueprint for scientists searching for new ways to disable the pathogens and stop the diseases they can cause.

Buchko’s expertise is with nuclear magnetic resonance or NMR, which is very similar to the magnetic resonance imaging technique widely used by physicians to diagnose all manner of medical conditions. Buchko scrutinizes proteins from pathogens drawing upon the NMR technology at EMSL, the Environmental Molecular Sciences Laboratory, a DOE Office of Science user facility at PNNL.

While the end result is an atomic-level picture, it’s not as simple as snapping a photograph. Instead, Buchko places the protein inside an NMR spectrometer and records information about the orientation, energy and other properties of all the atomic nuclei in the molecule. Then he interprets the information and feeds the thousands of pieces of data into a computer program to calculate the position of every atom, resulting in a complete 3-D reconstruction of the protein. Data analysis is crucial to getting the structures correct.

Buchko has been an author on more than 20 of the team’s studies in the last 10 years. Among his targets are pathogens that cause tuberculosis, malaria, cat scratch fever, and hemorrhagic fevers, as well as water-based parasites that cause severe diarrhea and abdominal pain.

SSGCID scientists have published more than 100 manuscripts detailing their findings. In addition, all the structures are immediately shared with the scientific community through a public database called the Protein Data Bank. As a result, the structures have been used in nearly 600 scientific papers from other laboratories in academia, research institutes, and pharmaceutical companies around the world that are working on human pathogens. Sharing its findings so that scientists worldwide can make further discoveries is at the heart of SSGCID’s mission.

The Seattle-based center is one of two centers funded by NIAID (contract # HHSN272201200025C). The other, based in Chicago, is the Center for Structural Genomics of Infectious Diseases and includes another DOE laboratory, Argonne National Laboratory, among its participants. The SSGCID is led by Peter Myler, professor and director of core services at the Center for Infectious Disease Research.

“When the SSGCID solves protein structures, it lays the foundation for researchers at CID Research and around the world to find new drugs, therapies and vaccine candidates for diseases that kill thousands each year,” said Myler. “I’m very proud of the hard work carried out by our team and our dedicated partners.”

EMSL, the Environmental Molecular Sciences Laboratory, is a DOE Office of Science User Facility. Located at Pacific Northwest National Laboratory in Richland, Wash., EMSL offers an open, collaborative environment for scientific discovery to researchers around the world. Its integrated computational and experimental resources enable researchers to realize important scientific insights and create new technologies. Follow EMSL on Facebook, LinkedIn and Twitter.

Full information about the structures the team has solved is available on the SSGCID web site.

See the full article here .

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Pacific Northwest National Laboratory (PNNL) is one of the United States Department of Energy National Laboratories, managed by the Department of Energy’s Office of Science. The main campus of the laboratory is in Richland, Washington.

PNNL scientists conduct basic and applied research and development to strengthen U.S. scientific foundations for fundamental research and innovation; prevent and counter acts of terrorism through applied research in information analysis, cyber security, and the nonproliferation of weapons of mass destruction; increase the U.S. energy capacity and reduce dependence on imported oil; and reduce the effects of human activity on the environment. PNNL has been operated by Battelle Memorial Institute since 1965.

From Caltech: “Protein Chaperone Takes Its Job Seriously”

Caltech

02/02/2017

Whitney Clavin
(626) 395-1856
wclavin@caltech.edu

Structural rendering of a ribosomal protein (yellow and red) bound to its chaperone (blue). By capturing an atomic-resolution snapshot of the pair of proteins interacting with each other, Ferdinand Huber, a graduate student in the lab of André Hoelz revealed that chaperones can protect their ribosomal proteins by tightly packaging them up. The red region illustrates where the dramatic shape alterations occur when the ribosomal protein is released from the chaperone during ribosome assembly. Credit: Huber and Hoelz/Caltech

A diagram of the cell showing the process by which chaperone proteins (red) transport ribosomal proteins (beige) to the nucleus. The chaperones bind to the ribosomal proteins and usher them into the nucleus, while also protecting the proteins from liquidation machinery. Once a ribosomal protein reaches a growing ribosome (green and purple), the chaperone releases it. The nearly complete ribosome units exit the nucleus where they undergo final assembly. Credit: Huber and Hoelz/Caltech

For proteins, this would be the equivalent of the red-carpet treatment: each protein belonging to the complex machinery of ribosomes—components of the cell that produce proteins—has its own chaperone to guide it to the right place at the right time and protect it from harm.

In a new Caltech study, researchers are learning more about how ribosome chaperones work, showing that one particular chaperone binds to its protein client in a very specific, tight manner, almost like a glove fitting a hand. The researchers used X-ray crystallography to solve the atomic structure of the ribosomal protein bound to its chaperone.

“Making ribosomes is a bit like baking a cake. The individual ingredients come in protective packaging that specifically fits their size and shape until they are unwrapped and blended into a batter,” says André Hoelz, professor of chemistry at Caltech, a Heritage Medical Research Institute (HMRI) Investigator, and Howard Hughes Medical Institute (HHMI) Faculty Scholar.” What we have done is figure out how the protective packaging fits one ribosomal protein, and how it comes unwrapped.” Hoelz is the principal investigator behind the study published February 2, 2017, in the journal Nature Communications. The finding has potential applications in the development of new cancer drugs designed specifically to disable ribosome assembly.

In all cells, genetic information is stored as DNA and transcribed into mRNAs that code for proteins. Ribosomes translate the mRNAs into amino acids, linking them together into polypeptide chains that fold into proteins. More than a million ribosomes are produced per day in an animal cell.

Building ribosomes is a formidable undertaking for the cell, involving about 80 proteins that make up the ribosome itself, strings of ribosomal RNA, and more than 200 additional proteins that guide and regulate the process. “Ribosome assembly is a dynamic process, where everything happens in a certain order. We are only now beginning to elucidate the many steps involved,” says Hoelz.

To make matters more complex, the proteins making up a ribosome are first synthesized outside the nucleus of a cell, in the cytoplasm, before being transported into the nucleus where the initial stages of ribosome assembly take place.

Chaperone proteins help transport ribosomal proteins to the nucleus while also protecting them from being chopped up by a cell’s protein shredding machinery. The components that specifically aim this machinery at unprotected ribosomal proteins, recently identified by Raymond Deshaies, professor of biology at Caltech and an HHMI Investigator, ensures that equal numbers of the various ribosomal proteins are available for building the massive structure of a ribosome.

Structural rendering of a chaperone called Acl4 bound to ribosomal protein L4

Previously, Hoelz and his team, in collaboration with the laboratory of Ed Hurt at the University of Heidelberg, discovered that a ribosomal protein called L4 is bound by a chaperone called “Assembly chaperone of RpL4,” or Acl4. The chaperone ushers L4 through the nucleus, protecting it from harm, and delivers it to a developing ribosome at a precise time and location. In the new study, the team used X-ray crystallography, a process that involves exposing protein crystals to high-energy X-rays, to solve the structure of the bound pair. The technique was performed at Caltech’s Molecular Observatory beamline at the Stanford Synchrotron Radiation Lightsource.

“This was not an easy structure to solve,” says Ferdinand Huber, a graduate student at Caltech in the Hoelz lab and first author of the new study. “Solving the structure was incredibly exciting because you could see with your eyes, for the very first time, how the chaperone embraces the ribosomal protein to protect it.”

Hoelz says that the structure was a surprise because it was not known previously that chaperones hold on to their ribosomal proteins so tightly. He says they want to study other chaperones in the future to see if they function in a similar fashion to tightly guard ribosomal proteins. The results may lead to the development of new drugs for cancer therapy by preventing cancer cells from supplying the large numbers of ribosomes required for tumor growth.

The study, called “Molecular Basis for Protection of Ribosomal Protein L4 from Cellular Degradation,” was funded by a PhD fellowship of the Boehringer Ingelheim Fonds, a Faculty Scholar Award of the Howard Hughes Medical Research Institute, a Heritage Medical Research Institute Principal Investigatorship, a Kimmel Scholar Award of the Sidney Kimmel Foundation for Cancer Research, a Teacher-Scholar Award of the Camille & Henry Dreyfus Foundation, and Caltech startup funds.

See the full article here .

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The California Institute of Technology (commonly referred to as Caltech) is a private research university located in Pasadena, California, United States. Caltech has six academic divisions with strong emphases on science and engineering. Its 124-acre (50 ha) primary campus is located approximately 11 mi (18 km) northeast of downtown Los Angeles. “The mission of the California Institute of Technology is to expand human knowledge and benefit society through research integrated with education. We investigate the most challenging, fundamental problems in science and technology in a singularly collegial, interdisciplinary atmosphere, while educating outstanding students to become creative members of society.”

From UCSB: “Origami of the Cell”

UC Santa Barbara

January 30, 2017
Julie Cohen

These images show a reduction in the number of macrophages infiltrating atherosclerotic plaques (in green) in animals treated with the IRE1 inhibitor.
Photo Credit: Courtesy IMAGE

This shows a reduction in atherosclerotic lesions in the aorta of mice (in red) when treated with the IRE1 inhibitor.
Photo Credit: Courtesy IMAGE

In the ancient Japanese art of origami, paper must be folded precisely and following a specific order to create the desired result — say, a crane or lotus flower. It’s a complex pursuit that requires keen attention to detail and utmost accuracy.

An equally precise biological process in living cells gives rise to proteins, the large biomolecules essential for life.

Proteins begin life as long strings of amino acids that must fold into the three-dimensional shape prescribed for their particular biological function. When proteins don’t fold as expected — think badly misshapen crane — the cells activate stress responses meant to mitigate the problem. But severe or prolonged stress produces an acute response: Cell death is triggered to protect the organism.

Sustained activation of one such reaction — the unfolded protein response, or UPR — has been implicated in a number of diseases. Seeking to illuminate a piece of this biological puzzle, an international team of scientists, including UC Santa Barbara cell biologist Diego Acosta-Alvear, examined the role of a central UPR component, a stress sensor protein called IRE1 (inositol-requiring enzyme 1), in atherosclerosis.

The researchers found that blocking IRE1 with a small molecule prevented the progression of atherosclerosis in mice. The findings appear in the Proceedings of the National Academy of Sciences.

“A healthy cell has one type of stress response network wiring and it’s likely that a diseased cell accommodates that wiring to survive,” said Acosta-Alvear, an assistant professor in UCSB’s Department of Molecular, Cellular and Developmental Biology. “Stress response networks control the life vs. death decision in cells, and since a diseased cell is nowhere near its comfort zone, rewiring its stress responses allows it to avoid or delay cell death even when conditions are adverse. That’s what we wanted to understand: how a diseased cell does that and why it happens.”

The UPR is triggered when the normal functions of the endoplasmic reticulum — the cell’s largest organelle in charge of making and folding proteins — are compromised. Though the UPR usually promotes healthy endoplasmic reticulum function, sustained UPR activation sometimes results in diseases such as atherosclerosis, the deposition of fatty plaques on artery walls, among other conditions. Understanding what happens with the UPR in disease is key to illuminating the normal operation of this essential pathway — and to providing insights into the development of targeted therapies.

Endoplasmic reticulum stress is triggered not only by protein-folding problems, but also by fatty acids, explained Acosta-Alvear. Fat-induced stress and metabolic overload of the endoplasmic reticulum can alter its function, triggering chronic inflammation, which plays an important role in the development of atherosclerosis.

In this research, the scientists disturbed endoplasmic reticulum function by introducing saturated fatty acids into cells to induce lipotoxic stress. This in turn activated the UPR and IRE1.

Active IRE1 relays the protein-folding stress information to the cell nucleus by controlling the production of a very potent transcription activator, XBP1 (X-box binding protein-1). Transcription activators are proteins involved in the process of converting, or transcribing, DNA into RNA.

The investigators’ analyses demonstrated that XBP1 was responsible for turning on pro-atherogenic genes. They then treated mice with a compound that blocked IRE1.

“The end result was that if the transcription factor was not produced, the pro-atherogenic genes were not turned on, which mitigated the progression of the disease,” Acosta-Alvear said. “This research is a proof-of-concept study showing that blocking this single critical enzyme delivers a desirable therapeutic benefit. It’s a first step in mechanistically understanding how cellular stress responses are wired in specific contexts.”

See the full article here .

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The University of California, Santa Barbara (commonly referred to as UC Santa Barbara or UCSB) is a public research university and one of the 10 general campuses of the University of California system. Founded in 1891 as an independent teachers’ college, UCSB joined the University of California system in 1944 and is the third-oldest general-education campus in the system. The university is a comprehensive doctoral university and is organized into five colleges offering 87 undergraduate degrees and 55 graduate degrees. In 2012, UCSB was ranked 41st among “National Universities” and 10th among public universities by U.S. News & World Report. UCSB houses twelve national research centers, including the renowned Kavli Institute for Theoretical Physics.

From Scripps: “New Method Could Turbocharge Drug Discovery, Protein Research”

Scripps Research Institute

January 30, 2017
Mo writer credit

A team led by scientists at The Scripps Research Institute (TSRI) has developed a versatile new method that should enhance the discovery of new drugs and the study of proteins.

The new method enables researchers to quickly find small molecules that bind to hundreds of thousands of proteins in their native cellular environment. Such molecules, called ligands, can be developed into important tools for studying how proteins work in cells, which may lead to the development of new drugs. The method can be used even without prior knowledge of protein targets to discover ligand molecules that disrupt a biological process of interest—and to quickly identify the proteins to which they bind.

“This ,” said co-lead author Christopher G. Parker, a research associate in the laboratory of TSRI Professor Benjamin F. Cravatt, chairman of the Department of Chemical Biology.

This research was published ahead of print recently in the journal Cell.

Authors of the new study included (left to right) TSRI’s Andrea Galmozzi, Christopher Parker, Benjamin Cravatt and Enrique Saez. (Photo by Madeline McCurry-Schmidt.)

Finding New Partners for Un-targetable Proteins

About 25,000 proteins are encoded in the human genome, but public databases list known ligands for only about 10 percent of them. Biologists have long sought better tools for exploring this terra incognita.

The new method involves the development of a set of small, but structurally varied, candidate ligand molecules known as “fragments.” Each candidate ligand is modified with a special chemical compound so that, when it binds with moderate affinity to a protein partner, it can be made to stick permanently to that partner by a brief exposure to UV light. A further modification provides a molecular handle by which scientists can grab and isolate these ligand-protein pairs for analysis.

For an initial demonstration, the team assembled a small “library” of candidate ligands whose structural features include many that are found in existing drugs. By applying just 11 of them to human cells, the researchers identified more than 2,000 distinct proteins that had bound to one or more of the ligands.

These ligand-bound proteins include many from categories—such as transcription factors—that previously had been considered “un-ligandable” and therefore un-targetable with drugs. In fact, only 17 percent of these proteins have known ligands, according to the widely used DrugBank database.

The researchers used further methods to identify, for many ligand-protein interactions, the site on the protein where the coupling occurred.

The candidate ligands initially used to screen for protein binding partners are generally too small to bind to their partners tightly enough to disrupt their functions in cells. But the team showed that, in multiple cases, that these initial small (“fragment”) ligands could be developed into larger, more complex molecules that display higher-affinity interactions and disrupt their protein partner’s functions.

A New Type of Functional Screen

For a final demonstration, collaborating chemists at Bristol-Myers Squibb helped create a library of several hundred slightly more complex candidate ligands. With TSRI colleagues Associate Professor Enrique Saez and co-first author Research Associate Andrea Galmozzi, the team then tested these ligands to find any that could promote the maturation of fat cells (adipocytes)—a process that in principle can alleviate the insulin resistance that leads to type 2 diabetes.

Traditional functional screens of this type do not pinpoint the proteins or other molecules through which the effect on the cell occurs. But with this new discovery method, the researchers quickly found not only a ligand that strongly promotes adipocyte maturation but also its binding partner, PGRMC2, a protein about which little was known.

“We found a new ‘druggable’ pathway, and we also seem to have uncovered some new biology—despite the fact that adipocyte maturation and other diabetes-related pathways have been studied a lot already,” Parker said.

“With this method, we look forward to exploring much more thoroughly the druggability of human proteins and accelerating investigations of protein biology,” Cravatt added.

In addition to Parker, Cravatt, Saez and Galmozzim authors of the study, “Ligand and Target Discovery by Fragment-Based Screening in Human Cells,” included TSRI’s Yujia Wang, Kenji Sasaki, Christopher Joslyn and Arthur S. Kim; Bruno Correia of Ecole Polytechnique Federal in Lausanne, Switzerland; and Cullen Cavallaro, Michael Lawrence and Stephen Johnson of Bristol-Myers Squibb.

The work was supported by grants from the National Institutes of Health (DK099810; CA132630; 1S10OD16357), an American Cancer Society Postdoctoral Fellowship and a fellowship from the American Heart Association.

See the full article here .

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The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

From Weizmann: Women in STEM – “Staff Scientist: Dr. Miriam Eisenstein”

Weizmann Institute of Science

30.01.2017
No writer credit found

Name: Dr. Miriam Eisenstein
Department: Chemical Research Support

“The modeling of molecules on the computer,” says Dr. Miriam Eisenstein, Head of the Macromolecular Modeling Unit of the Weizmann Institute of Science’s Chemical Research Support Department, “is sometimes the only way to understand exactly how such complex molecules as proteins interact.”

Eisenstein was one of the first to develop molecular docking methods while working with Prof. Ephraim Katzir – over two decades ago – and she has worked in collaboration with many groups at the Weizmann Institute.

But even with all her experience, protein interactions can still surprise her. This was the case in a recent collaboration with the lab group of Prof. Hagit Eldar-Finkelman of Tel Aviv University, in research that was hailed as a promising new direction for finding treatments for Alzheimer’s disease. Eldar-Finkelman and her group were investigating an enzyme known as GSK-3, which affects the activity of various proteins by clipping a particular type of chemical tag, known as a phosphate group, onto them. GSK-3 thus performs quite a few crucial functions in the body, but it can also become overactive, and this extra activity has been implicated in a number of diseases, including diabetes and Alzheimer’s.

The Tel Aviv group, explains Eisenstein, was exploring a new way of blocking, or at least damping down, the activity of this enzyme. GSK-3 uses ATP — a small, phosphate-containing molecule — in the chemical tagging process, transferring one of the ATP phosphate groups to a substrate. The ATP binding site on the enzyme is often targeted with ATP-like drug compounds that by themselves binding prevent the ATP from binding, thus blocking the enzyme’s activity. But such compounds are not discriminating enough, often blocking related enzymes in the process, which is an undesired side effect. This is why Eldar-Finkelman and her team looked for molecules that would compete with the substrate and occupy its binding cavity, so that the enzyme’s normal substrates cannot attach to GSK-3 and clip onto the phosphate groups.

After identifying one molecule – a short piece of protein, or peptide – that substituted for GSK-3’s substrates in experiments, Eldar-Finkelman turned to Eisenstein to design peptides that would be better at competing with the substrate. At first Eisenstein computed model structures of the enzyme with an attached protein substrate and the enzyme with an attached peptide; she then characterized the way in which the enzyme binds either the substrate or the competing peptide. The model structures pinpointed the contacts, and these were verified experimentally by Eldar-Finkelman.

This led to the next phase, a collaborative effort to introduce alterations to the peptide so as to improve its binding capabilities. One of the new peptides was predicted by Eisenstein to be a good substrate, and Eldar-Finkelman’s experiments showed that it indeed was. Once chemically tagged, the new peptide proved to be excellent at binding to GSK-3 – many times better than the original – and this was the surprise, because normally, once they are tagged, such substrates are repelled from the substrate-binding cavity and end up dissociating from the enzyme. Molecular modeling explained what was happening. After initially binding as a substrate and attaining a phosphate group, the peptide slid within the substrate-binding cavity, changing its conformation in the process, and attached tightly to a position normally occupied by the protein substrate.

Experiments in Eldar-Finkelman’s group showed that this peptide is also active in vivo and, moreover, was able to reduce the symptoms of an Alzheimer-like condition in mice. The results of this research appeared in Science Signaling.

“This experiment is a great example of the synergy between biologists and computer modelers,” says Eisenstein. “Hagit understands the function of this enzyme in the body, and she had this great insight on a possible way to control its actions. I am interested in the way that two proteins fit together and influence one another at the molecular and atomic levels, so I can provide the complementary insight.”

“Molecular modeling is such a useful tool, it has enabled me to work with a great many groups and take part in a lot of interesting, exciting work, over the years,” she adds. “Computers have become much stronger in that time, but the basic, chemical principles of attraction and binding between complex molecules remain the same, and our work is as relevant as ever.”

See the full article here .

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Stem Education Coalition

The Weizmann Institute of Science is one of the world’s leading multidisciplinary research institutions. Hundreds of scientists, laboratory technicians and research students working on its lushly landscaped campus embark daily on fascinating journeys into the unknown, seeking to improve our understanding of nature and our place within it.

Guiding these scientists is the spirit of inquiry so characteristic of the human race. It is this spirit that propelled humans upward along the evolutionary ladder, helping them reach their utmost heights. It prompted humankind to pursue agriculture, learn to build lodgings, invent writing, harness electricity to power emerging technologies, observe distant galaxies, design drugs to combat various diseases, develop new materials and decipher the genetic code embedded in all the plants and animals on Earth.

The quest to maintain this increasing momentum compels Weizmann Institute scientists to seek out places that have not yet been reached by the human mind. What awaits us in these places? No one has the answer to this question. But one thing is certain – the journey fired by curiosity will lead onward to a better future.