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It is now possible to map the activity of nearly all the neurons in a vertebrate brain at cellular resolution. What does this mean for neuroscience research and projects like the Brain Activity Map proposal?

 

In a recent publication, Misha Ahrens and Philipp Keller from the HHMI’s Janelia Farm Research Campus used high-speed light sheet microscopy to image the activity of 80% of the neurons in the brain of a fish larva at speeds of a whole brain every 1.3 seconds. This represents—to our knowledge—the first technology that achieves whole brain imaging of a vertebrate brain at cellular resolution with speeds that approximate neural activity patterns and behavior.

 

In an Article that just went live in Nature Methods, Misha Ahrens and Philipp Keller from HHMI’s Janelia Farm Research Campus used high-speed light sheet microscopy to image the activity of 80% of the neurons in the brain of a fish larva at speeds of a whole brain every 1.3 seconds. This represents—to our knowledge—the first technology that achieves whole brain imaging of a vertebrate brain at cellular resolution with speeds that approximate neural activity patterns and behavior.

 

Interestingly, the paper comes out at a time when much is being discussed and written about mapping brain activity at the cellular level. This is one of the main proposals of the Brain Activity Map—a project that is being discussed at the White House and could be NIH’s next ‘big science’ project for the next 10-15 years. [Just for clarity, the authors of this work are not formally associated with the BAM proposal].

 

The details of BAM’s exact goals and a clear roadmap and timeline to achieve them have yet to be presented, but from what its proponents have described in a recent Science paper the main aspiration of the project is to improve our understanding of how whole neuronal circuits work at the cellular level. The project seeks to monitor the activity of whole circuits as well as manipulate them to study their functional role. To reach these goals, first and foremost one must have technology capable of measuring the activity of individual neurons throughout the entire brain in a way that can discriminate individual circuits. The most obvious way to do this is by imaging the activity as it is occurring.

 

With improvements in the speed and resolution of existing microscopy setups and in the probes for monitoring activity, exhaustive imaging of neuronal function across a small transparent organism was bound to be possible—as this study has now shown.

 

The study has also made interesting discoveries. The authors saw correlated activity patterns measured at the cellular level that spanned large areas of the brain—pointing to the existence of broadly distributed functional circuits. The next steps will be to determine the causal role that these circuits play in behavior—something that will require improvements in the methods for 3D optogenetics. Obtaining the detailed anatomical map of these circuits will also be key to understand the brain’s organization at its deepest level.

 

Via Julien Hering, PhD, Dr. Stefan Gruenwald

Combining two cancer immunotherapy drugs in patients with advanced melanoma produced rates of tumor regression that appeared greater than in prior trials with either drug alone.

 

Researchers from Memorial Sloan-Kettering Cancer Center (lead author Jedd Wolchok, M.D., Ph.D.), and Yale Cancer Center (senior author Mario Sznol, M.D.), discussed the safety and activity of combining two immune stimulating antibodies — nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4, Yervoy) — in treating advanced melanoma. Ipilimumab alone is known to prolong survival and produce durable tumor regressions in some patients, and nivolumab also produced durable tumor regression in a subset of advanced melanoma patients in an early-phase clinical trial. However, combining them produced rapid and deep tumor regressions in approximately 30% of patients, a result that was not observed before with either drug administered individually.

 

Both CTLA-4 and PD-1 are targets for cancer immunotherapy because they shut down the immune system’s ability to respond to foreign invaders. Antibodies blocking PD-1 or CTLA-4 take the brakes off the immune system and permit the development of strong immune responses against the cancer. Nivolumab targets the PD-1 receptor on the surface of T-cells, and ipilimumab targets the CTLA-4 receptors. Both nivolumab and ipilimumab are manufactured by Bristol Myers Squibb.

 

Researchers provided data for 86 patients in this Phase 1 trial. They report that responses were generally durable, even in patients whose treatment was terminated early.

 

According to Sznol, clinical research leader of the melanoma program at Yale Cancer Center, this early success in combining drugs will pave the way for large-scale combination immunotherapy trials. “After many years, we are finally realizing the promise of immunotherapy in providing real and durable benefit for advanced cancer patients. Although this trial was focused on melanoma, the combination will be studied in other cancer types. This is only one of many combinations of agents that will likely lead to even more significant advances in cancer treatment,” Sznol said.

Via Dr. Stefan Gruenwald

A new method of manufacturing short, single-stranded DNA molecules can solve many of the problems associated with current production methods.

The new method can be of value to development of drugs consisting of DNA fragments and to DNA nanotechnology research.

 

The novel technique for manufacturing short, single-stranded DNA molecules — or oligonucleotides — has been developed by researchers at Karolinska Institute in Sweden and Harvard University.

 

Such DNA fragments constitute a basic tool for researchers and play a key part in many fields of science. Many of the recent advances in genetic and molecular biological research and development, such as the ability to quickly scan an organism’s genome, would not have been possible without oligonucleotides.

 

The new method is versatile and able to solve problems that currently restrict the production of DNA fragments.

 

“We’ve used enzymatic production methods to create a system that not only improves the quality of the manufactured oligonucleotides but that also makes it possible to scale up production using bacteria in order to produce large amounts of DNA copies cheaply,” says co-developer Björn Högberg at the Swedish Medical Nanoscience Center, part of the Department of Neuroscience at Karolinska Institutet in Sweden.

 

The process of bioproduction, whereby bacteria are used to copy DNA sequences, enables the manufacture of large amounts of DNA copies at a low cost. Unlike current methods of synthesising oligonucleotides, where the number of errors increases with the length of the sequence, this new method according to the developers also works well for long oligonucleotides of several hundred nitrogenous bases.

 

The DNA molecules are first formed as a long string of single-stranded DNA in which the sequence of interest is repeated several times. The long strand forms tiny regions called hairpins, where the strand folds back on itself. These hairpins can then be cut up by enzymes, which serve as a molecular-biological pair of scissors that cuts the DNA at selected sites. Several different oligonucleotides can thus be produced at the same time in a perfectly balanced combination, which is important if they are to be crystallised or used therapeutically.

 

“Oligonucleotide-based drugs are already available, and it’s very possible that our method could be used to produce purer and cheaper versions of these drugs,” says Dr Björn Högberg.

Via Dr. Stefan Gruenwald

A dream of scientists has been to visualize details of structures within our cells in real time, a breakthrough that would greatly aid in the study of their function.  However, even the best of current microscopes can take minutes to recreate images of the internal machinery of cells at a usable resolution.

Thanks to a technical tour de force, Yale University researchers can now generate accurate images of sub-cellular structures in milliseconds rather than minutes.

 

This image of microtubules, which act as a cellular scaffolding, was captured in just 33 milliseconds. “We can now see research come to life and tackle complex questions or conditions which require hundreds of images, something we have not been able to do before,” said Joerg Bewersdorf, assistant professor of cell biology and biomedical engineering and senior author of the research, published in the journal Nature Methods.

Via Dr. Stefan Gruenwald