gene expression profiling

What Science is Launching to Space?

The tenth SpaceX cargo resupply mission launched to the International Space Station on Feb. 18, and is carrying science ranging from protein crystal growth studies to Earth science payloads. Here’s a rundown of some of the highlights heading to the orbiting laboratory.

The CASIS PCG 5 investigation will crystallize a human monoclonal antibody, developed by Merck Research Labs, that is currently undergoing clinical trials for the treatment of immunological disease. Results from this investigation have the potential to improve the way monoclonal antibody treatments are administered on Earth.

Without proteins, the human body would be unable to repair, regulate or protect itself. Crystallizing proteins provides better views of their structure, which helps scientists to better understand how they function. Often times, proteins crystallized in microgravity are of higher quality than those crystallized on Earth. LMM Biophysics 1 explores that phenomena by examining the movement of single protein molecules in microgravity. Once scientists understand how these proteins function, they can be used to design new drugs that interact with the protein in specific ways and fight disease.

Much like LMM Biophysics 1, LMM Biophysics 3 aims to use crystallography to examine molecules that are too small to be seen under a microscope, in order to best predict what types of drugs will interact best with certain kinds of proteins. LMM Biophysics 3 will look specifically into which types of crystals thrive and benefit from growth in microgravity, where Earth’s gravity won’t interfere with their formation. Currently, the success rate is poor for crystals grown even in the best of laboratories. High quality, space-grown crystals could improve research for a wide range of diseases, as well as microgravity-related problems such as radiation damage, bone loss and muscle atrophy.

Nanobiosym Predictive Pathogen Mutation Study (Nanobiosym Genes) will analyze two strains of bacterial mutations aboard the station, providing data that may be helpful in refining models of drug resistance and support the development of better medicines to counteract the resistant strains.

During the Microgravity Expanded Stem Cells investigation, crew members will observe cell growth and morphological characteristics in microgravity and analyze gene expression profiles of cells grown on the station. This information will provide insight into how human cancers start and spread, which aids in the development of prevention and treatment plans. Results from this investigation could lead to the treatment of disease and injury in space, as well as provide a way to improve stem cell production for human therapy on Earth.

The Lightning Imaging Sensor will measure the amount, rate and energy of lightning as it strikes around the world. Understanding the processes that cause lightning and the connections between lightning and subsequent severe weather events is a key to improving weather predictions and saving life and property. 

From the vantage of the station, the LIS instrument will sample lightning over a wider geographical area than any previous sensor.

Future robotic spacecraft will need advanced autopilot systems to help them safely navigate and rendezvous with other objects, as they will be operating thousands of miles from Earth. 

The Raven (STP-H5 Raven) studies a real-time spacecraft navigation system that provides the eyes and intelligence to see a target and steer toward it safely. Research from Raven can be applied toward unmanned vehicles both on Earth and in space, including potential use for systems in NASA’s future human deep space exploration.

SAGE III will measure stratospheric ozone, aerosols, and other trace gases by locking onto the sun or moon and scanning a thin profile of Earth’s atmosphere.

These measurements will allow national and international leaders to make informed policy decisions regarding the protection and preservation of Earth’s ozone layer. Ozone in the atmosphere protects Earth’s inhabitants, including humans, plants and animals, from harmful radiation from the sun, which can cause long-term problems such as cataracts, cancer and reduced crop yield.

Tissue Regeneration-Bone Defect (Rodent Research-4) a U.S. National Laboratory investigation sponsored by the Center for the Advancement of Science in Space (CASIS) and the U.S. Army Medical Research and Materiel Command, studies what prevents other vertebrates such as rodents and humans from re-growing lost bone and tissue, and how microgravity conditions impact the process. 

Results will provide a new understanding of the biological reasons behind a human’s inability to grow a lost limb at the wound site, and could lead to new treatment options for the more than 30% of the patient.

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How White Blood Cells Become Serial Killers

To develop vaccines against microbial infections and immunotherapy against cancer, researchers are looking for ways to enhance white blood cells called CD8+ T lymphocytes. Specifically, they want to bump up how well they work and how long they live.

Naïve T lymphocytes patrol the front lines of the human body’s defense against infection, circulating in blood and tissues, searching for invasive microbes and other foreign antigens. They’re called “naïve” because they have not yet encountered an invader. When they do, these T lymphocytes activate and divide, giving rise to at least two types of specialized cells: 1) effector lymphocytes or “serial killers” responsible for immediate killing of infected host cells; and 2) memory lymphocytes that provide long-term protection from similar infections. Researchers have been trying for a very long time to understand how activated naïve T cells give rise to effector and memory cells during an infection.

Taking advantage of technological advances in single-cell gene expression profiling and computational modeling that trace the destiny of individual cells, University of California San Diego School of Medicine researchers, led by John T. Chang, MD, associate professor in the Department of Medicine, and Gene W. Yeo, PhD, professor in the Department of Cellular and Molecular Medicine and Institute for Genomic Medicine, constructed a roadmap with detailed instructions that tell CD8+ T lymphocytes how to become serial killers or long-lived memory cells.

The findings are published in the February 20 online issue of Nature Immunology.

According to Chang, the primary purpose of vaccines is to produce strong and durable immune protection, which depends heavily on memory lymphocytes.  

“Our work suggests that early instructions that T lymphocytes receive during a microbial infection seem to be critical to whether or not they give rise to long-lived memory cells,” Chang said. “Strategies that exploit this process could potentially enhance durable immunity and help us to design more effective, longer-lasting vaccines against microbial pathogens and develop better approaches to boost the anti-cancer activity of white blood cells.

Pictured: a graphical representation of T cells attacking a cancer cell.

Scientists Catalogue “Parts List” of Brain Cell Types in a Major Appetite Center

Using Harvard-developed technology, scientists at Beth Israel Deaconess Medical Center (BIDMC) have catalogued more than 20,000 brain cells in one region of the mouse hypothalamus. The study, published in Nature Neuroscience, revealed some 50 distinct cell types, including a previously undescribed neuron type that may underlie some of the genetic risk of human obesity. This catalog of cell types marks the first time neuroscientists have established a comprehensive “parts list” for this area of the brain. The new information will allow researchers to establish which cells play what role in this region of the brain.

“A lot of functions have already been mapped to large regions of the brain; for example, we know that the hippocampus is important for memory, and we know the hypothalamus is responsible for basic functions like eating and drinking,” said lead author John N. Campbell, PhD, a postdoctoral fellow in the lab of co-corresponding author, Bradford Lowell, MD, PhD. “But we don’t know what cell types within those regions are responsible. Now with the leaps we’ve had in technology, we can profile every gene in tens of thousands of individual cells simultaneously and start to test those cell types one by one to figure out their functional roles.”

Each cell in an animal’s body carries the same genetic information. Cells take on specific roles by expressing some genes and silencing others. Drop-Seq technology – developed by study co-authors Steven McCarroll, PhD, and Evan Macosko, MD, PhD, both geneticists at Harvard Medical School – makes it possible to assess every gene expressed by individual cells. The automated process means the BIDMC researchers could profile tens of thousands of cells in the same amount of time it once took to profile about a dozen cells by hand.

Campbell and colleagues profiled more than 20,000 adult mouse brain cells in the arcuate hypothalamus (Arc) and the adjoining median eminence (ME) – a region of the brain that controls appetite and other vital functions. The cells’ gene expression profiles help scientists determine their functions.

In addition to identifying 50 new cell types, the researchers also profiled the cell types in adult mice under different feeding conditions: eating at will; high-fat diet (energy surplus); and overnight fasting (energy deficit). The technology allowed the researchers to assess how changes in energy status affected gene expression. The cell types and genes that were sensitive to these changes in energy status provide a number of new targets for obesity treatment.

“Sometimes a cell’s true identity doesn’t come out until you put it through a certain stress,” said co-corresponding author, Linus Tsai, MD, PhD, an assistant professor of medicine in the Division of Endocrinology, Diabetes and Metabolism at BIDMC. “In fasting conditions, for example, we can see whether there is further diversity within the cell types based on how they respond to important physiologic states.”

Finally, the scientists analyzed previous human genome-wide association studies (GWAS) that revealed gene variants linked to obesity. Noting which brain cell types express such obesity-related genes, the researchers implicated two novel neuron types in the genetic control of body weight.

Campbell and colleagues have posted their massive data set online, making it available to researchers around the world. The open-source information should accelerate the pace of scientific discovery and shape the research questions asked in the field of obesity research.

“The classic way of doing science is to ask questions and test hypotheses,” said Lowell, who is a professor of medicine in the Division of Endocrinology, Diabetes and Metabolism. “But the brain is so complex, we don’t even know how much we don’t know. This information fills in some of the unknowns so we can make new hypotheses. This work will lead to many discoveries that, without these data, people would never have even known to ask the question.”

Discovery of Neurotransmission Gene May Pave Way for Early Detection of Alzheimer's Disease

A new Tel Aviv University study identified a gene coding for a protein that turns off neurotransmission signaling, which contributes to Alzheimer’s disease (AD).

The gene, called RGS2 (Regulator of Protein Signaling 2), has never before been implicated in AD. The researchers report that lower RGS2 expression in AD patient cells increases their sensitivity to toxic effects of amyloid-β. The study, published in Translational Psychiatry, may lead to new avenues for diagnosing Alzheimer’s disease — possibly a blood test — and new therapies to halt the progression of the disease.

The research was led by Dr. David Gurwitz of the Department of Human Molecular Genetics and Biochemistry at TAU’s Sackler School of Medicine and Prof. Illana Gozes, the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors; Head of the Elton Laboratory for Molecular Neuroendocrinology at TAU’s Sackler School of Medicine; and a member of TAU’s Adams Super Center for Brain Studies and TAU’s Sagol School of Neuroscience. Also participating in the research were their PhD student Adva Hadar and postgraduate student Dr. Elena Milanesi, in collaboration with Dr. Noam Shomron of the Department of Cell and Developmental Biology at TAU’s Sackler Faculty of Medicine and his postgraduate student Dr. Daphna Weissglas; and research teams from Italy and the Czech Republic.

Identifying the suspect

“Alzheimer’s researchers have until now zeroed in on two specific pathological hallmarks of the chronic neurodegenerative disease: deposits of misfolded amyloid-β (Aβ) peptide plaques, and phosphorylated tau protein neurofibrillary tangles found in diseased brains,” Dr. Gurwitz said. “But recent studies suggest amyloid-β plaques are also a common feature of healthy older brains. This raises questions about the central role of Aβ peptides in Alzheimer’s disease pathology.”

The researchers pinpointed a common suspect — the RGS2 gene — by combining genome-wide gene expression profiling of Alzheimer’s disease blood-derived cell lines with data-mining of previously published gene expression datasets. They found a reduced expression of RGS2 in Alzheimer’s disease blood-derived cell lines, then validated the observation by examining datasets derived from blood samples and post-mortem brain tissue samples from Alzheimer’s patients.

“Several genes and their protein products are already known to be implicated in Alzheimer’s disease pathology, but RGS2 has never been studied in this context,” Dr. Gurwitz said. “We now propose that whether or not Aβ is a primary culprit in Alzheimer’s disease, neuroprotective mechanisms activated during early disease phases lead to reduced RGS2 expression.”

Sensitizing brain neurons to potential damage

The new TAU study furthermore proposes that reduced RGS2 expression increases the susceptibility of brain neurons to the potentially damaging effects of Aβ.

“We found that reduced expression of RGS2 is already noticeable in blood cells during mild cognitive impairment, the earliest phase of Alzheimer’s,” Dr. Gurwitz observed. “This supported our theory that the reduced RGS2 expression represents a ‘protective mechanism’ triggered by ongoing brain neurodegeneration.”

The team further found that the reduced expression of RGS2 was correlated with increased Aβ neurotoxicity. It acted like a double-edged sword, allowing the diseased brain to function with fewer neurons, while increasing damage to it by accumulating misfolded Aβ.

“Our new observations must now be corroborated by other research groups,” Dr. Gurwitz concluded. “The next step will be to design early blood diagnostics and novel therapeutics to offset the negative effects of reduced expression of the RGS2 protein in the brain.”