Welcome to our 5th monthly science round up for the year. This edition takes a look at how the CRISPR technology is aiding Zika virus research and cancer therapy. We also profile a new gene editing technology called NgAgo that could replace the CRISPR system. Exciting discoveries in the areas of neuroscience, immunology, infectious diseases and veterinary science are also featured. Happy reading!
The cerebral cortex plays a critical role in regulating higher-order functions such as motor learning and attention. It does this through its connections to brain structures such as the dorsal striatum. However, despite the important role of the dorsal striatum in motor learning, it has been a previously scientifically uncharted region of the brain. In a recent study published on June 20 2016, in the Nature Neuroscience journal, researchers at the University of Southern California are the first to create the most comprehensive map of the connections between the dorsal striatum and the cerebral cortex in any mammal. Through the analysis of 150 mouse brain structures, the researchers identified 29 distinct areas of the dorsal striatum responsible for pain information processing as well as eye, mouth and facial movement. Disorders such as Parkinson’s disease, Huntington’s disease and other movement disorders, all involve connections in this region of the brain. This study allows scientists to further investigate which circuit disruptions in this brain region cause disease. This could lead to the development of new drugs and medical therapies for neurological diseases that develop from circuit interruptions in the dorsal striatum.
Hintiryan H et al. (2016). The mouse cortico-striatal projectome. Nat Neurosci doi: 10.1038/nn.4332. [Epub ahead of print]
Colorectal cancer (CRC) is the third most common cancer worldwide. To date, the genetics of this cancer is poorly understood. In a study published in Nature Communications, The Institute for Cancer Research London reported their findings on the largest ever study on the genetics of CRC. The researchers investigated the impact of rare germline mutations on CRC by sequencing the exome of more than 1000 people with CRC and comparing to more than 1600 healthy individuals. Their analysis also included individuals with familial CRC caused by inherited genetic risk. The researchers found that 16% of familial CRC cases had highly penetrant rare mutations in known genes as well as three new candidate CRC genes, namely POT1, POLE2 and MRE11. This study provides significant insight into the genetic architecture of CRC and paves the way for future research on the impact of the newly identified CRC genes.
Chubb D et al. (2016). Rare disruptive mutations and their contribution to the heritable risk of colorectal Cancer. Nat Commun 7, 11883.
The hygiene hypothesis proposes that the increase in food allergies in western countries is due to a lack of early childhood exposure to environmental microbes. However, immunologists have challenged this idea by exploring the alternative hypothesis that the increased incidence of food allergies relates to diet and our own microbiome. In a new study published in Cell Reports, scientists from Monash University in Australia added evidence to the impact of diet on food allergies by demonstrating that mice fed a high fiber diet from birth had less severe peanut allergies than mice receiving an average amount of fiber. The researchers identified a number of mechanisms for the observed protection from peanut allergy. They demonstrate that the gut microbiota breaks down dietary fiber to short chain fatty acids and that these fatty acids are responsible for mediating protection from food allergy through their increased levels and activity of their GPR43 and GPR109a receptors. They also show that high fiber increased tolerogenic CD103+ dendritic cell activity leading to increased T regulatory cell (Treg) differentiation. They propose that the high fiber diet reshapes the gut microbiota to promote the predominance of beneficial bacteria that encourage the development of Tregs, which ensure the bacteria have an anti-inflammatory environment to thrive in. Interestingly, the researchers also demonstrate that food allergy protection through a high fiber diet was also dependent on the presence of vitamin A. Further pre-clinical research will be needed before the relationship between a high-fiber diet and food allergy can be studied in humans. A major limitation will be identification of exactly what type of fiber will produce similar effects in people.
Tan J et al. (2016). Dietary fiber and bacterial SCFA enhance oral tolerance and protect against food allergy through diverse cellular pathways. Cell Rep 15, 2809-2824.
Malabsorption syndrome (MAS) is a gastrointestinal disease that is associated with reduced growth rates of broilers (domestic chicken reared for meat production). Accordingly, this disease is responsible for major economic losses to the poultry industry, however; its etiology in chickens is poorly understood. Previous studies proposed a link between chicken parvovirus (ChPV) and MAS, however, other studies countered this argument with findings that ChPV is present in both healthy and MAS affected chickens. To address this discrepancy, Finkler et al. set out to detect and quantify ChPV loads in sera and tissues of 59 age-matched healthy and MAS-affected broilers. They found that ChPV DNA loads were higher in MAS-affected broilers than in their healthy counterparts. Similarly, genome viral loads were also higher in the tissues of MAS-affected broilers than in healthy broilers. Interestingly, however, serum genome viral loads were absent in healthy broilers whereas they were very high in MAS-affected animals. This distinct difference between healthy and MAS-affected broilers suggests that detection of viral loads in the serum can be applied as a diagnostic measure for detecting MAS in the poultry industry. However, further experiments using a larger sample size are required to confirm these results before this detection strategy can be applied.
Finkler F et al. (2016). Chicken parvovirus and its associations with malabsorption syndrome. Res Vet Sci 107, 178-181.
The CRISPR technology has certainly taken center stage in biomedical research as the premier gene editing tool used in a wide range of research areas. However, a recent study published in the journal Nature Biotechnology, describes a potential rival to the acclaimed technology. This newly identified DNA-guided gene editing system utilizes the endonuclease Natronobacterium gregoryi Argonaute (NgAgo). NgAgo was discovered by a group of scientists in China who searched the US National Center for Biotechnology Information databases for proteins with sequences similar to DNA cutting Argonautes used in RNAi technology. Similar to Cas 9, the RNA-guided endonuclease used in the CRISPR system, NgAgo can cleave DNA at 37°C, indicating its potential for gene editing of human cells. NgAgo however, has a few advantages over the CRISPR/Cas 9 system. One of its most useful features is that it is more specific than Cas 9, as it demonstrates low tolerance of mismatches between the guide and target DNA sequence. The NgAgo technology is also able to target GC-rich DNA sequences, which is another CRISPR limitation. Further research will be required to determine NgAgo’s potential for producing off-target cleavage, which refers to unintended genome editing.
Gao F et al. (2016). DNA-guided genome editing using the Natronobacterium gregoryi Argonaute. Nat Biotechnol doi: 10.1038/nbt.3547 [Epub ahead of print].
Similar to other viruses such as HIV, Zika virus and Dengue virus hijack the host’s resources and proteins in order to replicate and spread within the body. Understanding exactly which proteins these viruses utilize can provide important insight into how to prevent or stop infection. Researchers at the University of Massachusetts Medical School have done exactly that and reported their findings in the journal Cell Reports. Using the RNAi and CRISPR/Cas 9 gene screening technologies, they discovered a handful of human proteins that the viruses need in order to replicate. Their approach involved knocking out or depleting each protein in the human genome one at a time, and testing the effect on viral replication. Among the proteins identified was AXL, which the viruses use to enter the cell as well as the endoplasmic reticulum membrane protein complex (EMC), which is critical for early stage infection. These proteins represent potential therapeutic targets that could aid the development of effective treatment for the diseases caused by these viruses.
Savidis G et al. (2016). Identification of zika virus and dengue virus dependency factors using functional genomics. Cell Rep doi: http://dx.doi.org/10.1016/j.celrep.2016.06.028 [Epub ahead of print].
The CRISPR/Cas 9 system has proven quite popular among researchers. More than 1700 studies have been published using the technology since it was first introduced in 2013. However, it has now made its transition from the bench to the bedside. On June 21, an advisory committee at the US National Institutes of Health (NIH) approved a proposal to use the CRISPR/Cas9 system in a T cell based cancer immunotherapy clinical trial. The study is led by Dr. Edward Stadtmauer, a physician at the University of Pennsylvania, and will be funded by an immunotherapy foundation formed by Sean Parker, former Facebook president. The therapeutic strategy is similar to adoptive T cell therapy, and involves three major edits to T cells isolated from patients with melanoma, sarcoma or myeloma. The first edit will alter a patient’s T cells by inserting a gene coding for a protein that detects cancer cells and facilitates tumor killing. The second edit will remove a native T cell protein that blocks tumor detection and killing, and the third will remove the gene for a protein that mediates inhibition of T cell function by cancer cells. The first phase of the trial will assess the efficacy of using the CRISPR/Cas 9 system in humans. Although this clinical trial could be a breakthrough for cancer therapy, the investigators will need to overcome challenges such as “off-target” edits, in which the CRISPR-Cas 9 technology removes unintended parts of the genome. For more information on the trial check out this Nature News report.