Among other new discoveries in cancer, infectious disease, veterinary research and cell biology, this month’s science round-up includes interesting findings that significantly enhance our current understanding of immunology and Zika virus biology. We also feature the latest news in the on-going debate concerning the patent rights to the revolutionary CRISPR-Cas9 technology. Happy reading!
New neurological disorder associated with the Zika virus
Researchers at the Restoration Hospital in Recife, Brazil, have determined that a small percentage of individuals infected with the Zika virus will develop an autoimmune disorder that attacks the brain’s myelin, similar to multiple sclerosis. This disease is known as acute disseminated encephalomyelitis (ADEM), and this is the first time it has been associated with the Zika virus. Out of 151 patients that tested positive for the Zika virus between December 2014 and December 2015 in the Restoration Hospital, six had neurological manifestations. Of the six, two patients developed ADEM, and the other four patients developed Guillain-Barré syndrome, which has a previously reported association with the Zika virus. ADEM presents as swelling of the brain and spinal cord that attacks the myelin, which is the coating around nerve fibers. In contrast to multiple sclerosis in which patients experience multiple attacks, ADEM is a single attack on the brain that is typically resolved within six months. However, the disease can reoccur in some patients. The results of this study were recently presented at the American Academy of Neurology 68th Annual Meeting in Vancouver Canada, April 15 -21, 2016. Future studies will focus on exploring whether there is a causal link between Zika and ADEM, and confirming the association in a larger subset of patients.
Combating drug resistance by studying individual cancer cells
Cancer cells often thrive despite treatment because they are adept at developing resistance mechanisms to targeted therapy. Understanding why this occurs has been a key area of research in cancer. To address this issue, a team of scientists investigated individual cancer cells using a technology called single-cell phosphoproteomics (Wei et al. 2016). Using a patient-derived glioblastoma model demonstrating resistance to mTOR targeted therapy, they demonstrate that cells begin to alter their protein signaling to resist targeted therapy in as little as 2.5 days post treatment, long before the changes are clinically manifested. Accordingly, the single-cell proteomics approach allowed identification of combination strategies that resulted in complete and sustained tumor suppression in vivo. The researchers also indicate that the single-cell proteomics approach could also be used to study how melanoma cells develop resistance to a class of drugs called BRAF inhibitors. This approach will need to ultimately be tested in clinical trials; however it sets the stage for a new wave of personalized medicine that deals with cancer on the level of individual cells.
Wei et al. (2016). Single-cell phosphoproteomics resolves adaptive signaling dynamics and informs targeted combination therapy in glioblastoma. Cancer Cell 29, 563-573.
The mechanism of how activated T cells decide their fate identified
When T cells become activated by antigen presenting cells, they undergo asymmetric cell division in which the daughter cells can differentiate into either effector or memory like T cells. This has long been understood as a major tenet of immunology, however, the mechanism underlying the process was unknown until now. In an article published in the Nature journal, scientists at St. Jude Children’s Research Hospital and Nationwide Children’s Hospital demonstrate that the distribution of a key regulatory protein called c-Myc in daughter cells influences the fate and roles of activated T cells (Verbist et al. 2016). They demonstrate that during asymmetric division of activated T cells, high levels of c-Myc were associated with high proliferation and differentiation to effector T cells, whereas daughter cells with low levels of c-Myc differentiated into memory T cells. The researchers also demonstrate that altering the expression of c-Myc or the upstream metabolic and signaling pathways that mediate c-Myc expression, can alter T cell fate. These findings suggest that the immune system can easily be manipulated by altering c-Myc production, which could have significant implications for T cell cancer immunotherapy and the development of more effective vaccines.
Verbist KC et al. (2016). Metabolic maintenance of cell asymmetry following division in activated T lymphocytes. Nature doi: 10.1038/nature17442. [Epub ahead of print].
Immunohistochemical and Immunofluorescence techniques for diagnosing gangliosidoses in dogs and cats
GM1 and GM2 gangliosidoses are progressive neurodegenerative lysosomal diseases that are more likely to occur in animal species such as dogs and cats, compared to other lysosomal diseases. Diagnosis of GM1 and GM2 gangliosidoses is conducted based on comprehensive findings which include clinical, biochemical, histopathological and genetic analysis using various specimens. However, incorrect diagnosis using these approaches is possible due to the partial absence of specimens for biochemical, histological, ultrastructural and genetic examination. In addition, these methods of diagnosis are further limited by a lack of specificity in symptoms and diagnostic markers, as well as the need for specialized expertise for performing thin layer chromatography and fluorometric enzymatic assays. To simplify the diagnostic process and ensure more accurate diagnoses, researchers at Kagoshima University Japan, developed immunohistochemical and immunofluorescence techniques for accurately diagnosing GM1 and GM2 gangliosidoses in paraffin embedded tissue sections. Using these techniques, the researchers were able to accurately determine that eosinophilic granular materials in swollen neurons in dogs and cats were indicative of GM1 or GM2 gangliosidoses. The researchers state that these techniques are useful for the auxiliary diagnosis of gangliosidoses in dogs and cats before a definitive diagnosis can be made by molecular analyses.
Kohyama M et al. (2016). In situ detection of GM1 and GM2 gangliosides using immunohistochemical and immunofluorescent techniques for auxiliary diagnosis of canine and feline gangliosidoses. BMC Vet Res 12, 67.
A new cell death pathway in vertebrate development discovered
Programmed cell death, or apoptosis is a prominent form of cell death in mammals that is necessary for maintaining homeostasis. However, it has been shown that this process plays only a minor role in overall animal development. Although other cell death mechanisms such as autophagy and necrosis have been molecularly characterized, none have been shown to play a role in developmental cell death. Linker-cell-type-death (LCD) is a conserved form of non-apoptotic cell death that has been shown to operate in vertebrate development. However, the details of LCD execution were unknown until now. Using a Caenorhabditis elegans model, researchers at Rockefeller University demonstrated that LCD resembles the cell death process responsible for the loss of neurons in people with neurodegenerative disorders. They also determined that the stress response protein, heat shock factor 1 (HSF-1) mediated LCD. This is in contrast to the established role of HSF-1, since it is known to play a protective role in cells. HSF-1 was shown to induce LCD by activating the protein degradation pathway referred to as the ubiquitin proteasome system. These findings highlight a unique mechanism for cell death during development and provide testable predictions for analyzing the process in vertebrates.
Kinet MJ et al. (2016). HSF-1 activates the ubiquitin proteasome system to promote non-apoptotic developmental cell death. Elife doi: 10.7554/eLife.12821.
A combination vaccine against virulent streptococci shows enhanced efficacy
Streptococcus pyogenes (group A Streptococcus (GAS)) is a human pathogen responsible for more than 500,000 premature deaths every year. The pathogen causes deep tissue infections and autoimmune sequelae such as rheumatic heart disease. Mutation of the cluster of virulence responder/sensor (CovR/S) in this pathogen is responsible for infection and subsequent disease. There is currently no vaccine to prevent GAS infections, although several are under development. The efficacy of one such vaccine was recently reported in the current issue of the Journal of Immunology (Pandey et. al 2016). The authors present a two-component peptide vaccine that is targeted against the virulence factors IL-8 protease S. pyogenes cell envelope proteinase (SpyCEP) and the M protein. It contains a minimal epitope (S2) conjugated to diphtheria toxoid, which is a target for SpyCEP antibodies and J8-DT, a conserved peptide vaccine from the M protein. The researchers show that the combination vaccine induced complete protection, which correlated with an influx of neutrophils to the infection site. This study represents a significant step forward in the development of a vaccine to prevent infection with virulent streptococci.
Pandey et al. (2016). Combinatorial synthetic peptide vaccine strategy protects against hypervirulent CovR/S mutant streptococci. J Immunol 196, 3364-3374.
Legal trial to determine the inventors of the CRISPR-Cas9 gene-editing technology
The CRISPR-Cas9 gene-editing technology is arguably the most revolutionary scientific discovery of our time. However, who should own the patent to the technology has been the focus of intense debate in recent months. Researchers at University of California, Berkeley led by Professors Jennifer Doudna and Emmanuelle Charpentier (then at the University of Vienna, Austria) filed a patent application in May 2012 for the CRISPR-Cas9 technology. Seven months later, Professor Feng Zhang at Broad Institute of MIT and Harvard in Cambridge Massachusetts also filed a patent for the technology, which was granted in April 2014 after the institution requested that the United States Patent and Trademark Office (USPTO) fast track the application. This meant that the application by Professors Doudna and Charpentier languished (Sherkow JS, 2016). In January, the USPTO agreed to conduct a specialized legal trial, called a patent interference, to determine which institution should own the patent to the CRISPR-Cas9 technology. As has been the case in other historical scientific patent disputes, lab notebooks will play a crucial role in determining who was first to invent the technology. It is stated that the patents are worth hundreds of billions of dollars, indicating that the financial stakes are high (Sherkow JS). Accordingly, both institutions and their respective researchers have launched start-up companies that will focus on commercializing the technology— Caribou Biosciences (UC Berkeley) and Editas Medicine (Broad Institute).
Sherkow JS (2016). CRISPR: Pursuit of profit poisons collaboration. Nature 532, 172-173.