In this edition of our monthly science round up, we feature exciting research from around the world. The new discoveries feature unprecedented strategies for cancer immunotherapy and the discovery of a potential target for developing a vaccine against the Zika virus. We also provide information on the development of new guidelines for the ethical practice of stem cell research. Stay up to date on the new and exciting research that is helping to improve healthcare. Happy Reading.
High vitamin E serum levels correlate with future glioblastoma development
Vitamins have an excellent reputation for enhancing our health. However, researchers at Umeå University in Sweden and the cancer registry of Norway have discovered that elevated serum levels of vitamin E are associated with future risk of developing glioblastoma, the most common and aggressive cancer originating in the brain. Glioblastoma has a poor prognosis with a median survival of one year. Moreover, the underlying cause of the disease is currently unclear. Therefore, studies to identify biomarkers that determine the risk of developing glioblastoma are necessary for controlling this disease. The research group led by Professor Beatrice Merlin embarked on an exploratory study to generate a novel hypothesis regarding molecular events resulting in glioblastoma development. They profiled serum samples collected from patients six months to 22 years before tumor diagnosis and compared them to serum collected from healthy individuals. The results showed significant differences in the expression of molecules known as metabolites, of which the greatest difference observed was high levels of vitamin E in future glioblastoma cases compared to controls. The researchers point out that these findings are preliminary and further studies with a larger subset of patients are needed to verify the link between vitamin E and brain tumors.
Björkblom B et al. (2016). Metabolic screening of pre-diagnostic serum samples identifies association between α- and γ-tocopherals and glioblastoma risk. Oncotarget doi: 10.18632/oncotarget.9242 [Epub ahead of print].
Future cancer therapy could involve “borrowing” an immune system
The field of cancer immunotherapy is rapidly evolving, and several promising therapies have already been developed for a number of cancers. The goal of cancer immunotherapy is to help the body’s immune system effectively fight cancer. The predominant strategy has been to remove the brakes on the immune system that limits its cancer fighting ability through the use of immune checkpoint inhibitors. However, researchers at the Netherlands Cancer Institute and University of Oslo/Oslo University Hospital recently published a novel strategy for cancer immunotherapy that involves utilizing immune cells from a donor to fight cancer— essentially borrowing someone else’s immune system when yours might not work as well. The researchers observed that a cancer patient’s immune cells recognized only a small portion of the tumor antigens expressed by their cancer cells. Therefore, the immune response to the cancer is insufficient for tumor eradication. To address this, the research team identified DNA mutations from cancer cells and combined them to form synthetic DNA. This was then inserted into antigen presenting cells isolated from a healthy donor. These donor-derived antigen presenting cells then present the mutant proteins to T cells from healthy donors. T cells that recognize the mutant proteins multiply allowing DNA encoding the T cell receptors (TCR) to be isolated. The antigen specific TCR encoding DNA is then inserted into the cancer patient’s T cells, making them efficient killer cells that recognize and kill patient-derived melanoma cells. The results of this study provide a rationale for the use of “outsourced” immune responses in cancer immunotherapy.
Strønen E et al. (2016). Targeting of cancer neoantigens with donor-derived T cell receptor repertoires. Science doi: 10.1126/science.aaf2288 [Epub ahead of print].
Endogenous mechanism for the treatment of sepsis now identified
Sepsis, also known as blood poisoning, is a life threatening condition that occurs when the body’s response to infection results in damage to multiple organ systems. It is a leading cause of mortality in the United States. High mobility group box 1 (HMGB1) is a damage-associated molecular pattern protein that plays a key role in lethal infection and injury, including sepsis. It is actively secreted by activated immune cells, or passively released from dying cells. Researchers led by Professor Kevin Tracey at the Feinstein Institute for Medical Research recently reported on a method to inhibit the inflammatory action of HMGB1, which led to reduced mortality in standardized models of intra-abdominal sepsis in mice. They show for the first time that haptoglobin, the acute phase protein that binds extracellular hemoglobin, also binds HMGB1 forming haptoglobin-HMGB1 complexes. These complexes act via CD163 to induce an anti-inflammatory response. Therefore, the findings demonstrate that haptoglobin acts as an endogenous HMB1 inhibitor, suggesting that haptoglobin-based therapies could potentially be used to treat HMGB1 mediated inflammatory diseases such as sepsis.
Yang H et al. (2016). Identification of CD163 as an anti-inflammatory receptor for HMGB1-haptoglobin complexes. JCI Insight 1, e85375.
Natural modification of canine influenza virus strain increases its virulence
Avian origin H3N2 canine influenza virus (CIV) was recently found to be circulating in Chinese dogs. In 2010, it was discovered that this strain naturally acquired two additional amino acids in the neuraminidase (NA) stalk of the virus. To investigate the effect of this 2-amino acid insertion on virus replication and virulence, researchers at the College of Veterinary Medicine, Nanjing Agricultural University in China compared the new long NA-stalk strain to a shorter version lacking the 2-amino acid insertion. They found that the newly developed virus strain was more virulent, demonstrating higher peak titers in both canine and avian cells and fibroblasts. Furthermore, mice inoculated with the new long NA-stalk strain demonstrated enhanced pathological damage in the lung and a higher proportion of detectable RNA in tissues. However, in chickens, there was no detectable difference between the new long NA-stalk strain and the shorter strain in terms of viral RNA load in tissues. These findings demonstrate that the observed natural mutation of avian origin H3N2 CIV results in enhanced viral replication, and is likely the result of adaptive evolution in canine hosts.
Lin Y et al. (2016). Enhanced replication of avian-origin H3N2 canine influenza virus in eggs, cell cultures and mice by a two-amino acid insertion in neuraminidase stalk. Vet Res 47, 53.
Challenges associated with mitochondrial replacement therapy discovered
Mutations in mitochondrial DNA can result in serious health problems such as seizures, developmental delays, dementia, heart failure, liver dysfunction or death. Mitochondrial replacement therapy has emerged as a novel strategy for preventing the inheritance of mitochondrial DNA diseases. This procedure is currently approved in the United Kingdom, and the National Academies of Sciences, Engineering and Medicine recently approved clinical trials in the United States using this procedure. The goal of mitochondrial replacement therapy is to generate an egg cell that contains the intended mother’s nuclear DNA (mitochondrial DNA is exclusively transmitted through the mother’s egg cells) and a female donor’s healthy mitochondrial DNA. Since the process involves transfer of the nucleus from the egg cell containing the defective mitochondria, Yamada et al. (2016) investigated the consequences of small amounts of carryover mitochondrial DNA to the healthy cell. They found that in the majority of cases, the transferred mitochondrial DNA vanished over time, demonstrating that complete mitochondrial DNA replacement was indeed possible. However, in a significant number of cases, complete reversion was observed, with up to 100% of the mitochondrial DNA in the healthy egg cell matching that of the transferred mutated mitochondrial DNA. This therefore demonstrates that the safety and efficacy of mitochondrial replacement therapy can be compromised and strategies to prevent this outcome need to be explored. The authors state that possible strategies could involve reducing the transfer of cytoplasm during nuclear transfer or selecting embryos without detectable levels of “extra” mitochondrial DNA.
Yamada M et al. (2016). Genetic drift can compromise mitochondrial replacement by nuclear transfer in human oocytes. Cell Stem Cell 18, 1-6
Zika virus protein identified as a possible target for vaccine development
This year, the Zika virus rapidly spread beyond its endemic regions of Africa and Asia to the Americas. There is currently no treatment for the Zika virus, and in light of the recent outbreak, several scientists expanded their research portfolios to explore the development of new vaccines targeting the Zika virus. Professor Adolfo Garcìa-Sastre and his research team at the Icahn School of Medicine at Mount Sinai in New York had been studying the immune suppressive mechanisms utilized by flaviviruses, the virus family to which the Zika virus belongs, when the outbreak began. They recently reported in the journal Cell Host and Microbe that one of the Zika virus’s non-structural proteins, NS5, was solely responsible for blocking the action of interferons in human cells but not in mouse cells. Interferons are key inflammatory proteins that can block viral replication. The research team determined that NS5 specifically inhibits human interferon responses by blocking the STAT2 protein, which is necessary for activating interferon signaling. Based on these findings, they propose that it may be possible to design a Zika virus vaccine using a live, weakened form of the virus with an altered form of the NS5 protein.
Grant A et al. (2016). Zika virus targets human STAT2 to inhibit type I interferon signaling. Cell Host Microbe 19, 1-9
New guidelines for stem cell research and translation
On May 12 2016, the world’s largest professional organization of stem cell scientists, the International Society for Stem Cell Research (ISSCR), issued updated guidelines for research and development of new stem cell therapies. The new guidelines were created by an international task force (9 countries represented) of 25 experts in stem cell biology, clinical research, and bioethics, with review and feedback from 85 external individuals and organizations. The new guidelines emphasize widely held principles in scientific research, such as oversight, rigor and transparency in all areas of practice. They also address ethical, social and policy challenges raised by new stem cell technologies. Stem cell therapy, despite its ability to cure devastating diseases, poses serious social and ethical implications. The guidelines, therefore aim to provide assurance that stem cell research is conducted with scientific and ethical integrity, and that new therapies are evidence based. The new ISSCR issued guidelines can be found here.