Korea Research Institute of Bioscience & Biotechnlogy

Scientists have found a way to boost ethanol production via yeast fermentation, a standard method for converting plant sugars into biofuels. Their approach relies on careful timing and a tight division of labor among synthetic yeast strains to yield more ethanol per unit of plant sugars than previous approaches have achieved. Scientists have found a way to boost ethanol production via yeast fermentation, a standard method for converting plant sugars into biofuels. Their approach, detailed in the journal Nature Communications, relies on careful timing and a tight division of labor among synthetic yeast strains to yield more ethanol per unit of plant sugars than previous approaches have achieved. "We constructed an artificial microbial community consisting of two engineered yeast strains: a glucose specialist and a xylose specialist," said Yong-Su Jin, a professor of food science and human nutrition at the University of Illinois Urbana-Champaign, who co-led the new research with U. of I. bioengineering professor Ting Lu. "We investigated how the timing of mixing the two yeast populations and the ratios in which the two populations were mixed affected the production of cellulosic ethanol." Postdoctoral researcher Jonghyeok Shin and Siqi Lao, a Ph.D. student in the Center for Biophysics and Quantitative Biology at the U. of I., carried out the work. Glucose and xylose are the two most abundant sugars obtained from the breakdown of plant biomass such as agricultural wastes. The team was trying to overcome a common problem that occurs when using yeast to convert these plant sugars into ethanol. In the wild, the yeast strain of interest, Saccharomyces cerevisiae, prefers glucose and lacks the ability to metabolize xylose. Other scientists have used genetic engineering to alter the yeast so that it also consumes xylose, but these engineered strains still prefer glucose, reducing their overall efficiency in ethanol production. Some scientists have pursued the idea that communities of microbes, each with its own special function, can operate more efficiently than a single, highly engineered strain. "My group is dedicated to the design, analysis and engineering of synthetic microbial communities. Jin's lab specializes in yeast metabolic engineering and biofuel production," Lu said. "Our complementary expertise enabled us to test whether a division-of-labor approach among yeast might work well in biofuels production." The researchers conducted a series of experiments testing the use of their two specialist yeast strains. They altered the order in which the different strains were added to the sugar mixture and the timing of each addition. "We also investigated the ratios at which the two populations were mixed to determine their effects on the rapid and efficient production of cellulosic ethanol," Jin said. The team also developed a mathematical model that accurately predicts their yeasts' performance and ethanol yields. "We used the data from the experiments to train our mathematical model so that it captures the characteristic ecosystem behaviors," Lu said. "The model was then used to predict optimal fermentation conditions, which were later validated by corresponding experiments." The researchers discovered that adding the xylose-fermenting yeast specialist to the mixture first, followed 14 to 29 hours later by the glucose specialist, dramatically boosted ethanol production, more than doubling the yield. "This study demonstrates the functional potential of division of labor in bioprocessing and provides insight into the rational design of engineered ecosystems for various applications," the authors wrote. Yong-Su Jin and Ting Lu also are professors in the Biosystems Design theme in the Carl R. Woese Institute for Genomic Biology at the U. of I. Jonghyeok Shin is now a scientist at the Korea Research Institute of Bioscience and Biotechnology. The Department of Energy and the Korea Research Institute of Bioscience and Biotechnology supported this research.

While vaccination can provide life-saving protection against COVID-19, scientists are still searching for ways to treat severe infections, including in people who cannot get vaccinated or in the event that dangerous new strains of the virus arise that could bypass vaccine protection. Now, a new study from a team of researchers led by Amy S. Lee, PhD, professor of biochemistry and molecular medicine at the Keck School of Medicine of USC, shows that a chaperone protein known as GRP78, implicated in the spread of other viruses, plays an essential role in the spread of SARS-CoV-2, the virus that causes COVID-19. The study also shows that blocking the production of GRP78, or inhibiting its activity with a new targeted drug, greatly reduced the replication of SARS-CoV-2. The research, just published in the journal Nature Communications, suggests this drug could potentially offer a new type of protection against COVID-19, one that might remain effective even as new strains develop. "A major problem in fighting SARS-CoV-2 is that it is constantly mutating and adapting itself to more efficiently infect and multiply in its host cells," said Lee, also the Judy and Larry Freeman Chair in basic science research. "If we keep chasing the virus around, this could become quite challenging and unpredictable." GRP78's role in the spread of viruses Searching for a more stable way to combat COVID-19, Lee and her colleagues at the Keck School of Medicine of USC and the Cleveland Clinic Florida Research and Innovation Center began exploring the role of GRP78, a key cellular chaperone protein that helps regulate the folding of other cellular proteins. While healthy cells need a fraction of GRP78 to function normally, cells under stress need more GRP78 to cope. The Keck School of Medicine researchers showed in a 2021 paper that when SARS-CoV-2 enters the scene, GRP78 is hijacked to work in tandem with other cellular receptors to bring the SARS-CoV-2 virus inside cells, where it can then reproduce and spread. But questions remained about whether GRP78 is necessary and essential for SARS-CoV-2 replication inside human lung cells. Examining human lung epithelial cells infected with SARS-CoV-2, the research team observed that as the viral infection intensifies, the infected cells produce higher levels of GRP78. The power of inhibiting GRP78 Then Lee and her team used a special messenger RNA tool to suppress production of the GRP78 protein in human lung epithelial cells in cell culture, without interrupting other cellular processes. When those cells were later infected with SARS-CoV-2, they produced a lower amount of the viral spike protein and released much less of the virus to infect other cells, proving that GRP78 was necessary and essential for viral replication and production. "We now have direct evidence that GRP78 is a proviral protein that is essential for the virus to replicate," Lee said. To further explore whether targeting GRP78 could work to treat COVID-19, the researchers tested a recently identified small molecule drug, known as HA15 on the infected lung cells. This drug, developed for use against cancer cells, specifically binds GRP78 and inhibits its activity. "Lo and behold, we found that this drug was very effective in reducing the number and size of SARS-CoV-2 plaques produced in the infected cells, in safe doses which had no harmful effect on normal cells," Lee said. The researchers then tested HA15 in the body of mice that were genetically engineered to express a human SARS-CoV-2 receptor and infected with SARS-CoV-2, finding that the drug greatly reduced viral load in the lungs. Drugs that target GRP78 Separately, Lee and her colleagues at the Keck School of Medicine are studying the efficacy of HA15 in cancer, as well as another GRP78 inhibitor, YUM70, in collaboration with researchers at the University of Michigan. They discovered that HA15 and YUM70 can suppress the production of mutant KRAS proteins - a common mutation that tends to resist drug treatment - and reduce the viability of cancer cells bearing such mutations in pancreatic, lung and colon cancer. Those findings, just published in the journal Neoplasia, suggest targeting GRP78 may help combat these deadly cancers. These are basic proof of principle studies; further research, including clinical trials, is needed to establish that HA15 and YUM70 are safe and effective for use in humans. These and other GRP78 inhibitors are now being tested as treatments for both COVID-19 and cancer. These drugs may also prove useful for treating future coronaviruses that depend on GRP78 for entry and replication, Lee said. About this study In addition to Lee, the Nature Communications studys other authors are Dat Ha of the Department of Biochemistry & Molecular Medicine, Keck School of Medicine of USC; Keigo Machida of the Department of Molecular Microbiology and Immunology, Keck School of Medicine of USC; and Woo-Jin Shin of the Florida Research and Innovation Center, Cleveland Clinic. This research is facilitated by USCs Biosafety-Level 3 containment laboratory, allowing the team to safely study the SARS-CoV-2 infection in genetically engineered mice. The study was supported by the National Institutes of Health [R01 CA238029, R01 CA027607, R01 AA025204-01A1], a pilot grant from a gift by the W. M. Keck Foundation to support COVID-19 research and the Korea Research Institute of Bioscience and Biotechnology [KGM9942011]. Shin, WJ., Ha, D.P., Machida, K. et al. The stress-inducible ER chaperone GRP78/BiP is upregulated during SARS-CoV-2 infection and acts as a pro-viral protein. Nat Commun 13, 6551, 2022. doi: 10.1038/s41467-022-34065-3

DAEJEON, South Korea , Aug. 2, 2022 /PRNewswire/ -- GenKOre (homepage: ), a biotech start-up in Korea, had a study on the development of hypercompact adenine base editors (ABEs) published on Nature Chemical Biology on August 2, 2022. The hypercompact ABEs newly developed by GenKOre feature a hypercompact size that can be delivered using a single AAV vector and boast of high base editing efficiency and specificity. The company also validated base-editing feasibility in mouse in vivo. Continue Reading Gene editing Previously, GenKOre developed a hypercompact CRISPR system with AAV delivery compatibility, coined TaRGET (Tiny nuclease/augment RNA-based Genome Editing Technology), which was published in Nature Biotechnology in 2021. Adeno-associated virus (AAV) is one of the most validated delivery vehicles for gene therapy, but has a limited payload size to 4.7 kb. Previous base-editing technology was developed based on such a 'big' SpCas9 nuclease that it cannot be delivered by payload-limiting AAV vectors and has been thus confined for hepatic delivery. The hypercompact base editing system developed by GenKOre was developed based on TaRGET system and is amenable to AAV delivery. This new base-editing technology is expected to provide various in vivo treatment options for genetic diseases through AAV delivery. GenKOre is a start-up spun off from the Korea Research Institute of Bioscience and Biotechnology (KRIBB), which is a government-invested research institute in Korea. It has platform business through hypercompact genome editing platform. GenKOre develops AAV/ non-AAV-based gene therapy and animals/plants using its own genome editing system. Recently, GenKOre expanded its research facility in Seoul to attract more researchers and aim to develop a gene therapy based on hypercompact genome editing technology and to seek collaborations with pharmaceutical companies and academia. Details of the new developed system made by GenKOre can be checked at: . GenKOre website: SOURCE GenKOre