Genetics News & Researches

Research by Marta de Los Reyes Jiménez, Antonie Lechner, Francesca Alessandrini, Sina Bohnacker, Sonja Schindela, Aurélien Trompette et al.

Scientists at the Center of Allergy and Environment (ZAUM) at Technical University of Munich and Helmholtz Zentrum München say they have succeeded in isolating, identifying, and analyzing a protein that the larvae of a roundworm (Heligmosomoides polygyrus) use to trick the immune system of their host to survive.

Hpb glutamate dehydrogenase activates various immunoregulatory metabolic pathways. These pathways ensure the formation of anti-inflammatory mediators in the immune cells of the host organism. At the same time the number of inflammatory mediators is reduced.

“Eicosanoids are key mediators of type-2 inflammation, e.g., in allergy and asthma. Helminth products have been suggested as remedies against inflammatory diseases, but their effects on eicosanoids are unknown. Here, they show that larval products of the helminth Heligmosomoides polygyrus bakeri (HpbE), known to modulate type-2 responses, trigger a broad anti-inflammatory eicosanoid shift by suppressing the 5-lipoxygenase pathway, but inducing the cyclooxygenase (COX) pathway,” write the investigators.

Research by Dipak K. Raj, Alok Das Mohapatra, Jenna Zuromski, Ambrish Jha, Gerald Cham-Kpu et al.

In the past several months, many of us have become uniquely aware of global pandemics that have ripped their way across the globe. Whether it was the black plague of the 14th century, the 1918 flu pandemic, or the current COVID-19, there is still one pandemic disease that eclipses all others in terms of its death toll and persistence. By all accounts, malaria has been around since the dawn of humankind, and many scientists have hypothesized that since the stone age, this parasitic infection has killed half of all human life that has lived on this planet. It’s a sobering thought given that the disease still claims close to a half-million people each year — mainly children under the age of five years old — and that useful therapeutics and control measures have eluded researchers or become ineffective due to resistance.

While a vaccine would be the ideal method for eliminating malaria from the human population, all attempts thus far to create an effective vaccine have been thwarted by the parasite. However, now, a team of investigators led by scientists at Brown University has discovered a promising new strategy for combating malaria that could prove useful as a novel vaccine candidate.

In the current study, the researchers screened blood samples from children who had natural immune resistance to severe malaria infection. They identified an antibody to a particular malaria protein, called PfGARP, that appears to protect resistant children from severe disease. Findings from the new study were published recently in Nature through an article entitled “Anti-PfGARP activates programmed cell death of parasites and reduces severe malaria.”

Additionally, lab tests showed that antibodies to PfGARP seem to activate a malarial self-destruct mechanism, causing parasite cells living inside human red blood cells to undergo a form of programmed cell death.

Research by Philipp Ilinykh, Kai Huang, Rodrigo I. Santos, Pavlo Gilchuk, Bronwyn M.Gunn, Marcus M.Karim, Jenny Liang, Mallorie E. Fouch, Edgar Davidson, Diptiben V. Parekh et al.

Marburg virus, a member of the filovirus family — which also contains the five species of Ebola virus — typically causes a serious disease of hemorrhagic fever, with a fatality ratio of up to 88%. There is no treatment for Marberg infection and although experimental treatments have been validated in nonhuman primates models, they have never been tried in humans.

A detailed study of the monoclonal antibodies from a person who survived a Marburg infection led researchers to identify novel mechanisms that contribute protection against the disease, according to the latest findings of a collaborative team led by the University of Texas Medical Branch (UTMB) at Galveston and Vanderbilt University Medical Center.

The findings are now available in a paper titled, “Non-neutralizing Antibodies from a Marburg Infection Survivor Mediate Protection by Fc-Effector Functions and by Enhancing Efficacy of Other Antibodies” in Cell Host & Microbe.

In an earlier study, the research team had isolated a large panel of monoclonal antibodies (mAbs) from B cells of a human survivor with previous naturally acquired Marburg virus infection. In this new study, they characterized the functional properties of these mAbs and identified non-neutralizing mAbs targeting the glycoprotein (GP) of the virus.

Research by Neha Nagpal, Jianing Wang, Jing Zeng, Emily Lo, Diane H. Moore et al.

Scientists at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center have published a study “Small-Molecule PAPD5 Inhibitors Restore Telomerase Activity in Patient Stem Cells” in Cell Stem Cell that may offer a breakthrough in treating dyskeratosis congenita (DC) and other so-called telomere diseases, in which cells age prematurely. Using cells donated by patients with the disease, the researchers identified several small molecules that appear to reverse this cellular aging process.

Source: Cell Stem Cell

Suneet Agarwal, MD, PhD, the study’s senior investigator, hopes at least one of these compounds will advance toward clinical trials. If so, it could be the first treatment for DC that could reverse all of the disease’s varying effects on the body. The current treatment, bone marrow transplant, is high-risk, and only helps restore the blood system, whereas DC affects multiple organs.

“Genetic lesions that reduce telomerase activity inhibit stem cell replication and cause a range of incurable diseases, including dyskeratosis congenita (DC) and pulmonary fibrosis (PF). Modalities to restore telomerase in stem cells throughout the body remain unclear. Here, we describe small-molecule PAPD5 inhibitors that demonstrate telomere restoration in vitro, in stem cell models, and in vivo. PAPD5 is a non-canonical polymerase that oligoadenylates and destabilizes telomerase RNA component (TERC),” write the investigators.

Research by Shruthy Suresh, BeiBei Chen, Jingfei Zhu, Ryan J. Golden, Changzheng Lu, Bret M. Evers, Nicole Novaresi, Bethany Smith, Xiaowei Zhan et al.

Scientists at the University of Texas (UT) Southwestern Medical Center used CRISPR-based screening to help identify a mechanism by which cancer cells can regulate the production of a protein that suppresses immune system responses against the tumor. The team’s combined studies in human lung cancer cells and in mice found that blocking heme production activated the integrated stress response (ISR), which led to increased production of programmed death-ligand 1 (PD-L1) and suppression of antitumor immunity. PD-L1 is a key target of immunotherapy drugs known as checkpoint inhibitors.

The scientists also showed that the effects of heme inhibition could be replicated by overexpressing a single gene, eIF5B, which they subsequently found is upregulated in human lung cancers. Headed by UT Southwestern associate professor Kathryn A. O’Donnell, PhD, the team said their results suggest that eIF5B functions as an oncogene, and that the findings could point to new approaches to boosting the effectiveness of anticancer immunotherapy.

“… these findings revealed an unanticipated mechanism of immune checkpoint activation in lung cancer with important therapeutic implications,” they concluded in their published paper in Nature Cancer, which is titled, “eIF5B drives integrated stress response-dependent translation of PD-L1 in lung cancer.”

Cancer cells, including non-small cell lung cancer (NSCLC), frequently express high levels of PD-L1, a ligand of the programmed cell death protein 1 (PD-1) receptor on T cells, allowing tumors to directly suppress the host immune response by inhibiting T cell proliferation and function, the authors explained. Antibody-based immune checkpoint inhibitor drugs that block PD-L1 have yielded “remarkable results,” they continued, and anti-PD-1 immunotherapy is approved as first-line therapy for lung cancer.

Research by Matteo Andrea Lucherelli, Yue Yu, Giacomo Reina, Gonzalo Abellán, Eijiro Miyako, Alberto Bianco

Scientists from the Japan Advanced Institute of Science and Technology (JAIST) and Centre national de la recherche scientifique (CNRS), and their colleagues say they have developed a type of nanomedicine based on multi-functional graphene that allows for targeted cancer treatment at molecular level.

Single molecular sheet graphene is a promising carbon nanomaterial for various fundamental and practical applications in the next decade because of its excellent physico-chemical features, according to the researchers, who published their study “Rational chemical multifunctionalization of graphene interface enhances targeting cancer therapy” in Angewandte Chemie International Edition.

Figure 1. Schematic illustration of multi-functional graphene. [JAIST, CNRS]

Graphene has been also known to have good biocompatibility and biodegradability, thus leading to explore this nanocarbon as a drug delivery carrier. However, it is not easy to modify a lot of individual functional molecules onto a graphene nano-sheet at the same time for its biomedical applications, note the scientists.

“The synthesis of a drug delivery platform based on graphene was achieved through a step‐by‐step strategy of selective amine deprotection and functionalization. The multifunctional graphene platform, functionalized with indocyanine green, folic acid and doxorubicin showed enhanced anticancer activity,” write the investigators. “The remarkable targeting capacity for cancer cells in combination with the synergistic effect of drug release and photothermal properties prove the great advantage of combined chemo‐ and phototherapy based on graphene against cancer, opening the doors to future therapeutic applications of this type of material.”

Research by Fu Sun, Anurup Ganguli, Judy Nguyen, Ryan Brisbin, Krithika Shanmugam, David L. Hirschberg, Matthew B. Wheeler, Rashid Bashir, David M. Nashf and Brian T. Cunningham

Researchers headed by a team at the University of Illinois, Urbana-Champaign, have developed what they claim is an inexpensive, sensitive smartphone-based device that can detect viral and bacterial pathogens in about 30 minutes, and could be adapted to test for SARS-CoV-2. The platform comprises a cartridge-housed microfluidic chip that carries out isothermal amplification of viral nucleic acids from nasal swab samples, which are then detected using the smartphone camera. The investigators report on their use of the system to detect equine viruses as a non-biohazard surrogate for SARS-CoV-2, but say that when adapted to test for coronavirus, the smartphone accessory, costing about $50, could be used to reduce the pressure on testing laboratories during pandemics such as COVID-19.

“This test can be performed rapidly on passengers before getting on a flight, on people going to a theme park, or before events like a conference or concert,” said University of Illinois, Urbana-Champaign electrical and computer engineering professor Brian Cunningham, PhD, who, together with bioengineering professor Rashid Bashir, PhD, led the development of the device. “Cloud computing via a smartphone application could allow a negative test result to be registered with event organizers or as part of a boarding pass for a flight. Or, a person in quarantine could give themselves daily tests, register the results with a doctor, and then know when it’s safe to come out and rejoin society.”

The multi-institutional researchers described their development and use of the device, in Lab on a Chip. The paper is titled, “Smartphone-Based Multiplex 30-minute Nucleic Acid Test of Live Virus from Nasal Swab Extract.”

As the COVID-19 pandemic has escalated, a “key failure” of health systems across every country has been the ability to rapidly and accurately diagnose disease, the authors stated. Contributing factors include “ … a limited number of available test kits, a limited number of certified testing facilities, combined with the length of time required to obtain a result and provide information to the patient.”

Draft results accidentally published by the World Health Organization (WHO) on its website showed that Gilead Sciences’ closely watched COVID-19 candidate remdesivir failed to show clinical improvement in severely infected patients in a Chinese Phase III trial.

According to the draft, whose findings were disclosed by The Financial Times, remdesivir had not reduced the presence of SARS-CoV-2 in the bloodstream of 158 patients treated with the antiviral candidate in the 237-patient trial (NCT04257656). Eighteen patients were taken off the drug due to side effects.

“Remdesivir use was not associated with a difference in time to clinical improvement,” or mortality after 28 days, or in time to SARS-CoV-2 PCR, the draft stated, according to several published reports.

Twenty-eight days after treatment, 13.9% of the patients in the remdesivir cohort died, compared to 12.8% of untreated control patients — a difference the researchers concluded was not statistically significant.

“In this study of hospitalized adult patients with severe COVID-19 that was terminated prematurely, remdesivir was not associated with clinical or virological benefits,” according to the draft.

Gilead stopped short of calling the trial failure in a statement that acknowledged that the study was halted early. The drug developer said it believed the draft contained “inappropriate characterizations of the study,” and added that the trial’s investigators did not give permission for publication of their results.

Research by Ngoc Uyen Nhi Nguyen, Diana C. Canseco, Feng Xiao, Yuji Nakada, Shujuan Li, Nicholas T. Lam, Shalini A. Muralidhar, Jainy J. Savla, Joseph A. Hill, Victor Le, Kareem A. Zidan et al.

UT Southwestern Medical Center scientists have discovered a protein that works with others during development to put the brakes on cell division in the heart, they report in Nature. The findings could eventually be used to reverse this developmental block and help heart cells regenerate, offering a whole new way to treat a variety of conditions in which heart muscle becomes damaged, including heart failure caused by viruses, toxins, high blood pressure, or heart attacks

Research by Bart MH Bruininks, Paulo CT Souza, Helgi Ingolfsson, Siewert J Marrink

Diseases with a genetic cause could, in theory, be treated by supplying a correct version of the faulty gene. However, in practice, delivering new genetic material to human cells is difficult. A promising method for the delivery of such genes involves the use of DNA/lipid complexes (lipoplexes). Scientists at the University of Groningen have now used advanced simulations to investigate how these lipoplexes deliver DNA fragments into cells. The results, which were published in the journal eLife on 16 April, can be used to improve their efficiency.

The idea behind gene therapy is very simple: if a disease is caused by a particular version of a single gene, it could be cured by replacing this gene. For example, in cystic fibrosis, a mutation in the gene that codes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein causes the disease. Replacing it in mucosal cells with a copy that does not carry the mutation could reverse this.

Unprecedented 3D images of live cells plus details of molecules inside — No damage caused by strong light, no artificial dyes or fluorescent tags needed

Research by Miu Tamamitsu, Keiichiro Toda, Hiroyuki Shimada, Takaaki Honda, Masaharu Takarada, Kohki Okabe, Yu Nagashima, Ryoichi Horisaki, Takuro Ideguchi

The insides of living cells can be seen in their natural state in greater detail than ever before using a new technique developed by researchers in Japan. This advance should help reveal the complex and fragile biological interactions of medical mysteries, like how stem cells develop or how to deliver drugs more effectively.

“Our system is based on a simple concept, which is one of its advantages,” said Associate Professor Takuro Ideguchi from the University of Tokyo Research Institute for Photon Science and Technology. The results of Ideguchi’s team were published recently in Optica, the Optical Society’s research journal. The new method also has the advantages of not needing to kill the cells, damage them with intense light, or artificially attach fluorescent tags to specific molecules. The technique combines two pre-existing microscopy tools and uses them simultaneously. The combination of these tools can be thought of simply as like a coloring book.

“We gather the black-and-white outline of the cell and we virtually color in the details about where different types of molecules are located,” said Ideguchi.

Research by Oleg Simakov, Ferdinand Marlétaz, Jia-Xing Yue, Brendan O’Connell, Jerry Jenkins, Alexander Brandt, Robert Calef, Che-Huang Tung, Tzu-Kai Huang, Jeremy Schmutz, Nori Satoh, Jr-Kai Yu, Nicholas H. Putnam, Richard E. Green, Daniel S. Rokhsar

To look at how life evolved, scientists usually turn to the fossil record, but this record is often incomplete. Researchers from the Okinawa Institute of Science and Technology Graduate University (OIST), alongside an international team of collaborators, have used another tool — the chromosomes of living animals — to uncover clues about our past. The study, published in Nature Ecology and Evolution, reveals early events in the evolution of vertebrates, including how jawed vertebrates arose through hybridization between two species of primitive fish.

“It’s remarkable that although these events occurred almost half a billion years ago, we can figure them out by looking at DNA today,” said Professor Daniel Rokhsar, who leads OIST’s Molecular Genetics Unit.

Picking up threads of cotton genomics — Analysis reveals cotton genome stability across global lineages

Research by Z. Jeffrey Chen, Avinash Sreedasyam, Atsumi Ando, Qingxin Song, Luis M. De Santiago, Amanda M. Hulse-Kemp, Mingquan Ding, Wenxue Ye, Ryan C. Kirkbride, Jerry Jenkins, Christopher Plott, John Lovell, Yu-Ming Lin et al.

A multi-institutional team including researchers at the U.S. Department of Energy (DOE) Joint Genome Institute (JGI), a DOE Office of Science User Facility located at Lawrence Berkeley National Laboratory (Berkeley Lab) has now sequenced and assembled the genomes of these five cotton lineages. Senior authors of the paper published April 20, 2020 in Nature Genetics include Jane Grimwood and Jeremy Schmutz of JGI’s Plant Program, both faculty investigators at the HudsonAlpha Institute for Biotechnology.

“The goal has been for all this new cotton work, and even the original cotton project was to try to bring in molecular methods of breeding into cotton,” said Schmutz, who heads JGI’s Plant Program.

He and Grimwood were also part of the JGI team that contributed to the multinational consortium of researchers that sequenced and assembled the simplest cotton genome (G. raimondii) several years ago. Studying the cotton genomes provides breeders with insights on crop improvements at a genetic level, including why having multiple copies of their genomes (polyploidy) is so important to crops. Additionally, cotton is almost entirely made up of cellulose and it is a fiber model to understand the molecular development of cellulose.

DNA may not be life’s instruction book — just a jumbled list of ingredients: Researcher develops a potentially revolutionary framework for heredity and evolution in which inheritable information is stored outside the genome.

Research by Antony M. Jose

The common view of heredity is that all information passed down from one generation to the next is stored in an organism’s DNA. But Antony Jose, associate professor of cell biology and molecular genetics at the University of Maryland, disagrees.

In two new papers, Jose argues that DNA is just the ingredient list, not the set of instructions used to build and maintain a living organism. The instructions, he says, are much more complicated, and they’re stored in the molecules that regulate a cell’s DNA and other functioning systems. Jose outlined a new theoretical framework for heredity, which was developed through 20 years of research on genetics and epigenetics, in peer-reviewed papers in the Journal of the Royal Society Interface and the journal BioEssays.

Diabetes reversed in mice with genetically edited stem cells derived from patients — CRISPR corrects genetic defect so cells can normalize blood sugar

Research by Kristina G. Maxwell, Punn Augsornworawat, Leonardo Velazco-Cruz, Michelle H. Kim, Rie Asada, Nathaniel J. Hogrebe, Shuntaro Morikawa, Fumihiko Urano, Jeffrey R. Millman.

Using induced pluripotent stem cells produced from the skin of a patient with a rare, genetic form of insulin-dependent diabetes called Wolfram syndrome, researchers transformed the human stem cells into insulin-producing cells and used the gene-editing tool CRISPR-Cas9 to correct a genetic defect that had caused the syndrome. They then implanted the cells into lab mice and cured unrelenting diabetes in those mice. The findings, from researchers at Washington University School of Medicine in St. Louis, suggest the CRISPR-Cas9 technique may hold promise as a treatment for diabetes, particularly the forms caused by a single gene mutation, and it also may be useful one day in some patients with the more common forms of diabetes, such as type 1 and type 2.

Research by Chan C. Heu, Francine M. McCullough, Junbo Luan, Jason L. Rasgon.

Whiteflies are among the most important agricultural pests in the world, yet they have been difficult to genetically manipulate and control, in part, because of their small size. An international team of researchers has overcome this roadblock by developing a CRISPR/Cas9 gene-editing protocol that could lead to novel control methods for this devastating pest.

According to Jason Rasgon, professor of entomology and disease epidemiology, Penn State, whiteflies (Bemisia tabaci) feed on many types of crop plants, damaging them directly through feeding and indirectly by promoting the growth of fungi and by spreading viral diseases.

“We found a way to genetically modify these insects, and our technique paves the way not only for basic biological studies of this insect, but also for the development of potential genetic control strategies,” he said.

Proteins may halt the severe cytokine storms seen in COVID-19 patients — Team designs antibody-like receptor proteins that can bind to cytokines, as possible strategy for treating coronavirus and other infections

Research by Shilei Hao, David Jin, Shuguang Zhang, Rui Qing.

One of the defining features of Covid-19 is the excessive immune response that can occur in severe cases. This burst of immune overreaction, also called a cytokine storm, damages the lungs and can be fatal. A team of MIT researchers has developed specialized proteins, similar in structure to antibodies, that they believe could soak up these excess cytokines.

“The idea is that they can be injected into the body and bind to the excessive cytokines as generated by the cytokine storm, removing the excessive cytokines and alleviating the symptoms from the infection,” says Rui Qing, an MIT research scientist who is one of the senior authors of the study.

The researchers have reported their initial findings in the journal Quarterly Review of Biophysics (QRB) Discovery, and they now hope to begin testing their proteins in human cells and in animal models of cytokine release and coronavirus infection.

Shuguang Zhang, a principal research scientist in the MIT Media Lab’s Laboratory of Molecular Architecture, is also a senior author of the paper. Shilei Hao, a visiting scientist at MIT, is the lead author of the study, and David Jin, CEO and president of Avalon GloboCare, is also an author.

Research by Vidhi Pareek, Hua Tian, Nicholas Winograd, Stephen J. Benkovic.

For more than 40 years, scientists have hypothesized the existence of enzyme clusters, or “metabolons,” in facilitating various processes within cells. Using a novel imaging technology combined with mass spectrometry, researchers at Penn State, for the first time, have directly observed functional metabolons involved in generating purines, the most abundant cellular metabolites. The findings could lead to the development of novel therapeutic strategies that disrupt the progression of cancer.

“Our study suggests that enzymes are not haphazardly located throughout cells, but instead occur in discrete clusters, or metabolons, that carry out specific metabolic pathways,” said Stephen Benkovic, Evan Pugh University Professor and Eberly Chair in Chemistry. “Not only did we find proof that metabolons exist, but we also found that this metabolon occurs near mitochondria in cancer cells.”

Research by Hanna L. Sladitschek, Ulla-Maj Fiuza, Dinko Pavlinic, Vladimir Benes, Lars Hufnagel, Pierre A. Neveu.

Researchers from EMBL Heidelberg and from the University of Padua School of Medicine have created the first complete description of early embryo development, accounting for every single cell in the embryo. This ‘virtual embryo’ will help to answer how the different cell types in an organism can originate from a single egg cell. The results are published on 20 April in the journal Cell.

“How are the many different cell types in the body generated during embryonic development from an egg, which is only a single cell? This is one of the most fundamental questions in biology,” explains Dr. Pierre Neveu, group leader at EMBL Heidelberg, setting out the rationale behind the research he and his group have performed in collaboration with the group of Dr. Lars Hufnagel.

Research by Carly G. K. Ziegler, Samuel J. Allon, Sarah K. Nyquist, Ian M. Mbano, Vincent N. Miao, Constantine N. Tzouanas, Yuming Cao, Ashraf S. Yousif, Julia Bals, Blake M. Hauser, Jared Feldman, Christoph Muus et al.

There is pressing urgency to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) which causes the disease COVID-19. SARS-CoV2 spike (S)-protein binds ACE2, and in concert with host proteases, principally TMPRSS2, promotes cellular entry. The cell subsets targeted by SARS-CoV-2 in host tissues, and the factors that regulate ACE2 expression, remain unknown. Here, they leverage human, non-human primate, and mouse single-cell RNA-sequencing (scRNA-seq) datasets across health and disease to uncover putative targets of SARS-CoV-2 amongst tissue-resident cell subsets. They identify ACE2 and TMPRSS2 co-expressing cells within lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells. Strikingly, They discover that ACE2 is a human interferonstimulated gene (ISG) in vitro using airway epithelial cells, and extend their findings to in vivo viral infections. the data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection.