Proteomic 'Lght-Bites'

Proteomic & Genomic news & views to share

 

                                                 

 

A new approach for generating bispecific antibodies based on a common light chain format and the stable architecture of human immunoglobulin G1.

Camilla De Nardis, Linda J. A. Hendriks, Emilie Poirier, Tudor Arvinte, Piet Gros, Alexander B. H. Bakker, John de Kruif .

Journal of Biological Chemistry, 2017; jbc.M117.793497 DOI: 10.1074/jbc.M117.793497.  (Sept. 2017)

A group of researchers has developed an approach to efficiently produce antibodies that can bind to two different target molecules simultaneously, a long-desired innovation in the field of cancer immunotherapy.  The researchers combined different approaches -  the computational tools with the biochemistry and structural biology to achieve the end results.

 

Antibodies are proteins produced by the immune system that specialize in recognizing and binding to molecular targets unique to bacteria, viruses or other foreign cells. Because antibodies are stable and long-lasting in the human body and can precisely recognize specific targets, they have been exploited to develop new treatments for diseases. For example, modified antibodies can be used to bind to targets in cancer cells, recruiting the immune system to attack the cancer or preventing the cancer cells from multiplying. Because of their precision and capacity to stimulate the body's immune response, antibody-based therapies typically have fewer side effects than chemotherapy or radiation.

 

Antibodies are "Y" shaped, and typically bind a target, or antigen, through the tip of each arm of the "Y." In naturally produced antibodies, both arms of a single antibody typically are the same and bind to the same target. One approach to increasing the versatility of antibody therapies is to engineer what are called bispecific antibodies, in which each arm binds to a different molecule. This expands the range of what antibodies can be used for. For example, a bispecific antibody could target a cluster of proteins made up of multiple protein types, or it could bring two different molecules or cell types together.  Antibodies are capable of being so specific, and with bispecific antibodies, one can choose the affinities of both arms and balance them so that you can more specifically target tumors, and also recruit other cells or molecules to attack the tumor cells without many side effects. 

 

FDA Needs Help Assessing Cutting-Edge Technologies  - Nature Editorial, August, 2017

The US Food and Drug Administration (FDA) is increasingly being tasked with evaluating cutting-edge therapies and technology that its in-house expertise may not be able to address, according to a Nature editorial, which recommends academic scientists help the agency.  Using the example of the 12 July 2017 meeting of the Oncologic Drugs Advisory Committee that voted unanimously in favor of the benefit-risk profile for the first of a new kind of cancer therapy, the editorial notes that much of the meeting discussed the manufacturing of the new therapy, noting that it "offers a glimpse of the regulatory complexity that cutting-edge therapies present."

FDA "needs academic scientists to get involved," the editorial adds, offering ways for them to do so via the agency’s centers of excellence and collaborations with academic institutions.  "The Academics have traditionally shown little taste for the dry details of drug development. Many have fallen prey to the misconception that the FDA is not engaging with the latest science. The agency realizes that it has an image problem and, to its credit, is trying to change," the editorial says.

In addition, the editorial notes FDA’s "legendary struggle to retain its employees," particularly for "key positions such as those of bioinformaticians, where supply falls well short of demand," and as competition with industry for skilled job candidates is "particularly intense."  FDA will need much more to remain effective in the face of future challenges.

 

Correction of a pathogenic gene mutation in human embryos: Hong Ma, Nuria Marti-Gutierrez, Sang-Wook Park, Jun Wu, Yeonmi Lee, Keiichiro Suzuki et. al.

Nature (2017) doi:10.1038/nature23305  / Published online  02 August 2017

Genome editing has potential for the targeted correction of germline mutations. Here the authors describe the correction of the heterozygous MYBPC3 mutation in human preimplantation embryos with precise CRISPR–Cas9-based targeting accuracy and high homology-directed repair efficiency by activating an endogenous, germline-specific DNA repair response. Induced double-strand breaks (DSBs) at the mutant paternal allele were predominantly repaired using the homologous wild-type maternal gene instead of a synthetic DNA template. By modulating the cell cycle stage at which the DSB was induced, they were able to avoid mosaicism in cleaving embryos and achieve a high yield of homozygous embryos carrying the wild-type MYBPC3 gene without evidence of off-target mutations. The efficiency, accuracy and safety of the approach presented suggest that it has potential to be used for the correction of heritable mutations in human embryos by complementing preimplantation genetic diagnosis. However, much remains to be considered before clinical applications, including the reproducibility of the technique with other heterozygous mutations.

 

CRISPR gene editing can cause hundreds of unintended mutations

Kellie A. Schafer (Stanford University), Wen-Hsuan Wu (Columbia University Medical Center), and Diana G. Colgan (Iowa) et. al - Nature Methods, May 29, 2017  

As CRISPR-Cas9 starts to move into clinical trials, a new study published in Nature Methods has found that the gene-editing technology can introduce hundreds of unintended mutations into the genome.  CRISPR-Cas9 editing technology—by virtue of its speed and unprecedented precision—has been a boon for scientists trying to understand the role of genes in disease. The technique has also raised hope for more powerful gene therapies that can delete or repair flawed genes, not just add new genes.

But even though CRISPR can precisely target specific stretches of DNA, it sometimes hits other parts of the genome. Most studies that search for these off-target mutations use computer algorithms to identify areas most likely to be affected and then examine those areas for deletions and insertions.  These predictive algorithms seem to do a good job when CRISPR is performed in cells or tissues in a dish, but whole genome sequencing has not been employed to look for all off-target effects in living animals.

​In this new study, the researchers sequenced the entire genome of mice that had undergone CRISPR gene editing in the team's previous study and looked for all mutations, including those that only altered a single nucleotide.  Researchers who aren't using whole genome sequencing to find off-target effects may be missing potentially important mutations.

 

The power of tears: how tear proteomics research could revolutionize the clinic

Lei Zhou and Roger W. Beuerman - EXPERT REVIEW OF PROTEOMICS, VOL. 14, NO. 3, 189–191, 2017

Tear ‘omics’ research over the past decade has demonstrated the future applications of tear biomarkers for patient stratification or what is now often referred to as precision medicine. Tear collection is fast, safe, and noninvasive and offers a chance to determine the local pathology close to the disease site. The relatively simple chemical composition and sample preparation procedures make tear fluid an ideal source for diagnosis and prognosis. Proteomic studies can easily be translated into antibody-based assays for clinical use.  It is hoped that a ‘tear test’ that will eventually become like a ‘blood test’ or ‘urine test’ used in eye clinics in the near future.  Its application could also be extrapolated to other areas of proteomic and precision medicine.

 

Neuro-inflammation, neuro-protection and microglial activation

Understanding of microglial-induced neuro-inflammation is a key to understanding various neurological diseases.  Microglia are the brain's resident immune cells, transitioning from resting to activation state upon sensing damage or a foreign substance. Activated microglia release a wave of chemical mediators, including chemokines, cytokines, and proteases, all of which promote the neuroinflammatory milieu. Understanding how microglia trigger 'neuro-microglial induced neuro-inflammation' may help understand the disease process, progression and the role of:

  • Factors that induce microglial activation in neurodegenerative diseases
  • Better understanding of ‘neuro- protection’ in the brain

 

Y. J. Choi et al., “Deficiency of microRNA miR-34a expands cell fate potential in pluripotent stem cells,” Science, doi:10.1126/science.aag1927, 2017. 

Pluripotent stem cells are capable of generating all embryonic cell lineages but, until now, scientists could seldom manipulate induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) to generate extra-embryonic cell types, such as placental cells. A study published rcently (12th January,2017) in Science has now shown that removing one particular microRNA—miR-34a—from a stem cell can kick off a molecular pathway that induces endogenous retroviruses and, at the same time, enables iPSCs and ESCs to consistently form extra-embryonic cells in a dish.

The results suggest that a particular class of noncoding RNA works in concert with the latent viral elements of the genome work to limit stem cell potential, and that removing a key miRNA can lift this limitation—at least in vitro.  Although stem cells can give rise to virtually any cell type inside the embryo, they have limited potential to give rise to extra-embryonic cell types. They are now trying to understand how the body restricts iPSC and ESC potential.

 

              

Exosomes

Exosomes encapsulate and transport a wide variety of molecules generated by their ‘cell-of-origin’, a process now thought to be a form of cellular signalling. Exosome signalling is common across cell types and species, but it is of particular interest in diseases with an inflammatory component. While exosome isolation and analysis is useful to understanding the mechanisms behind these multifaceted diseases, exosomes may also be exploited for their therapeutic potential.  Scientists are reviewing the current knowledge on exosomes in inflammation, and exploring the potential for exosome-based therapeutics with reference to:

  • The exosomal cargoes released during inflammation, and their potential as therapeutic targets
  • How inflammatory diseases are uniquely suited to exosome analysis

 

The Cancer Genome Atlas (TCGA) project

Building on data from The Cancer Genome Atlas (TCGA) project, a multi-institutional team of scientists has completed the first large-scale "proteogenomic" study of breast cancer, linking DNA mutations to protein signaling and helping pinpoint the genes that drive cancer. Conducted by members of the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC), including Baylor College of Medicine, Broad Institute of MIT and Harvard, Fred Hutchinson Cancer Research Center, New York University Langone Medical Center, and Washington University School of Medicine, the study takes aim at proteins, the workhorses of the cell, and their modifications to better understand cancer. Appearing in the Advance Online Publication of Nature on May 25, 2016 the study illustrates the power of integrating genomic and proteomic data to yield a more complete picture of cancer biology than either analysis could do alone.

 

Antibodypedia

Systems biology, functional genomics and high-throughput proteomics efforts have massively expedited gene-product annotation and characterization. However, identifying affinity reagents suitable for secondary analyses of proteins can pose a challenge. While antibodies are widely used, their efficacy in different biological systems and experimental applications often varies depending on their immunogen or the organism in which they were produced. In fact, the likelihood that an antibody will function in a novel application or cell/ tissue type depends heavily on its affinity for the antigen and the type of epitope recognized, as well as on the antigen's concentration, folding status and post-translational modifications. Without detailed understanding of the properties of both the antibody and the biological system in which it will be used, antibody selection can require guesswork.

Antibodypedia is a searchable database of antibodies against human proteins. It aims to provide the research community with information on the effectiveness of specific antibodies in specific applications—to help scientists select the right antibody for the right application.

The Antibodypedia database was originally developed within the 6th framework EU program Proteome Binders and the project is part of the Human Antibody Initiative.

Antibodypedia contains information about publicly available antibodies generated by academic or commercial providers and directed against human protein targets; we hope to extend coverage to a range of model organisms in the near future. The database is organized in a ‘gene-centric’ manner to provide users with an overview of all antibodies available against a particular target. All antibody pages link directly to the provider for ease of access and use of the database is free-of-charge.

 

Precision medicine

The influence of gut microbiota on human health has been well documented, particularly in the case of metabolic disorders, such as type 1 and type 2 diabetes. In light of the strong association between the composition of one’s microbiome and human health, researchers have begun to develop targeted therapies that restore optimal balance among microbial populations.  For a detailed look at the state of the microbiome and its role in precision medicine, researchers are examining:

  • The human microbiome’s influence on health
  • The challenges of translating microbiome studies into precision medicine therapies

 

A drug that heals broken bones faster and better

Author: Victoria White - Southampton University, UK

These esearchers are developing a new type of drug that may help bones heal faster and better.

bones

Colony of human bone stem cells

Using bone samples from people undergoing hip replacement surgery, the researchers were able to show that the drug – a protein that activates a molecular pathway called the ‘Wnt’ pathway – causes stem cells found within bones to divide and to turn into more bone cells. The Wnt plays a fundamental role in animal development and disease. It is involved in controlling the growth of stem cells, which are ‘master cells’ that help restore tissues after injury. One example of this is in amphibians like salamanders. If these animals lose a leg, they can just regrow a new one.

Regenerative effect reverses if Wnt pathway switched on too long

Dr Nick Evans, Associate Professor in Bioengineering at the University of Southampton and lead author of the study, says: “Bone fractures are a big problem in society, especially in older people. It is getting worse as more people get older and their risk of fracture increases. Most fractures heal completely by themselves, but a surprising number, around 10 per cent, take over six months to heal, or never heal at all. In the worst cases this can lead to several surgical operations, or even amputation.

“Through our research, we are trying to find ways to chemically stimulate Wnt signaling using drugs. To achieve this, we selectively deliver proteins and other molecules that change Wnt signalling specifically to stem cells, particularly in the bone. This may help us find cures for many diseases, including bone disease, and speed up bone healing after fracture.”

 

Tumor microenvironment in tumorigenesis

The tumor milieu is the site of complex interactions between immune cells, tumor cells, and the surrounding tissue. Innovative technologies and strategies are being employed to characterize these interactions to understand the role of the tumor microenvironment in tumorigenesis and metastasis. Scientists are discussing advances in understanding of the tumor microenvironment and how this knowledge is being harnessed to develop targeted therapies with reference to:

  • The role of the immune system as a mediator of the tumor microenvironment
  • Modulation of the tumor microenvironment as a means of inhibiting tumor growth and suppressing metastasis

 

Power of microRNAs as Research Tools

microRNA (miRNA) expression provide valuable insight into disease-related transcripts, both protective and predisposing. Therapeutic design based on these data sets has enabled both supplementation with protective miRNAs such as miRNA mimics, and silencing of predisposing miRNAs using complementary RNAs.  Disease-specific miRNA profiles and miRNA-based therapeutic approaches is helping researchers to understand:

  • The various roles of miRNAs in disease progression and recovery
  • Steps for developing miRNA-based therapeutics

 

Bioinformatics

Bioinformatics is specifically premeditated with a unifying axiom providing pulpit to widen the imminent scientific creations and to enlighten Bioinformatics technologies, clinical research and computational methods. It will enable to put forth the holistic scientific approach to showcase the trends and challenges in bioinformatics.

Trends and topics in Bioinformatics include: Novel technologies, Genomics & Proteomics, Computational Systems Biology, Computational Immunology, Translational & Cancer Bioinformatics, Big data & Cloud computing, Molecular & Clinical Bioinformatics, Pharmacy Informatics, Biostatistics Approaches, Neuro-Bioinformatics, Biomedical Informatics, Bioinformatics Business Trends and more.  These topics are encouraged at the CEEP Conferences !

 

 

                                                                                                                 

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