Category Archives: Transhuman News

June 4, 2013 In the gonads of animals, genome parasites such as transposons pose a serious threat to evolutionary fitness. With their ability to bounce around in the genome, they often cause dangerous mutations. To protect genomic integrity, animals evolved a sophisticated mechanism -- the so called piRNA pathway -- to silence the deleterious transposons. Not much is known about the molecular processes and the involved factors that constitute the piRNA pathway. Researchers at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences (AW) in Vienna have now identified ~50 genes, that play important roles in the piRNA pathway of the fruitfly Drosophila melanogaster.

With roughly 50%, the human genome is densely populated with genome parasites, and so is the DNA of other animals, plants and fungi. Many of these selfish DNA elements are able to freely move around in the host's genetic material. They are referred to as transposons and their mobility causes DNA breaks and mutations that can lead to severe genome damage. Although they are harmful, most organisms do not specifically eliminate transposons from their DNA. Such a massive intervention might bear too much of a risk for germ cell genomes and hence a species reproductive fitness.

To deal with the potential dangers, plants and animals possess defense systems -- also seen as sort of a 'genome immune system'. In all cases, these are based on small RNA silencing mechanisms and hence date probably back to the early days of eukaryotic evolution. The ancient silencing systems are able to selectively interfere with transposon expression preventing them from causing damage.

In animals, the most prominent of these silencing pathways is the so-called piRNA pathway. At its core act so-called RNA induced silencing complexes (RISC) that are composed of PIWI proteins bound to 22-30nt long piRNAs. Via the small RNA, PIWI complexes recognize transposon RNAs and this induces degradation of the transposon RNA and feeds back negatively on the encoding locus on the host DNA to inhibit transposon transcription.

Fly library as goldmine of knowledge

For their screen, Brennecke and his group took advantage of the Vienna Drosophila RNAi Center (VDRC) library, a collection of ~30.000 fly stocks each allowing the silencing of a specific gene in a desired cell type. The VDRC library was established at the IMBA/IMP campus under leadership of Barry Dickson and Krystyna Keleman and is now run by the Campus Support Facility (CSF). From there, flies are sent out to institutes and research centers all over the globe. "The Vienna fly library is a worldwide unique resource that allows systematic studies of gene function in virtually every aspect of fruitfly biology," compliments Brennecke. In their two years of work, Brennecke and his group discovered around 50 genes that are important for a fully functional piRNA pathway. Dominik Handler, PhD student in Brennecke's lab and first author of the study, explains: "For many of the identified genes, orthologous genes can be identified in the human genome, too. Our results will therefore have a broad impact on the general understanding of this transposon silencing system." Some of the identified genes are required for the biogenesis of piRNAs, but others connect the defense system to basic processes such as mitochondria-metabolism, RNA transport, transcription or chromatin-biology.

Signalling-pathway with great potential

The obtained results set the stage for multiple lines of future investigations, underlines Brennecke. The identified factors will play key roles in understanding the mechanistic framework of the pathway, but they will also be unique entry points into understanding how this silencing system is embedded into the general process of oogenesis. Key question along those lines are how piRNAs are passed from generation to generation and what evolutionary benefit the host might have from transposons. Brennecke is fascinated by the close interplay between possible advantages and dangers that transposons and other repetitive sequences have for host genome regulation. He is confident: "Core concepts of the piRNA pathway are highly conserved amongst organisms. I have no doubt, that our results will have far reaching implications for the understanding of genome evolution and possibly even aspects of human medicine."

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The fight against genome parasites

SAN BRUNO, Calif., June 5, 2013 /PRNewswire/ --Second Genome, Inc. announced today that the company has entered into an agreement with Janssen Biotech, Inc. (Janssen) focused on microbiome drug discovery. With the goal of advancing novel drug targets, the agreement is focused on therapeutic mechanisms in ulcerative colitis mediated by the bacterial ecosystem living within the human gut, referred to as the microbiome. Second Genome will apply its microbiome modulation discovery platform to characterize the role of bacterial populations in ulcerative colitis.

"Foundational microbiome research over the past several years has demonstrated that alterations to the microbiome are central to the development of inflammation and metabolic disorders," saidPeter DiLaura, President and CEO at Second Genome."The role of the microbiome in health and disease has arrived as a significant area of focus in pharmaceutical R&D. This collaboration with Janssen will identify mechanisms by which microbial populations in the gut have an impact in ulcerative colitis."

Under the terms of the agreement, Second Genome will receive an upfront payment and support for research activities conducted by Second Genome in collaboration with Janssen. In addition, Second Genome is eligible to receive potential payments upon the achievement of certain research milestones. The research will be funded through the Johnson & Johnson Innovation Center and the Immunology Therapeutic Area within Janssen Research & Development, LLC.

The human microbiome is the population of more than 100 trillion microorganisms that live in our gut, mouth, skin and elsewhere in and on the body. These microbial communities play critical roles in supporting life and health. They are needed to digest food, to prevent disease-causing bacteria from invading the body, and to synthesize essential nutrients and vitamins. Pioneering a path for translating microbiome discoveries into novel therapeutics, Second Genome has developed a proprietary approach for generating therapeutic candidates that modulate microbe-microbe and microbe-human interactions that contribute to health and disease.

"A breakdown in the normal relationship between the human immune system and the bacterial communities that reside in the gut appears to play an important role in development of the hallmark chronic inflammation of ulcerative colitis," said Dr. Susan Lynch, scientific advisor to Second Genome and Director of the Colitis and Crohn's Disease Microbiome Research Core and Associate Professor, Gastroenterology at University of California, San Francisco. "Second Genome has a powerful platform to mine the microbiome for potential targets which have the potential to translate into effective therapeutics that dramatically impact patient health."

Series A Financing and Board Appointments

Separately, Second Genome announced today it has received an additional $6.5 million in Series A financing, bringing the total amount raised in the Series A round to $11.5 million. Current investors participated in the financing, including Advanced Technology Ventures, Morgenthaler, and Wavepoint Ventures, and individuals including Dr. Corey Goodman, co-founder and Chair of the Board of Directors, and Dr. Matt Winkler, also on the Board of Directors. The new funding will be used to accelerate programs in metabolic disease, inflammation, and infection.

Second Genome also announced the appointment of Brad A. Margus, former CEO and co-founder of Envoy Therapeutics, to its board of directors; and Jerrold M. Olefsky, Professor of Medicine at the University of California, San Diego to its scientific advisory board.

Mr. Margus co-founded Envoy Therapeutics Inc. in 2009, serving as Chief Executive Officer prior to its acquisition by Takeda Pharmaceutical Company in 2012. Earlier, Mr. Margus co-founded Perlegen Sciences, Inc. and served as its Vice Chairman and Chief Executive Officer. Mr. Margus has been a member of numerous IRBs, NIH advisory committees and corporate boards. He currently serves as Chairman and volunteer President of the A-T Children's Project; as a Harvard Business School Global Advisor; on the Board of Children's Neurobiological Solutions, an organization aimed at applying brain repair and regeneration to pediatric neurological disorders; as an advisor to the Rare Disease Network; and as Co-chair of the Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) External Oversight Board.

Dr. Olefsky is Professor of Medicine at the University of California, San Diego (UCSD) Division of Endocrinology and Metabolism and the Associate Dean of Scientific Affairs for the UCSD School of Medicine. His work has been instrumental in defining the basic genetic and cellular mechanisms responsible for the pathogenesis of Type II Diabetes, metabolic syndrome, and other diseases. Dr. Olefsky is a member of the Institute of Medicine and was the 1998 recipient of the American Diabetes Association's Banting Medal for Scientific Achievement.He currently serves on the scientific advisory boards of NGM Biopharmaceuticals, Metabolex, and the Profil Institute.

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Second Genome Announces Agreement with Janssen on Microbiome Drug Discovery in Ulcerative Colitis