Evans D.S.,University of California at San Francisco |
Kapahi P.,Buck Institute |
Hsueh W.-C.,University of California at San Francisco |
Kockel L.,University of California at San Francisco
Ageing Research Reviews | Year: 2011
The target of rapamycin (TOR) signal transduction network monitors intra- and extracellular conditions that favor cell growth. Research during the last decade has revealed a modular structure of the TOR signaling network. Each signaling module senses a particular set of signals from the cellular milieu and exerts regulatory control towards TOR activity. The TOR pathway responds to growth factor signals, nutrient availability, and cellular stresses like hypoxia and energy stress. The signaling modules and their molecular components constituting the TOR network are remarkably conserved in both sequence and function across species. In yeast, roundworms, flies, and mice, the TOR pathway has been shown to regulate lifespan. Correspondingly, genetic, dietary or pharmacological manipulation of individual signaling modules as well as TOR activity itself extends lifespan in these model organisms. We discuss the potential impact of manipulating TOR activity for human health and lifespan. © 2010 Elsevier B.V.
Dvorak-Ewell M.,BioMarin Pharmaceutical |
Wendt D.,BioMarin Pharmaceutical |
Hague C.,BioMarin Pharmaceutical |
Christianson T.,BioMarin Pharmaceutical |
And 4 more authors.
PLoS ONE | Year: 2010
Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is a lysosomal storage disorder caused by deficiency of Nacetylgalactosamine-6-sulfatase (GALNS), an enzyme that degrades keratan sulfate (KS). Currently no therapy for MPS IVA is available. We produced recombinant human (rh)GALNS as a potential enzyme replacement therapy for MPS IVA. Chinese hamster ovary cells stably overexpressing GALNS and sulfatase modifying factor-1 were used to produce active (~2 U/mg) and pure ($97%) rhGALNS. The recombinant enzyme was phosphorylated and was dose-dependently taken up by mannose-6-phosphate receptor (Kuptake = 2.5 nM), thereby restoring enzyme activity in MPS IVA fibroblasts. In the absence of an animal model with a skeletal phenotype, we established chondrocytes isolated from two MPS IVA patients as a disease model in vitro. MPS IVA chondrocyte GALNS activity was not detectable and the cells exhibited KS storage up to 11-fold higher than unaffected chondrocytes. MPS IVA chondrocytes internalized rhGALNS into lysosomes, resulting in normalization of enzyme activity and decrease in KS storage. rhGALNS treatment also modulated gene expression, increasing expression of chondrogenic genes Collagen II, Collagen X, Aggrecan and Sox9 and decreasing abnormal expression of Collagen I. Intravenous administration of rhGALNS resulted in biodistribution throughout all layers of the heart valve and the entire thickness of the growth plate in wild-type mice. We show that enzyme replacement therapy with recombinant human GALNS results in clearance of keratan sulfate accumulation, and that such treatment ameliorates aberrant gene expression in human chondrocytes in vitro. Penetration of the therapeutic enzyme throughout poorly vascularized, but clinically relevant tissues, including growth plate cartilage and heart valve, as well as macrophages and hepatocytes in wild-type mouse, further supports development of rhGALNS as enzyme replacement therapy for MPS IVA. © 2010 Dvorak-Ewell et al.
Lukavsky P.J.,Masaryk University |
Lukavsky P.J.,ETH Zurich |
Daujotyte D.,Medical Research Council Laboratory of Molecular Biology |
Daujotyte D.,Lexogen GmbH |
And 9 more authors.
Nature Structural and Molecular Biology | Year: 2013
TDP-43 encodes an alternative-splicing regulator with tandem RNA-recognition motifs (RRMs). The protein regulates cystic fibrosis transmembrane regulator (CFTR) exon 9 splicing through binding to long UG-rich RNA sequences and is found in cytoplasmic inclusions of several neurodegenerative diseases. We solved the solution structure of the TDP-43 RRMs in complex with UG-rich RNA. Ten nucleotides are bound by both RRMs, and six are recognized sequence specifically. Among these, a central G interacts with both RRMs and stabilizes a new tandem RRM arrangement. Mutations that eliminate recognition of this key nucleotide or crucial inter-RRM interactions disrupt RNA binding and TDP-43-dependent splicing regulation. In contrast, point mutations that affect base-specific recognition in either RRM have weaker effects. Our findings reveal not only how TDP-43 recognizes UG repeats but also how RNA binding-dependent inter-RRM interactions are crucial for TDP-43 function. © 2013 Nature America, Inc. All rights reserved.
News Article | February 3, 2016
The cells in our bodies are constantly under stress from all kinds of sources. In response, they can recover or die. But some cells experience a state of "cellular senescence," where the cells stop dividing altogether but remain in the body in a kind of purgatory. As the number of these cells increase, it's theorized that they will start to produce inflammatory by-products that result in aging. For decades, scientists have been fascinated with cellular senescence and its role in age-related diseases. But researchers have only shown in the past five years that clearing these cells might keep common ailments at bay that occur as we age, like osteoarthritis, glaucoma, and atherosclerosis. And now, investors are starting to see opportunities to bring new therapies to market. A startup called Unity Biotechnology, which is launching today, is building off of soon-to-be published research in the journal Nature. The research, which was led by a small team at the Mayo Clinic, explores how removing these senescent cells in naturally-aging mice can extend their life span and delay age-related decline. This paper follows recent research, published in Nature Medicine, which found that it's possible to clear these cells in mice by targeting an important pathway for their survival. In other words, by making it near-impossible for these retired cells to stay alive and wreak potential havoc in the body. "The researchers have shown that clearing these cells profoundly impacts quality of life of a mammal," says Nathaniel David, chief executive officer and cofounder of Unity Biotechnology in an interview. "It remains to be seen how it will work in humans, but we're betting that it will translate." These are still early days for Unity, but health care investors are jumping on opportunities to fund promising anti-aging research. The initial funding was led by ARCH Venture Partners, with contributions from the Mayo Clinic, and Venrock, a health-focused venture capital firm. The company says it is also working with top anti-aging researchers and lead investigators, including Mayo Clinic professor and biochemist Jan M. van Deursen, and Buck Institute of Research on Aging professor Judith Campisi. "This is the coolest biology I've seen in a while," said Camille Samuels, an investor at Venrock who joined Unity's board. "Finally legitimate science is coming to a space (anti-aging technology) that has seen a lot of snake oil." "There are a lot of researchers working on this, but not a lot of companies," says Sabah Oney, a geneticist formerly of Roche. "It's very interesting." But before it releases a magic anti-aging pill, the company will need to invest in further research as well as a clinical trial phase that involves humans and not mice. That process typically takes years. From there, the drugmakers would need to apply for approval from federal regulators. Unity says its leadership team has collectively moved more than 90 promising therapies to human clinical trials, and created more than 13 FDA-approved medicines. David says the company will initially focus on osteoarthritis and other conditions that "make it hurt to be old," before expanding the scope to cancer and other diseases. In the coming years, the company might compete with Calico, the mysterious anti-aging company that spun out of Alphabet (Google's parent company). Calico was announced in 2013, but it has revealed few details about its research objectives since then. However, the company did recruit some impressive names in the anti-aging community, including UC San Francisco's Cynthia Kenyon (watch her fascinating TED talk here). Kenyon's research has centered on the increasing the life span of microscopic roundworms by suppressing a single gene. Calico also scooped up Robert Cohen, a senior oncologist at Genentech; and David Botstein, the former director of the Lewis-Sigler Institute for Integrative Genomics at Princeton University. This story has been updated with quotes from Unity Biotechnology's CEO.
Free tasty food, brightly coloured bicycles and high salaries are well-known hallmarks of the Googleplex — Google’s famed headquarters in Mountain View, California. But it was not these perks that led cardiologist Jessica Mega to pause her thriving academic career at Harvard Medical School to become the chief medical officer of the company’s life-sciences team. She was lured by the ambitions of the effort, soon to be incorporated under Google’s parent firm Alphabet. Nurtured by Google’s expertise in data analytics and engineering, the biology team is expected to create miniaturized electronic devices and to use these and other means to collect and analyse more health data, more continuously, than is possible today. “What I find compelling is the immersion of people with strong technology backgrounds — hardware and software engineers — sitting next to people like myself,” says Mega. “The impact feels very, very large.” Mega’s decision to move in March to Google was one in a string of announcements by top-flight scientists and physicians who are enlisting in the mission, and pioneering a new type of career path in the process. Although academic researchers from fields such as computer science and engineering have led innovative Google projects (such as the Internet-connected eyewear known as Glass), Google and other technology companies are increasingly recruiting life scientists as Silicon Valley broadens its reach into health care. “I have a feeling we’re going to see a lot more recruitment of leading lights,” says Eric Topol, director of the Scripps Translational Science Institute in La Jolla, California. In September, Thomas Insel, director of the US National Institute of Mental Health in Bethesda, Maryland, announced that he would soon be joining Google’s life-sciences company to help develop ways to apply technology in mental health. And last year, molecular biologist Cynthia Kenyon, a leader in ageing research at the University of California, San Francisco, joined the Google-backed biotech company Calico in San Francisco, California. Cardiologist Euan Ashley of Stanford University, which sits in the thick of Silicon Valley, says that academic data scientists are constantly tempted by the companies that await them just off campus. “They’re being continuously recruited away,” he says. “We’re in competition with Google and other tech companies, and generally they can pay a lot more than Stanford can.” But money is not the only lure. Silicon Valley offers strong technology resources that are hard to access in academia, Topol says, as well as the opportunity to pursue goals that are difficult to reach for in academia, where scientists are not typically rewarded for pursuing real-world applications. “The resources are exponentially greater than what you can get through academic circles. And the metrics are different: instead of publications, it’s just, ‘Get stuff done’,” he says. Getting stuff done was foremost in the mind of electrical engineer Brian Otis when he left his tenured position at the University of Washington in Seattle in 2012 to work for Google. He went there to work on a ‘smart’ contact lens for people with diabetes that measures the level of glucose in tears. When the project began, it faced two big questions: first, could the electronics needed to make a functional wireless glucose sensor be embedded in a wearable contact lens? And second, would it provide the relevant measurements of glucose levels? The motivation and means to answer those unknowns was a powerful incentive, Otis says. He recalls thinking: “If I come into Google life with these questions, I have the entire runway and resources to answer these two questions.” The project was successful; drug giant Novartis licensed the contact-lens technology last year and Otis is now director of the Google life-sciences team’s hardware and medical-device development. “To go all the way from foundational first principles to execution of vision was the initial draw, and that’s what has continued to keep me here,” he says. Apple, too, has entered the health-care game. In March, it debuted ResearchKit, a framework through which researchers can write apps that collect data from patients’ mobile phones. And in April, IBM launched IBM Watson Health and the Watson Health Cloud, services that use the company’s cognitive computing technology to process large amounts of health data from diverse sources. The service could help physicians to manage patients’ health by streaming data from personal electronic devices, or enable drug companies to manage clinical trials more efficiently with cloud computing. Intel, meanwhile, is developing cloud-computing services to provide more personalized cancer care; and Facebook, Microsoft and Amazon are all also getting involved. But Google’s approach sets it apart: the company expends more resources on potential health applications and is exploring in more directions than others are. Observers estimate that Google puts more than a billion dollars per year into life-sciences research, although the company says that it does not break down its spending in that way. Google’s life-sciences team is working on a range of projects that involve developing new ways of monitoring health. As well as the smart contact-lens project, there is the Baseline Study, which aims to collect large amounts of data about people to better quantify health and disease, with the goal of earlier and more-effective preventive care. The company also funds a huge array of external collaborations with academics. Google Genomics, for instance, is studying the application of cloud computing to genomics, and Calico has signed a slew of collaborations with companies and academic institutes. “They’re reaching out to academia in a way that biotechnology companies often don’t,” says cell and molecular biologist Judith Campisi of the Buck Institute for Research on Aging in Novato, California. That enables scientists to collaborate with Google instead of joining it wholesale. “For some academics, joining a technology company would be an exciting new opportunity,” says physician Steven Hyman of the Broad Institute of MIT and Harvard in Cambridge, Massachusetts. But it is “not a likely destination for those interested in mitigating risk,” he says. “After all, the life-science goals of the Googles, Apples and Microsofts of the world are likely to change in the near term as the companies explore an area that is new to them.”