EVENTS | VIEW CALENDAR
2017 ASCB-EMBO Show Preview: Showing love for cells in Philly
American Society for Cell Biology (ASCB)
2017 ASCB | EMBO Meeting
Pennsylvania Convention Center
December 2-6, 2017
Showing love for cells in Philly
For the first joint outing of ASCB and EMBO in annual meeting form, the ‘City of Brotherly Love’ will play host
As ASCB CEO Dr. Erika C. Shugart put it last year when we asked her about 2017 plans: “As our President-elect Pietro De Camilli observes, ‘Science is an international endeavor. The ASCB has become a beacon for this not only in America, but in the world. Many members of EMBO, one of the strongest European scientific societies, are already ASCB members. The joint meeting will acknowledge and consolidate our partnership.’”
Now, a year later De Camilli is soon to be immediate past president and Shugart has gone from helping to helm a vessel nicknamed ASCB 2016 to helping oversee one with the moniker 2017 ASCB | EMBO.
And, it would seem, the vessel is sailing ahead smoothly so far, as Shugart told DDNews this year, “We will continue our partnership with EMBO next year, so we are looking forward to featuring the best international science for our participants.”
Also, as 2017 ASCB | EMBO Program Committee Co-Chairs Laura Machesky of the Beatson Institute for Cancer Research and Tobias Walther of the Harvard Medical School and Howard Hughes Medical Institute tell us: “Usually, EMBO holds a separate meeting in Europe to showcase new developments in molecular and cell biology, but this year the two groups have teamed up to make this year’s meeting truly international. The program reflects the international aspect, with the EMBO Gold Medal Lecture and the Louis Jeantet Prize Lectures being included in the program alongside the usual ASCB E.B. Wilson and Porter Lectures.”
But that’s not all that’s new, with Machesky and Walther noting, “For the first time, we will have a special emphasis on neurobiology and the cell biology of the nervous system in addition to the regular program.”
As part of that, prior to the meeting there will be a “Doorstep Meeting,” which is a concentrated one-day neurobiology meeting organized by Frank Bradke of German Center for Neurodegenerative Diseases and Kelsey C. Martin of the UCLA David Geffen School of Medicine.
“Several talks in the main meeting will also highlight the latest developments in neurobiology,” Machesky and Walther add, “such as a keynote lecture by Cori Bargmann, head of the Chan Zuckerberg initiative and an investigator at The Rockefeller University on ‘Building Knowledge by Integrating Levels: Genes, Cells and Behavior.’ We will also have symposium talks dedicated to neurobiology.”
They also point out that the main symposia sessions “provide a real opportunity to hear a comprehensive presentation and overview of the most exciting hot topics in cell and molecular biology presented by the world leaders in each area.” This is useful, they say, for non-specialists to quickly get up to date with the latest and anticipate the future developments in diverse fields.
“In addition, our three scientific workshops showcasing new developments in molecular methods might be of particular interest to pharma/biotech companies,” they say.
These workshops are run by leading academics in each of the areas and cover:
And finally, Machesky and Walther tell DDNews by way of potential highlights, “Jacques Dubochet, Joachim Frank and Richard Henderson were awarded the 2017 Nobel Prize in Chemistry for developing cryo-electron microscopy for the high-resolution structure determination of biomolecules in solution. This year’s ASCB meeting has several talks highlighting amazing discoveries using cryo-electron microscopy, as well as from other hot or emerging fields, such as proteostasis, RNA biology and metabolism.”
ADDITIONAL SHOW-RELATED STORIES:
Keynote Lecture and Symposia
Fred Kavli Keynote Lecture
Saturday, Dec. 2, 6 p.m.
Symposium 1: Structure of the Cell
Sunday, Dec. 3, 8 a.m.
Symposium 2: Metabolism
Sunday, Dec. 3, 9:45 a.m.
Symposium 3: Cell Biology of Neurons
Monday, Dec. 4, 8 a.m.
Symposium 4: Cell Interactions
Monday, Dec. 4, 9:45 a.m.
Symposium 5: DNA/RNA Biology
Tuesday, Dec. 5, 8 a.m.
Symposium 6: Quality Control
Wednesday, Dec. 6, 11:20 a.m.
Scientific Award Lectures
ASCB E.E. Just Award Lecture
Sunday, Dec. 3, 11 a.m.
Cell Signaling by Protease-activated Receptors
JoAnn Trejo, University of California, San Diego
ASCB Porter Lecture
Sunday, Dec. 3, 3:15 p.m.
Sorting Out Protein Traffic in the Endocytic Pathway
Scott D. Emr, Weill Institute for Cell and Molecular Biology, Cornell University
EMBO Gold Medal Ceremony and Lecture
Monday, Dec. 4, 3:15 p.m.
Systematic Cell Biology of Organelles
Maya Schuldiner, Weizmann Institute of Science, Israel
Louis-Jeantet Prize Lectures
Tuesday, Dec. 5, 9:45 a.m.
Circuits for Movement
Silvia Arber, Biozentrum, University of Basel and Friedrich Miescher Institute for Biomedical Research
Sensing Infection and Tissue Damage
Caetano Reis e Sousa, The Francis Crick Institute
ASCB E.B. Wilson Medal Presentation and Address
Tuesday, Dec. 5, 3:15 p.m.
Protein Folding in the Cell: The Role of Molecular Chaperones
F. Ulrich Hartl, Max Planck Institute of Biochemistry, Martinsreid, Germany
Chaperonin-mediated Protein Folding
Arthur L. Horwich, Yale School of Medicine/HHMI
All minisymposia sessions run concurrently on Sunday and Monday afternoon froms 4:15 p.m. to 6:50 p.m., on Tuesday afternoon from 4:40 p.m. to 7:15 p.m. and on Wednesday morning from 8:30 a.m. to 11:05 a.m.
Sunday, Dec. 3
Monday, Dec. 4
Tuesday, Dec. 5
Wednesday, Dec. 6
ASCB-NCI Emerging Topic Symposium
Mitochondrial Crosstalk in Cancer Cell Biology
Jointly supported by the National Cancer Institute, NIH and the ASCB
Session Description: All cells coordinate the number, connectivity and organization of their various organelles to perform an assortment of specialized functions. Cancer cells can exploit inter-organelle networks in unique ways to transit functional states, generate heterogeneity and overcome obstacles in adaptive responses. This interdisciplinary symposium will highlight basic mechanistic advances in how mitochondrial-organelle crosstalk is altered in cancer and inform on the dynamic integrative nature of inter-organelle communication.
BONUS CONTENT CELL BIOLOGY / CELL THERAPY NEWS ROUNDUP
Not news directly related to the 2017 ABCS | EMSO annual meeting, but all the same, thematically in line with the cell biology focus of the show
Researchers use light-sensitive molecules to track proteins critical to cell signaling
HOUSTON—The ability to track the movements of single molecules has revealed how proteins on the surface of nerve cells control gates that turn chemical signals into electrical signals, and this finding, according to researchers at Rice University and the University of Texas Health Science Center at Houston (UTHealth), is a step forward in detailing mechanisms involved in neurological disease.
Using sophisticated imaging and statistical methods, the scientists employed single-molecule FRET (Förster resonance energy transfer) imaging techniques to establish a beachhead at the NMDA receptor gate that, when activated, allows ions to flow through the nerve cell’s membrane.
Rice chemist Dr. Christy Landes, an expert in single-molecule FRET, and Dr. Vasanthi Jayaraman, a professor of biochemistry and molecular biology at UTHealth’s McGovern Medical School, whose expertise is in NMDA receptor biochemistry, teamed up to gather the first experimental evidence detailing the dynamics of how the receptors alter their shapes to control the sensitivity of the gate to chemical signals. The new study appears in Nature Chemical Biology.
The NMDA receptor is a set of four protein subunits, each with four domains, and each of those domains has a particular function. Collectively, they span the cell membrane. Each subunit can have many “states,” or shapes, that regulate which electrical signals—and how many of them—pass through. The subunits sit on each side of the channel and activate when they bind both glutamate and glycine neurotransmitter ligands and trigger the signaling pathway that allows positively charged ions to pass into the cell.
“These receptors are critical for normal physiological function,” Jayaraman said. “A lot of times you may not want to turn signaling on or off. You may want to dial in the extent of signaling. Once we understand all the protein’s states, we can start thinking about ways to do this, thus keeping the protein active but to varying degrees as needed. It’s important for drug development to understand these dynamics because the motions and the energetic properties of these proteins dictate their specific functions. We were able to do both.”
This knowledge could lead to multifunctional drugs that influence the channels in subtle ways, Landes said. Known NMDA receptor antagonists include common anesthetics, synthetic opioids like methadone and dissociative drugs like ketamine and nitrous oxide. Depressed NMDA receptor function is suspected in memory deficits commonly associated with aging. Alcohol is known to inhibit glutamate, one of two neurotransmitters that bind to NMDA.
“A lot of drug design has as its core principle that there’s one way to bind, and you basically either turn something on or turn something off,” Landes said. “But it’s obvious that this type of receptor protein isn’t just on or off. There are multiple conformational interactions that either improve or degrade the signaling.”
In an earlier study, the team analyzed the conformations of a smaller and simpler but related system, the C-clamp-like agonist binding domain of another receptor, AMPA. AMPA mediates fast signal transmission in the central nervous system. The single-molecule FRET technique allowed the researchers to get the first snapshots of the AMPA protein’s various clamp conformations at rest and also when bound to a range of target molecules by measuring the distance between two light-activated molecular tags.
3D bioprinting tech aims at treating liver disease
CARLSBAD, Calif.—International Stem Cell Corp. (ISCO), a clinical-stage biotechnology company that develops novel stem cell-based therapies and biomedical products, announced in early October a significant advancement in 3D bioprinting of liver tissue.
ISCO’s R&D team has developed a 3D bioprinter which utilizes proprietary liver progenitor cells (LPCs), which differentiate into cholangiocytes, hepatocytes and stellate cells. Once 3D liver-like structures are produced from the LPC, they are expected to provide a treatment for various liver diseases once transplanted into the damaged liver. The LPCs can be derived from any kind of pluripotent stem cells, including human embryonic, induced pluripotent or parthenogenetic stem cells, via ISCO’s proprietary highly efficient and scalable differentiation method.
“I’m excited to announce that we have developed a new efficient technology to produce 3D liver tissue, which may be able to replace damaged tissue to restore liver functions. Additionally, the developed liver tissue potentially can be used not only in liver treatment, but also in drug discovery as a model for drug screening, which opens up a potential multibillion-[dollar] market for ISCO,” commented Dr. Russell Kern, executive vice president and chief scientific officer of ISCO. “We have already developed a master cell bank of the liver progenitor cells, and we are proceeding to test safety and efficacy of the cells in various models of liver diseases like liver cirrhosis and fibrosis,” he continued.
According to the American Liver Foundation, approximately 17,000 patients are on the U.S. liver transplant waiting list, with only 6,000 liver transplants performed each year. Currently, there are no alternatives available for patients in need of a liver transplant other than to join the waiting list. Cirrhosis is the end stage in patients who have chronic progressive liver disease. While liver transplantation is a viable treatment option for these candidates, increasing waiting times for organ transplantation has led to the deaths of nearly 17 percent of those who were on the waiting list.
Cancer cell genome secrets unveil new drug targets
SAN DIEGO—Cancers driven by mutations in the KRAS gene are among the most deadly. For decades, researchers have tried unsuccessfully to directly target mutant KRAS proteins as a means to treat tumors. Instead of targeting mutant KRAS itself, researchers at University of California, San Diego (UC San Diego) School of Medicine are now looking for other genes or molecules that, when inhibited, kill cancer cells only when KRAS is also mutated.
The team used the CRISPR/Cas9 gene-editing technique to systematically inactivate every gene in the genome of human colorectal cancer cells with and without mutant KRAS. They found that growth of KRAS-mutant colorectal cancer cells in mice was reduced by approximately 50 percent when two genes that encode metabolic enzymes—NADK and KHK—were also inactivated.
The study, published Sept. 27 in Cancer Research, provides potential new drug targets for KRAS-driven cancers.
“We did not get these same results with cancer cells grown in the lab—the growth inhibition we saw when the NADK and KHK genes were inactivated only occurs in tumors in a mammalian system, in a more realistic microenvironment where the tumor has to survive,” said senior author Dr. Tariq Rana, a professor of pediatrics at UC San Diego School of Medicine and Moores Cancer Center. “That suggests that the metabolic dependencies of tumor cells growing in a laboratory dish may differ dramatically compared to the same cells growing in a living system, underscoring potential limitations of standard laboratory-based cancer cell growth tests.”
Approximately 20 to 30 percent of all human cancers have mutations in the KRAS gene. KRAS mutations occur in many of the most lethal and most difficult to treat cancers, including lung, pancreatic and colorectal cancer. KRAS mutant cancer cells are able to rewire their metabolism in a way that gives them a growth advantage compared to normal cells.
Rana’s approach to treating KRAS-driven cancers—inhibiting other genes or molecules in addition to KRAS — is called “synthetic lethality” because the intervention is only lethal to the mutated cells. In a previous study, Rana’s team used a library of microRNAs, small pieces of genetic material, to systematically block protein production and look for those inhibitions that are synthetically lethal in combination with KRAS mutations.
In their latest study, Rana’s team used CRISPR/Cas9 to systematically inactivate genes in two human colorectal cancer cell lines—one with normal KRAS and one with a mutant KRAS. They then tested the ability of each of these cell lines to grow as tumors in mice. They found that inactivating two metabolic enzymes, NADK and KHK, reduced the growth of KRAS-mutant tumors by approximately 50 percent, but had no effect on normal KRAS tumors. They also blocked these same enzymes with commercially available small-molecule inhibitors and saw significant reduction in tumor growth in mice only in tumor cells with mutant KRAS.
Rana and team also identified several new genes that, when inactivated, had the opposite effect—they increased KRAS-mutant tumor growth, but not the growth of normal KRAS tumors. These types of genes are known as tumor suppressors because they normally keep cancer cell growth in check.
“One of the most surprising findings from our study is how performing this type of genetic screen directly in a mammalian microenvironment revealed not only new synthetic lethal interactions, but also new tumor suppressor genes that are dependent on KRAS mutations,” said first author Dr. Edwin Yau, a hematology/oncology and Cancer Therapeutics Training Program fellow in Rana’s lab.
One of these new tumor suppressor genes encodes INO80C, a large multi-subunit protein that, among other things, stabilizes the genome. Rana, Yau and colleagues are now taking steps to carry their findings forward, with the ultimate goal of better understanding how KRAS-mutant cancers develop and translating these insights into developing new therapies to stop them.
A better way to make stem cells?
LA JOLLA, Calif.—Scientists at The Scripps Research Institute (TSRI) have found a new approach to the “reprogramming” of ordinary adult cells into stem cells. In a study published recently in an advance online paper in Nature Biotechnology, the TSRI scientists screened a library of 100 million antibodies and found several that can help reprogram mature skin-like cells into stem cells known as induced pluripotent stem cells (IPSCs).
Making IPSCs from more mature types of cells normally involves the insertions of four transcription factor genes into the DNA of those cells. The antibodies identified by the scientists can be applied to mature cells—where they bind to proteins on the cell surface—as a substitute for three of the standard transcription factor gene-insertions.
“This result suggests that ultimately we might be able to make IPSCs without putting anything in the cell nucleus, which potentially means that these stem cells will have fewer mutations and overall better properties,” said study senior author Dr. Kristin Baldwin, an associate professor in TSRI’s department of neuroscience.
IPSCs can be made from patients’ own cells, and have a multitude of potential uses in personalized cell therapies and organ regeneration. However, none of IPSCs’ envisioned clinical uses has yet been realized, in part because of the risks involved in making them.
The standard IPSC induction procedure, developed a decade ago and known as OSKM, involves the insertion into adult cells of genes for four transcription factor proteins: Oct4, Sox2, Klf4 and c-Myc. With these genes added and active, the transcription factor proteins they encode are produced and in turn reprogram the cells to become IPSCs.
One problem with this procedure is that the viral insertion events or overproduction of the nuclear reprogramming factors may damage cell DNA in a way that turns the cell cancerous. Another is that this nuclear reprogramming typically yields a collection of IPSCs with variable properties. “This variability can be a problem even when we’re using IPSCs in the laboratory for studying diseases,” Baldwin said.
In contrast, during ordinary animal development, cell identity is altered by molecular signals that come in from outside the cell and induce changes in gene activity, without any risky insertions of DNA. To find natural pathways like these—through which ordinary cells could be turned into IPSCs—Baldwin and her laboratory teamed up with the TSRI laboratory of Richard Lerner, the Lita Annenberg Hazen Professor of Immunochemistry. Lerner has helped pioneer the development and screening of large libraries of human antibodies for finding new antibody-based drugs and scientific probes.
$7.9M to study Pluristem’s PLX-PAD cells
HAIFA, Israel—Pluristem Therapeutics Inc., a leading developer of placenta-based cell therapy products, announced in October that a $7.9-million (€6.8 million) non-dilutive grant from the European Union’s Horizon 2020 program has been awarded to nTRACK, a collaborative project carried out by an international consortium led by LEITAT.
The goal of the nTRACK project, initiated and led scientifically by Prof. Rachela Popovtzer of Bar-Ilan University in Israel, is to develop a safe, scalable and highly sensitive nanotechnology-based imaging approach to enable non-invasive, whole body monitoring of injected stem cells in humans, thereby providing early predictions of cellular therapy treatment outcomes. The nTRACK consortium will utilize Pluristem’s PLX-PAD cells to predict treatment success for muscle regeneration following a gastrocnemius muscle injury. Final approval of the grant is subject to the finalization of the consortium and Horizon 2020 grant agreements.
This marks Horizon 2020’s third grant to support development of Pluristem’s PLX-PAD cell therapy product, following an award of $8 million announced in August 2016 for Pluristem’s ongoing multinational Phase 3 trial in the treatment of critical limb ischemia and an $8.7-million award announced in September 2017 for the company’s Phase 3 study in the treatment of muscle recovery following arthroplasty for hip fracture.
Advancing delivery of cell therapies with thawing tech
CHALFONT ST. GILES, U.K.—In early September, GE Healthcare introduced the first in its VIA Thaw series, the VIA Thaw CB1000 for thawing large volumes of cell therapies cryopreserved in cryo-bags. This range of innovative automated, dry thawing units provides users with control over the thawing of sensitive therapies, and addresses key challenges faced by cell therapy companies. Designed to overcome the multiple inconsistent elements in standard water bath thawing practice, the VIA Thaw series delivers a simple, reproducible and traceable recovery system that maintains cell viability to prevent loss of therapeutic effect.
With around 900 cell therapy clinical trials underway worldwide and a handful of products approved as treatments, the emergence of cell therapies will potentially change the landscape of healthcare, GE notes; however, maintaining cell potency throughout the manufacture and cryogenic cold chain (cryochain) of these treatments is a major challenge.
Cell thawing is the final and least controlled part of the cryochain, the company notes, and the process is often carried out in water baths across multiple sites, with inconsistencies due to subjective determination of the thaw endpoint and risk of water-borne contamination. The collection and collation of data from thaw sites, often by paper records, also impedes therapy development. In 2015, the leading UK-based cell therapy organization, the Cell and Gene Therapy Catapult, identified these barriers to the commercialization of cell therapies and approached Asymptote (now part of GE Healthcare) to apply its expertise in cryochain technology to find the solution.
Ger Brophy, general manager of cell therapy at GE Healthcare said: “As the number of cell therapies increases, GE Healthcare has been focusing on creating solutions that safeguard the manufacture and delivery of these therapies. The new VIA Thaw series will provide certainty in cell thawing, through an automated, dry process, and complete visibility over the thawing procedure. This technology has the ability to transform the final stage of cell therapy and help advance the industrialization and delivery of these potentially life-saving therapies.”