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Reprogramming</a></h1><p class="wpn-byline"><time datetime="2014-04-15T20:41:19+01:00" pubdate><span class="published"><abbr class="value" title="2014-04-15">15 Apr 2014 </abbr>|<abbr class="value" title="20:41:19+0100"> 20:41 BST</abbr></span></time><span class="divider"> | </span>Posted by <span class="author vcard"><a class="url fn n" href="https://blogs.nature.com/freeassociation/author/Brooke-LaFlamme-2" title="Brooke LaFlamme">Brooke LaFlamme</a></span><span class="divider"> | </span><span class="category"><span class="before">Category: </span><a href="https://blogs.nature.com/freeassociation/category/conference-highlights" rel="tag">Conference Highlights</a>, <a href="https://blogs.nature.com/freeassociation/category/stem-cells" rel="tag">Stem cells</a></span> </p> </header> <section> <div class="wpn-entry-content content"> <div id="attachment_345" style="width:300px" class="wpn-caption alignright"><a class="wpn-image-link" href="https://blogs.nature.com/freeassociation/files/2014/04/Squaw-Creek.jpg"><img class="size-medium wp-image-345 wpn-image" title="Squaw Creek" alt="View from the Resort at Squaw Creek. Not a bad place for a conference!" src="https://blogs.nature.com/freeassociation/files/2014/04/Squaw-Creek-300x214.jpg" width="300" height="214" srcset="https://blogs.nature.com/freeassociation/files/2014/04/Squaw-Creek-300x214.jpg 300w, https://blogs.nature.com/freeassociation/files/2014/04/Squaw-Creek.jpg 448w" sizes="(max-width: 300px) 100vw, 300px" /></a><div class="wpn-caption-text"><p class="caption">View from the Resort at Squaw Creek. Not a bad place for a conference!</p><p class="credit">Brooke LaFlamme</p></div> </div> <p>I recently attended the joint Keystone Symposium “<a href="https://www.keystonesymposia.org/14Z4" target="_blank">Stem Cells & Reprogramming</a>” and “<a href="https://www.keystonesymposia.org/14Z3" target="_blank">Engineering Cell Fate & Function</a>” at the beautiful <a href="https://www.squawcreek.com/" target="_blank">Resort at Squaw Creek</a>. In addition to gorgeous weather, there was an amazing lineup of talks demonstrating the power and promise of stem cells and cell/tissue engineering. Here are just a few of the highlights from the meetings:</p> <p><span style="text-decoration: underline"><b>Keynote: Optogenetics</b></span></p> <p><a href="https://www.stanford.edu/group/dlab/about_pi.html" target="_blank">Karl Deisseroth</a> from Stanford University kicked off the joint meeting with an overview of his lab’s research in <a href="https://www.stanford.edu/group/dlab/optogenetics/" target="_blank">optogenetics </a>and how they’ve used the technology both to control and map neuronal networks in live animals or intact tissues. The Deisseroth lab has used optogenetics to better understand the neuronal architecture and genetic structure underlying complex behaviors, such as those associated with anxiety. In his talk, Prof. Deisseroth outlined how they are using optogenetic tools to target neuronal wiring using Boolean-like genetic systems to identify neurons expressing specific combinations of markers.</p> <p>The second part of his talk focused on <a href="https://clarityresourcecenter.org/" target="_blank">CLARITY</a>, a method developed in the Deisseroth lab to allow for 3D imaging of neurons in intact tissues or whole brains. You can see some of the amazing videos generated with this technique <a href="https://clarityresourcecenter.com/clarity_movies.html" target="_blank">here</a>.</p> <p>To learn more, you can find a list of Deisseroth lab publications <a href="https://www.stanford.edu/group/dlab/publications.html" target="_blank">here</a>.</p> <p><span style="text-decoration: underline"><strong>Stem cells and reprogramming in human disease modeling and treatment</strong></span></p> <p>There were a ton of talks (and posters) demonstrating the utility of stem cells and directed differentiation for human disease modeling and treatment development. I’ll only mention a few here, but all the talks were excellent. <span id="more-337"></span></p> <p><a href="https://stemcell.stanford.edu/about/Laboratories/wernig/index.html" target="_blank">Marius Wernig</a> from the Stanford School of Medicine presented his lab’s research on reprogramming cells to the neural lineage. The Wernig lab has shown that a number of different cell types, including fibroblasts and hepatocytes, can be <a href="https://www.ncbi.nlm.nih.gov/pubmed/24243019" target="_blank">directly differentiated into neurons</a> (induced neurons, or iNs) using only 3 transcription factors: AscI, Brn2 and Myt1l. These lab-made neurons are completely functional and form synapses聽<em>in vitro</em>. Using this reprogramming protocol, researchers can model neuronal disorders in a petri dish.聽Finally, he gave a preview of data from recent single-cell mass spectrometry experiments performed at different stages during cellular reprogramming. This new method will be able to give important insights into the reprogramming process.</p> <p>Prof. Wernig’s talk was an excellent segue into a talk by <a href="https://bio.psu.edu/directory/guc2" target="_blank">Gong Chen</a> from Penn State. Prof. Chen spoke about reprogramming reactive glial cells into functional neurons聽<em>in vivo</em>聽to repair injury resulting from <a href="https://en.wikipedia.org/wiki/Gliosis" target="_blank">gliosis</a>. Gliosis is often a consquence of traumatic brain injuries, stroke, Alzheimer’s disease, Parkinson’s disease, and many other disorders that affect the brain. In its most extreme form, gliosis can lead to neuronal scarring. The Chen lab has <a href="https://www.cell.com/cell-stem-cell/abstract/S1934-5909(13)00550-X" target="_blank">developed a way to reprogram reactive glial cells,</a> which cause gliosis, into working neurons by injecting a retrovirus expressing a single factor, NeuroD1, into mouse brains. Prof. Chen is now working to optimize the method to work in human cells, where it is currently working聽<em>in vitro</em>, and hopes to move into clinical trials in the near future.</p> <p>On the topic of clinical trials, <a href="https://www.med.umich.edu/neurology/faculty/feldman_research_bio.htm" target="_blank">Eva Feldman</a> from the University of Michigan showed some amazing videos of a method that she has developed together with a team of physicians to transplant neural stem cells into the spinal cord to repair damage from ALS and other spinal cord injuries/disorders. The method is currently<a href="https://www.pnrdfeldman.org/" target="_blank"> in Phase II clinical trials</a>.</p> <p>Adam Rosenthal from <a href="https://www.ipierian.com/" target="_blank">iPierian, Inc.</a> presented exciting results of Alzheimer’s disease modeling in induced pluripotent stem cells (iPSCs) that has led to the discovery of a pathogenic form of Tau, <a href="https://www.ipierian.com/tau/biology" target="_blank">called eTau</a>, and to the development of a promising new drug to treat early stages of the disease.</p> <p><a href="https://www.robertlanza.com/" target="_blank">Robert Lanza</a> from Advanced Cell Technology presented an immense amount of work using iPSCs and iPSC-derived cells to treat a wide range of diseases, from age-related macular degeneration to inflammatory diseases.</p> <p>In a separate session, <a href="https://lmrt.mit.edu/about.html" target="_blank">Sangeeta Bhatia</a> from MIT spoke about using <a href="https://lmrt.mit.edu/research/hepatic-interract.html" target="_blank">iPSC-derived hepatocytes</a> to understand the complex host-pathogen interactions in liver infections, including hepatitis B and C and malaria (yes, <em>Plasmodium</em> infects your liver!). The Bhatia lab has developed <a href="https://lmrt.mit.edu/research/hepatic-interract.html" target="_blank">a microplatform for high-througput screening</a> of small molecules to treat infections. This platform can also be used with iPSCs derived from patients with different susceptibility to infection to help to uncover the genetic host factors that contribute to disease resistance.</p> <p><a href="https://www.mskcc.org/research/lab/lorenz-studer" target="_blank">Lorenz Studer</a> from The Rockefeller University changed his presentation’s topic at the last minute to tell us about modeling late-onset diseases with iPSCs. Normally, cells derived from iPSCs are in an immature state, and there hasn’t been a good way to “age” them in order to better understand late-onset diseases such as Alzheimer’s or Parkinson’s. Prof. Studer wondered if the gene involved in Progeria, p<i>rogerin</i>, might be used as a factor to accelerate the aging process of cells in the lab. <a href="https://en.wikipedia.org/wiki/Progeria" target="_blank">Progeria </a>is a devastating disease that affects young children, making them look much older than their years, and leading to early death (usually by age 13) due to normally age-related complications. The Studer lab found that聽<em><a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=studer+progerin" target="_blank">progerin</a></em><a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=studer+progerin" target="_blank"> does in fact “age” the cells</a>, providing better models for the diseases of old age.</p> <p>All amazing stuff. I’m sure we’ll be seeing quite a few breakthroughs in this area in the next few years!</p> <p><span style="text-decoration: underline"><strong>Epigenetics in reprogramming and differentiation</strong></span></p> <p>Again, there were far too many interesting talks involving epigenetic regulation of reprogramming and differentiation, but I’ll briefly mention 3 here.</p> <p><a href="https://labs.gladstone.ucsf.edu/yamanaka/home" target="_blank">Shinya Yamanaka</a>聽(Gladstone), Nobel laureate famous for identifying the 4 factors required to turn somatic cells into stem cells (iPSCs) gave an illuminating talk on the challenges in reprogramming. He explained how the real roadblock in obtaining true, mature pluripotent cells is cell maturation, not initiation. His lab has identified a factor required for intitation and maturation, but that is epigentically silenced in the majority of cells during reprogramming. Hopefully we’ll hear more about this story soon!</p> <p><a href="https://labs.gladstone.ucsf.edu/bruneau" target="_blank">Benoit Bruneau</a>, also of Gladstone Institutes, talked about<a href="https://www.ncbi.nlm.nih.gov/pubmed/21304516" target="_blank"> the critical role of聽<em>Brg1</em></a>, also known as聽<a href="https://en.wikipedia.org/wiki/SMARCA4" target="_blank"><em>SMARCA4</em></a>, in the differentiation of embryonic stem cells to cardiomyocytes.聽<em>Brg1</em> is a member of the SWI/SNF chromatin remodeling complex. Prof. Bruneau also presented new data on the origin and fate of cardiac progenitor cells that was obtained through a very creative application of the Cre recombinase system. To learn more about the Bruneau lab research and how heart cells are made, check out this <a href="https://youtu.be/TUIsmcKj7ok" target="_blank">YouTube video</a>.</p> <p><a href="https://younglab.wi.mit.edu/" target="_blank">Rick Young</a> at the Whitehead Institute then told us about how <a href="https://www.biotechniques.com/news/Up-In-The-Sky-Its-Super-Enhancers/biotechniques-343598.html#.U02E6vldUXI" target="_blank">super-enhancer</a> function is regulated by the <a href="https://www.ncbi.nlm.nih.gov/pubmed/20720539" target="_blank">topology of the surrounding chromatin</a>. Specifically, he showed genome-wide data of intra-chromosomal interactions and presented a model that could explain how these loops drive high levels of master transcription factor gene expression.</p> <p><span style="text-decoration: underline"><strong>Using stem cells to understand human evolution</strong></span></p> <p>Even though the majority of talks and posters at this meeting were focused on using stem cells and cellular engineering to understand and treat diseases, there were some very interesting and insightful talks on how stem cells can be used to answer more fundamental questions about human evolution. There were 聽2 talks that I found to be particularly spectacular.</p> <p><a href="https://stemcellphd.stanford.edu/faculty/joanna-wysocka.html" target="_blank">Joanna Wysocka</a> from Stanford told us about<a href="https://www.ncbi.nlm.nih.gov/pubmed/22981823" target="_blank"> the role of neural crest-specific enhancers</a> in determining <a href="https://stemcell.stanford.edu/news/wysocka1.html" target="_blank">facial characteristics.</a> To study the evolution of these enhancers, the Wysocka lab has derived iPSCs from humans and chimpanzees. The patterns of epigentic marks at these enhancers in the different species appears to have been an important factor in the evolution of the human face.</p> <p><a href="https://www.salk.edu/faculty/gage.html" target="_blank">Fred “Rusty” Gage</a> from the Salk Institute also used iPSCs derived from humans and our closest relatives (including chimpanzees and bonobos), in this case to understand why genetic diversity in most primate species appears to be increasing, but human genetic diversity is decreasing. Prof. Gage presented data showing that genes important for repressing transposable element mobility are upregulated in humans and this is correlated with an increase in transposon-derived RNA in non-human primates. He speculated that this difference in transposable element regulation may be part of the answer as to why human genetic diversity is lower than other primates. He also mentioned his lab’s recent work <a href="https://www.ncbi.nlm.nih.gov/pubmed/24198348" target="_blank">implicating transposable elements in neuronal plasticity</a>.</p> <p><span style="text-decoration: underline"><strong>New technology for genetics research</strong></span></p> <p>I won’t say that I’ve saved the best for last, because there is no way to pick a “best” talk or topic from this meeting. However, I do think it’s true that some of the most exciting talks at conferences have to do with the development of new technologies that can be applied to a wide variety of research questions. At this meeting, there were 4 talks that really stood out to me, which I’ll highlight here.</p> <p>Patrick David Hsu, a senior Ph.D. student with <a href="https://zlab.mit.edu/team.html" target="_blank">Feng Zhang at MIT</a>, gave an excellent overview of both the history of the聽<a href="https://www.nature.com/news/365-days-nature-s-10-1.14367" target="_blank">CRISPR/Cas9</a>聽genome editing system and the <a href="https://zlab.mit.edu/publications.html" target="_blank">developments in that technology</a> since it was first described.</p> <p><a href="https://qi.ucsf.edu/" target="_blank">Lei Stanley Qi</a>, a Systems Biology Fellow at聽UCSF, presented some very exciting work on using the CRISPR/Cas9 system to do more than edit DNA. His group is working to develop ways to modify specific epigenetic elements to better understand the cause/effect relationship between chromatin marks and gene regulation. This system could also be used to <a href="https://www.ncbi.nlm.nih.gov/pubmed/24136345" target="_blank">control gene expression</a> much more robustly than what is currently possible with RNAi. He also presented data on his group’s recent work with <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=10.1016%2Fj.cell.2013.12.001" target="_blank">visualizing chromatin dynamics in real time</a>. Read more about applications of CRISPR/Cas9 <a href="https://www.sciencemag.org/content/341/6148/833.full" target="_blank">here</a>.</p> <p><span style="line-height: 1.5em"><a href="https://groups.csail.mit.edu/synbio/" target="_blank">Ron Weiss</a> of MIT described the use of “smart viruses” to <a href="https://www.sciencemag.org/content/333/6047/1307.abstract" target="_blank">specifically target and kill cancer cells</a>. His lab works on building <a href="https://nar.oxfordjournals.org/content/41/16/e156" target="_blank">synthetic gene circuits</a> to control processes in cells. By including binding sites for both repressing and activating factors, they have engineered circuits that will only produce an output protein (for example, a toxin) when certain conditions are met, such as a cell expressing a cancer-specific ensemble of proteins. They have already shown that these engineered cells can work聽<em>in vitro,聽</em>and the next step will be testing them in mice. Since their 2011 publication, the group has significantly improved the delivery system to be much safer for eventual use in clinical trials.</span></p> <p><span style="line-height: 1.5em">And last but certainly not least, <a href="https://limlab.ucsf.edu/" target="_blank">Wendell Lim</a> from UCSF presented his lab’s work on understanding the design principles of cellular networks. As he said in his talk, they’re interested in thinking about biology “beyond what exists to what聽<em>can聽</em>exist.” The Lim lab is working to <a href="https://limlab.ucsf.edu/papers/maf_2013.html" target="_blank">engineer cells to use as smart therapeutic devices</a>, in a similar vein to Ron Weiss’s research. To improve upon existing methods (for example <a href="https://www.ncbi.nlm.nih.gov/pubmed/21830940" target="_blank">this</a>), the Lim lab is working to develop ways to control the engineered cells once they’ve entered the body. Prof. Lim demonstrated proof-of-principle solutions involving regulated chemotaxis coupled with homodimerizing receptors that can only activate in the presence of a specific drug.聽</span></p> <p><span style="text-decoration: underline"><strong>The future of stem cells and cellular engineering</strong></span></p> <p>The main thing I took away from this joint meeting was that this is an absolutely amazing time to be in biomedical research. The ability to culture embryonic stem cells and derive pluripotent cells聽<em>in vitro,聽</em>together with new tools for manipulating the genome, has opened up entirely new avenues of research. The novel methods for treating what are currently un-curable diseases were especially exciting to learn about. I hope all the researchers at the meeting went back to their labs re-energized and inspired to continue developing these technologies and to dig deeper into the underlying biology of pluripotency and differentiation. I’m looking forward to what the future will bring!</p> <p> </p> <p>Author: Brooke LaFlamme, assistant editor聽<em>Nature Genetics</em></p> <p>Follow me on Twitter: @Brooke_LaFlamme</p> </div> </section> <div class="wpn-entry-meta"> <aside> <div class="article-tools cleared"> <h2 class="hidden">Article tools</h2> <ul id="wpn-share-post-337" class="wpn-entry-user-actions"> <li class="wpn-entry-comment-link"><a class="comments-link" href="https://blogs.nature.com/freeassociation/2014/04/highlights-from-the-keystone-symposium-on-stem-cells-reprogramming.html#respond" title="Comment on Highlights from the Keystone Symposium on Stem Cells & Reprogramming">add a comment</a></li> <li class="sendtofriend"><a href="https://blogs.nature.com/freeassociation/tell-a-friend?id=337">Email</a></li> <li class="print"><a id="print-link" class="track" href="javascript:window.print();">Print</a></li> <li class="wpn-share-bookmark"> <h3 class="toggle-bookmarking-links">Share/bookmark</h3> <div 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