Author: Christine Ferguson

A Faster Reset Button for Stem Cells

Modified logo wth textBeing able to restore function to organs damaged through disease or injury is a goal that has not only inspired work on programming robots to act on our thoughts (see ‘We have the technology…’) but has also stimulated scientists to explore whether our bodies’ cells can be reprogrammed to take on the missing functions. The 2012 Nobel Prize committee recognised the potential for therapy in adult cell reprogramming and rewarded John Gurdon and Shinya Yamanaka for their pioneering work in this area. These two stem cell biologists realised that a key step in the process is to return the adult cells to a primitive state before persuading them to take on another role, and that this would involve resetting the cells’ nuclear programme.

Shinya Yamanaka published his nobel prize winning work in 2006, in which he showed that treating fully developed adult cells with four protein factors would drive the necessary changes in the cells’ nucleus to return them to a stem cell-like state called pluripotency; and hence the name, “induced pluripotent stem cells”, iPS cells for short.  Since then teams the world over have sought to tweak and streamline this promising technology to obtain greater numbers of pluripotent stem cells, in shorter time, from adult tissue.

Reprogrammed adult cells  (Silva et al. PLOS Biology)

Reprogrammed adult cells
(Silva et al. PLOS Biology)

Austin Smith and colleagues at the Stem Cell Institute in Cambridge, UK asked whether adult stem cells, such as neural stem cells, which are naturally available in small numbers in adult organs, could be more rapidly and efficiently converted to a state of pluripotency than their fully differentiated neuronal neighbours. As published in their PLOS Biology article in 2008, the answer turned out to be yes – neural stem cells are easier to reprogram to a pluripotent state and therefore better starting material than mature fully developed adult brain cells are! The team also made some important discoveries along the way.

One such key discovery was that these neural stem cells don’t return to the pluripotent state in a single step. Using the reprogramming treatment identified by Yamanaka’s lab (the use of viral vectors to introduce genes encoding four reprogramming factors), Smith and his lab found that neural stem cells showed signs of reprogramming much earlier (3 days versus 3 weeks) and at higher frequency than did fully differentiated cells. There was a problem, however, in that these early appearing cells arrested on the verge of full pluripotency.

José Silva, the first author of the PLOS Biology article, told me of his initial disappointment “My passion has been the study of the biology of nuclear reprogramming for many years now. When Kazutoshi Takahashi and Shinya Yamanaka published their seminal work on induced pluripotency, my imagination ran loose with ideas. The irony is that it was the initial failure to generate Induced Pluripotent Stem cells using the conventional Yamanaka factors and traditional Embryonic Stem Cell culture conditions that guided the creation of the PLoS biology work. All we could make initially were highly proliferative cells that looked like Embryonic Stem Cells but were not like these at the molecular level. Somehow these cells were not able to go all the way.”

To tackle this issue, the team broke down the differentiation process  into several steps - starting from embryonic stem cell, and ending with neural stem cell (embryonic stem cells can form any cell type in the body, whereas neural stem cells are restricted to forming only nerve cells). They then worked out which signals might be getting in the way of complete reprogramming. Using chemicals to neutralize these signals (inhibitors ERK and GSK – termed “2i”) and adding a factor called LIF, which encourages self- renewal, the team found that this chemical cocktail (called 2i/LIF) could push the early appearing, partially reprogrammed cells to adopt a fully pluripotent state. 

José Silva explains: ‘we discovered the importance of the culture environment, together with the Yamanaka factors, in instructing the conversion of a differentiated cell back into an embryonic stem cell. “

That the group were able  to generate greater numbers of iPS cells is down to their recognising the potential in these partially reprogrammed “pre-iPS” cells which may have been  previously dismissed by others;  as Kathrin Plath and colleagues at UCLA wrote in 2012,While it is not absolutely clear that pre-iPS cells represent an intermediate that occurs transiently during the reprogramming process, they are not simply an aborted reprogramming artifact because pre-iPS cells can convert into iPS cells upon addition of ERK and GSK inhibitors.’

Finally, Austin Smith’s team noticed that their 2i process enabled the complete reprogramming of neural stem cells that intriguingly contained only very few copies of the ‘Yamanaka factor’ genes, supporting the suggestion that genetic manipulation of cells might not be obligatory for reprogramming them to pluripotency. The use of genetic reprogramming has been a key concern for those in the field, as put forward by distinguished British stem cell biologist, Fiona Watt and her postdoc Ryan Driskell who wrote: ‘ Discovering how the pluripotent state can be efficiently and stably induced and maintained by treating cells with pharmacologically active compounds rather than by genetic manipulation is an important goal.

The paper by Smith and colleagues has gone on to be one of our research gems of the past 10 years and was picked out as a favourite by two of our Editorial Board members, Susan Gasser and Alfonso Martinez-Arias.

Looking back on this research, José Silva, who was a postdoctoral researcher at the time,  reminisces: “This work had a significant impact on my career, as it helped placing me on the path to becoming a Principal Investigator. Most importantly, it gave me a great platform to interrogate the underlying biology of nuclear reprogramming.


 

collection logoSee the Tenth Anniversary PLOS Biology Collection or read the Biologue blog posts highlighting the rest of our selected articles.

 

 
ResearchBlogging.org
Silva J, Barrandon O, Nichols J, Kawaguchi J, Theunissen TW, & Smith A (2008). Promotion of reprogramming to ground state pluripotency by signal inhibition. PLoS biology, 6 (10) PMID: 18942890

Category: Biology, Cell biology, Developmental biology, Epigenetics, PLOS Biology, Regeneration, Research, Stem cells | Tagged | Leave a comment

Open for microbiology: PLOS Biology at ASM 2013

As we have discussed in previous posts, PLOS Biology believes strongly that we are Open for a Reason; one of our key aims is to publish high quality research in areas of importance to ensure that it reaches the widest possible audience without any barriers to access.  Microbiological research is an area of research that we believe should be as openly available as is possible  by being published in an open access, CC-BY journal with associated data mineable and reusable.

PLOS Biology publishes many interesting and high profile studies from the field of microbiology – to give you a taste of what we’ve recently published, check out the links  we’ve provided below to access latest research in this field.

From tomorrow, I will be attending the 113th General Meeting of the American Society for Microbiology in Denver, Colorado, together with my colleagues from PLOS ONE, where I look forward to meeting with our Academic Editors, authors and reviewers in the microbiology research community.

If you’re also attending and would like to find out more about how to publish in an Open Access journal, please visit us at the PLOS booth, number 350, where you can meet with myself and my fellow PLOS colleagues. PLOS Biology is also planning a Meet the editor session from 1:30-3.30pm on Sunday 19th May, so come by then, or stop by another time to leave me a message (or alternatively email me at biologue[at]plos.org). Looking forward to meeting you in Denver.

 

If you’re interested in microbiology, you might want to read ….

(and of course you can because they are published in PLOS Biology and all Open Access….)

Cooperation and the Fate of Microbial Societies

The Evolution of Mutualism in Gut Microbiota Via Host Epithelial Selection

Selecting One of Several Mating Types through Gene Segment Joining and Deletion in Tetrahymena thermophila

Conformational Change-Induced Repeat Domain Expansion Regulates Rap Phosphatase Quorum-Sensing Signal Receptors

Structural Basis of Rap Phosphatase Inhibition by Phr Peptides

Candida albicans Commensalism and Pathogenicity Are Intertwined Traits Directed by a Tightly Knit Transcriptional Regulatory Circuit

When the Most Potent Combination of Antibiotics Selects for the Greatest Bacterial Load: The Smile-Frown Transition

The Human Microbiome Project: A Community Resource for the Healthy Human Microbiome

Microtubules in Bacteria: Ancient Tubulins Build a Five-Protofilament Homolog of the Eukaryotic Cytoskeleton

 

 

 

 

 

 

 

 

Category: Conference, Microbiology, PLOS Biology | Leave a comment

Calling all researchers in tuberculosis

Editors are sometimes asked while out and about in the community, why it is that we attend conferences. Most folk presume we’re there to gather material, perhaps to write up a meeting report for the journal.  For conference-going PLOS Biology editors, meeting reports are not really on our agendas (since at PLOS Biology, we  don’t routinely publish these), but we’re certainly there to gather information: about the topic (what’s new, trending, old news) and about the community (who’s who; who would be well-placed to review articles in this field; who could write a fabulous Essay or Unsolved Mystery for our magazine section; and who could bring their wisdom and charisma to our editorial board – which, incidentally, we’re striving to diversify).

We’re also there to spread information about what we’re doing at PLOS and about what our journals can offer you. I’d like to start this conversation here, ahead of attending the joint Keystone symposia on tuberculosis, which are due to take place this week at the mountain resort of Whistler in Canada.

Since the last double-billed Keystone meeting on Tuberculosis (TB) in January 2011, PLOS has published 702 papers on tuberculosis – as copyright for these articles remains with the authors, and since they were published under the CC-BY licence, these articles are free to access and to reuse, as long as the authors are credited. While each of PLOS’ seven journals published a proportion of these, 608 papers appeared in PLOS ONE, which is now the largest journal in the world.

Below is a flavour of the breadth of PLOS Biology’s coverage in this field:

Metabolic Regulation of Mycobacterial Growth and Antibiotic Sensitivity by Seung-Hun Baek, Alice H. Li, Christopher M. Sassetti (2011)

Human Mucosal Associated Invariant T Cells Detect Bacterially Infected Cells by Marielle C. Gold, David M. Lewinsohn and colleagues (2010)

High Functional Diversity in Mycobacterium tuberculosis Driven by Genetic Drift and Human Demography by Ruth Hershberg, Sebastien Gagneux and colleagues (2008)

You’ll notice that the wider range of articles at PLOS Biology reflects the reach of this month’s Keystone symposia to include host immune responses to bacterial pathogens,  disease ecology, bacterial genetics, bacterial physiology and systems biology.

 

SEM of Mycobacterium tuberculosis bacteria. Photo credit: Janice Haney Carr at the CDC

Tuberculosis research is a field we deem to be of particular importance and broad impact and is one that warrants publication in an open access journal, such as PLOS Biology. We’d like to publish more TB-related papers than we do currently, and as such we invite you to submit your best work to us.

What can we offer you in return?

We can offer you the combined strength of two successful editorial models: the services of a team of professional staff editors, who bring to the table an impressive number of collective years of scientific training, and editorial experience to support a consistent, thoughtful, ethical and collaborative editorial process. We work in partnership with practicing scientists on our Editorial Board, who have been selected for their standing and experience in their fields. Together, we screen submissions to identify those with potentially significant findings for the field and we work to pursue the best-placed reviewers to assess the impact and strength of these select studies. Our partnership with academic editors ensures that requested revisions are limited to the essential and that decisions are fast and fair.

Beyond ensuring that your paper is published with a license that accredits you as the author and provides every opportunity for reuse, every published manuscript is accompanied by an author summary that is written with the non-specialist scientist in mind and that is edited carefully by the editorial team.  We also select the most noteworthy papers to feature in a synopsis that is commissioned from a professional science writer, or in a primer written by an expert in the field. After publication, PLOS tracks the impact of your paper on the community and presents real-time article-level metrics that reflect downloads, social media interest and citations.

As one of the editorial team who handles TB-related submissions for the journal, I will be attending the forthcoming Keystone meeting on TB.  I’d be pleased to meet you there and to talk with you about work you are ready to submit, or if you are interested  in joining the PLOS Biology community as a reviewer, editorial board member or blogger.  Please contact me at the Biologue email address (biologue[at]plos.org). If you are planning to attend the meeting, be sure to pick up one of our few remaining 2013 PLOS Biology calendars featuring our favourite issue images.

Category: Conference, Infectious disease, Microbiology, PLOS Biology | Tagged , | Leave a comment