We've got a new niche!

The SCN Blog has a new name and a new home: http://www.signalsblog.ca

After nearly four years and 207 blog posts, we finally outgrew our dish, so to speak. Late last year, we began planning with the newly-formed Centre for Commercialization of Regenerative Medicine, who indicated an interest to begin blogging in the sphere. (Perhaps you'll recall our name contest?) Why have two blogs competing when one can do the job? The result is Signals Blog (the new name came from an SCN staff member who sadly was not eligible for a prize), which will continue to bring the same level of insight, commentary and research news you've found on the SCN Blog, but will add new perspectives and news on biomaterials, regenerative medicine and commercialization.

We think it's a great partnership that will provide a more comprehensive view of the world of stem cells and regenerative medicine. 

To ease the transition for readers, all archived posts from the SCN Blog have been moved to their new home and RSS feeds will be updated to the new address. Comments will be closed on this site, but we'll keep a copy of the archives here for the short term. 

This is our final post on this site: please update your links and check out our new niche at www.signalsblog.ca!

2012 Cells I See winners

By all accounts, the 35 entries in this year's Cells I See Art Contest & Gallery Showing were among the best we've ever had. Certainly, there were more than we'd ever seen before (view them all here) -- so many, in fact, that we had to clear an entire lounge space at the host hotel just to set up the gallery. Of course, it was worth it, as nearly 200 people took the time during an already busy Till and McCulloch Meeting to view the entries and vote. And here's our winner:

Grand Prize (as determined by blind judging at the Till and McCulloch Meetings):

"Neuronal Wave" by Renee Head (Hospital for Sick Children, Toronto)

Description: Stem cells often lift off the glass slides they are grown on. These stained cells (Nestin and Sox2) formed, what I call my “neuronal wave”.

You might also recall that we had a little Facebook competition going as well, in advance of the meeting. This online contest collected more than 1,250 likes and shares, and brought us our first People's Choice award:

People's Choice (as determined by Facebook likes as of 8pm EST on April 27, 2012):

"Crystal Violets" by Holly Wobma (University of Calgary)

Description: This artwork represents skin-derived precursor (SKP) cells, which were captured growing on Cytodex 3 microcarriers in a floral arrangement. These microcarriers wer then "pulled" to look more petal-like in Adobe Photoshop CS5, and the floral image was isolated and pasted onto a pleasant background. The cells were stained with Crystal Violet. The name of this art thus represents the shape (floral), colour (purple) and transparent (crystalline) appearance of the flowers.

Congratulations to both winners!

The stem cell fraction

An interview with Till & McCulloch Award winner, Dr. Aaron Schimmer, whose paper, entitled “Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia,” published in Cancer Cell, November 2011, was selected by committee as the most important stem cell publication by a Canadian in the past year. Dr. Schimmer will present the Award lecture on April 30, 2012 at 2pm as part of the Till and McCulloch Meetings in Montreal. Interviewed by Lisa Willemse, SCN Blog editor.

Lisa Willemse: Congratulations on winning the award. I understand that this comes as a bit of a surprise to you because you’ve only been working with stem cells for a relatively short time.

Aaron Schimmer: Yes, this is correct. If you look back five or six years ago, I wouldn’t say I had a focus on stem cells. But it is thanks in large part to Stem Cell Network members such as John Dick, David Kaplan and John Hassell that we acquired the ability to extend our work to stem cells. They’ve made an effort to allow others to enter the stem cell field. John Dick has done this particularly well -- he has directed a large amount of resources to making these platforms accessible to the broader community.

So it’s really an honour to get this award, but it’s particularly touching because it is due to this group that we’re actually working on stem cells.

LW: How much of your work today is focused on stem cells?

AS: We’ve always had a focus on developing novel therapeutic strategies for leukemia, but now we are able to look not only at the bulk leukemia cells, but we are also able to target the stem cell fraction which is so critical. If you were to ask me five years ago, I would have said that perhaps 20 per cent had relevance to stem cells, but now stem cells account for roughly 80 per cent of my work.

LW: Why the switch for you? Aside from that door being opened by John Dick in terms of access to techniques and other supports, was there a shift in your understanding or belief in this area of research as a potential way to tackle leukemia?

AS: I think it was a combination of two things. Clearly it was having the people like John and David and John that we were able to extend our assays into the stem cell platform, but it really came from the observations on the clinical side. When you treat patients with leukemia, you can kill off 99 per cent of their leukemic cells with just about anything, and yet, 80 per cent or more of patients relapse. So when we examined this in a really objective way, the question was not how to kill off those bulk cells – we already knew how to do that -- but are we really missing a critical component of what we should be targeting? And when you look at it, more and more studies continue to validate that new therapeutic strategies are going to have to account for the stem cell fraction.

LW: Specific to the compound, tigecycline, that you detail in this paper, can you give a summary of how it was identified as a possible target and the timelines involved?

AS: The assay itself was done over a period of 2-3 weeks, during which we screened through a few thousand compounds. We were able to go from the hit from the screen to the first patient treated in a phase 1 clinical trial in under two years. What’s interesting about the high throughput screening approach using approved drugs is that because of what’s known about the pharmacology and toxicology of tigecycline, we can move rapidly from the lab to the clinic as a way to test proof of concept very early in clinical trials. What we can learn through the early human studies can help validate the therapeutic strategy so that greater resources can be placed into developing those second-generation compounds or formulations that will have improved anti-leukemic and anti-leukemic stem cell activity. This agent will likely be most effective in combination with other standard or other novel agents and ultimately it’s where I think the development of this drug will go.

LW: What is it about this agent that makes it work on leukemic stem cells and can it be broadly applied to all patients?

AS: In our studies, tigecycline appeared to work by essentially shutting down the energy supply of the leukemia cells and stem cells, which occurs in the mitochondria through oxidative phosphorylation process [the process of electron transfer using oxygen within the mitochondria of a cell]. Leukemia cells appear unique in their reliance on mitochondrial oxidative phosphorylation. Essentially it is like producing a selective power outage in leukemia cells but not normal cells. Most cancers get their energy from glycolysis but there might also be other malignancies that are unique in their reliance on this process. Not all leukemia cells respond to this drug in culture and we have been able to relate this response to mitochondrial mass and oxygen consumption, with those leukemic cells with the highest mitochondrial mass demonstrating the greatest response to the drug. So theoretically, if this holds up in clinical trial, in the future it could be possible to identify those leukemia patients whose cells and stem cells have high mitochondrial mass and would most benefit from this therapeutic strategy.

LW: In your dual role as a clinician-scientist, what do you enjoy most?

AS: You end up with the best of both worlds. There’s the aspect of patient care -- when you’re treating leukemia, it is a very devastating disease, and there’s an opportunity to make an impact and contribution on a very personal level. And one balances that with the lab-based career where one tries to be a part of advancing therapeutics, but on a much bigger level. What’s also nice is to be able to translate the findings from the lab into the clinic and to really try to address some of the problems that patients are experiencing.

LW: In your career, what has given the most satisfaction thus far?

AS:  Every so often, we’ll have a patient that’s enrolled in one of our phase 1 studies where nothing else has worked, and they’re enrolled in a phase 1 agent where the expectations of success are low. And yet, that patient will enter remission and that’s really what validates all that one is doing. So, the reason one is a clinician-scientist, caring for patients and advancing the latest therapies to them, and recognizing that that therapeutic the patient ultimately got was the combination of work, not just in our lab, but in labs everywhere. This is why we are doing this – whether it was the drug that I made or that someone else had made – the idea that it’s all building, and it’s those moments where you say, “this is what it’s all about.”

 

Gene deletion to create insulin-producing cells

by Angela C.H. McDonald

Most research on stem cells involves the manipulation of gene expression, to some degree or another. During stem cell differentiation, the expression of specific genes orchestrates the choices cells make along the path from stem cell to adult cell -- a process known as differentiation.

Here’s how it works: the expression (or lack thereof) of single or combinations of genes will direct a specific cell fate. The guiding hand behind this expression is a collection of genetic interactions – or gene regulatory network. In addition to specifying a particular cell lineage, regulatory networks simultaneously repress networks that specify other cell types. For example, the pluripotency regulatory network maintains embryonic stem cell self-renewal while repressing regulatory networks that direct differentiation.  

35 reasons to like stem cells

by Lisa Willemse

2010 Cells I See winner: The Beauty of Pluripotency by Kamal Garcha

For the past four years, the Stem Cell Network has held a small image/art contest, known as Cells I See. You may have viewed announcements of the winners in previous blog posts. The contest, by and large, was a quiet affair, known only to a few who weren't part of the Network's annual scientific conference -- where the entries were displayed and conference attendees selected the winner via blind judging.

We were content to keep it this way, until we realized that we were, in essence, hiding some of the most incredible stem cell images we've ever seen. Prompted by interest from the Ontario Science Centre, we installed a small exhibit in their museum and the response was incredible. Most people had no idea what stem cells looked like and were amazed at their beauty and complexity. The overriding message was that people are interested not just in the science of stem cells, but in stem cell images and art.

In response, Cells I See has gone social -- we've opened up the 2012 voting to the world. Anyone with a Facebook profile can participate by "liking" any of the 35 entries in this year's contest. Of course, we invite you to share it with your friends and colleagues as well -- the images are breathtaking, displaying a range of cell types, colours and patterns. 

But don't take my word for it, go see them for yourself. 

 

Good start to the year for umbilical cord blood stem cells

by Angela C.H. McDonald

In 1988, the first umbilical cord hematopoietic stem cell transplant was conducted and since that time, over 20,000 umbilical cord blood transplants have been reported around the world. The technique offers several advantages over bone marrow in the treatment of blood disorders including noninvasive accessibility to umbilical cord blood as well as decreased graft versus host disease and superior immune recovery following transplantation. 

Despite these advantages, umbilical cord blood transplantation remains best suited to small children due to the low cell numbers available in a single umbilical cord blood unit that make it of limited use in adult patients. Transplantation of two cord blood units has improved the outcome of adult patients, but there are simply not enough cords available to make this a viable strategy in the long term. 

To overcome this hurdle, researchers have been looking for methods to culture cord blood in vitro with an aim to expand the numbers of stem cells found in a single cord unit and thus to circumvent the need to use two umbilical cord blood units for an adult patient.

It would seem we are getting close. Last month, a method for expanding human umbilical cord blood hematopoietic stem cells was published in Cell Stem Cell. Lead researcher Peter Zandstra and colleagues used computational and experimental approaches to design a strategy that yields an 11-fold increase of self-renewing, multi-lineage repopulating hematopoietic stem cells within 12 days of umbilical cord blood culture. 

In culture, hematopoietic stem cells rapidly produce mature blood cell types that subsequently produce secreted factors inhibiting hematopoietic stem cell expansion. The trick is to dilute accumulating inhibitory factors to allow expansion of the stem cell pool. The researchers computationally simulated hematopoietic stem cell population dynamics and culture strategies and identified a culture system to do just that.

Simulations predicted that an input stream of fresh media into the culture would lead to an increase in total volume over time and would be the most effective strategy for expanding the stem and progenitor cell pools. This prediction was tested experimentally and proved to increase stem and progenitor cell number by reducing the concentration of accumulating inhibitory factors as well as maintaining lower cell densities in culture, effectively slowing the rate and impact of inhibitory factor accumulation.

This culture system – known as a fed-batch culture system – provides multiple advantages over other inhibitory factor dilution methods of umbilical cord cell expansion, including lower costs due to a decreased requirement for culture media as well as a shorter culture time window. The researchers hope to move this technology into clinical trials in the near future.

While significant steps forward in the optimization of cord blood transplantation for the treatment of blood disorders are being made, a number of researchers are exploring alternative therapeutic uses for cord blood stem cells. Earlier this year, a Phase I clinical trial was approved to treat hearing impairment in small children with their own cord blood stem cells.

In a mouse model of hearing loss, studies have demonstrated that cord blood can restore inner ear organization and structure two months following transplantation. How do cord blood stem cells treat hearing loss? Researchers aren’t quite sure. Cord blood stem cells may regenerate lost hair cells in the cochlea, restoring function or they may home to the site of injury in the ear and induce the body’s repair mechanisms (click here to read more). Research is underway to uncover the mechanism of cord blood-mediated hearing restoration. While this research is preliminary, results from animal studies are intriguing and I know I will be waiting to hear about this study’s progress. 

 

A crack in the origin of eggs: policy and fertility implications of oogonial stem cells

by Lisa Willemse, with Ubaka Ogbogu and Timothy Caulfield

The announcement last week that a team of researchers had identified stem cells responsible for generating human eggs caused a ripple of excitement for several reasons. Not only does the news end a controversy regarding an assertion by the same research team that such oogonial stem cells even existed in humans (based on research done in mice), it would appear that this finding will rewrite medical textbooks and change a long-held belief that women are born with all the eggs they will ever have.

Indeed, if oogonial stem cells can give rise to full developed oocytes, it represents a significant crack in the entire notion of fertility and the possibility that adult women of any age could reproduce, as many have noted. If this is the case, IVF clinics could one day find their doors wide open, with fewer limitations on what and who could be a potential client for treatment. 

A seemingly obvious question, then, would be whether such procedures to create eggs for fertilization from oogonial stem cells, either for research or reproductive purposes, would be legal. As we have seen many times before, policy is rarely able to anticipate the directions of science, and thus there is no provision that explicitly deals with the use of stem cells to create oocytes.

In Canada, such activities fall under the Assisted Human Reproduction Act (AHRA). Ubaka Ogbogu, Assistant Professor in the Faculty of Law at the Universtiy of Alberta (and regular contributor to this blog) notes:

Under the AHRA the process of creating oocytes from oogonial stem cells is not banned, but likely regulated (Assisted Human Reproduction Canada license required), however, if the recent Supreme Court of Canada decision is implemented by the federal government, the activity might not even be regulated at all or fall to the provinces to regulate. This would apply for oocytes created for reproductive purposes, but not necessarily for research purposes -- using the oocytes for stem cell research would be likely banned depending on the method, which would follow the same rules as for using normal oocytes for stem cell research. 

A further question that complicates matters, is whether the eggs, when created using this method, can be considered reproductive material. Answers to that question may have to wait until science has taken the time to both replicate the initial study and assess the quality and exact nature of the resulting eggs. As with many new findings, it will be some time before any of it translates into clinical options.

 

Breakfast in the shire: How is the UK reacting to Brüstle v Greenpeace?

by David Kent

Last week I attended a breakfast at Eversheds, a law firm in Cambridge entitled Stem cell patenting, Brüstle v Greenpeace: business breaker or business as usual? which focused on the practical implications of the recent decision from the Court of Justice of the European Union on human embryonic stem (ES) cells. The event organizer, Adrian Toutoungi began the session with a summary of where things stand for hopeful patent applicants which included much of the information that Ubaka Ogbogu reported in his recent article on this site with two interesting supplements:

1. If the implementation of the invention requires the destruction of human embryos, it will not be patentable and it is irrelevant that such destruction may occur at a stage long before implantation
2. Inventions are also not patentable even if the claims of the patent do not cover the actual use of human embryos.

Following this groundwork, two speakers gave their viewpoints on where this leaves the field, both with respect to pursuing patents in the current climate and with the future of ES cell research in the UK. 

First up, Neil Thornton provided historical context for the ruling.  Prior to this new ruling, the status quo was the Wisconsin Alumni Research Foundation (WARF) patent that prohibited human ES cells and cells derived from human embryos from being patented. This new ruling extends the prohibition to cells derived from human ES cell lines or cells derived from human ES cells. Whereas the WARF ruling allowed for patents on inventions that utilized previously created ES cell lines, the Brüstle v. Greenpeace ruling very clearly does not. Dr. Thornton pointed out that the European Patent Office (EPO) is not bound by the Court of Justice of the European Union and has not yet made an official statement regarding the Brüstle v. Greenpeace ruling (though one is expected soon). However, he did quote EPO president Benoit Battistelli from his blog where he said, “If the judges rule in favour of a restrictive interpretation of biotech patentability provisions, the EPO will immediately implement it.” 

Dr. Thornton also speculated on the way forward for those pursuing patents, saying that inventions excluded because they use human ES cells could be viewed as applying to only those technologies where there is no plausible alternative. Therefore, depending on what exactly ends up in the EPO statement, there may be room to patent an invention that could plausibly have used cells from these alternate sources at the time of patent filing (i.e.: using a non-embryo destructive cell source or technique like induced pluripotent stem cells (iPS) or single blastomeres.

Dr. Thornton elaborated with a clever analogy of a obtaining a patent on a method to open a locked safe, which would have a morally acceptable use (by a locksmith) and a morally unacceptable use (by a burglar). Under the EPO's current guidelines, he continued, a morally unacceptable use for an invention is not sufficient to deny patent protection if the invention can also be used in a morally acceptable way. He then speculated that if inventions relating to human ES cells were treated in the same way, the EPO could possibly grant claims that would cover the use of cells produced by embryo destructive or non-destructive techniques. There was some discussion following this point around how similar iPS cells are to ES cells and whether or not they could be viewed as a plausible alternative. 

The second speaker was Cathy Prescott of Biolatris (I featured Dr. Prescott in a previous entry on the Royal Society meeting in 2010), who presented on the impact of this ruling for venture capitalists, industry, and academics. Dr. Prescott started with some numbers that made very clear the low level of investment from members of the BVCA (British Venture Capital Association) into the biotechnology field (1% of all technology investments in the UK) citing reasons of uncertain risk management especially in the area of intellectual property which is viewed as the major currency in the biotech sector. According to Dr. Prescott, “No IP = a non starter.” 

From an industry perspective, she noted that the products and services focused on human ES cells were largely either “tools and reagents” or “therapeutics” and quoted a major company delivering tools and reagents into the research market as saying “if this ban were to prevent patenting of downstream methods… [it would] negatively affect business.” The final area that Dr. Prescott commented on was academic research. The most obvious impact, which has precedence in the United States, is that scientists themselves may relocate to those more permissive environments – in this case, to those where they can protect their of applied research. Secondly, it is entirely possible that various EU states may query whether or not it is worth funding non-commercializable research. For now though, Dr. Prescott stressed that both the EC and the UK are committed to continuing to fund ES cell research as a priority area despite patent concerns, including the major government investment made last autumn.

Overall, as an academic researcher, I found the event particularly useful as a high quality synthesis of the ruling’s implications. It certainly left the impression that things were far from decided. For now, it seems that we will have to wait and see what the EPO decides with respect to ES related patents and how stem cell scientists and universities will move forward with respect to patenting in this sector. 

 

News roundup: open access, new funding for personalized medicine and spinal cord injury update

by Lisa Willemse

Some updates and news items of note:

Call for boycott of subscriber-based journals gains momentum

The ongoing friction between proponents of open access and the academic publishers has jumped into the spotlight once again with calls from a number of academics, most notably from prominent British mathmetician Tim Gowers, who publicly announced his decision to stop submitting and reviewing for Elsevier. His objections are worth reading. Within days of his comments, a web site was created that allows other researchers to pledge their support for open access and against the practices of Elsevier and other academic publishers. At time of writing, there were over 2400 signatures. Of course, this is not the first time such calls for open access have surfaced from within the research community, the last big push resulted in the formation of the Public Library of Science in 2000. 

Nor are the sentiments limited to the mathematics field -- within stem cells, Jim Till has long been a proponent of open access and keeps a close eye on relevant news on his blog and Alexey Bersenev has several posts on the topic on his blog, Stem Cell Assays. His summary of the current events includes a good list of the reasons for open access as well as links to other sources for the interested reader.

Shift to personalized medicine finds federal support

Yesterday, the Canadian Minister of Health, Leona Aglukkaq, announced a new initiative worth upwards of $135 million ($67.5M from federal sources, to be matched by partner funds) with a focus on personalized medicine -- the use of genetics, biomarkers and environmental conditions to tailor disease treatments to individual patients. The announcement was essentially a call for applications and while specific projects are not yet known, they will have a strong genomics component and be readily translatable into a clinical setting. More reason for those working in translational research to be happy, and yet another sign that basic research is in trouble.  

A good chunk of the funds is coming from Genome Canada, with other support from the Canadian Institutes of Health Research and the Cancer Stem Cell Consortium. Specifically, the contribution from the Cancer Stem Cell Consortium will support the highest ranking cancer stem cell research project. All projects are expected to last four years.  

Update to spinal cord injury summary

Finally, a note that the entry on spinal cord injury within the Stem Cell Network's patient section has been updated and expanded. We are working to update all the entries in this section and to add new ones in the coming year. 

Good news for hESC trials: transplanted human embryonic stem cell-derived retinal pigment epithelium… and it’s safe!

by Angela C.H. McDonald

As has been reported broadly this week, transplantation of human embryonic stem cell-derived retinal pigment epithelial cells appears to be safe in human patients, and it may even be efficacious (although this can only be confirmed via a Phase II trial). 

Advanced Cell Technology (of California) published a preliminary clinical report of their Phase I clinical trials online this Monday in the Lancet. The two Phase I clinical trials were initiated at UCLA’s Jules Stein Eye Institute in July 2011. These trials aimed to treat Stargardt’s Macular Dystrophy and Dry Age-Related Macular Degeneration (two major causes of blindness in the developed world). Each trial will enroll up to 12 patients, with a safety endpoint at 12 months. Four months following transplantation, no adverse affects such as tumorigenicity, ectopic tissue formation, inflammation or cell proliferation could be detected in patients.

The subretinal space of one eye in each patient was injected with retinal pigment epithelial cells generated from human embryonic stem cells. The retinal pigment epithelium is a single cell-thick protective layer in the eye. In the eye of a macular degeneration patient, retinal pigment epithelial cell degeneration causes dysfunction of photoreceptors (which sit on top of the retinal pigment epithelium) and vision in that area of the eye is lost.

Although visual acuity assessments revealed functional improvements in the transplanted eye of each patient, these results should be interpreted with caution. While the Stargardt’s Macular Dystrophy patient only showed improvement in the transplanted eye, the Dry Age-Related Macular Degeneration patient showed improved visual function in both. However, the injected eye did show more improvement than the non-treated eye.

Despite the fact that Monday’s report is very preliminary (results from only two patients at the four-month mark), the company must have a great deal of confidence in the trial for it to have made this public announcement. Additionally, Advanced Cell Technology announced in a press release published on their website Monday that patient enrollment has now begun in the UK for a Phase I clinical trial for Stargardt’s Macular Dystrophy and the first patient was treated in London last Friday.

This exciting news comes just two months after Geron’s announcement to end the first ever FDA-approved human embryonic stem cell Phase I clinical trial, a move described as a strategic financial decision by Geron (covered in a previous blog entry). Disappointment and controversy surrounded the sudden halt of the Geron trial and some question the motive behind this decision. Some speculate that a lack of efficacy in this safety trial is what lead Geron to pull the plug.

Although it felt like the stem cell community took a number of hits in 2011 (including the shut down of the Geron trial and the prohibition of patents for human embryonic stem cell products by the EU), it seems that 2012 is off to a great start.