We’ve all heard the idiom “it’s in my blood”.

For me, this applies to hockey and rock climbing. And a quick survey of my class suggests that everything from Southern BBQ sauce and ice cream to tea and motorcycle fluid (yikes!) runs in theirs. Given our usage of the phrase, one might suspect that there is something about blood that defines our unique attributes as individuals. So it’s rather ironic that the most clinically relevant component of blood to transfusion medicine, i.e. red blood cells, are the only cells in our bodies that completely lack genetic material.

It is, of course, this characteristic that allows blood to be the most highly “transplanted” tissue in modern medicine. With over 93 million donations annually in the U.S. alone, it doesn’t seem like industrialized nations are doing so poorly in terms of blood supply.

So then why are numerous research groups and donor organizations across the globe investing in blood engineering and the development of synthetic blood? (Hint: It’s got nothing to do with vampirism.)

According to an excellent review article in Cell Stem Cell, some motivations for synthetic blood include:

1. Some patients have rare blood types that even an abundant blood supply cannot accommodate well enough;
2. Our current supply may not be adequate in a state of emergency during which additional donor drives may be challenging to perform;
3. The demand is projected to increase over the next several decades; and
4. There may be increasing restrictions on who can donate, especially with the emergence/spread of infectious disease.

This is absolutely not to say that we should stop donating, but the above challenges could be addressed by having a supplementary supply of synthetic red blood cells (RBCs) made from stem cell precursors. Ideal precursor lines include embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) because of their long-term proliferative capabilities. Furthermore, because mature RBCs lack DNA, we don’t have to worry about transfusing products with potential genomic instability (a concern of ESCs and iPSCs in other applications).

While this enterprise may sound like something from a science fiction novel, numerous research groups have made functional RBCs from stem cells precursors, and the Scottish Centre for Regenerative Medicine has recently received a license to manufacture blood for the first human clinical trials.

Their trials will focus on using iPSCs as precursors, which can be made from skin cells of patients with rare blood types, and thus be used to manufacture blood types currently in shorter supply.

One of the greatest challenges will be to develop methods for the production of RBCs at an industrial scale. However, even as we’re progressing towards higher efficiency and higher density expansion, we can already make RBCs in smaller concentrations that have numerous other applications. For example, they can be used as substrates for in vitro testing platforms, including RBCs for antigen cross-matching studies that are often done when patients receive blood in non-emergent conditions. Another example is synthesizing RBCs for screening drugs such as anti-malarials.

Overall, I think these studies reflect a fascinating concept, which I’ll be following closely. What can I say? I’m a scientist. Curiosity is in my blood.

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Research cited:
Migliaccio A., Whitsett C., Papayannopoulou T. & Sadelain M. (2012). The Potential of Stem Cells as an In Vitro Source of Red Blood Cells for Transfusion, Cell Stem Cell, 10 (2) 115-119. DOI: 10.1016/j.stem.2012.01.001
Migliaccio A.R., Whitsett C. & Migliaccio G. (2009). Erythroid cells in vitro: from developmental biology to blood transfusion products, Current Opinion in Hematology, 16 (4) 259-268. DOI: 10.1097/MOH.0b013e32832bcaa2

So, as a final summary for a very busy and rewarding conference, here’s a snapshot of what happened in the day 4 plenary sessions, the poster hall and elsewhere around the conference, through the eyes of bloggers and tweeps. We’ve also posted coverage of day 1, day 2 and day 3, each of which includes a poster pick of the day, along with twitter blog and a daily highlight.

Daily blog roundup

With additional posts still to come from a few sources over the next few days, here is some more recent coverage from the conference:

• The Node’s summary of day 3 by Harry Leitch
• Alexey Bersenev’s list of all blog posts as of June 16
• A survey – what did you think of ISSCR 2013? on Paul Knoepfler’s blog
• And another video on research challenges from Life Technologies that I somehow missed on day 2:

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The day according to twitter

Here’s our storify of the day’s tweets:

Highlight of the day

Despite the anticipation over Shoukhrat Mitalipov’s talk, the highlight belongs to Shinya Yamanaka, whose personality was evident throughout the meeting, but never more than in his final remarks about the host city of Boston. A marathon runner himself, Yamanaka’s tribute to the character of Boston following the bombings in April, as well as that of the runners, and ofthe marathon organizers in announcing that all 2013 runners will be invited back for the 2014 event, was both elegant and poignant.

Daily blog roundup

Plenty of freshly posted articles for your reading pleasure. I’ve attempted to group them as best possible.

Overview/commentary:
If you want to get a jump on two of today’s presentations (by Benoit Bruneau and Shoukhrat Mitalipov), take a look at the long conference summary posted by Genetic Engineering & Biotechnology News. The Node also published a summary of Day 2 activities by Harry Leitch, which notes some of the highlights of the day’s sessions. And Signals’ David Brindley challenged the field to begin thinking more about reproducibility for therapy, not merely for the sake of a journal publication.

Specific topics/speakers:

• Gene therapy (David Williams talk) posted by CIRM
• Doug Melton presentation by Angela C.H. McDonald here on Signals
• Bioengineering strategies for repair in the central nervous system (Molly Shoichet presentation and follow-up interview) by John Farrell on Forbes
• Heart regeneration (Chuck Murray talk) posted by CIRM
• Surgical injection of cells into the spinal cord to treat ALS (Nicholas Boulis presentation), also posted by CIRM

Conference life:
We assembled some photos of the conference and Boston that we shared via our Right Turn feature. Kevin McCormack at CIRM also captured some images of the chalkboard questions that are hard to miss around the conference venue. Finally, Life Technologies posted a second video, this one asking attendees their thoughts on the most promising research/technology they’ve seen at the conference:

The day according to twitter

Here’s our storify of the day’s tweets:

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Highlight of the day

The cell therapy session in the afternoon had many people talking, but it you weren’t in the lecture halls, then the magic word was, well, magic. Regular shows draw a constant crowd at the Life Technologies booth.

Poster of the day

Selected by the Stem Cell Network’s Paul Cassar:
Omics Landscape Of Hematopoietic Stem Cells And Multipotent Progenitors Nina Cabezas-Wallscheid et al. (F-1167) This study is a comparative genome-wide analysis at an RNA and protein level of both long term and short term HSCs. In order to perform this study, the group had to extract these populations from the bone marrow of 700 mice. They found that over 100 proteins were differentially expressed between the two populations and at the RNA level they found over 300 genes that were differentially expressed. The group believes this is the first comprehensive systems level analysis of long term and short term repopulating cells and believes that this study will form the basis of discriminating the molecular events that define these two clinically relevant populations.

As I reflect on the first few days of the annual ISSCR meeting, the highlight for me thus far has been Melton’s progress update on the quest to develop functional pancreatic beta cells (I missed Hongwei Chen’s musical poster teaser). But in all seriousness, Melton has made significant headway in the pancreatic beta cell differentiation field.

Pancreatic beta cells secrete insulin, a protein that regulates blood glucose levels. Following an increase in blood glucose levels, beta cells secrete insulin, causing glucose uptake and normalization of blood glucose levels. In a type I diabetes patient, beta cells do not sufficiently secrete insulin, leaving diabetic patients unable to regulate blood glucose levels. Stem cell researchers, including Melton, hope that one day pluripotent stem cells will be a source of functional beta cells that could be transplanted into the pancreas of individuals with type I diabetes.

In his talk, Melton described the greatest challenge the beta cell differentiation field faces: the ability to create a functional beta cell that is capable of sensing glucose.

To date, there has been much success creating insulin-producing beta cells from human pluripotent stem cells however, these cells cannot accurately detect blood glucose. To overcome this challenge, Melton’s team performed a chemical screen in hopes of identifying a small molecule that would induce the ability of pluripotent stem cell-derived beta cells to sense glucose. They found that the combination of four chemical compounds can convert glucose-unresponsive pluripotent stem cell-derived beta cells to glucose-responsive cells.

Following chemical treatment, beta cells underwent a sequential glucose challenge in a petri dish. As the concentration of glucose increased, the level of insulin secretion increased. When these cells were transplanted into mice, human insulin could be detected in vivo following a glucose challenge, suggesting that these cells can respond to glucose levels following transplantation.

To end his talk, Melton outlined his vision for the future of diabetes research and treatment:

1. stem cell-derived functional beta cells used as research tools to understand the pathophysiology of this condition, and
2. transplantation of functional beta cells into patients, giving these individuals the ability to regulate blood glucose levels.

Transplantation of beta cells has stem cell researchers excited but as Melton outlined, there are still many challenges ahead. Type I diabetes is an autoimmune condition. The immune system attacks beta cells in these patients and would also attack transplanted beta cells. One potential solution could be to encapsulate beta cells, protecting them from the immune system. Melton pointed out that his lab is not focused on bioengineering but he challenged the audience to think about this.

Who’s up for the challenge?

In the cell therapy industry, our audience is a society with significant unmet medical needs: members who care little for the manner in which we may feel aggrieved by the negative decision of a regulator. The medical problems of the people we attempt to help – our opportunity to contribute to sustainable improvements in global health – remain constant. We need to swiftly dust ourselves off and get on with the job at hand, and be willing to approach the task in a different way the second time around. Even if this necessitates engaging unfamiliar stakeholders and techniques in the development pathway earlier than has been historically observed.

And with this ethos at hand, after a pleasant evening with a truly multi-disciplinary group exchanging their views on cell therapy translation in a waterfront restaurant (and later in an old prison, now converted into a bar), TAP Biosystems’ Kim Bure coined my top phrase of ISSCR 2013: “The process must go on.”

Almost all of the extraordinary stem cell science presented at ISSCR 2013 has been produced using highly labour intensive and poorly reproducible manual processes. This is perfectly acceptable if one’s end goal is to produce a high impact publication in a leading journal. But to me, and I hope to a growing tranche of the cell therapy industry, such publications are merely a stepping-stone towards clinically relevant cellular therapeutics. Products that, for reasons of patient safety, efficacy and commercial viability, need to be highly reproducible.

Reproducible and cost-effective aren’t necessarily characteristics that one ascribes with manual bioprocesses; but with good staff training and significant resources it is of course possible. Nevertheless, in an industrial setting it is mostly unrealistic. Staff illness alone could compromise the production process of a potentially life saving product. Therefore, it is essential to consider the scalability and practicability of protocols employed in a laboratory setting earlier than ever, as engagement with industrial partners is occurring progressively earlier in the development pathways of cellular therapies compared to existing biologics.

Part of the challenge is “removing the art from the process” as convincingly stressed by Lonza’s Thomas Fellner, charged with delivering the company’s collaboration with the NIH to produce large volumes of clinical grade iPS cell lines. For example, if we are to consider process development from laboratory to marketplace as a spectrum between entirely manual and poorly reproducible through to highly automated and highly reproducible, it is evident that progressive, as opposed to aggressive process development, is a mission critical aspect of the development of the Cell Therapy Industry 2027.

No one would suggest that overly aggressive process development, leading to overly engineered lab scale processes, is anything other than unnecessary. Similarly, we would all agree that hindering the progress of life-saving therapies to the clinic due to failing to ensure scalability and reproducibility earlier in the development pathway is anything other than unacceptable.

However your lab decides to conduct its work, remember that “the process must go on”. And, while ‘brute force’ overtly manual techniques may produce nice figures for a publication, they may not always best support the clinical translation of your processes – and patient benefit.

Our regular feature, Right Turn, showcases the “lighter” side of stem cells and regenerative medicine. Every Friday, we will bring you cartoons, photos, videos and other content that may be just as thought provoking as the written submissions that you are used to finding here, but they definitely won’t be blogs.

As always, we welcome your feedback and we also welcome suitable submissions. Be creative! Use the right (!) side of your brain. Make us laugh! Let’s see if we can make this new direction a positive one for all of us. Send your submission to info(at)ccrm.ca.

Daily blog roundup

Forbes writer John Farrell posted a terrific summary of Shinya Yamanaka’s opening address on Wednesday in which he recounted the events that kept him in research and led to his Nobel winning discovery.

There were more posts based on the first day’s opening plenary: CIRM’s Don Gibbons provided a great summary of the Doug Melton and George Daley talks and David Brindley took a closer look at what George Daley presented and then went on to outline some of the barriers need to be overcome before synthetic blood will advance to the clinic.

If you missed the incredibly moving address by patient advocate Andres Trevino, have a look at the summary by Kevin McCormack of CIRM to get a sense of what it’s like to battle a disease – and win.

(Update: CIRM has been very busy as I just noticed they posted 3 more articles from the conference, here here and here. Nice work with the fast typing!)

The Node also posted a succinct overview of Day 1 events, and the folks over at Life Technologies enhanced their dynamic conference presence by putting up a video in which scientists spoke about what motivates them to attend ISSCR.

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The day according to twitter

Here’s our storify of the day’s tweets:

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Highlight of the day

Definitely the Patient Advocate Address. In case anybody had forgotten why they pursue stem cell research, Andy Trevino offers a compelling reminder.

Poster of the day

Selected by the Stem Cell Network’s Paul Cassar:
A High-Throughput Gene Expression-Based Screen for Factors that Modulate In-Vitro Chondrogenesis of Stem Cells Identifies Optimal Conditions and Novel Factors. Rune B. Jakobsen et al. (T-3081) Jakobsen T-3081Twenty-five percent of all people with crucial ligament injury stand a very high chance of needing cartilage repair, so it is important to have an available source of chondrocytes. This study is trying to optimize media composition for the in vitro differentiation of human bone marrow derived MSCs. Using a factorial design small molecule screen coupled with high throughput digital microarray profiling Jakobsen was able to screen 38 different compounds for the most optimal combination. He found that this screening method, which relies on a chondrocyte gene signature readout, is a novel approach for this problem. The findings validated the current formulation, but because he looked at MSCs (which make chondrocytes and bone), it suggests that the current formation is still not optimal if the goal is to make chondrocytes exclusively.

The production of synthetic blood from human cells is slowly becoming a genuine prospect for the cell therapy community, with licenses to manufacture clinical grade synthetic human blood granted only days ago to Scottish company Roslin Cells. This complements on-going DARPA funding for U.S. based Arteriocyte to develop cell-based blood substitutes for servicemen. Nevertheless, there are a number of multi-stakeholder challenges separating this scientific promise from a widely accessible clinical practice – a number of which are scientific in nature.

1. Development of Functional Blood Units: The derivation of HSCs from ESCs is well studied, promoting genes, including Cdx4 and HoxB4, into the vernacular. To date, however, HSCs generated in such a manner have not been representative of in vivo HSCs; in part, due to their tendency to exhibit a myeloid bias.
2. Mechanism of Hematopoietic Ontogeny: Despite the familiar diagrams of the haematopoietic differentiation pathway, we are still unable to effectively and reproducibly control HSC proliferation and differentiation in vitro, in a manner that would yield sufficient cells to support a therapeutic and meet the expectations relating to critical quality attributes (CQAs) required by a regulator.
3. Culture Systems: At an elementary level, blood is a fluid and as such is subject to three- dimensional hydro-dynamic forces. Conversely, the majority of laboratory scale efforts to produce cell-based blood products relies on two-dimensional static cultures. Subsequently, the bioprocess forces experienced by cells are poorly representative of in vivo conditions, contributing to differences in cellular polarity during formation and differences in subsequent cellular functionality.
4. Our Choice of Cell: While we are aware of the characteristics of the cells we wish to reproduce in the haematopoietic lineage, we are less certain of the optimal characteristics of the optimal cell(s) to be used as the source material for such a process. For example, a major challenge to utilizing cells already committed someway down the haematopoietic lineage is limitations in their ability to self-renew.

Therefore, while stem cell sources offer great long-term promise as a route to scalable and effective synthetic blood products, and are currently experiencing a peak of interest, it is important to remember that a number of factors constituting the “blood-clinic barrier” remain. It is our shared responsibility as members of the cell therapy industry to work collaborative and efficiently to resolve these challenges.

Daily blog roundup

A few years back, you would have been hard pressed to find more than one or two blog posts covering the ISSCR conference (and one of them was us!). Now there are many providing excellent coverage. We’ll try to sample as many as we can over the next few days. Here’s some from day one:

Even Nobel Prize winners sometimes feel like giving up. CIRM has two bloggers contributing over the course of the conference, with multiple posts planned each day. They also provided a summary of the public outreach event that took place on Tuesday night.

Even though he’s not actually in Boston, Paul Knoepfler has a candid summary of Jamie Thomson’s talk, courtesy of Jeanne Loring. And of course, there was our own conference intro by David Brindley.

The day according to twitter

It’s also fantastic to see an increase in twitter activity this year. Have a look at a selection of tweets, mostly from the session talks.

Unexpected highlight of the day

Hongwei Chen. Hongwei Chen. Hongwei Chen. Your words are music. And your poster (W-2331) was busy!

Poster of the day

Chosen each day (using a combination of four factors, of course):

Transplantation of pluripotent stem cell derived human neural precursor cells into the MHV model of multiple sclerosis leads to stable clinical recovery. Ronald Coleman et al. (poster W-2255) Coming out of the lab of Jeanne Loring from the Scripps Research Institute, this poster shows some promising research in which human neural precursor cells were used to successfully reverse MS – demonstrating remylenation and complete reversal of the disease in a mouse model. The result they are currently looking for is a shortlist of proteins that can be used for treatment in humans, rather than the cells themselves.

We’ll do this for each day of the conference, so if you’re blogging or have something interesting (or unusual) to share, post a comment or send us a tweet @stemcellnetwork

To extend the tennis analogy, cell therapy, amongst many stellar year round events, probably boasts four Grand Slams: the World Stem Cell Summit, the World Stem Cells and Regenerative Medicine Congress, the Till & McCulloch Meetings and, of course, ISSCR.

Analogous to tennis, where playing surfaces exist on a spectrum from grass to clay, each meeting has its own thrust and characteristics, ranging from the overtly translational Till & McCulloch and the densely scientific ISSCR. However, each rightfully holds its revered place in the psyche of the cell therapy elite. Consequently, despite my personal passion and expertise in the clinical and commercial translation of cellular therapies, on my flight to Boston, I have been filled with a volatile mix of excitement and expectation.

Excitement born from the tangible energy that ISSCR generates in the community. And an expectation that, as in every previous year, ISSCR will live up to its billing.

As any committed sports fan would attest, it would be grossly inappropriate of me to do anything less than to contribute to this expectation by touting my own “must see” ISSCR performances.

Wednesday: Presidential Address, Shinya Yamanaka, RIKEN Institute, co-recipient (with John Gurdon, University of Cambridge), of the 2012 Nobel Prize for Medicine. A tip that doesn’t really require any justification!

Thursday: Human Induced Pluripotent Stem Cells for Cardiovascular Disease Modeling, Joseph Wu, Stanford University. Cutting edge fundamental science with potentially near term commercial potential – not just another cellular therapeutic!

Friday: Integrating Viral Vectors, Gene Transfer into Hematopoietic Stem Cells and Therapies in Human Monogenic Diseases, David Williams, Boston Children’s Hospital, USA. Integration: one of the big dilemmas in the clinical translation of cellular therapies – I’ll be listening closely!

Saturday: Secrets of the Human Genome, Eric Lander, Broad Institute of MIT and Harvard University, USA. Cellular therapies share many of the same opportunities and challenges as genomics – potentially a disruptive technological platform; despite immense investment has delivered   limited; but growing commercial applications to date; and shares the need for standardization, including Good Genomic Practice.

With my passport now stamped by a reassuringly gruff New England TSA agent, and a cab waiting to whisk me to Brigham and Women’s Hospital Regenerative Medicine Center Inaugural Symposium (with Advanced Cell Technology’s Robert Lanza delivering the keynote), my ISSCR 2013 journey has begun. As your “ISSCR 2013 Correspondent,” I will be producing posts throughout the conference, and whether you will be joining me in Boston or not, I thoroughly hope that you enjoy the event.