Nepalese terraces. Photo: strudelt via Flickr

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Picture traveling back in time to an era before cell phones (*shudder*). Before radios. Before germ theory. In fact, try taking yourself back to when written language was first being developed around 6000 BC. It’s hard to imagine.

And yet while these societies may have lacked our freeways and our Facebook, they did have complex irrigation systems. Throughout the millennia, these water networks have brought life to three-dimensional space, from the aqueducts of Ancient Rome to the terraced hills of Nepal. Orderly arranged. Tightly controlled. It seems that from the very onset of civilization humans have been masters of fluid dynamics.

So with all of our modern technologies, can we live up to the ingenuity of our ancestors to tackle current problems in fluid flow? If we want to advance the field of tissue engineering, then we’ll have to. I’m, of course, referring to the challenge of vascularization.

If you’re up to speed on the status of tissue engineering, you’ll know that scientists have been able to engineer cellular patches of heart, bone, skin, liver … the list goes on. But for these tissues to actually be useful to a patient, they need to somehow be vascularized. Thus far, at least two broad strategies have been explored.

Strategy 1: You try to engineer pre-vascularized tissues. This means de novo engineering of both the blood vessel and the tissue together.

• Pros: You could control the architecture of the vascular network and it would enable you to engineer larger tissues in the lab (since they would have oxygen delivery throughout).
• Cons: You have to co-coordinate the development of both the tissue that you are trying to make with the growth of the blood vessel (not trivial).  The vessels you make must function physiologically, permit gas exchange, not clot or stenose, and be durable enough to suture into a patient.

Strategy 2: Implant your engineered tissue and let the body’s vasculature grow into it over time.

• Pros: Body takes responsibility for making the vessel, which may be anatomically and physiologically similar to other vessels in the body.
• Cons: Lack control of vessel architecture, and the ingrowth of host vessels can be very slow (implanted tissue may die).

While the strategies outlined above are not completely inclusive of everything being tried, you can start to appreciate that both have some very compelling advantages but also notable shortcomings. Wouldn’t it be nice to combine the advantages of both into an innovative new strategy?

That’s basically what Dr. Christopher Chen’s group has recently done at the University of Pennsylvania. In their approach, which was published in this month’s issue of PNAS, they made networks of tiny “cords” out of collagen and endothelial cells (the cells that line blood vessels). These cords are not substitute blood vessels, but when they are implanted into an animal model, the endothelial cells send signals to the body to replace the cords with capillaries.

The brilliance of this technique is that the patient’s body forms natural blood vessels, but in an accelerated fashion due to signals from the endothelial cells in the cords. Furthermore, you have some control over the 3D network of vessels that form, because the cords serve as template that gets replaced. This geometric control is important because many tissues in our bodies have a specific vascular architecture. In fact, the investigators go onto show that when they implant engineered liver tissue along with their cords, the liver becomes more functional (based on an enzyme assay) than if it were implanted alongside random cell seeding. Overall the technique is creative, inspiring, and a useful step forward for vascular engineering.

I think it’s curious to reflect that our ancestors were able to sustain life by using hydraulic networks to bring water to their fields, and now we are learning how to engineer vessels to sustain life through regenerative medicine. I can only conclude that while our technologies and interests change over time, human ingenuity remains the same.

Research cited:
Baranski J.D., Chaturvedi R.R., Stevens K.R., Eyckmans J., Carvalho B., Solorzano R.D., Yang M.T., Miller J.S., Bhatia S.N. & Chen C.S. & (2013). Geometric control of vascular networks to enhance engineered tissue integration and function., Proceedings of the National Academy of Sciences of the United States of America, PMID: 23610423

Vunjak-Novakovic G., Tandon N., Godier A., Maidhof R., Marsano A., Martens T.P. & Radisic M. Challenges in cardiac tissue engineering., Tissue engineering. Part B, Reviews, PMID: 19698068

Marolt D., Knezevic M. & Novakovic G.V. (2010). Bone tissue engineering with human stem cells., Stem cell research & therapy, PMID: 20637059

Metcalfe A.D. & Ferguson M.W.J. (2007). Tissue engineering of replacement skin: the crossroads of biomaterials, wound healing, embryonic development, stem cells and regeneration, Journal of The Royal Society Interface, 4 (14) 413-437. DOI: 10.1098/rsif.2006.0179

We’re looking for the following:

• Scientific accuracy
• Skill at communicating science
• A topic related to stem cell and/or regenerative medicine

The deadline is June 28, 2013. Please e-mail your infographic to info@ccrm.ca. Winners will be announced July 31, 2013.

The prize
The winner, as decided by a panel of experts, will receive an iPad mini!

To help you
We found this site http://piktochart.com to help you design your infographic, but there may be another one that you prefer.

Contest rules
These will be shared soon. In the meantime, start thinking about how to create a great infographic to win that iPad mini.

Questions?
Please send them to info@ccrm.ca

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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.

These ‘small steps’ forward are indicative of a far greater ‘giant leap’ for health care. I recently attended a talk by Canadian Oxfordite Professor Sir John Bell, and was struck by an example he used to illustrate progress in medicine – taxonomy. The way we classify diseases has radically changed over the last 50 years. From describing someone as having “cancer” to “metastasized colorectal carcinoma” to “metastasized colorectal carcinoma with MLH1 silencing” to “metastasized colorectal carcinoma with MLH1 silencing and KRAS mutation,” our understanding of disease pathology and how to treat it has changed astronomically. But, more importantly, this meteoric rise in understanding is already being used to improve patient outcomes.

Using such information, we’re now able to predict responders to certain types of chemotherapy and identify optimal treatment regimens based on an individual’s genetic code. Furthermore, huge advances in sequencing technology mean that genomics is already being applied in a meaningful way, and with no sign of deceleration in the companies developing such technologies, the once distant dream of a $1000 genome has been obliterated (see Figure 1), as we instead begin to consider the widespread implications of the $100 genome.

At this modest cost, significantly less than the current $20,000 deposit for a ride with Virgin Galactic, any of us could walk into our local sequencing centre and walk out with a printout of our individual fundamental make-up. Right now, with that information, we can perform health assessments, determine suitable therapeutic approaches and approximately predict the likelihood of certain diseases (see Angelina Jolie’s recent decision to get a preventative double mastectomy after finding out she had the BRCA1 mutation and an 87% chance of developing breast cancer). But it becomes really interesting when we pull all of this information together with a patient’s medical history. Deciphering the genetic code, and finding ways to process the huge volumes of data generated, are undoubtedly the next ‘giant leap’.

The potential gain for bioinformatics companies is enormous. In fact, much of the data required already exists. In the UK, the National Health Service houses over 60 years of detailed medical records for every patient it has ever treated. Yet trudging through this data and extracting useful information – whilst respecting patient confidentiality – is challenging at best, and something the UK government has struggled with. Furthermore, the data generated by complex genome-wide association studies (GWAS), a technique commonly used to find links between genes and diseases across a substantial population, could overwhelm the majority of servers.

And yet we are finding ways around this. Fields that end in ‘-omics’ are making significant progress and realizing the benefit of collaboration, enabling us to consider differences in protein expression, lipid expression and metabolites across patient groups. This evolving health care paradigm, where we have an increased understanding of not only the disease, but also the individual patient, will be key in the commercialization of novel therapeutics, particularly those with regenerative capacity.

Regenerative medicine products will be expensive by definition, and demonstrating the efficacy needed to justify this cost will undoubtedly stem from increased understanding of the underlying mechanisms. Cells and tissues are complex, and deciphering the genetic differences between responders and non-responders will be key in unlocking their true therapeutic potential – and ultimately curing disease.

In the future, the key will be to integrate health care and research systems, where every willing patient is a research patient, and every bit of data generated contributes another piece to our understanding of the genetic puzzle. Combine this with patient stratification and adaptive licencing (topics to be explored at a later time) to enable earlier access to new therapeutics, and what we get is a dynamic health-care system, where each patient is optimally treated in their own mini clinical trial. And, in my opinion, that is a celestial goal worth reaching for.

In last week’s Right Turn, we talked about how stem cells are responsible for the colours and patterns of bird feathers—and birds, as the graphic on the right demonstrates, are basically just tiny dinosaurs. Given that there is much promise in stem cell research (and also a great deal of hype), it makes one wonder: What, if anything, can stem cells do for the big reptilian dinosaurs that lived tens of millions of years ago?

The April 2013 issue of National Geographic’s cover story featured the headline, “Reviving extinct species,” and explored in detail the so-called de-extinction movement that’s becoming more and more realistic as research in stem cells and genetics moves forward. The article was followed up by a TEDx talk on de-extinction.

But unfortunately, this research might not be of much help to the forebears of today’s bird species; the idea of cloning dinosaurs (or any creature that went extinct significantly long ago) remains out of the realm of possibility due to the deterioration of any remaining DNA.

For more recently-extinct species, though—ones like the woolly mammoth, passenger pigeon, Tasmanian tiger and the dodo, to name a few—it might just be possible. Researchers, most notably Spanish biologists who’ve worked with the now-extinct Pyrenean ibex, have been trying to manipulate the preserved DNA of one species in order to splice it into the genome of a similar relative through somatic-cell nuclear transfer (SCNT). With the Pyrenean ibex, a regular goat was used as the surrogate, and although their attempts haven’t been entirely successful (of 57 implanted embryos, only one highly disfigured clone was born, and it died within minutes), the technique is still seen as one that should work. For the passenger pigeon, the common rock pigeon could be a surrogate; for a mammoth, it is possible the African elephant would be used.

As Dr. Hendrik Poinar of McMaster University told National Geographic, the technique is there and researchers have ample mammoth genetic material to work from, so “[i]t’s just a matter of finances now.”

Setting aside the fact that it’s theoretically possible, one more question remains to be asked—one that was quite prominent on the cover of the April issue of National Geographic: Should we? As is usually the case with such questions, there’s a diversity of opinions about that.

Thylacines (Tasmanian tiger) in Washington D.C., c. 1906 (Wikipedia)

On one hand, many of these animals are thought to have gone extinct due to anthropogenic causes, so some have argued that we have a moral obligation to restore these species if we can. That’s the argument put forward by Dr. Michael Archer of the University of New South Wales, who has been working for over a decade to bring the Tasmanian tiger back to life. Others simply want to test the boundaries of modern science to discern whether or not it’s possible, and what we can learn in the process.

On the other side, however, is a question of what end we seek by bringing back these species. Constraints will limit the populations, at least initially, so it will be generations before they can be re-introduced to the wild (if that is even possible). A point brought up by American author Jackson Landers in a recent panel discussion is whether or not these species will actually resemble their now-extinct forebears, or simply be simulations of them. Learned behaviours will certainly be lost on any cloned specimens.

More to the point, given the fact that habitat destruction and poaching are the biggest reasons species continue to be pushed to (or past) the brink of extinction, and they haven’t come close to being resolved, then it’s unclear where the de-extinction movement moves forward. As conservation paleoecologist Jacquelyn Gill said on the Scientific American blog, “[p]erhaps the best course of action is to first demonstrate that we can effectively manage living rhinos and elephants before resurrecting their woolly counterparts in a warming, fragmented, overpopulated world.” Given that Endangered Species Day is this Friday, it’s a good time to talk about what we might do for some of the world’s critically endangered animals right now.

Gill’s idea is in the works, though. And extinct animals aren’t the only ones benefiting from stem cell research, even if they are the most heavily covered thanks to the cachet of bringing them back from the dead. A research team from The Scripps Research Institute in California is working to generate iPSCs from highly endangered species (including the drill and the northern white rhino) to preserve genetic material. (The group also tried for crowdfund a Regenerative Zoo project, which would have generated iPSCs of the Javan Banteng, Somali Wild Ass and the Black-footed Cat.) Artificial insemination has already boosted captive breeding programs for some species, including the panda and the koala, and including iPSC techniques in the arsenal of conservationists may enable greater genetic diversity and simplify the process of retrieving reproductive material and developing embryos for implantation.

It remains to be seen whether or not the woolly mammoth will once again roam the planet, but stem cell research will surely play a role in the return of any now-extinct species. Either way, stem cells are already being used to help protect critically endangered species, so there’s another feather in the cap of the incredible stem cell.

Research cited:
Friedrich Ben-Nun I., Montague S.C., Houck M.L., Tran H.T., Garitaonandia I., Leonardo T.R., Wang Y.C., Charter S.J., Laurent L.C. & Ryder O.A. & (2011). Induced pluripotent stem cells from highly endangered species, Nature Methods, 8 (10) 829-831. DOI: 10.1038/nmeth.1706

Pea Hen Feather. Credit: Bill Gracey

The arrival of summer’s songbirds to much of Canada over the past month makes this a fitting time to talk about feathers. Coincidentally, a paper was released in Science in late April that revealed how stem cells function to create an incredible array of colours and patterns in bird feathers. While on the surface, this might appear to be curiosity-driven exercise, Chuong Cheng-Ming, who led the study, says there are far greater implications for regenerative medicine in learning how the stem cell environment produces organized tissues:

“…there is much to learn about the principles that can guide stem cells to form specific tissues and organs required for medical treatment. Our approach is to ask Nature how she does it – using the feather as a Rosetta stone to decipher these principles…”

When you look closely at feathers, such as those included here, and consider that the colours differ based on age and gender of the bird, and that each of these feathers is replaced at least once per year during moult, you begin to appreciate what a well-orchestrated micro-environment this must be.

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.

Reference: Lin S.J., Foley J., Jiang T.X., Yeh C.Y., Wu P., Foley A., Yen C.M., Huang Y.C., Cheng H.C., Chen C.F. & Chuong C.M. Topology of Feather Melanocyte Progenitor Niche Allows Complex Pigment Patterns to Emerge, Science, DOI: 10.1126/science.1230374

Please click here to watch the 50-minute press conference about the surgery, which took place on April 9, 2013. You will hear from Hannah’s doctors and Hannah’s parents. A question and answer period begins at 30 minutes.

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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.

The work by Joe Landolina and Suneris Inc., highlighted by Stacey Johnson in her recent post, helps bring to the forefront the industry’s motivation to utilize “smart biomaterials”.

Smart biomaterials refers to biomaterials that have the ability to morph or communicate, which scientifically means to change their physical or chemical properties when an external physical or chemical stimulus is applied. There are a variety of stimuli that can be employed. For example, in my post on “the tooth tattoo”, the external stimulus was a pathogenic bacteria that got the electrons flowing in the material and sent an electrical signal to a nearby receiver. For Landolina’s VetiGel, the stimulus is the blood.

VetiGel demonstrates how biomaterials can have every day applications – in this case, wound healing.

Other biomaterial work, which I think pushes boundaries, is the research being conducted by the Armed Forces Institute of Regenerative Medicine (AFIRM). Believe it or not, AFIRM has successfully performed face and hand transplants and is in the process of recruiting for multiple clinical trials. Our biomaterial team at CCRM had the privilege of meeting the director of AFIRM, Dr. Joachim Kohn, and seeing a presentation on their latest work.

AFIRM receives most of its funding from the United States Armed Forces. The research focuses on four distinct areas of repair and regeneration: limbs, nerves, face and skin (burns and scars). Their work is aimed at helping wounded soldiers who get injured through combat in the field. I see the wound-healing device VetiGel as a good fit with this new era of biomaterials for dynamic real-time wound repair and that is, no doubt, why the U.S. military is in discussions with Suneris for the technology. Soldiers in the field do not have time to go to a hospital, so a product like VetiGel, which is easy to apply and works instantly upon contact, is an ideal solution.

There is one more note-worthy technology I would like to mention here and it falls under the category of 4D printing. We’ve all heard about 3D printing, but are you aware of 4D printing? Just as the name implies, this concept introduces a fourth dimension: time. As depicted in this CNN video, with the passage of time and extended exposure to an environmental cue such as water, the linear material contracts and changes its shape to form the letters MIT. This is unique because it’s not the normal swelling that you witness from materials exposed to water. I interpret this to mean that stimuli responsive biomaterials, or smart biomaterials, work in the fourth dimension too because, over time, the material’s architecture and physical traits change.

Since my introductory post on the evolution of biomaterials, and my meeting with Dr. Kohn, I realize that another evolution may be just around the corner. A big push appears to be coming from the defense community for targeted innovation of new smart biomaterials for real-time dynamic application. Actually, looking at current research and the tremendous progress made thus far, it appears this wave of biomaterial evolution in the fourth dimension is already here.

In most adult stem cell populations (e.g. blood, skin, etc), the goal is to balance these types of divisions, keeping a sufficient stem cell reserve while also producing differentiated daughter cells to supply the system each day. On an individual cell basis, the easiest way to maintain this balance is to have stem cells divide asymmetrically. But how does a cell mechanically arrange itself to distribute different components to one daughter compared to the other?  Earlier this month I attended a special Royal Society meeting in London focused on cellular polarity where leading scientists came together to discuss how cells arrange themselves. This free meeting was an excellent mix of new technological advances and lessons from developmental biology that stem cell biologists should be aware of when thinking about asymmetric division.

The conference emphasized the importance of actin and myosin in the control of establishing polarity in cells with presentations from multiple different tissues and model organisms. The discussions ranged from the modeling of chemical movements through membranes to the decoupling of the machinery used for yeast bud site selection from that involved in bud formation.

The most exciting presentation in my opinion was given by Orion Weiner of UCSF, who used optogenetics to study membrane tension in blood cells. In essence, he showed the ability to pull selected proteins to the membrane by turning a light on and off. He showed that pulling actin toward the plasma membrane increases the membrane tension and alters the behaviour of molecules located long distances from the membrane. Most importantly, future experiments that can specifically control the location, timing and amount of particular proteins on one side of a cell will allow biologists to study the impact of proteins on the asymmetric partitioning of molecules in a cell.

From a stem cell biologist’s point of view, this is exactly the kind of tool that we could use to understand the role of various proteins in the asymmetric partitioning of stem cell determinants and it will be exciting to see how this technology is applied in the future.

Additional information and the proof of principle experiments can be found in the original Nature paper and lead authour Anselm Levskaya has set up a neat website with videos for how this light controlled protein modulation works.

However, it seems that when it comes to tail regrowth in some lizards, the cells take a short cut and do not regenerate all the original tissues. Cartilage tubes replace the original vertebrae, and long muscle tissue replaces shorter muscle fibres. Since the dropped tail is a defence mechanism for the animal, perhaps it’s a matter of the speed of replacement rather than functionality — I have no doubt this is a topic of current research. In the meantime, here’s a video produced by Slate that provides a (somewhat cheesy) look at the process.

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.

The afternoon session on Day 2 at the Understanding Stem Cell Controversies workshop began picking apart the complex relationship between research and the public, specifically where they intersect in clinical trials and experimental therapies.

Two case studies illustrate the gap in expectations vs. reality that exist in this context.

First, Dr. Harry Atkins spoke about his ongoing trial at the Ottawa Hospital Research Institute, in which MS patients are being treated with transplants of their own harvested blood-forming stem cells. This is transplant can have considerable side effects and some risk of death for the patient. A recent publication on the trial spurred a flurry of media attention in Canada, after which, understandably, Dr. Atkins received a number of emails from patients and patient caregivers seeking to get involved in the trial.

Looking broadly at these requests, as well as comments emerging from the media coverage, Dr. Atkins identified the following challenges and perceptions that require thought and an approach from the scientific and medical community:

• The medical message has not been transmitted or received – there is a lack of understanding on method, biology, medicine
• Patient decisions (on wanting to take part in a trial, for example) are often made based on sound bytes and there is a lack of desire to learn more about the risks and benefits of participation
• There are misperceptions on the part of patients about the severity of their health issues
• A sense of desperation on the part of patiets – they will go to all lengths even if there is no visible impact of disease. This is coupled with a feeling there is a need to do something at all costs – it’s never too late for a “hail mary”
• There is anger on behalf of patients/public at the regulatory environment for holding things back
• Conflicts of interest are not understood or are twisted for self-interest (i.e. conspiracy theories to explain barriers to treatment)

Of course, the gulf of understanding is not generated by the public alone. Researchers and medical professionals bring their own perceptions and biases to the table and these were highlighted by Judy Illes of the University of British Columbia. Using the Geron trial and spinal cord injury as a case study, Illes identified the position of the scientific field:

• There is a focus on cause, methodology, statistics and data, adverse effects
• Lack of emotion; delivery of the information is dispassionate
• Decisions are often made without input from patients – in the spinal cord example, there was a significant mismatch between when a patient was informed and willing to engage in risk (~18 months post-injury) vs. the timeline of therapy identified by researchers (7-14 days post injury). See more on this here.

One of the key points to be made about the two examples, MS and spinal cord injury, is the nature of the illness itself. On one hand, there is an injury that is has an immediate impact on a patient (spinal cord injury), from which a patient has a reasonable expectation of possible improvement or, at the very least, no significant further deterioration post injury. On the other hand, MS patients may begin with very minimal impact to quality of life, but the disease progressively gets worse. These two realities greatly shape the decisions and perceptions of patients and should therefore shape the method of communication from the research community.

This topic continued in this morning’s sessions. Debra Matthews from the Johns Hopkins Berman Institute of Bioethics discussed the influence of public opinion on policy. She emphasized the importance of science “being informed by public opinion.” She used the example of embryo donation for research. She cited surveys showing that individual who have completed infertility treatment have a deep sense of responsibility for remaining embryos. The survey results indicate that research donation is viewed as a responsible choice for a majority of those surveyed. These results are consistent with the views of individuals in California (CIRM wrote about that here).

Dr. Matthews contrasted the stem cell experience with a recent experience in Texas where 5 million blood samples from a newborn screening program had to be destroyed (more about that here).

The blood samples were to be used for responsible research, but the problem in Texas was that people were not asked for their permissions for such use. Matthews pointed out that the vast majority of families are supportive of responsible research but want to be asked before their materials are used.

The Texas example underscores the importance of providing comprehensive informed consent for research donation. CIRM, SCN and our collaborators have placed emphasis on obtaining consent for research; a case of science being informed by public opinion.