One of the most memorable images I can recall on the effect of catalytic dynamics for me during these years of scientific curiosity was the explosive result of sperm enzyme successfully impacting a human egg - almost Big Bang like in all its microscopic potential.
One can now extend that impact phenomena analogy to the very pertinent research and translational effect Induced Pluripotent Stem Cell (iPSC) technology has had on the field of molecular biology and regenerative medicine.
As a community body the International Society for Stem Cell Research provides leadership and guidance on all matters related to the research and development of safe and effective stem cell science. It's mandate speaks to not only supporting discovery but also to the sound translation of ethical research into potential treatments for those in need. The draft on new guidelines was presented last June and has since received comments and has been edited into a final format which was recently published.
I recently chatted on this topic with Dr. Ross Macdonald CEO of a seemingly under the radar Australian iPSC therapeutics company called Cynata, an early mover in the evolving induced pluripotent space. Ross was kind enough to walk me through the history and plans the company has on developing and launching next generation mesenchymal stem cells (MSC) products.
Pluripotent stem cells have been an invaluable tool to progress fundamental basic research. There isolation and maintenance in animal and human cell lines have furthered the study of cell systems and their function, fueling the rapid rise of scientific discovery and translational application.
Recent news points to a significant addition to the pluripotent landscape. Scientists at the Hebrew University of Jerusalem, Columbia University Medical Center (CUMC) and the New York Stem Cell Foundation Research Institute (NYSCF) have presented a novel method to add to the existing pluripotent toolkit by creating a new form of human embryonic stem cell with the capacity to develop all three germ layers in-vitro and in-vivo. The teams’ findings were reported in the journal Nature¹.
Designing an adaptable system without the known variables is often an exercise in caution, unless of course you have been down a similar road before and can rely on established templates for creating repurposed guidelines. In some cases however old parameters simply don't fit any longer and the opportunity to engage in the development of more flexible rules with the benefit of hindsight becomes a net positive in the never ending cycle of innovation driven progress.
A series of high profile developments along this path have taken place of late on the topic of genetics and the advent of gene editing technologies that have the potential to alter the fate of human disease and the burden it represents to society. These policy reviews and the resulting position statements have been brought on by concerns that human gene editing presents a challenge to the perceived boundaries by which scientific discovery and possible therapeutic interventions are applied.
Strategy, survival, direction, competition and growth opportunities are but a few fundamental elements in the maze of everyday life all professionals must navigate - no more so than those on the leading edge of managing scientific innovation.
Being at the forefront of change often elicits backdraft currents and polarization of entrenched positions. This is natural and can be seen as a positive reinforcement of the high threshold one must strive to in order to achieve acceptance. A sort of quality assay if you will - one which is analogous to peer review in a business setting.
24 hours after the news of the Ocata/Astellas deal a lot has been written on the value front and little on the actual merits of Validation for Ocata’s science, the step forward in its development plan and the broader implications for the stem cell sector.
Move over X-ray crystallography. Cryo-electron microscopy is kicking up a storm by revealing the hidden machinery of the cell.
Imagery has long been used as a map by which we seek direction and understanding. The visual construct of the world we inhabit is often taken for granted, yet the loss of visual sensory function profoundly impacts everything we do. It is the one sense we would opt to keep, by a large majority1, if we had to make that tough decision.
The blurry eyes of scientists often reveal an essential aspect of their day to day - experimental lab studies using visual tools. This dependence on imagery cannot be overstated as it is fundamental to the exploratory and discovery process. Anything that enhances that capability is a welcome addition to the arsenal of technical tools in their kit.
Enter the latest such step improvement which looks set to uncover yet another layer in the ever increasingly focused lens on the inner working of our molecular machinery.
By revealing in such precision the basic structural formation and interconnected aspects of the biology of our cells it is envisioned that the speed of understanding and subsequent application towards translational science will help propel the field forward.
"...the gates have opened" says Eva Nogales of the University of California, Berkeley. In this case not to Dante's Inferno but to a new era of discovery which heralds an awakening of the very essence our the living systems within.
Hi-res 3D visualization in biology will change the way we understand2 biology opens up a new methodology to view & create animated snap shots of what's going on and how the diverse constructs in living tissue interact. A frontier where no one has gone before.
The transitioning of the stem cell field from a unique lab based protocol system to establish proof of concept to a fully industrialized process that manufactures reliable and consistent batches in the volumes required is fast occurring.
The methodologies, micro-biology systems, optimization technologies, medias and mechanized operations et al are now being developed.
This evolutionary step is perhaps the tell-tale sign that the cell therapy industry is maturing towards commercialization. Another would be consolidation within the sector.
The University of Nottingham is an international leader in the field and is amongst an increasingly important and growing group of pioneers spearheading the complex effort to bring next generation cell therapies to market.
Major step for implantable drug-delivery device. MIT spinout signs deal to commercialize microchips that release therapeutics inside the body.
An implantable, microchip-based device may soon replace the injections and pills now needed to treat chronic diseases: Earlier this month, MIT spinout Microchips Biotech partnered with a pharmaceutical giant to commercialize its wirelessly controlled, implantable, microchip-based devices that store and release drugs inside the body over many years.
The Koch Institute at MIT is a hotbed of activity these days. One of the more recent spin-outs from this diverse innovative brain trust is work by Robert Langer and Michael Cima labs to productize a novel drug delivery technology that can be administered as a platform for long term patient medication.
Teva Pharma paid $35 million upfront plus milestones to collaborate on developing the technology. A significant validation which points to a future patient centric solution for easily controllable - wireless! - self contained treatments of up to 16 years.
An in-development birth control chip is being worked on with support from the Bill & Melinda Gates Foundation.
Intercellular communication has been a keen focus of researchers for some time now. How the cells of our body manage the myriad of complex system actions and reactions is still largely being discovered. The world within I would imaging is somewhat akin to a person walking through a busy city during rush hour while being cerebrally wired head to toe with bidirectional sense nodes, carrying a backpack full of a variety of biological iCookies and a mission impossible travel kit.
The latest snapshot of this scifi world comes courtesy of advanced photo imagery of our citizen's dramatic finale. Here the sequence shows a white blood cell going through a transformation and cell signaling metamorphosis before dying. John Carpenter would be proud - the real Thing!
The hypothesis here is that cell death isn't entirely random but in certain cases it is a communication event. Nature's self defense system is impressive and highly developed, on all levels great and small.
If a stem cell derivative can be injected systemically and have a distal effect on disease without cell migration then that is powerful - especially if it can be isolated and a biologic made.
"What if you could 3D print a brain or a working neurosystem? It's not outside the realm of the possible - at least in a structural sense - as a new graphene-nanoflake ink has just been used to print strong 3D structures which resemble neurons in shape and electrical conductivity..."
Interesting work in nano bioengineering which is a hot new area of science. The interdisciplinary focus of the applications using nano material is far reaching and one which has captured the attention of many in the next gen medical field.
Graphene in itself is considered so versatile that it's uses could be pervasive once product specific manufacturing issues are solved. Light, strong and conductive are but a few of it's features.
Use in biomaterial is an intriguing research area, especially when combined with cell science. Substrates and matrix formulations are diverse nowadays but with the advent of 3D bioprinting the adaption of technologies will be paramount in it's scope and usefulness.
There's still a very long way to go for this synthetic biotech but it may very well be the real deal when it comes to truly integrated human bionics.
As significant as the potential of gene editing is to the future of medicine, the practical advancements of the field to make the technology applicable and safe is what will drive clinical adoption.
Ease of use, utility and precision are the hallmarks of next generation gene editing and even more so with the advent of innovative solutions to deliver the worker payloads into the cellular system. Research & discovery will pave the way to understanding the mechanistic pathways of disease for which treatments are needed.
Add clinical effectiveness, personalized treatments, integrated solutions, scale-up, off-the-shelf to the vocabulary and the technology impact factor exponentially amplifies...
Leading the charge forward are an expanding list of international academic institutions and industry players that are fast applying cutting edge discoveries into working models and pre-clinical studies. The field is Hot for a reason and the coming combination of the gene and cellular fields with bioengineering to apply towards personalized diagnostics is Molten!
No more so that in Boston at the Broad Institute, MIT and Harvard where the latest discovery was made, in collaboration with the NIH, of a smaller Cas9 enzyme that is as efficient as the current larger version but now can be packaged into the cargo hold of the preferred current delivery vehicle - the Adeno-associated virus (AAV) vector.
The progress is fast a furious and the future is now.
While controversial to some the use of Eggs to research and develop cellular solutions is necessary as a player in the age old two step union and potentially as an invaluable starting source for embryonic cells via a non-fertilization development pathway. This process is called Parthenogenesis and is the unique domain of International Stem Cell Corporation ("ISCO").
ISCO was formed as a continuation of scientific endeavors establishing primary cell technology and regenerative therapies for the skincare market. As early leaders in the research business they established the foundation and management reached out to pioneering Russian scientists to employ proprietary techniques in the use of Eggs for parthenogenetically derived pluripotent stem cell lines for therapeutics. The company's focus on chemically activating Eggs to stimulate cell division without fertilizing side-stepped the then burning issue of the use of embryos in science. Independence and solid support from the scientific management team has brought the technology front and center with the start of the first parthenogenetic derived stem cell trial for Parkinson's disease.
Having followed ISCO for some time I reached out the Dr. Russell Kern, ISCO's CSO, for a Q&A on their technology, the data and progress the company has made getting it's lead program into the clinic and to review where things stand overall as they move ahead with proof of concept.
Mesenchymal Stromal Cells (MSCs) - Safe and Effective?
The prospect of MSC utility for therapeutics has been due in large part to the evident immunological privileged nature of MSCs and their potential for universal application without immunosuppressive drugs – unlike HSCs themselves. Although MSCs have an antigen profile they lack major class antigens which makes them relatively immune-privileged to the host system thereby allowing for donor derived cell treatments without treatment rejection in low dose regimes.
Two related science developments last month illustrate the expanding potential of cellular biology to offer possible solutions for tissue regeneration. Both investigative teams published their work in Nature and they represent bookends in the field of potential treatments for sight preservation and restoration, a leading edge segment of the emerging regenerative medicine sector.
General interest in exosomes is now growing for many reasons. One is because of the observation of their natural activity with antigen-presenting cells and in immune responses in the body. Their potential as very powerful biomedical tools of both diagnostic and therapeutic value is now being more widely reported. Applications described include using them as immunotherapeutic reagents, vectors of engineered genetic constructs, and vaccine particles. They’ve also been described as tools in the diagnosis or prognosis of a wide variety of disorders, such as cancer and neurodegenerative diseases. Also, their potential in tissue-level microcommunication is driving interest in such therapeutic activities as cardiac repair following heart attacks. Their potential as biomarkers is being explored because their content has been described as a “fingerprint” of differentiation or signaling or regulation status of the cell generating them. For example, by monitoring the exosomes secreted by transplanted cells, one may be able to predict the status or potentially even the outcome of cell therapy procedures. Clinical trials are in progress for exosomes in many therapeutic functions, for many indications. One example is using dendritic cell-derived exosomes to initiate immune response to cancers.
Coming up with a way to sustain science innovation in an ever increasingly competitive funding environment is one of the keys to unlocking the potential for next generation treatments and increasing the number of active research projects in-play.
One such method is crowdfunding science projects. A topic that has been in the news on and off for a couple of years but which is now gaining deserved traction.
To illustrate, Experiment.com ran a successful fund raising campaign recently for Batten Disease and more than doubled the target sum of $1m with donations of $2.6m. These types of sums, if indicative of the trend moving forward, bodes well for participatory science and can have a meaningful impact on progress in the field.
Some new entries have appeared in the space lately which are geared mostly to smaller scale investigative projects which often go unfunded but which nonetheless have merit and may further the knowledge pool or even bring new treatments that much closer to patients in need.
One stat which was associated with a recent crowd funding start-up from Australia called Researchable noted that 86% of all government applications for funding in Australia are left without resources to proceed. This sounds similar to other stats I've seen elsewhere with regard to funding ratios.
To be able to tap the public directly for specific projects that interest them is a novel and socially dynamic method of outreach and engagement at the most fundamental level. Tying in a support network of individuals can propel science forward in breath and scope.
Crowdfunding generally reflects on the successful and privileged world of "angel investing," which looks to individual investors for capital in entry level rounds for new companies. However, in contrast to the selective world of angel investing the advent of online media platforms, with reach to the general public, leverages an ever increasing stream of interest in scientific engagement and furthers the development of potentially impactful progress for the benefit of all.
This development can work in a non-profit or for-profit manner and therefore can be geared towards the entire spectrum of independent, institutional and commercial projects, while the data generated can serve as a model for open access feedback.
Scientists that have been unable to fund promising lines of investigation can now look to a new window of opportunity with a view to driving outreach and public benefit eduation.
This shift is being supported by new laws that allow for more individual participation in the support/investment arena and as a result the potential for successful direct marketing of project funding through the internet is becoming real, albeit on a relatively modest yet growing scale.
Some of the other names in the crowd funding biotech scene are:
Gene-editing study reveals pathway that could help short circuit sickle cell disease.
As the methodologies of disease states become known and the mechanisms of their genetic regulation & interactions within their biological micro-environments are studied inventive solutions that present a working treatment to diseases are becoming possible.
One such discovery, presented here, is from Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. By cutting out pieces of DNA in blood stem cells the team were able to show that they could effectively resync the resulting cell population to produce more beneficial hemoglobin without altering the properties of other important cell types. The result being a potential pathway to a therapeutic treatment for severe sickle cell patients.
In addition to the above featured research, there are a number of other promising next generation gene based technologies to potentially treat hemoglobin conditions, including sickle cell disease.
One program has entered the clinic in a Phase 1 trial and is backed by CIRM out of UCLA, with the collaboration of USC. It's focus is on using the patient's own blood stem cells and modifying them via a viral vector to create a therapeutic treatment of functioning cells. (see Dr. Donald Kohn's video presentation and the clinicaltrials.gov doc https://www.youtube.com/watch?v=L6o0rVmaICM&feature=youtu.be
As a result of the fast pace of development in the cancer space for blood based cell therapies the opportunities to tackle next generation patient centric solutions using hematopoietic stem cells is v.real and within reach.
A new goggle technology will allow surgeons to distinguish between cancerous and healthy tissue during operations.
Identifying cancer cells during surgery is a difficult task and one which surgeons have struggled with, often having to operate on the same patient more than once to remove additional tissue. Also, in certain circumstances excess tissue is removed which could remain if the surgeons were able to better distinguish diseased tissue from non-diseased.
Enter a novel and important tool for the O.R. - a dye/device combo for illuminating cells that are cancerous. Sci-Fiction it is not and it's a welcome advance to advancing the efficiency of required surgeries.
Of course in the longer term the hope is we'll reduce the number of operations with alternative non-invasive procedures using next generation treatments that are in development - including the promising field on immunotherapy.
An international team of researchers has developed a method of fabricating nanoscale electronic scaffolds that can be injected via syringe. The scaffolds can then be connected to devices and used to monitor neural activity, stimulate tissues, or even promote regeneration of neurons.
Further on the theme previously reported in my last Scoop.it on the research being done for 3D printed graphene ink in synthetic biology substrates (http://sco.lt/8DLE5h) - this Harvard example of a practical application for a cellular substrate using bio friendly electrically conductive mesh is exciting.
The mere fact that the substrate can be injected makes it that much more interesting. Not sure if the graphene matrix is that flexible to be injectable or as biocompatible in situ.
Perhaps there is some synergy between the 3D graphene ink and a this state-of-the-art neuro flex technology...
Either way the field is moving quickly and bioengineering is as it's core.
The recent reiteration by the Director of the NIH, Dr. Francis Collins, that the long held legal position of the US Federal Government is to not fund destructive embryo research, brings the US debate on germ line editing front & center in practical terms.
"Use" of human embryos, for their own benefit, is written into the established Directive 98/44/EC of the European Parliament and of the Council of 6 July 1998 Recital(42) on the legal protection of biotechnological inventions in European states et al and is a foundational document addressing this area. The interpretation of this document has led to the European Patent Office guidelines and appeal rulings.
Researchers at the Moscow Institute of Physics and Technology (MIPT) report that genetically engineered fibers of the protein spidroin has proven to be a perfect substrate for cultivating heart tissue cells.
As this article & paper outline, one of the challenges facing regenerative cell based treatments is the development of appropriate support niches to mimic optimal natural environments for the survival and proliferation of cell populations - either cultured ex-vivo then placed in-vivo or placed in-vivo directly, as a injectable or otherwise. Either way the assistance of biomaterials engineered for the purpose and optimized for the cell type(s) is fast becomes a critical component of the development landscape.
In certain cases free floating cell suspension products administered to the site of injury, or systemically for distal effect, is perhaps sufficient and preferred. However, there are many instances where a more robust and structural fabric or support is required which necessitate bio-material integration.
A novel approach to this topic is outlined in this Russian study where a synthetic protein was spun into a cell supportive fabric. The versatile and stronger than steel biomatrix was conceived from studying the structural nature of spider's web. The result being a home where heart cells thrive...
Application specific uses of bio-fabricated methods to support cells are becoming numerous and inventive - so much so that this support structure in itself is proving to be a mini-industrial sector within the space.
When you combine the unique properties of bio-engineered structures, proprietary potent cell derivatives, genetics and supportive biologic products you have the makings of a deep tool-kit capable of delivering numerous bespoke iterations for superior clinical translation.
The companies and partnerships groups that are structured to realize this will have a distinct competitive advantage to interlock unique product attributes and lead.
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