Applying Induced Pluripotent Stem Cells in Treating Brain Diseases

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The work conducted by the Yamanaka lab led to the discovery that somatic cells can be reprogrammed into pluripotent cells (hiPSCs’s) by introducing four transcription factors (TFs): Oct4, Sox2, Klf4 and c-Myc—the infamous gene believed to be linked to cancer. Given the highly controversial role of c-Myc, additional studies were conducted to see if those factors could be replaced. It was found that only Oct4 and Sox2 are crucial to induce pluripotency, however, the efficiency suffered significantly. The exact mechanism by which this induction happens is still poorly understood today. It is believed that the expression of the two transcriptions factors among others—that are still being tested—leads to epigenetic modifications in the cell, from which little is known, resulting in inducing a pluripotent state within said cells. This process takes several weeks before yielding a very small percentage of pluripotent cells. This poses a serious problem, which needs to be resolved before using hiPSC’s in therapeutic applications.

Another difficulty, which will also have to be addressed, is the reprogramming technique itself.  Indeed, the three most used reprogramming methods all have flaws that forbid them from being used in therapy.

The initial techniques used were done with lentiviral or retroviral transduction. They were and still are very efficient methods of inducing pluripotency, however, both vectors were found to integrate into the genome. This has for consequence to disrupt the gene at site of entry often leading to tumourigenesis. Furthermore, the expression of the TFs themselves must be regulated, as they are only needed for a set period of time, this leads to problems with differentiation. In order to respond to the difficulties engendered by this method, adenoviral vectors have been developed that do not integrate into the genome. However, the efficiency suffers and prolonged expression of the TFs remains a problem.

Given the difficulties encountered when using viral methods, non-viral methods were developed. Plasmid vectors containing the TFs’ complementary DNA’s were transfected into the cells and resulted for the most part with non-genomic integration. Because of contradictory results, another method was used: fusion of the TFs proteins to a membrane permeable peptide (constructs recombinant cell-penetrating reprogramming proteins). These peptides are broken down by the cell itself and nothing of the constructs remain inside the cells. It is labor intensive however as it requires multiple rounds of addition of recombinant proteins to ensure sufficient presence of the TFs proteins for long enough.  A new method is showing great promises with microRNAs (miRNAs), the regulatory RNAs that repress the expression of a large set of target genes post transcriptionally. It was shown that reprogramming with miRNAs was faster and approximately 100-fold more efficient than with standard viral vectors. However, viral vectors are still used to deliver the miRNAs to the cell. There are ongoing works to overcome this problem with very promising results.

Once the reprogramming techniques perfected, methods to accurately measuring pluripotency must be in place in order to determine if the end product is achieved or not after reprogramming. This in itself is a difficulty as stemness must be clearly defined before being able to qualify an iPSC as having achieved an embryonic stem cell (ESC) like state: stemness is still ill understood and poorly quantified. For those reasons, molecular assays have been created to identify ESC-like condition as well as the epigenetic status of the hiPSCs based on the detection of mRNA associated with pluripotency and promoter activity. However, even after extensive testing it is still difficult to draw conclusive results about the success of the reprogramming technique as even if resemblance to ESCs is attained it might just be that in end, resemblance. Additionally, the efficiency of the reprogramming technique, percentage of viable hiPSC colony forming cells, is usually very low and is dependent on a combination of cell state and reprogramming strategy making the entire process that much more complicated.

Nonetheless, the application of hiPSCs in cell replacement therapy for neurodegenerative diseases including PD, Alzheimer’s Disease and ALS has been the subject of great interest given its potential to repair the damaged brain. And more importantly they can be obtained from the patient own somatic cells and thus bypass immune rejection issues, the ethical issues surrounding ESCs and the very invasive protocols to obtaining neural stem cells.

In the case of PD there were very positive outcome of several studies for developing cell therapies and therefore the use of hiPSCs is being explored extensively. Different labs are trying to optimize in vitro protocols to produce large amounts of functional dopaminergic cells. There are no clinical trials for PD as of yet, but animal studies have shown promising results. Indeed, transplantation performed with iPSC-derived dopaminergic neurons improved motor function in a rat model of PD, and even resulted in an improvement of PD signs, both functionally and behaviorally. There is one major issue however the survival rate of transplanted cells is often low.  Another disease where the use of hiPSCs might be very useful is in vanishing white matter disorder (VWM), a progressive disease in which the white matter of the brain becomes increasingly abnormal and eventually virtually disappears. Indeed, the disease-causing mutations are known and, thus, genetic modification is possible using hiPSCs expanded in sufficient numbers in-vitro before transplantation. Of course the procedure still lacks safety and efficiency and no clinical trials or animal testing is underway as of today since there are no confirmed animal model of the disease yet.

In conclusion, even though hiPSCs show great promises in treating neurodegenerative diseases while avoiding the ethical concerns of ESCs and the problematic immune rejections, there are still many limitations preventing using hiPSCs in clinical settings. Furthermore, even if we overcome the known limitations, we must be aware of potential novel issues arising from using hiPSCs. Indeed, new ethical issues would have to be addressed, such as using patient-specific iPSCs derived cells without the consent of the donor, especially in the production of gametes for reproductive purposes, and, also, we would still need to confirm that differentiated hiPSCs would not trigger an immune response in the patient as well.

Y.S.H.

Regulatory Strategy in Biopharmaceuticals: Centerpiece of Corporate Planning

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As you all know, the costs associated with the development of a new drug have been and still are extremely high. Furthermore, the process itself is very risky, very lengthy and highly regulated. Nonetheless, it is still an endeavor all the big biopharmaceutical companies undertake regularly and start-ups are created everyday with similar objectives. Just to give you rough numbers, in 2009, the total dollar amount spent on research and development of new medicines by pharmaceutical companies was of approximately $65 billion ($65,300,000,000)! The average cost to develop one drug was estimated to be of about $1.3 billion in 2005 and the time required to make said medicine was, and still is, of about 10-15 years.  Additionally the number of new medicines that reaches the break-even point or makes a profit is in the number of 2 out of the 10 that actually made it through. And each drug results from the screening of about 5,000-10,000 compounds and has no more than 12 years of effective patent life… and there is always the risk of a similar product hitting the shelves at the same time or few years later or even worse, few years earlier!

So why do biopharmaceuticals invest so much in drug development and why so many start-ups are being created? Well, the returns on the 1 drug that succeeds are huge and keep on increasing.  For example, Humira, the anti-TNF inhibitor from Abbott, had annual sales amounting to $9.3 billion for the year 2012, more than 7 times the cost of developing it in just one year!

Given these huge investments and potential returns, you can imagine that the critical factors for those kinds of endeavors are to get to the market quickly, ahead of competition and in the safest and most effective way possible: welcome to the science of regulatory intelligence and strategies.

Contrary to common beliefs, regulatory affairs is not just about preparing, submitting, and maintaining an investigational new drug application, and then submitting adverse event reports if needed and then just coordinating other routine communications with the FDA. It is not just about ensuring compliance… it is much more than that. Regulatory affairs is intertwined with every department in the company, and proper cooperation and coordination is of essence to insure corporate success. Indeed, regulatory affairs guides the direction of various corporate activities from a regulatory point of view with serious implications on the management and growth of the entire company or department. It is of the upmost necessity for corporate management to include regulatory thinking and planning in day-to-day decisions, as they not only affect drug development plans but also market determination, marketing, business development, finance, human resource, technology, manufacturing, risk management, insurance policies, etc.

Regulatory strategy is based on those exchanges with different internal, external and regulatory influences and is an ever changing, highly dynamic and determining science for any biopharmaceutical company, no matter its size. Indeed, it is the regulatory strategy that determines the plan for developing the drug with the objective of obtaining the right regulatory approval in the target market faster, safer and in a more cost effective manner than anyone else while properly managing and maintaining the life cycle of the drug after the approval was obtained.

The regulatory group must be aware of the very frequent changes in regulations and must be able to comply with or make use of them in the case they encompass the drug their company is developing—in consequence guiding the corporate management to take the appropriate measures to show that the drug does indeed meet expectations of the newly adopted regulations. The regulatory group must do so in record times while maintaining cost efficiency and safeguarding the competitiveness of their product compared to the competitors. A very good example of a regulatory influence that drastically changed drug development to treat serious diseases and fill an unmet medical need is the FDA Fast Track Development Program.

The reason behind why the FDA introduced that program was to get important new drugs on the market faster to patients suffering from a serious disease. The FDA considers a disorder serious on a case per case basis. However, it is generally centered on the impact the drug will have on clear factors such as survival, day-to-day functioning, or on the probability that the disease might progress from a less severe condition to a more severe one if left untreated. Examples of disorders considered serious are AIDS, Alzheimer’s, heart failure and cancer. Though, epilepsy, depression and diabetes are considered serious disorders as well. Unmet medical need on the other hand is defined as introducing a therapy, which was nonexistent or is potentially superior to the existing one(s), i.e. any drug to treat or prevent a disease which has no treatment available would qualify. Furthermore, even if there are existing therapies, the drug would still qualify for the Fast Track designation if it showed superior effectiveness, avoided grave side effects of the existing therapies, improved the diagnosis of a serious disease resulting in an enhanced outcome, or decreased accepted significant toxicity of available treatments.

That designation is quite useful and very sought-after by pharmaceutical companies since, if the drug qualifies for it, it becomes eligible for early and more frequent meetings with the FDA in order to ensure the drug’s development plan and collection of the needed data in order to support drug approval. But there is much more! The drug becomes entitled to more frequent written correspondence from the FDA about matters like the design of the proposed clinical trials. The drug can also become eligible for the Accelerated Approval regulation where surrogate endpoint—an indirect laboratory measurement that is used in clinical trials to represent a clinically meaningful outcome, such as survival, without however being itself a direct measure of it—becomes sufficient to likely predict clinical benefits of the drug, i.e. it shortens considerably the time required prior to receiving FDA approval… we are talking years shorter! Additionally, the drug becomes also eligible for Rolling Review where the biopharmaceutical company can submit completed sections of its New Drug Application for review by the FDA without having to wait until every section of the application is completed before the entire application can be reviewed—The New Drug Application does not usually starts before the company has submitted the entire application to the FDA! And of course, any drug in the Fast Track Program receives a Priority Review, and we all know how important that is when it comes to the FDA.

The pharmaceutical company can request the Fast Track designation at any time during drug development and, usually, the FDA will make its decision available within 60 days! It is important to note however, that the FDA requires the biopharmaceutical company to conduct additional clinical trials after it receives approval under the accelerated approval program, and while its drug is on the market, to confirm the drug’s direct benefits and validity.The regulatory affairs group cannot elaborate a strategy the same way when aiming for Fast Track designation as it would for the normal track. The average time saved using the Fast Track is between 3 and 6 years compared to the normal track—and sometimes half the time of the normal track is sufficient to have the new drug on the shelves with the associated cost savings and that much longer effective patent life! In fact, the strategy elaborated by the regulatory affairs group will determine how corporate management will handle company growth, day-to-day decisions, finance, human resource, technology, research and development, marketing, etc. In truth, the regulatory affairs group is in the “hot seat” in the drug development process.

Y.S.H.

Social Entrepreneurship in Biotechnology

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We all know the biotech start-up life cycle and how it is valued. It all starts when the founders meet with the seed investors. The founders are usually people with technical expertise from academic institutions or even large biopharma companies who possess the intellectual property of a new technology, discovery or even simply to an innovative idea that is generally valued at an average of $1M. The seed capital usually comes from the 3F—friends, family and fools—or from angel companies or even government grants. The usual amount needed is of $2M, which put the start-up company at a value of $3M; 33% shares for the founders and 67% for the seed investors. The company is then brought to maturity if all goes well by going through the infancy and adolescence stages—raising additional funds, advancing drug candidates, building a strong structure and management team till the company has led candidates in phase 2/3 trial and is robust. Usually, at the maturity stage, the company is valued at about $24M, with 62% of the shares for the venture investors, 25% for the seed investors and 13% for the founders. At this stage, the start-up is either acquired and assimilated by one of the large biopharma companies for 150% of its market value, or it becomes an independent public biotech company in hope of conquering the market for the duration of its patent(s)—in order for the investors to make their money back, usually they sell their shares during the IPO for 4-6 times its market value. This is typically how a new biotech company functions…it is all about return on investment…you would be surprised at how many discoveries and new technologies go down the drain every year because investors can’t see the adequate return on investment on them. But what if there were a different way, a better way to create and value a new biotech company?

The recent years have seen a growing trend in the bioscience field, the partnership of the public and private sector in order to mobilize resources to be able to develop new technology based solutions to incur long and lasting positive social development and changes: Social Entrepreneurship. I know you probably think that it is just another social initiative created to generate some kind of awareness to raise funds, in other words, for most of you social entrepreneurship merely provides a different “social” setting in which to implement a new entrepreneurial project…and you might be right…might be. Social entrepreneurship is still in its infancy and is barely understood. Without any available real empirical knowledge to set it apart from anyone who claims to be bringing in social changes and still lacks a successful model even though there are plenty of successful social entrepreneurs today all around the world. Those people have not only impacted positively on their communities, their cities, but also on their countries and even on the world. But before we tackle social entrepreneurs who should be taken as an example, let me first try to better define social entrepreneurship, or at least try to!

First, it is good to remember that starting a business, according to economists Say and Schumpeter, is not the main goal of entrepreneurship. Stimulation of economic progress through innovation and action is actually the main objective of entrepreneurship. Social entrepreneurship on the other hand is about compassion for humankind and about inducing positive social changes. Social entrepreneurship should not be confused with charity, as social entrepreneurship is about investing in social ventures, which can then generate their own revenues to sustain themselves without relying heavily on donor funds. Social entrepreneurship aims to bridge the gap between business and benevolence by applying conventional entrepreneurship in the social sphere; it integrates economic and social value creation in order to achieve a long heritage and a global presence…how do you integrate economic and social value creation do you ask?

Well, economic value is basically a measure of return on investment, deb/equity ratios, price/earning ratios and various other econometrics. Social value on the other hand is created when resources, inputs, processes or policies are combined to result in improvements in the lives of individuals or society as a whole, such as anti-racism efforts, community organizing, and environmental protection. Social value is difficult to quantify into dollar value. In order to integrate both values, a social enterprise must be able to increase the value of the resources or inputs it utilized and then generate cost savings and/or revenues for the public sector—its community. By doing so, it is possible to quantify and monetize the elements of an activity’s social value. Indeed, these cost savings and revenues can be achieved in decreased public dollar expenditures and in increased revenues to the public sector through additional taxes collected, effectively translating the enterprise’s activity’s social value into socio-economic value.

It is not an easy task for a social entrepreneur to achieve such a goal, and it is even more difficult to convince potential investors to become social investors at the price of sacrificing financial return in favor of social return—the social investor takes on more financial risks compared to the traditional investor, twice or even thrice the risk, in order to achieve social or environmental impact. Social entrepreneurs and social investors are different breeds of people altogether. A social entrepreneur is by definition an individual, group, network, organization, or alliance of organizations that seeks sustainable, large-scale change through pattern-breaking ideas in what or how the governments, nonprofits, and businesses do to address significant social problems. Social investors are people, more often than not called philanthropists, who wish to invest their money in causes they feel most passionate about in order to incur social changes.

One of the most famous social entrepreneurs of our time would be Virgin founder Sir Richard Branson, and one of his latest “folly”, Virgin Stem Cell Bank, one of the pioneer hybrid model of cord blood banks, was created in order to respond to the fact that an increasing number of children were dying through lack of umbilical cord blood. Initially, Sir Richard had offered 3 million pounds to the National Health Service (NHS) to help them increase their storage capacity, but the NHS was not comfortable accepting funds from private sources, so Sir Richard decided to set up a company to do the job with a unique approach: “an individual’s cord blood is harvested at his expense and divided in two, one will go into a national blood center where anybody can get access to; the other half will be stored for the child. Furthermore, the generated profits will go to a charity to help groups who have difficulty sourcing cord blood due to lack of sample matching.”

So readers, what say you? Is social entrepreneurship in bioscience real or does it merely provide a different “social” setting in which to implement a new entrepreneurial project? If you think it is real, what are you waiting for? Stop looking for the right opportunity to fall on your lap and start creating it for your community and yourself!

Y.S.H.

Public and Private Cord Blood Banking: United We Stand!

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The recent years have been witness to revolutions in the medical fields in many aspects, and more specifically in the development of applications in regenerative medicine. One of the most promising and fastest growing fields of regenerative medicine is cellular therapy for both personalized and generalized treatments. Indeed, incredibly innovative approaches have been and are being developed to treat degeneration of tissues and organs due to aging or damage using stem and progenitor cells. This led to an increase in cell therapy revenues from $410M in 2008 to $5.4B in 2012, truly marking our entry into the age of the cell and making cell-based therapeutics the next pillar of medicine; virtually every branch of medicine will see direct application of cell therapies.

Stem and progenitor cells are undifferentiated cells, which, under the right conditions, can differentiate to become virtually any type of cell that makes up the tissues and organs in the body. This ability makes stem and progenitor cells ideal for use in proven and novel clinical therapies to replace defective or damaged cells resulting from a variety of disorders and injuries as well as for use in research. Stem and progenitor cells provide the foundation for cell therapies and, amongst the different types of stem and progenitor cells, none has been more researched, funded and commercialized than mesenchymal and hematopoietic stem and progenitor cells (MSPC’s & HSPC’s respectively) typically found in bone marrow in large quantities.

Recent data show however that umbilical cord blood obtained from the umbilical cord and placenta is a rich source of MSPC’s and HSPC’s; the latter can be used for transplantation to treat a range of malignant, genetic, metabolic, and immune disorders. In fact, it was shown that cord blood HSPC’s are more proliferative and have a greater chance of matching family members than stem cells from bone marrow. Additionally, cord blood is not only widely available and easily accessible—collection is relatively non-invasive, safe and painless—but its derived HSPC’s can even be safely infused when they are an incomplete match for the recipient due to their immunologically naïve quality. In spite of this, cord blood is still routinely discarded as hospital waste along with the umbilical cord and placenta following birth when it should be collected, processed, tested and banked for future therapeutic use, especially since, until now, 50 percent of all patients seeking a transplant cannot find a match.

There have been more than 30,000 transplants worldwide using cord blood derived HSPC’s and the demand is still growing fast. Indeed, the National Marrow Donor Program estimates that by the year 2015, there will be 10,000 cord blood transplants worldwide per year as opposed to 3,000 per year in 2010. From 23 active cord bloods as of 2005, the Bone Marrow Donors Worldwide (BMDW) currently list 44 public cord banks from 26 different countries and there are approximately 225 private cord blood banks worldwide. That is an eleven fold increase (1,100 percent) in the companies involved in the industry over only a seven year period, and yet, the market is far from being saturated as the offer still cannot meet the demand—both in number and quality.

There are two main types of cord blood banks: licensed public banks, which ask mothers to donate their umbilical cord blood—only the umbilical cord blood—for future use by anyone who may be a potential match, and private or family banks, which will store cord blood, tissue and/or MSPC’s from either or both the umbilical cord and placenta for future use by the donor or matching family members for an average fee of $1,600 per item plus an annual storage fee of around $100 per item. Historically, public banks have been not-for-profit while private or family banks have been for-profit enterprises. The private cord blood industry has been criticized by a number of professional bodies including the EU ethics Committee and the Royal College of Pediatrics because the medical utility of private cord blood banks is believed to be more potential than actual and, thus, private cord blood banks threaten the supply of cord blood units to the public system which is based on actual needs and not potential ones.

It is important nonetheless to point out that the private banks are founded on the autologous (cells derived or transferred from the same individual’s body) business model, where cells are harvested from the patient to be treated in a facility before being shipped back to the physician for delivery into the same patient, who is thus both the donor and recipient. The allogeneic (cells derived from separate individuals of the same species) business model on the other hand is based on mass production of aliquots of cells from a single healthy donor to be shipped to the physicians for subsequent delivery into the patient—the allogeneic model being the preferred one by the big biopharmaceuticals companies of course. Against common belief, the autologous business model is far from being unsupported or unsound since there are currently over 650 FDA clinical trials involving autologous and allogeneic applications of MSPC’s and HSPC’s with a clear bias to autologous approaches as they don’t provoke an immunological response by the patient. In fact, recent data have shown that, in reality, it is not autologous vs. allogeneic but autologous and allogeneic as there is room for both therapies in treating patients, even within a single diagnosis.

Until recently, only one alternative existed to both the public donation and private storage: directed donation of cord blood donated to public banks to siblings who have an existing condition that may in the future require an allogeneic transplant. This alternative nonetheless was simply not good enough for parents who wanted to take a form of biological insurance to safeguard their children’s future and who understood the potential of autologous therapies and the advantages early-stage stem cells as opposed to adult stem cells—many studies showed greater proliferative capacity and greater plasticity of newborn stem cells as opposed to same types of stem cells harvested from adults. Furthermore, with the growing awareness of parents of stem cell therapeutics, a deeper commitment to research and development of stem cell therapeutics by the banks was expected: regenerative medicine is to be included in the world of tomorrow today. This situation gave rise to new kinds of umbilical cord blood banks—hybrid models that combine aspects of both the public and private systems with a clear commitment to research and development in the field of stem cell therapeutics.

The hybrid models can be classified into two broad categories: the cord blood banks that offer both options, either private storage or public donation, and the cord blood banks that make the privately stored cord blood available to the public system. The first category is the most prominent one in North America and Belgium and keeps gaining popularity with the recent announcement that the major public banks have agreed to expand their services to offer private storage. The second category is the most popular one in Spain, Turkey, the U.K. and Germany, each with its own characteristics. Indeed, In the Turkish model, according to government legislation, 25 percent of all privately stored cord blood is donated to the public system. In the Spanish model, cord blood stored in a private bank is registered on the Official Spanish Register of Bone Marrow Donors and should a patient in need of a transplant find a match in a private bank, parents are obliged to donate said cord blood and the storage fee is reimbursed. In the U.K., the Virgin model comes to mind where 80 percent of the privately stored cord blood is donated to the public system for allogeneic transplantation. And finally, in Germany, should a patient needing a transplant find a match in a private bank, the bank asks for permission to the parents for release, however, as opposed to the Spanish system, the parents are under no obligation to accept.

No matter the outcome of which hybrid model is the best, both public and private cord blood banks are now working together to implement new stem cell therapeutics and allow for a greater number of patients needing a transplant to actually find a matched donor.

Y.S.H.

Stemness, Neural Stem Cells and their Applications to Treat Neurodegenerative Disorders!

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The last decade has seen scientist progress from isolating pluripotent stem cells from early embryos and growing them in the laboratory to being able to generate them from terminally differentiated adult cells using viral insertion of key transcription factors. These remarkable advancements opened the doors, in theory, to a vast array of applications in cell therapy, gene therapy and disease modeling to treat and/or study numerous degenerative illnesses that had remained elusive until now. More specifically, these recent discoveries finally opened the door to potential cures to neurodegenerative disorders, such as ALS, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, or even Schizophrenia and Bipolar disorder, and even spinal cord injuries using neural stem cells therapies—by directly injecting them into the patient at specific locations for example. However, before I embark on the nature of neural stem cells and the current ongoing clinical trials to determine the extent of their applications, it might be wise to first remind ourselves of what we understand today to be a stem cell, or even what stemness means. Indeed, as our understanding of the biology and unique properties of stem cells grow, so must we refine the scope of what it is we are studying!

Our initial understanding of all stem cells is based on their functionality, as having three characteristics that set them apart from other cells: they are unspecified, they can divide and renew themselves for very long periods of time, and they can be induced, under certain conditions, to become differentiated cells with specialized functions. This definition seems simple and broad enough to encompass all stem cells you say? Well, not exactly.  Indeed, this definition only works for embryonic or fetal stem cells that are only present for a short period in the lifetime of an organism. This definition can no longer be used when we try to separate transient progenitor cells from adult stem cells (or somatic stem cells). Efforts have thus been put in to refine this definition to adult stem cells that self-renew for the entire life span of an organism. However, this, also, wasn’t enough to take into account the different differentiating characteristics of adult stem cells: potency. Is a somatic stem cell that can only differentiate into one type of differentiated cell (unipotent) really a stem cell? Maybe a stem cell should be set apart based on its gene regulations, but again, this characteristic is not unique to stem cells. This makes you wonder about induced pluripotent stem cells doesn’t it? Are they really stem cells or simply pluripotent cells? Some scientists even define stemness as a system-level property as the environment has been shown to play a direct role in defining the nature of the stem cell (the niche makes the stem cell!). This subject is so complex that the majority of scientists decided to agree on a working definition for a stem cell, to be a clonal, self-renewing entity that is multipotent and thus can generate several differentiated cell types, while preserving numerical homeostasis—even though this definition is not applicable in all instances!

The origin of stem cells itself remains to be elucidated—not embryonic stem cells of course, which are derived from the inner cell mass of the blastocysts, but somatic stem cells. Everything gets complicated at the gastrulation event, after fertilization of the egg and the implantation of the zygote in the uterine wall. During gastrulation every cell in the embryo changes its position to become committed to one of the three germ layers, which themselves become properly positioned with respect to another within the context of the embryo. It is possible, thanks to numerous fate mapping studies, to determine what cells in various regions of the embryo will become. Remember that the three germ layers are the ectoderm, on the outside of the embryo, the endoderm, on the inside of the embryo and the mesoderm, in the middle, and that, after gastrulation, once a cell is committed to a germ layer, it will no longer form structures based on its location. Now, back to the origin of somatic stem cells dilemma; the common understanding is that development is achieved essentially through successive cell fate restrictions controlled by both intrinsic and extrinsic factors after gastrulation, and, thus, stem cells occur right after the formation of germ layers, restricted to their respective lineage by said germ layer. A second major theory implies that stem cells follow a similar developmental path as primordial germ cells, in that they avoid completely lineage commitment during gastrulation and migrate subsequently to specific tissues and organ niches. This matter remains to be elucidated and is actively researched by scientists all over the globe—it is an important matter and does imply determination of biomarkers of the different types of stem cells.

To get back to the subject at hand, and since we are not going to answer the question on the origin of somatic stem cells in this article, the common understanding on the development of neural stem cells (NSCs) is that it begins with the formation of nervous tissue from the ectoderm after gastrulation. It was observed that appearance of NSCs coincides with the induction of the neural plate and the appearance of restricted progenitor cells. It was also observed that developing and adult NSCs seem to acquire temporal and positional information, i.e. they give rise to region-appropriate progeny and earlier NSCs gives rise more frequently to neurons than glia compared to more mature NSCs. It is important to note that it was observed that NSCs for the most part do not give rise to all the neurons types in the adult brain. Indeed, they were found to be mostly limited to the production of GABA and glutamate neurons. The subject of NSCs is still relatively new, since they were first isolated in the early 1990s in the adult rodent striatum. Since then, many NSCs have been isolated from adult animals from a variety of locations in the central nervous system (CNS), including the spinal cord, the hippocampus, and the neocortex, as well as the striatum, and the search for NSCs’ new niches is still ongoing!

Despite having discovered so many endogenous NSCs in mammals, it was observed that their potential in “self-repair” after injury was not met because of, it is believed, constrains due to their environment, their restricted mobility and their limited numbers. Thus, the logical hypothesis followed: if NSCs were expanded ex vivo and implanted into regions needing repair, overcoming the in vivo limitations, the true potential of NSCs would be unlocked. Extensive research and experimentations were conducted based on this assumption, and are still conducted today with astonishing results and even more surprising discoveries about the properties of NSCs. For example, it was observed that exogenous NSCs are capable of sensing, homing in on, and responding adequately to neurogenic signals produced during degenerative processes in order to resume development. Additionally, it was observed that NSCs not only differentiate very efficiently into neural cells but also evade most of the obstacles that must be overcome by other gene or cellular therapies, i.e. NSCs can cross the blood-brain barrier. NSCs seem to be the answer scientists have been waiting for to treat extensive neurodegenerative processes as was previously said, dementia conditions, as well as spinal contusion and cerebellar degeneration, and many more. What are we waiting for to get these therapies up and running you ask? Nothing; scientists have been working hard at them for years, ever since they discovered the different NSCs’ niches!

Just to cite the pioneer in the field, Neuralstem, using its patented technology for “isolation and expansion of human neural stem cells from each of the NSCs niche regions of the developing central nervous system in virtually unlimited numbers from a single donated tissue,” is currently in phase II to treat ALS after having successfully demonstrated the safety of its procedure on 18 patients in phase I—using its patented world’s first intraspinal surgical device for the delivery of neural stem cells. From what I was able to gather, there were observations in several of the patients of slowed progression of lower extremity weakness, and one patient may have even improved just from the first intervention! Neuralstem is also in phase I/II to treat ischemic stroke and spinal cord injury, and is in pre-clinical phase to treat glioblastoma, multiple sclerosis, optic neuritis, Alzheimer’s disease, traumatic brain injury, peripheral nerve injury, diabetic neuropathy, lysosomal disease, Parkinson’s disease, cerebral palsy, and ischemic spastic paraplegia! As you might have guessed, one of the major difficulties lies in getting the right NSCs to the site of repair in order to produce only the right kind of neural cell types. At least, that is until we find the sacred grail of NSCs: a multipotent NSC that can produce all the different kinds of neural cells at the right time and place…or maybe not. A very recent paper, published by researchers at the Stanford University School of Medicine on April 14th, inspired by Shinya Yamanaka’s Nobel prize winning work, shows successful transformation of skin cells directly into oligodendrocyte precursor cells (direct lineage reprogramming !), the cells that wrap nerve cells in the insulating myelin sheaths that help nerve signals propagate. Could Shinya Yamanaka’s work on human induced pluripotent stem cells have opened the way to tomorrow’s neural stem cell (and stem cell in general) therapies? Many seem to think so; what about you?

Y.S.H.