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8 posts from May 2010

May 31, 2010

In the blood - part one

Part one in a series looking at the processes involved in the most clinically applied form of stem cell therapy: hematopoietic stem cell transplantation

By Michelle Ly

Dale Tidy photoLeukocytes, or white blood cells (WBCs), are an essential part of the immune system. Produced in the bone marrow, healthy WBCs protect the body against infection and pathogens. Cancers such as leukemia or multiple myeloma have the effect of producing abnormal, non-functional white blood cells. To treat these patients and attempt to restore normal WBC levels, chemotherapy and hematopoietic stem cell transplantation is often used.

Hematopoietic stem cell transplantation involves the use of hematopoietic progenitor cells (HPCs) collected from either the bone marrow or the blood. These cells are able to differentiate into all the different lineages of blood cells, including the white blood cells. While both types of stem cell collection are still performed, the use of HPCs derived from blood has grown in popularity.  

The process of preparing transplantable HPCs from blood is performed by a specialized team of technicians working in conjunction with medical staff. HPCs are collected from either autologous or allogenic donor blood. Autologous donations are taken from the patient prior to chemotherapy treatment, while allogenic donations are taken from siblings or unrelated donors. The actual donation process takes place within a hospital through a process called apheresis. During apheresis, the donor's blood passes through a machine which separates the blood into its constituent parts. The HPC-containing layer of the blood is kept for further processing, while the remainder is returned to the donor's circulation. 

The role of facilities such as the Clinical Cell Therapy group at the BC Cancer Agency is to take the HPC-containing blood product and turn it into a form that is rich in HPCs and capable of being stored until the patient requires a transplant. As this timeline may vary from days to months to years, it is essential that the stem cells are processed and preserved carefully.

How do they do this? In my next post, we'll meet the people behind the process and take a look at how blood product gets from the patient, to the freezer, and back to the patient again.  

(Photo by Dale Tidy)

May 27, 2010

Scaling up stem cells for clinical use

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Please read in on its new home, Signals BlogScaling up stem cells for clinical use

May 25, 2010

Latest WARF patent decision further underlines legal questions about ownership of life

Lymphoid-Progenitor 

 by Ubaka Ogbogu

On April 28, 2010, the Board of Appeals and Interference (BPAI) of the U.S. Patent and Trademark Office (USPTO) reversed an earlier decision that upheld the claims of U.S. Patent Number 7,029,913, one of the trio of patents commonly known as WARF or Thomson patents. The patents cover the first isolation of non-human primate and human embryonic stem cells (hESCs) by James Thomson. Thomson successfully patented these cell lines and assigned the patents to the Wisconsin Alumni Research Foundation (WARF).

The WARF patents have a history of controversy and legal challenges. In April 2007, the USPTO revoked the patents on the grounds that Thomson’s work was obvious in the light of previous scientific work and thus unpatentable. In 2008, the Patent Examiner reversed the revocation order and upheld the patent claims. The April 28 BPAI decision is the latest episode in the patents’ controversial history.

The issue at the heart of the WARF patents legal dispute is somewhat of a red herring; the real trigger stems from objections to the patents on the basis that they are overly broad and restrictive, and inhibit researchers’ access to stem cell lines due to high licensing costs. Some critics also feel that hESC lines are products of nature, and as such, no one has an ethical right to own them. While these objections have little or no import in the world of patent law and litigation, they have fueled critics’ successful efforts to overturn the patents.

Much like the WARF patents dispute, the recent Myriad Genetics case highlights a now familiar trend in the world of biotechnology patents, whereby social controversy acts as the main driver for legal regulation. On March 29, 2010, a U.S. District Court held that isolated human DNA sequences and the methods for comparing or analyzing their sequences are not patentable. These famously controversial patents, owned by Myriad Genetics and the University of Utah Research Foundation, relate to two genes (BRCA 1 & 2) and a test developed by Myriad to assess susceptibility to hereditary breast and ovarian cancer. While Myriad plans to appeal the ruling, the court’s decision is significant to legal trends relating to biotechnology patents on “products of nature”, a class that includes stem cell patents.

The question of whether or not patents can be granted on products of nature in an altered or unaltered form is one of the most vexing and controversial issues facing biomedical research today. Patents on biotechnology products and applications, such as transgenic mice, higher life forms, stem cell lines, and human DNA have been the focus of legal / regulatory disputes and policy action in many jurisdictions around the world. The specific triggers for controversy vary, but have mainly focused on claims that such patents could result in inappropriate commodification of life, impede research, and frustrate public access to biomedical products, procedures and applications.

Nonetheless, social controversies associated with the above-noted claims have resulted in successful legal challenges against biotechnology patents, as the Myriad case illustrates. Much like the WARF patents situation, the Myriad challenge appears to have been triggered by reactions to the company’s approach to marketing the genetic tests, which involved a monopoly on the sequencing and commercial exploitation of the genes. Indeed, several of the plaintiffs and amici curiae in the case were motivated to join either because Myriad had sent them a cease-and-desist letter, or because they could not afford Myriad’s exclusive testing services.

In Canada, the legal scope of biotechnology patents is somewhat uncertain. Although stem cell patents have been granted in Canada, none pertains to hESCs. The patentability of higher life forms is also an open question; although the Supreme Court of Canada held in 2002 that a transgenic mouse with cells genetically altered by a cancer-promoting gene was not patentable under Canadian law, the decision did not settle the question of whether higher life forms are patentable. However, given that many scientists consider the U.S. to be perhaps the most important market to protect their inventions, the fact that hESC patents are less controversial in Canada offers no solace – Canadian stem cell researchers have as much reason to be interested in and concerned about legal developments in the WARF and Myriad Genetics cases.

May 20, 2010

High-dose antioxidants may cause abnormalities in stem cells

by Chris Kamel

One hurdle facing the use of lab-grown stem cells for therapeutic or experimental purposes is the accumulation of genetic abnormalities over time. The nature of these changes varies, but some may affect therapeutic usefulness and many mirror changes seen in tumour-forming cells. One of the more difficult variables to change when culturing stem cells is the air they are grown in. Typical lab conditions are 20% (atmospheric) oxygen, much higher than the physiological levels found in tissue (about 1-5%). This oxygen-rich environment can lead to an increased generation of reactive oxygen species (ROS) which are a natural byproduct of metabolism, but also highly reactive and known to cause oxidative damage to DNA and protein. In a recent paper published in the journal Stem Cells, researchers tried to counteract ROS generation with some interesting results.

In the experiments, human cardiac and embryonic stem cells were cultured under both normal and low-oxygen conditions and supplemented with different antioxidant cocktails. The researchers found that compared to those grown in atmospheric oxygen, high doses of antioxidants were successful in reducing reactive oxygen but also resulted in more chromosomal abnormalities and lower levels of DNA repair proteins. In contrast, cells grown under physiological oxygen (5%) had fewer genetic aberrations compared to the other groups, indicating that standard growth conditions are sub-optimal. Other data addressing this question are sparse, though previous research has shown that in a mouse model of cancer, low doses of the antioxidant vitamin E protected against tumour formation while high doses enhanced tumorigenesis.

None of this is to say that people should be throwing away their nutritional supplements. While genetic abnormalities were seen at antioxidant levels similar to those reached in the blood with high-dose supplementation, it's important to remember that effects on stem cells in a petri dish are different from effects in a human body. It does raise a small red flag and call into question a “more is better” approach, but warrants further study before drawing hard conclusions.

May 18, 2010

New summary on stem cell research for ALS

Rchaddahseeingisbelievingsmall Amyotrophic lateral sclerosis (ALS), known as Lou Gehrig’s Disease and motor neuron disease (MND), is a progressive neuromuscular disease that attacks nerve cells in the brain and spinal cord. As these neurons slowly waste away, they become unable to transmit signals through the body, such that over time the body loses the ability to do basic functions such as eating, speaking, walking, and even breathing. There is currently no cure for ALS; the disease usually causes death within 3-5 years.

Around the world, stem cell scientists are looking for ways to stop ALS once it begins—and, hopefully, to  restore nerve function once lost. The research is still in its early stages, but there have been promising findings recently in the field of stem cell research. Recent news in the field includes a Phase 1 clinical trial in the United States, which is the first FDA-approved trial of stem cells for ALS.

The Stem Cell Network has just published another in a series of disease summaries, this latest issue focuses on ALS: its symptoms, current treatment, ongoing research, and whether or not stem cell therapy may hold the key to helping cure this devastating illness.

May 17, 2010

Stem cell science across the pond: organizations in the UK

by David Kent

After being spoiled with six years’ worth of camaraderie with the stem cell community in Canada via the Stem Cell Network’s annual meeting and countless other interactions, I recently made the journey from  Connie Eaves’ lab in Vancouver to pursue post doctoral research at the Cambridge Institute for Medical Research under Tony Green’s supervision. I came with a very open mind, but knew that the Canadian network was going to be a hard act to follow. Almost immediately upon touching down, I went on a hunt for all things stem cell in Ol’ Blighty.

It appears the UK has an extremely vibrant stem cell community that can address the scientific questions along with pursuing an understanding of the complicated ethical, legal, and social issues that arise. They have also recognized that public outreach is a critical component of well-supported science and science policy. Some selected organizations that showcase the breadth and depth of the UK’s stem cell involvement are:

  • The UK National Stem Cell Network is a great politically-driven initiative, founded on the recommendation of the Government-commissioned Pattison Report which presented a 10-year vision for stem cell research in the UK. The UKNSCN brings together members of the stem cell community and is the primary disseminator of information regarding UK stem cell research to the public and to international scientists.
  • The UK Stem Cell Foundation, which among other things, hopes to raise a £100 million endowment to fund research and scientists where funding gaps exist.
  • The Social Science Stem Cell Initiative recognizes the importance of getting a handle on the social, ethical and legal issues and aims to build research capacity for high-quality social science research in the area of stem cells. 
  • The UK Stem Cell Bank was established to be a repository for stem cells of all sources and provides quality controlled cells to researchers across the country.

On top of this, individual cities have very active stem cell communities. In Cambridge alone, a tiny town of 100,000, there is a monthly Stem Cell Club which is an informal evening gathering of academics from all over town with excellent local speakers and occasional imports (e.g.: last month featured new investigator Steve Pollard, clinician scientist Brian Huntly and Anna Philpott speaking about embryonic, blood, and neural stem cells respectively). Also in Cambridge there is a government-funded Stem Cell Initiative which engages basic and clinical scientists with an interest in biomedical translation of stem cell and regenerative medicine research.  

With all of this activity, it will be difficult to attend everything, but where possible, I’ll get there and will report via this blog. Look forward to profiles of research findings, social and political groups and their activities, and reports on major talks and conferences from the UK and mainland Europe.

May 11, 2010

iPS cells can help speed traditional drug development

by Paul Krzyzanowski

Imagine that you've just discovered a novel drug that potentially solves a medical problem, one that accelerates wound healing in skin or can reduce the size of cancerous tumors. You can show the effects beautifully in your model tissue culture system and mice obviously respond to the treatment. You decide to call your technology transfer office and at the very last digit, you hesitate, and wonder whether the drug will show any adverse reactions in humans; one side effect can render it useless.

The likelihood of this scenario is quite high; an estimated 75% of drug toxicity problems are not detected until reaching at least preclinical stages of drug development, and only after large amounts of time, funds, and heartache have already been expended. The need for in vitro systems to test for human side effects is clear.

Both human embryonic stem cells (hES) and induced pluriplotent stem (iPS) cells can be coaxed to generate differentiated cells analogous to those in the human body. The Stem Cell Network's Mick Bhatia leads a recently awarded Ontario Government grant intended to identify novel compounds that can promote differentiation of pluripotent cells into different lineages. This work complements that of several other Ontario groups that are developing methods to create pancreatic islets, lung epithelial cells, cardiomyocytes (heart muscle cells), blood and endothelial cells, neural cells and retinal cells.

Two major goals of the project are to identify drugs promoting endogenous tissue repair and to develop tools to generate replacement tissues. However, differentiated cells that behave like their endogenous counterparts (both stem cell or otherwise) are also of use for traditional pharmaceutical development. Using derivative cells in toxicology screens can reveal higher order compound effects at cell or tissue levels instead of simply flagging drugs as being generally cytotoxic or non-toxic. So, the question of whether a potential drug compound inadvertently stops insulin secretion from pancreatic cells or disturbs cardiac rhythms can partially be answered in advance.

The benefits of using hES and iPS cells for this kind of screening have been noted by most of the larger industrial research companies, and many are pursuing either development of stem cell-based screening systems for their own research programs or for productization of screening technology. In 2006, Novocell (now ViaCyte) demonstrated conversion of hES into insulin-producing cells and in 2008 partnered with Pfizer in a drug discovery collaboration using this system. In the same year, GlaxoSmithKline partnered with the Harvard Stem Cell Institute to develop various stem cell-based screening technologies. The following year, Geron and GE Healthcare entered a deal to commercialize hES derived cellular assay products, and soon thereafter Cellartis and AstraZeneca extended their previous collaboration to continue developing hES derived hepatocytes (liver cells) and cardiomyocytes, specifically for developing products for compound screening, drug metabolism studies, and safety assessments.

These developments in toxicology screening suggests that in the not-too-distant future, broad based side-effect assays will become mandatory at earlier stages of pharmaceutical development, possibly prior to any interest being expressed by initial investors. Looking further forward, if conducting stem cell based toxicology screens becomes commonplace, this data might even be required to support claims in basic research publications.

May 06, 2010

Further challenges for research following AHRC resignations

by Ubaka Ogbogu

The recent resignation of two members of the Board of Directors of Assisted Human Reproduction Canada (AHRC), the federal regulatory agency responsible for implementing the provisions of the Assisted Human Reproduction Act, has once again raised questions regarding the composition, progress and relevance of the agency’s governing body, which I outline below. Such weaknesses have prevented the Board, which was constituted in December 2006, from enabling the agency to fulfill key aspects of its statutory mandate, including implementing and administering the licensing framework for controlled activities under the Act, and enforcing compliance with the Act. 

For many, the membership structure of the Board has been controversial since its inception. The Act expressly excludes licensees or license applicants, or persons affiliated with them, from eligibility and selection as Board members. This provision has received some criticism, chiefly because it prevents experts such as stem cell scientists or fertility experts from serving on the Board, thus ensuring that those most knowledgeable about the technologies regulated by the Act are excluded from their oversight and implementation. This strategy seems particularly injudicious when one considers that many of these technologies – stem cell research being a prime example – constitute emergent and constantly evolving areas of knowledge where specific expertise is most essential. In keeping with the provisions of the Act, the current Board does not include any obstetrician or gynecologist, patient representatives, or stem cell researchers. This is in sharp contrast to similar regulatory agencies in other jurisdictions, most notably in the U.K., where the board of the equivalent Human Fertilisation and Embryology Authority (HFEA) includes fertility experts and scientists.

The Canadian rule appears to have been motivated by concerns that interested experts will unduly influence policy implementation and enforcement in an area fraught with scientific and ethical uncertainties. However, it is not clear how the inclusion of experts in the agency’s Board will differ from other research contexts such as cancer research, where ethical oversight and governance is handled by scientists involved in the research. In any event, such fears can be met and addressed by instituting stringent conflict of interest disclosure and mitigation rules, as is indeed the case in other research contexts, and with the HFEA.

While what prompted the resignations is unknown at the present time (the Board members signed confidentiality agreements), one thing is clear – there is a need to reassess the rules regarding membership of the Board. The Board as currently constituted lacks the necessary expertise to perform the crucial functions mandated by the Act. Furthermore, in Canada, there is a very limited pool of knowledgeable persons – both in the scientific and research ethics realms – without ties to research developments in the fields regulated by the Act. This by itself does not translate to impropriety or unethical behaviour, but is in fact partly the product of persistent efforts by the Canadian government to mobilize Canadian research excellence and promote the training and concentration of highly skilled personnel in cutting-edge science and technology research. 

It may also be difficult to find replacement appointees – of the same calibre as the resignees or otherwise – who would not seem out of place on a board overseeing such a specialized field. This will further diminish the competence and representativeness of the Board’s membership, as well as the Board’s ability to render responsible and responsive governance in tune with rapid developments and advances in controlled areas like stem cell research.  

Lastly, the lack of any serious activity from the Board (or Agency) since its inception raises questions about its continued relevance, especially as regards the governance of embryo research. For regulated activities such as human embryonic stem cell research (using supernumerary IVF embryos), this lack of activity has had some stifling effect on research. However, Canadian stem cell scientists have continued to make important basic research discoveries (through methods outside the scope of the Agency’s regulatory authority). It is quite possible that by the time the Agency begins work in earnest, advancements in the field would have far outpaced its regulatory mandate.