regenerative medicine

Big pharmas and clinical stem cell research

Attila Csordas — Mon, 29 Sep 2008 10:01:30 -0700

Description

After many years of more or less ignoring the topic, big pharmaceutical companies (revenue in excess of $3 billion) finally are paying attention to stem cells as vehicles of drug testing and future regenerative medicine therapies. The pioneering and highly risky stem cell field has been so far mostly the domain of academic laboratories and small biotech companies.
But these days big pharmas finally started to cooperate with both academia and startups and invest in the range of couple millions of dollars. Some signs of the upcoming trend: GlaxoSmithKline and the Harvard Stem Cell Institute (HSCI) recently (in July, 2008) announced a five-year, $25 million-plus collaborative agreement while Pfizer has already invested $3 million in shares of EyeCyte a La Jolla based early stage stem/progenitor cell-based ophthalmology research and development company.
Stem Cells for Safer Medicines, or SC4SM, a collaboration to develop stem cells for safety testing of new drugs through a public-private partnership and an independent not-for-profit company is backed by 3 European big pharmas, GlaxoSmithKline, AstraZeneca and Roche.
A higher form of involvement means in-house research labs and Pfizer is on that road too with its functional “regenerative medicine unit” in Cambridge, Mass. and with the plans to open another similar shop in the other Cambridge, overseas around this November.
On the drug testing platform stem cell mediated results can be expected much sooner than in the case of an efficient and safe stem cell therapy. According to a 2006 data it takes $1.318 billion and 10-15 years to develop a traditional pharmaceutical drug but no data available on the costs and timeframe of a stem cell based regenerative therapy.

If big pharmas are really risk-taking and invest enough money in stem cell trials in the range of hundreds of million of dollars and if no serious complications occur during the trials then by 2020 or by and large within a decade we can expect some important results from those companies.

But here we should really consider the state of global economy as a big ballast and the tough times in the pharma industry.

What can be expect though with a bigger certainty is that within a decade most of the big pharmas will seriously flirt with stem cells the in the form of setting up in-house research labs, investing in biotech startups and collaborating with the academy.

Sources:

http://www.sc4sm.org/
http://seekingalpha.com/article/79266-pharmaceutical-facts-investors-should-know
http://en.wikipedia.org/wiki/List_of_pharmaceutical_companies

Signals

GlaxoSmithKline collaborates with the Harvard Stem Cell Institute

Pfizer's growing and various interests in stem cells

GlaxoSmithKline collaborates with the Harvard Stem Cell Institute

Attila Csordas — Fri, 26 Sep 2008 05:28:00 -0700

Description

GlaxoSmithKline, the world’s second-biggest pharmaceutical company and the Harvard Stem Cell Institute (HSCI) recently (in July, 2008) announced a five-year, $25 million-plus collaborative agreement.

GSK’s investment, one of the largest by a pharmaceutical company in stem cell science, will support innovative research at Harvard University and in at least four Harvard-affiliated hospitals in the areas of neuroscience, heart disease, cancer, diabetes, musculoskeletal diseases and obesity. In addition, GSK will fund an annual grant, which supports early stage research in stem cell biology, as part of HSCI’s seed grant program “GSK believes stem cell science has great potential to aid the discovery of new medicines by improving the screening, identification and development of new compounds. We have carefully chosen the Boston biomedical community to collaborate with on this important venture. It has the highest concentration of leading stem cell scientists, and the Harvard Stem Cell Institute is the epicentre of that community,” said Patrick Vallance, Head of Drug Discovery at GSK.

Biomedical Sciences and Biotechnology

Source

http://www.gsk.com/media/pressreleases/2008/2008_pressrelease_10089.htm
http://www.xconomy.com/boston/2008/07/25/harvard-stem-cell-institute-wins-25-million-investment-from-glaxosmithkline/
http://www.hsci.harvard.edu/
http://www.gsk.com/

The decellularized matrix: a shortcut in tissue engineering

Attila Csordas — Tue, 01 Jul 2008 23:57:04 -0700

Description

The concept of decellularizing complex organs in cadavers and reseeding the remaining matrix structure with differentiated, stem or progenitor cells, growing in a bioreactor and transplanting back to the organism could turn out to be a real technological shortcut in the field of tissue engineering:

Perfusion-decellularized matrix: using nature's platform to engineer a bioartificial heart

"About 3,000 individuals in the United States are awaiting a donor heart; worldwide, 22 million individuals are living with heart failure. A bioartificial heart is a theoretical alternative to transplantation or mechanical left ventricular support. Generating a bioartificial heart requires engineering of cardiac architecture, appropriate cellular constituents and pump function. We decellularized hearts by coronary perfusion with detergents, preserved the underlying extracellular matrix, and produced an acellular, perfusable vascular architecture, competent acellular valves and intact chamber geometry. To mimic cardiac cell composition, we reseeded these constructs with cardiac or endothelial cells. To establish function, we maintained eight constructs for up to 28 d by coronary perfusion in a bioreactor that simulated cardiac physiology. By day 4, we observed macroscopic contractions. By day 8, under physiological load and electrical stimulation, constructs could generate pump function (equivalent to about 2% of adult or 25% of 16-week fetal heart function) in a modified working heart preparation."

Biomedical Sciences and Biotechnology

Source

The concept of decellularizing complex organs in cadavers and reseed the remaining matrix structure in a bioreactor could turn out to be a
Perfusion-decellularized matrix: using nature's platform to engineer a bioartificial heart
Harald C Ott, Thomas S Matthiesen, Saik-Kia Goh, Lauren D Black3, Stefan M Kren, Theoden I Netoff & Doris A Taylor
Nature Medicine 14, 213 - 221 (2008)
http://www.nature.com/nm/journal/v14/n2/abs/nm1684.html

Regenerative medicine will heal (all war) wounds

Vivian Distler — Thu, 24 Apr 2008 13:18:26 -0700

Description

The federal government has announced a national $85 million program to use the science of regenerative medicine to develop new treatments for wounded soldiers. The project will be dedicated to repairing battlefield injuries through the use of regenerative medicine, science that takes advantage of the body’s natural healing powers to restore or replace damaged tissue and organs. Therapies developed by the Armed Forces Institute of Regenerative Medicine (AFIRM) also will benefit people in the civilian population with burns or severe trauma due to illness or injury.

Source

http://www.mirm.pitt.edu/news/article.asp?qEmpID=287

Beating heart tissue grown in lab : Nature News

Sean Ness — Thu, 24 Apr 2008 13:16:34 -0700

Description

Test-tube recipe produces three types of cardiac cell.

Michael Hopkin
Heart cells, grown from scratch.Heart cells, grown from scratch.Lei Yang

An international team of cell biologists has created heart tissue %u2014 complete with beat %u2014 in a test tube. The tissue culture contains three distinct cell types, each of which is important in functioning hearts, and is thus a step towards the advent of lab-grown heart-tissue transplants.

Researchers led by Gordon Keller of the McEwen Centre for Regenerative Medicine in Toronto, Canada, created the heart cells from human embryonic stem cells %u2014 cells found in developing embryos that have the potential to develop into any type of human tissue.

The team found that, by treating the embryonic stem cells with hormones called growth factors, they could encourage them to develop into a type of cell called cardiovascular progenitors. These cells, in turn, have the potential to become any of three specialized types of heart cell %u2014 two muscle cell types (cardiomyocytes and vascular smooth muscle) and endothelial cells, which form the lining of structures such as the heart's walls.

When these progenitor cells were grown in a dish, they developed their own intrinsic 'heartbeat' %u2014 one of the key characteristics of heart tissue %u2014 the researchers report online in Nature 1.

What's more, when Keller and his colleagues transplanted a mixture of the three cell types into the hearts of mice with simulated heart disease, their heart function improved significantly, although the researchers don't know whether the improvement would be sustained throughout life.
Mend a broken heart

"This is exactly what you would like to transplant into a heart," says heart physiologist Bernd Fleischmann of the University of Bonn, Germany. Although not yet tested in humans, the technique could offer a useful way to patch up heart muscle damaged by a heart attack.

However, absent from the mix is another type of cell called fibroblasts, which provide structural support for heart tissue, Fleischmann points out. "I am not sure whether these [cardiovascular progenitor] cells could also form fibroblasts," he says.

But fibroblasts may not even be necessary, says Keller. Three-dimensional cardiac grafts could potentially be grown on artificial structures instead, he says.

Researchers would also like to see the test done on a wider range of embryonic stem cell lines, to ensure that the trick is possible with any given embryonic stem cell.

Last year, Fleischmann's research team successfully repaired mouse hearts using muscle progenitor cells taken from mice embryos and nurtured to become implantable heart tissue (see 'Cells mend damaged mouse hearts'). The new treatment uses cells taken from an even earlier point in development, which are easier to obtain.
Patient matched

The next step, Fleischmann predicts, will be to develop similar treatments using patients' own cells. But this requires cell biologists to master a way of creating patient-matched embryonic stem cells, either through cloning, or by reprogramming adult cells into 'induced pluripotent' cells.

If the latter can be mastered, it would allow patients with heart disease to be given patches of new heart cells grown from their own adult cells, without using an embryo.

But it is hard to know if such a procedure can be made effective and safe. "That's the million-dollar question," says Chris Denning, who studies iPS cells and heart development at the University of Nottingham, UK. But he remains confident. "It will take time, but I think this problem will get cracked."

Keller's group is also pursuing the option of induced pluripotent cells. "That will be the next thing we'll go for aggressively," he says.

Source

http://www.nature.com/news/2008/080423/full/news.2008.775.html

Nanotope: Regenerative Medicine Company in IL

Matt Daniels — Fri, 18 Apr 2008 09:25:00 -0700

Description

"Nanotope is a regenerative medicine company that leverages a core set of proprietary technologies to address multiple therapeutic markets. This highly flexible and customizable platform was first developed at Northwestern University by Dr. Samuel I. Stupp, Professor of Materials Science & Engineering, Chemistry and Medicine and Director of the Institute for BioNanotechnology in Medicine (IBNAM). Nanotope is developing a suite of products, each customized to regenerate specific tissues; including neuronal, vascular, bone, myocardial, and cartilage. The products are injectable compounds that work with surviving cells in and around the point of damage to initiate and support tissue regeneration and growth. Once regeneration is complete, the compounds are safely broken down and removed by the body. Nanotope’s lead products target neuron regeneration for prevention or reversal of paralysis associated with spinal cord injury and angiogenesis for advanced wound healing and the treatment of peripheral artery disease."

The Technology:

Nanotope is building a suite of products to be injected into injured tissue, or in the case of wound healing, to be applied topically. Upon injection, the products form a substrate that actively directs surviving cells to re-grow damaged tissue. The technical basis underlying this is a customizable chemical matrix, or gel, of nanofibers that provides three-dimensional bioactive scaffolding in which cells and tissues may grow and differentiate. Two primary features of the gel are its customizable bioactivity and controlled gelation. These features result from engineered small individual molecules that self-assemble into nanofibers under physiological conditions. This proprietary technology was developed by Dr. Samuel Stupp at Northwestern University.

The molecules forming the gel have two distinct regions: a hydrophilic head region that confers bioactivity to the gel and a hydrophobic tail. The molecules are entirely customizable to control everything from the rate of self-assembling to the type of bioactivity conferred by the fully-formed gel of nanofibers. The bioactive head region is a short peptide sequence derived from a protein or peptide that exerts an influence of interest on target tissues. The number of different bioactive regions is limitless and may be engineered to elicit specific cell responses. It is this factor that allows Nanotope to use the same core technology for regeneration of different types of tissues.

This technology provides a flexible and broad platform of “smart” materials to elicit tissue regeneration and healing across diverse cell types when it would otherwise not occur.

Future of chemistry

Source

http://www.nanotope.com/index.php

Nanofibers Shown to Heal Spinal Cords in Mice

Matt Daniels — Fri, 18 Apr 2008 09:19:00 -0700

Description

Injected directly into the spinal cords of paralyzed mice, a new material restores use of the animals' hind legs.

From MIT Technology Review:

An engineered material that can be injected into damaged spinal cords could help prevent scars and encourage damaged nerve fibers to grow. The liquid material, developed by Northwestern University materials science professor Samuel Stupp, contains molecules that self-assemble into nanofibers, which act as a scaffold on which nerve fibers grow.

Stupp and his colleagues described in a recent paper in the Journal of Neuroscience that treatment with the material restores function to the hind legs of paralyzed mice. Previously, researchers have restored function in the paralyzed hind legs of mice, but those experiments involved surgically implanting various types of material, while the new substance can simply be injected into the animals. The nanofibers break down into nutrients in three to eight weeks, says Stupp.
...
Other researchers have tried to regenerate nerve fibers using various approaches. They have used natural materials such as collagen as well as synthetic biodegradable polymers to make scaffolds that support nerves, helping them to grow. Implanting these materials at the injury requires surgery.

The new material is different because the researchers can inject it as a liquid directly into the spinal cord. Negatively charged molecules in the liquid start clumping together when they come in contact with positively charged particles such as calcium and sodium ions in the body. The molecules self-assemble into hollow, cylindrical nanofibers, which form a scaffold that can trap cells. On the surface of the nanofibers are biological molecules that inhibit scars and encourage nerve fibers to grow.
...
The researchers stimulated a spinal cord injury in mice and injected the material 24 hours later. They found that the material reduced the size of scars and stimulated the growth of the nerve fibers through the scars. It promoted the growth of both types of nerve fibers that make up the spinal cord: motor fibers that carry signals from the brain to the limbs, and sensory fibers that carry sense signals to the brain. What is more, the material encouraged the nerve stem cells to mature into cells that create myelin--an insulating layer around nerve fibers that helps them to conduct signals more effectively.

Nine weeks after the injections, the mice that had been treated showed improvements over untreated mice. The animals could support their body weight on their hind legs and lift their lower bodies. "Animals that couldn't use hind legs at all now had improved ability to use their hind legs," Kessler says. "It was certainly not a cure but quite a substantial improvement in function. They're able to navigate around their cages."

Stupp has cofounded a Stokie, IL-based company called Nanotope, which is working on developing the self-assembling nanofiber therapy for human beings. The first step would be making a material that meets Food and Drug Administration standards and then testing it in clinical trials. So far, Kessler says, some basic tests of the material on human cell cultures have so far shown no apparent toxic effects.

Physics & Space Science

Source

http://www.technologyreview.com/Nanotech/20534/page1/

http://www.nanotope.com/

Selling Stem Cells

Matt Daniels — Wed, 09 Apr 2008 09:24:39 -0700

Description

BioTime's Michael West wants to standardize and commercialize stem cells for scientist.

A California biotech company headed by Michael West, a prominent scientist and entrepreneur involved in stem cell research, plans to supply scientists working with stem cells the tool they most need to develop and test novel therapies--a reliable and reproducible source of the cells.

Stem cells hold great promise for medicine, both as a potential source of replacement cells for damaged organs and as a scientific resource to study disease and develop and test new drugs. But to realize that promise, scientists have to figure out how to make their products on an industrial scale. "It's clear we'll need a much better strategy for reliably and reproducibly generating large numbers of specific cell types," says Arnold R. Kriegstein, director of the Institute for Regenerative Medicine at the University of California, San Francisco. "Most studies until now have stopped short of doing this."

The very qualities that make stem cells so desirable--the ability to self-replicate and develop into many types of cells--can also make them difficult to control. For example, two cell lines produced the same way but from different starting materials don't always behave the same, a property that's essential for both cell-based therapies and scientific studies.

West, CEO of BioTime and its subsidiary, Embryome Sciences, plans to sell lines of cells that he dubs "human embryonic progenitors"--cells that have inched partway along the continuum from embryonic stem cell to differentiated adult cell. West and collaborators published a paper last week describing their efforts to generate cells that reproduce only the same type of cells, theoretically creating a better-defined cell product.

Source

http://www.technologyreview.com/Biztech/20533/

http://www.biotimeinc.com/

Using by-product tissues as stem cell sources

Attila Csordas — Fri, 23 Nov 2007 19:01:35 -0800

Description

I call by-product human tissues the ones that are not needed for the human body after filling their essential function in the body, like menstrual blood, amniotic fluid, placenta and umbilical cord blood. It is a somewhat very positive idea that these human tissues previously considered as waste products, the placenta (1) the umbilical cord (2) are radically reinterpreted as valuable sources of prospective therapies due to the current results of stem cell research and regenerative medicine.

Exactly this reinterpretation is taking place now with the cells of the regularly produced menstrual blood flow as the first commercially available menstrual stem cell service (managed through Fedex), C’elle was launched by cord blood banker Cryo-Cell.

According to a freshly published article (3): "Angiogenesis is a critical component of the proliferative endometrial phase of the menstrual cycle. Thus, we hypothesized that a stem cell-like population exist and can be isolated from menstrual blood. Mononuclear cells collected from the menstrual blood contained a subpopulation of adherent cells which could be maintained in tissue culture for >68 doublings. and retained expression of the markers CD9, CD29, CD41a, CD44, CD59, CD73, CD90 and CD105, without karyotypic abnormalities. Proliferative rate of the cells was significantly higher than control umbilical cord derived mesenchymal stem cells, with doubling occurring every 19.4 hours. These cells, which we termed "Endometrial Regenerative Cells" (ERC) were capable of differentiating into 9 lineages: cadiomyocytic, respiratory epithelial, neurocytic, myocytic, endothelial, pancreatic, hepatic, adipocytic, and osteogenic. Additionally, ERC produced MMP3, MMP10, GM-CSF, angiopoietin-2 and PDGF-BB at 10-100,000 fold higher levels than two control cord blood derived mesenchymal stem cell lines. Given the ease of extraction and pluripotency of this cell population, we propose ERC as a novel alternative to current stem cells sources."

So the characteristics of these menstrual stromal cells could easily be compared to the more established mesenchymal stromal cells from the bone marrow but their collection is non-invasive and pain free I’d like to highlight 2 differences: the menstrual derived cells express embryonic like cell surface markers like SSEA and Oct4 (warning: maybe Oct4 is not important for self-renewal and maintenance of somatic stem cells at all) compared to the mesenchymal cells, while the mesenchymal stromal cells are better in their immunological properties as in some cases they are even able to suppress immunological reactions, while the menstrual cells said to be demonstrated a weak stimulatory response which suggests potential use in first-degree relatives (if the source is the mother, it is probably no good for the father) but not in distant relatives.

The professional jargon would rather call those cells stromal cells as they are not adult stem cells in the sense of being in the adult organism throughout the life and retaining some renewing capacity.

What are the implications of this work?

the collection and storing of by-product tissues as stem cell sources can easily be commercialized and opens up a big marketplace in biotech;
The recycling of by-product tissue as stem cell sources can become the strong rivals of embryonic or adult somatic stem cells concerning future regenerative medicine therapies;
The recycling of by-product tissue as stem cell sources is ethically uncontroversial compared to embryonic stem cells.

Peer review literature

1. Miki et al. Stem Cell Characteristics of Amniotic Epithelial Cells Stem Cells Vol. 23 No. 10 November 2005, pp. 1549 -1559 http://stemcells.alphamedpress.org/cgi/content/short/23/10/1549
2. Secco et al.: Multipotent Stem Cells from Umbilical Cord: Cord is Richer than Blood! Stem Cells. 2007 Oct 11
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17932423&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubm...
3. Meng et al. Endometrial regenerative cells: A novel stem cell population Journal of Translational Medicine 2007, 5:57doi:10.1186/1479-5876-5-57 http://www.translational-medicine.com/content/5/1/57

Blog:

Pimm: Collect and FedEx menstrual stem cells with the C’elle kit: the next flow
http://pimm.wordpress.com/2007/11/06/collect-and-fedex-menstrual-stem-cells-with-the-celle-kit-the-next-flow/

Signals

Finding new adult stem cell repair mechanisms

Attila Csordas — Fri, 23 Nov 2007 17:09:46 -0800

Description

A focus shift is taking place in current adult stem cell biology. So far the two main candidate repair mechanisms for adult stem cells were transdifferentiation and fusion. The concept that lineage specific adult stem cells can change their fate, is called transdifferentiation (Mezey et al., 2000). The other basic and proposed regenerative mechanism is cell fusion between the transplanted cells and the damaged tissue cells (Nygren et al., 2004, Nat Med. One population of bone marrow derived cells, the mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) (Prockop, Science) are able both to self-renew and differentiate into various cell types (cartilage, bone, muscle, tendon, ligament, and fat) in vitro and are present in many other tissues including fat, bone, skin, umbilical cord blood.(4)

Adult stem cells originally attracted attention because of the their stem cell-like properties, but the cells frequently repaired injured tissues and produced functional improvements without much evidence of either engrafment or differentiation. In transplantation trials the levels of donor MSCs detected in bone, skin and other tissues was less than 1% and it seemed probable that they are able to repair tissues in other and multiple ways too.

Impact:

Future areas of research based mainly on Prockop DJ. Clin Pharmacol Ther. 2007 Sep;82(3):241-3.;
Secreted cytokines and chemokines: Recently, stem cell based regeneration in the heart (reviewed in Srivastava-Ivey, 2006, Nature) by transdifferentiation has been challenged and it was indicated that bone marrow derived mesenchymal stem cells do not transdifferentiate into hepatocytes (Murry et al, 2004, Nature). Instead it was suggested for the myocardium at least, that paracrine factors secreted by the bone marrow cells, like thymosin beta4 could be cardioprotective or angiogenic. (Gnecchi et al, 2006, Bock-Marquette et al 2004, Nature);
Stimulation of tissue stem/progenitors;
Immunomodulatory effects of stem cells, anti-immune reactions: MSCs suppressed the mixed lymphocyte reaction in culture and shown to improve engraftment of bone marrow and graft versus host disease in patients (Le Blanc and Ringden, 2006);
Anti-inflammatory effects of MSCs: suppression of inflammation;
Mitochondrial transfer, in vitro: the transfer of mitochondria from hMSCs or fibroblast were able to rescue the aerobic respiration of respiration deficient cells in vitro (Spees et al, 2006).

Prockop DJ. "Stemness" does not explain the repair of many tissues by mesenchymal stem/multipotent stromal cells (MSCs).Clin Pharmacol Ther. 2007 Sep;82(3):241-3.
Spees JL, Olson SD, Whitney MJ, Prockop DJ. Mitochondrial transfer between cells can rescue aerobic respiration.
Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1283-8. Epub 2006 Jan 23.
Blog: Pimm: Bone marrow derived adult stem cells: which way to go? http://pimm.wordpress.com/2007/02/22/bone-marrow-derived-adult-stem-cells-which-way-to-go/

Signals

Using cancer stem cells for regenerative medicine

Attila Csordas — Fri, 23 Nov 2007 10:35:55 -0800

Description

The trendy cancer stem cell theory highlights that there is a functional hierarchy between different tumour cells and only a small portion, the so called cancer stem cells, have crucial role in initiating tumour growth. In a stronger form the assumption is that only a tiny minority of tumor cells have the ability to initiate tumor formation.

This assumption was confirmed in the case of blood (1) breast (2) and brain(3) for example. These cells are similar to stem cells in their renewing capability as they can maintain the population through the series of division as well as giving rise to a large population of differentiated progeny that make up the bulk of the tumor. Cancer stem cells are posing multiple threats: repairing the radiation induced DNA damage better than nonstem cancer cells, they can stimulate angiogenesis, the formation of new blood vessels that support tumor growth and can drive metastasis, the spread of tumor in the body. Indeed, in human pancreatic cancer a distinct subpopulation of migrating cancer stem cells turned out to be essential for tumor metastasis different from the ones responsible for tumor growth (4).

Based on the stem cell theory, a new therapeutic approach of cancer is delineated which can induce differentiation of tumour cells rather then killing them. Indeed a very natural and useful stem cell targeted therapy by concept: redifferentiate cancer stem cells into harmless and in some cases useful functional tissue cells. I call it the concept of cancer regenerative medicine: redifferentiate all the tumour initiating cancer stem cells in a patient into functional tissue and organ cells.

In a Nature article (5) Piccirillo et al. addressed the question whether the stem-like tumour initiating cell subpopulation of a glioblastoma, marked with a specific antigen, CD 133+ can be differentiated with Bone Morphogenetic Protein (BMP) into a functional type of brain cells? Glioblastoma (GBM) is the most common adult malignant brain tumour, CD133+ is a neural precursor cell marker and the members of the BMP family make neural precursor cells differentiatie into mature astrocytes, glial cells. So they were dissociating solid tumour samples into single-cell suspensions and were testing their response to BMP. The large picture is that BMP treatment (specially BMP4) reduced cancer cell proliferation, induced astrocyte-like differentiation, effectively blocks the tumour growth and prolonges survival:

These findings show that the BMP–BMPR signalling system—which controls the activity of normal brain stem cells—may also act as a key inhibitory regulator of tumour-initiating, stem-like cells from GBMs and the results also identify BMP4 as a novel, non-cytotoxic therapeutic effector, which may be used to prevent growth and recurrence of GBMs in humans.

Problem could be that certain cancer cells survived the BMP-treatment which can lead to recurrence at a longer latency. This problem could be solved with improved purification of the subpopulation of CD133+ cells, so true cancer stem cells are expected at the exit!

Combined with classical therapy BMP, redifferentiation treatment can reduce the lethality of cancer patients.

Skeptics of cancer stem cell theory have arguments too: Some argue that the original cancer-causing mutations can strike more developmentally advanced, although still immature, progenitor cells. Stem cells of a given type of cancer may arise from different cells and the origin varies from patient to patient- all the work has involved transplanting human cancer cells into immunodeficient mice. This has raised concerns that the experiments do not accurately reflect what happens during cancer development in humans.

There are several implications of this work.

“By gaining a sophisticated understanding of how normal and cancer stem cells differ, we’ll be able to design a new class of drugs that is less toxic”;
Searching for markers specific for cancer stem cell populations;
New clues on cancer development by examining cancer stem cells focusing on the different the signalling pathways needed for the maintenance and development;
Convergence of cancer and stem cell research, as both are very well funded.

Peer review literature:

1. Lapidot et al: A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994 Feb 17;367(6464):645-8.
http://www.ncbi.nlm.nih.gov/sites/entrez?holding=npg&cmd=Retrieve&db=PubMed&list_uids=7509044&dopt=AbstractPlus

2. Al-Hajj et al: Prospective identification of tumorigenic breast cancer cells PNAS 2003 100(7):3983-3988 http://www.pnas.org/cgi/content/abstract/100/7/3983

3. Singh et al. Identification of human brain tumour initiating cells. Nature. 2004 Nov 18;432(7015):396-401.
http://www.ncbi.nlm.nih.gov/sites/entrez?holding=npg&cmd=Retrieve&db=PubMed&list_uids=15549107&dopt=AbstractPlus

4. Hermann et al. Distinct Populations of Cancer Stem Cells Determine Tumor Growth and Metastatic Activity in Human Pancreatic Cancer. Cancer Stem Cell Volume 1, Issue 3, 13 September 2007, Pages 313-323 doi:10.1016/j.stem.2007.06.002

5. Piccirillo et al. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature. 2006 Dec 7;444(7120):761-5.
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17151667&query_hl=7&itool=pubmed_docsum

Professional media:

Jean Marx: Cancer's Perpetual Source? Science 24 August 2007:
Vol. 317. no. 5841, pp. 1029 - 1031 DOI: 10.1126/science.317.5841.1029
http://www.sciencemag.org/cgi/content/summary/317/5841/1029

Blogosphere:

Pimm: Redifferentiating brain tumour stem cells: the concept of cancer regenerative medicine
http://pimm.wordpress.com/2006/12/14/redifferentiating-brain-tumours-the-concept-of-cancer-regenerative-medicine/

Pimm: Biopolis profile and cancer stem cells in current Cell Stem Cell http://pimm.wordpress.com/2007/10/05/biopolis-profile-and-cancer-stem-cells-in-current-cell-stem-cell/

Signals

Reprogramming differentiated cells offers alternative to embryonic stem cells

Attila Csordas — Thu, 22 Nov 2007 08:47:03 -0800

Description

Stem cells are able to renew themselves and could differentiate into other type of cells. Regenerative medicine is the science and technology built around stem cells’ regenerative capacity. Successful reprogramming of differentiated human somatic cells into a pluripotent, embryonic stem (ES) cell-like state would allow creation of patient- and disease-specific stem cells instead of using controversial embryonic stem cells. The generation of induced pluripotent stem (iPS) cells, capable of germline transmission, from mouse somatic cells by transduction of four defined transcription factors was reported (1).

American (2) and Japanese (3) researchers recently demonstrated that the same technique (but with different set of 4 genes) can turn human cultured skin cells into induced pluripotent stem (iPS) cells that meet the defining criteria for human ES cells and are similar to ES cells in morphology, proliferation, surface antigens, gene expression, epigenetic status of pluripotent cell-specific genes, and telomerase activity. These cells could differentiate into cell types of the three germ layers in vitro and in vivo in teratomas. The significant exception is that iPS cell are not derived from the embryo nor were made by the therapeutical cloning technique in in which the nucleus of a differentiated cell is placed in an oocyte that is then activated to divide to form an embryo.

What are the future implications of these findings?

Similar to human ES cells, human iPS cells should prove useful for studying the development and function of human tissues.
Disease and patient specific cells: the reprogrammed induced pluripotent cells could be made from patients with known diseases. If the root causes of disease were genetic that could be a better way to study disease, say genetically matched cells from patients would enable them to study complex diseases, like Alzheimer’s, in the laboratory.
Discovering and testing new drugs: Human iPS cells should make it easier to generate panels of cell lines that more closely reflect the genetic diversity of a population, and should make it possible to generate cell lines from individuals predisposed to specific diseases.
For transplantation therapies based on these cells, with the exception of autoimmune diseases, patient-specific iPS cell lines should largely eliminate the concern of immune rejection.
If it works, the technique -- technically known as somatic cell dedifferentiation -- promises to solve the two great downfalls involved in producing embryonic stem cells: the controversial destruction of embryos and reliance on a limited supply of eggs.
The new method includes potentially risky steps, like introducing a cancer gene with engineered viruse. But stem cell researchers say they are confident that it will not take long to perfect the method and that today’s drawbacks will prove to be temporary. It is important to understand, however, that before the cells can be used in the clinic, additional work is required to avoid vectors that integrate into the genome, potentially introducing mutations at the insertion site.
The method is a direct rival of the other reprogramming technique called terapeuthical cloning based on somatic cell nuclear transfer.
The reprogrammed skin cells may yet prove to have subtle differences from embryonic stem cells that come directly from human embryos, and further work is needed to determine if human iPS cells differ in clinically significant ways from ES cells.

Peer-review literature:
1. K. Takahashi, S. Yamanaka, Cell 126, 663 (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006 Aug 25;126:663-76

2. Takahashi et al. (2007) Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined
Factors Cell (2007), doi:10.1016/j.cell.2007.11.019 PDF

3. Yu et al. (2007) Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells Science, Published online 20 November 2007; 10.1126/science.1151526

Media coverage:
Nature Reports Stem Cell: Human reprogramming changes everything, and nothing

Wired Science: Skin Cell-to-Stem Cell Alchemy 'Like Turning Lead Into Gold'

New York Times: Scientists Bypass Need for Embryo to Get Stem Cell

Signals

Stem Cell Research and Hopes for Cell-Based Medicine

Alex Soojung-Kim Pang — Tue, 23 Oct 2007 11:10:30 -0700

Description

Stem cell research is likely to lead to a new kind of cell-based medicine that regenerates the body, but practical and ethical challenges mean safe and effective treatments may be decades away.

Stem cells are undifferentiated cells that have the potential to develop into other more specialized cells. Stem cells are found in adults in the bone marrow, but also in embryos. While adult stems cells have been used to treat disease for several decades in bone marrow transplants, it is the progress in embryonic stem cell research that has been the source of great therapeutic hope, ethical and legal controversy, and international competition.

Unlike adult stem cells, embryonic stem cells have the potential to become any other kind of cell, which is the key to the intense interest. Novel therapeutic treatments could potentially be applied to every system in the human body. Possibilities include replacing malfunctioning liver cells or even growing entire livers to replace diseased ones, therapies for Parkinson's and Alzheimer's diseases, spinal cord injury, stroke, cancer, burns, cardiovascular disease, diabetes, osteoarthritis, and rheumatoid arthritis.

Interest in developmental biology, health and disease, medical economics, and national pride are all driving forward this relatively new research area. The technical challenges of acquiring and working with embryonic stem cells in a laboratory environment are significant but nevertheless, important breakthroughs are beginning to occur and progress in research practices in the next 5 to 10 years is possible. Practical applications of embryonic stem cell research however are likely to be decades away. Much more biological knowledge is needed before an embryonic stem cell can be guided and controlled into developing into just the right specialised, viable, and stable cell. The economic potential however is leading to immediate investment by biotechnology companies.

Because the research relies on using tissue from aborted fetuses, this research raises a number of moral, religious and political concerns about the sanctity of embryos and the use of fetal cells, as well as an uneasiness about cloning and hybridisation of species. A complicated set of rules, guidelines and practices has developed across nations, leaving considerable room for individual countries to respond to the views and concerns of their population. As a result of this lack of consensus, advances in stem cell research are most likely to be made in geographic areas with less restrictive legislation. Currently, China has the most permissive environment for research with little opposition, while the UK is a Western leader, with a strong scientific research pool and a relatively supportive public. The US restricts the flow of federal money for research but places no bans on private, state, or local government funding and American opinion fluctuates but on average is evenly divided over the issue of federal funding for stem cell research."

This will be enabled by:

"Technical improvements in handling and culturing of embryonic stem cells
Continuing lack of alternative therapies for fatal diseases
Resolution of ethical debates about the cloning and use of human embryonic stem cells and standardisation of regulations
Increased government funding driven by international competition
Greater investments from venture capitalists who are currently waiting for resolution of legal, regulatory, and medical issues"

Early indicators include:

"Development of dedicated research institutions at universities, such as the Harvard Stem Cell Institute (which has raised $30 million from foundations and private donors and is creating its own stem cell lines) and the Cambridge Stem Cell Institute (which has raised £16.5 million and plans to raise a further £33.5 million over the next five years to further its mission to 'deliver therapies in regenerative medicine at the earliest possible date')
Geron's intention to apply for FDA permission to conduct clinical trials of cells for a spinal therapy
Stem Cell Science's work on developing a treatment for Batten disease, a fatal brain disease
Public support of research by celebrities such as Michael J. Fox, Nancy Reagan, and Christopher Reeve in hopes of treatments for Parkinson's disease, Alzheimer's disease, and spinal injury
The South Korean government's issuance in February 2005 of a postage stamp in honor of Dr. Hwang Woo Suk, a pioneer of embryonic stem cell research, and its allocation of $43 million to build Dr. Suk a stem cell research centre
Passage in November 2004 of a California bill allocating $3 billion over 10 years to stem cell research"

What to watch:

Stem cell researchers become concentrated at centres focused on biomedical applications.
An international statement is issued on the ethics and practices of stem cell research encouraging a more permissive research environment.
The number of viable embryonic stem cell lines routinely used in research increases rapidly.
Large clinical trials testing treatments for incurable degenerative diseases are initiated.