Strengthening stem cell research
Published online 23 May 2012
Remarkable strides are being made in stem cell research at the A*STAR Institute of Bioengineering and Nanotechnology, leading to the development of novel therapeutic and diagnostic strategies
Stem cell research may continue to give rise to novel medical breakthroughs
As the world’s first bioengineering and nanotechnology institute, the A*STAR Institute of Bioengineering and Nanotechnology (IBN) has gained international prominence for its exceptional multidisciplinary approaches to biomedical research. Not limiting its scope to materials science and nanotechnologies, the Institute is also surging ahead on developments based on stem cell research.
In recent weeks, IBN has released breakthrough news on two fronts — a promising discovery for breast cancer therapy and a novel approach to drug screening, both of which demonstrate the power of harnessing stem cell-based research.
In a landmark finding that may impact future courses of cancer treatment, a group of IBN researchers at the Institute's Drug and Gene Delivery Research Group has shown that neural stem cells (NSCs) have an innate ability to target tumors outside the central nervous system1. Based on a series of mouse experiments, the IBN study is the first of its kind to demonstrate that NSCs derived from human induced pluripotent stem (iPS) cells could target cancerous tissues other than those in the brain, such as breast tumors and cancerous cells in the lung, stomach and bone.
“We have generated a new type of cells with tumor-homing property from freshly-produced human pluripotent stem cells. Using our in-house baculoviral transduction technology, we can engineer the cells into cancer gene therapy delivery vehicles," explains Shu Wang, IBN Group Leader.
In vivo imaging to demonstrate the tumor tropism of human iPS cell-derived neural stem cells (NSCs) in normal mice (without tumor) and in mice with tumor (4T1) using the dual-colored whole body imaging technology (DiR near-infrared fluorescence and bioluminescence imaging).
What makes the IBN group’s approach particularly outstanding is that using iPS cells to derive NSCs would enable an efficient and reliable method of standardizing and producing cell therapy products in large quantities. As the iPS cells are developed from the patient’s own cells, the new method would not only reduce the chances of immune system rejection, but also circumvent ethical concerns surrounding the use of human embryonic stem cells for innovative stem cell therapies. “It should also be possible to prepare cryopreserved iPS cell-derived cellular vehicles as commercial products in a ready-to-go format. Hence, these cellular vehicles hold great potential for commercialization,” adds Wang.
Conducting their in vivo experiments at A*STAR’s state-of-the-art Biological Resources Center at Biopolis, the research team is continuing to focus on optimizing their novel tumor-targeting approach so as to prevent any unwanted activation of the therapeutic gene in non-cancerous regions of the body and minimize potential side effects.
"Considering the short history of human embryonic stem cell research, this first human embryonic stem cell-based therapy is an extremely rapid development. In view of strong research interest in cell-based cancer therapy, the long-term outcome of the invention in commercial applications in the fields of biomedicine and biotechnology will be significant," says Wang. "We believe that our technology will be helpful for Singapore to capitalize on cell-based cancer therapy using human pluripotent stem cell-derived cellular biologics."
The 'Droplet Array'
The development of drug screening technologies is another significant area of research at IBN. In a move that may greatly facilitate cancer therapy research, a research team led by Jackie Y. Ying, Executive Director of IBN, has developed a biochip that is capable of analyzing the effect of drugs on cancer stem cells (CSCs)2, a rare form of cancer cells that are typically more resistant to chemotherapeutic drugs than other cells in a tumor.
The miniaturized technology, which has been patented and named the ‘DropArray™’, stands apart from other biochips developed to date in several respects: “In traditional biological assays, microplates — a flat plate with multiple wells in which samples are placed — are commonly used. Each well requires the presence of at least 2,500 or 5,000 cells, depending on the type of plate used, for viable analysis,” explains Ying. “By comparison, IBN’s Droplet Array is a flat, rectangular glass plate on which a series of spots, each two millimeters in diameter, are arranged.”
Sample ‘droplets’ can then be pipetted onto these two-millimeter-diameter spots, after which the Droplet Array is coated with a layer of proprietary oil to prevent evaporation and cross-contamination between the droplets during the rinsing process. “Being one-fifth the size of a well in a standard microplate, each spot on IBN’s Droplet Array requires only 500 cells for screening,” says Ying. “This massive reduction in sample volume not only saves money, but is also particularly advantageous for studying limited samples containing scarce cells, such as cancer stem cells.”
IBN’s Droplet Array technology
The Droplet Array could also potentially reduce industry reliance on animal experiments, as in vitro results may complement or replace those achieved through animal studies. “This is timely in light of the European Commission (EC) ban on testing cosmetic products and ingredients on animals and the EC ban on marketing cosmetic products that contain ingredients that have been tested on animals,” says Ying.
So far, the Droplet Array has been used to examine drug responses of CSCs extracted from breast, liver and colon cancer cells. (See also Nanoengineering: Targeting cancer stem cells). “It was found that chemotherapeutic drugs such as doxorubicin, which usually induce cell death in liver cancer cells, demonstrated poor efficacy in liver CSCs,” says Ying. “The CSCs from the breast and colon tumors also showed much greater ability to survive the effects of anti-cancer drugs. By providing a viable platform to investigate the effect of anti-cancer drugs on CSCs, the Droplet Array technology could boost the development of more effective cancer drugs.”
Commenting on some of the challenges faced by the research group during the development of the novel biochip, Ying notes, “The main challenge was to overcome the issues of sample scarcity and purity while deriving cancer stem cells for biological studies. We found the answer by using the Droplet Array technology to study drug resistance in cancer stem cells. Our novel platform can maximize the use of scarce and precious cells like cancer stem cells in drug screening.”
Success through collaboration
The type of collaborative work that led to the discovery of human neural stem cells with tumor targeting ability and the development of the Droplet Array demonstrates the effectiveness of interdisciplinary approaches to problem-solving, which have clearly become the order of the day at IBN.
Ying comments, “IBN advocates a multidisciplinary approach to solving exciting and challenging biomedical problems. The teams at IBN are project-based rather than discipline-based, and we encourage our researchers, who come from diverse backgrounds and specializations in science, engineering and medicine, to interact and collaborate with each other, because better and more comprehensive solutions emerge when different fields of expertise come together.”
About the Institute of Bioengineering and Nanotechnology
The Institute of Bioengineering and Nanotechnology (IBN) was established in 2003 and is spearheaded by its Executive Director, Professor Jackie Yi-Ru Ying, who was on the Massachusetts Institute of Technology's Chemical Engineering faculty between 1992 and 2005, and was among the youngest to be promoted to Professor in 2001. Under her direction, IBN conducts research at the cutting-edge of bioengineering and nanotechnology. Its programs are geared towards linking multiple disciplines across engineering, science and medicine to produce research breakthroughs for improved healthcare and quality of life.
- Lee, Y. Y., Narayanan, K., Gao, S. J. and Ying, J. Y. Elucidating drug resistant properties in scarce cancer stem cells using droplet microarray. Nano Today 7, 29–34 (2012). | article
- Yang, J. et al. Tumor tropism of intravenously injected human induced pluripotent stem cell derived neural stem cells and their gene therapy application in a metastatic breast cancer model. Stem Cells doi: 10.1002/stem.1051 (2012). | article