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FEATURE
Stem Cell Research — The New Growth Engine
Netherlands Foreign Investment Agency

Stem cells are unique cells of early
embryos as well as the adult body
that possess the ability to divide and differentiate into diverse cell types. At the same time they maintain their own presence by cell division, resulting in the continuous presence of cells capable of regenerating adult tissues. The use of adult stem cells has been successfully employed to treat bone and blood related disorders such as leukemia, through bone marrow transplants. Currently, stem cell therapy is being developed for a variety of damaged or diseased organs such as diabetes.

Stem cell therapy is an emerging field and a large amount of research is currently being carried out by institutions such as hospitals, universities and medical centers. In Asia-Pacific, 63% of pipeline molecules are being researched by academia. The emergence of institutional research has boosted stem cell discoveries. China and Japan witness only a negligible industry presence in stem cell research, as academic institutions dominate – however in contrast, India has the presence of both industry and academia. The major institutions engaged in stem cell research in India are LV Prasad Eye Institute (LYPEI) for Limbal Stem Cell Technology (LSCT), and the Post Graduate Institute of Medical Education and Research (PGIMER) for stem cell therapy for type 2 diabetes mellitus.

With the anticipated launch of JCR Pharmaceuticals’ JR-031 in Japan in 2014, and FCB Pharmicell’s Cerecellgram (CCG) in South Korea in 2015, the stem cell therapy market is expected to grow in value from $545 m in 2012 to $972 m in 2018, at a Compound Annual Growth Rate (CAGR) of 10%.

“Stem cells are the gateway to an understanding of how we form and how our tissues degenerate. Because of that, they are at the center of large investments in developed countries and continents. They represent our great chance to find cures for many still incurable diseases,” says Ms Suzanne Sweerman, Exeutive Director, South East Asia of the Netherlands Foreign Investment Agency (NFIA).

The Dutch-European Connection

For many years now, the European Commission has been supporting research in several disciplines by stimulating the creation of research consortia. These are short-term enterprises with long-term impacts: they bring together European scientists from different nations who are among the leading experts on topics that are considered strategic for Europe. European and Dutch scientists have always been at the forefront of stem cell research and regenerative medicine. Earlier this year, the University Medical Centre Groningen in the Netherlands (in collaboration with the Hubrecht Institute in Utrecht) together with MIT (USA) was selected for a large-scale infrastructure and scientific project to develop stem cell research in Russia. The Russian Vavilov Institute of General Genetics and Moscow’s Skolkovo Institute of Science and Technology (Skoltech) set up the first Center for Research, Education and Innovation (CREI) in the field of stem cell biology. The Center will focus on various research lines, including identifying and isolating adult stem cells from tissues and organs, producing induced pluripotent stem cells (iPS cells) and reprogramming cells. Designing stem cell models for research into neurodegenerative diseases, metabolic diseases, cancer and auto-immune diseases will eventually lead to new stem cell treatment and drugs for patients.

According to Ms. Sweerman, there will be strong financial support for the CREI from the Russian government to commercialize the considerable opportunities from biomedical research. Fifteen of these five-year long research projects will be founded by 2020 and possess a cumulative budget of $675 million.

The Netherlands has also established national stem cell centers. The breakthroughs generated in the Netherlands position these national initiatives among the leading groups in the world. The Netherlands Institute for Regenerative Medicine (NIRM) is an example of an innovative and integrative life sciences research and development program. It comprises two former existing research consortia: Stem Cells in Development and Disease (SCDD) and the Dutch Program for Tissue Engineering (DPTE). Integration of these consortia in NIRM combines cutting-edge research in stem cell biology with advances in tissue engineering, so as to improve existing and create novel regenerative medical treatments.

“Together, these biomedical research fields involving cells and biomaterials will lead to innovative approaches to promote the regeneration of damaged or diseased tissues and organs,” Ms. Sweerman says.

Some of the exciting research taking place in the Netherlands includes:

Stem Cells and Cancer

The same biological signals that cause the formation of wings in the fruit fly are responsible for tissue maintenance in our organs. One of the key regulators of this universal communication mechanism between cells in all organisms from mollusk to vertebrate is the Wnt signal pathway. The study of this pathway is one of the ongoing interests of Professor Hans Clevers of the Netherlands’ Hubrecht Institute. In numerous groundbreaking publications, the biologist and medical doctor deciphered the role of Wnt signals for stem cells and cancer.

The focus of his research is on the epithelial cells that form the inner lining of the intestine. In order to enhance the uptake of nutrients, the gut surface is enlarged by millions of small cavities and finger like protrusions or villi. The short-lived, specialized cells of the intestinal mucosa have to be permanently renewed by stem cells that are settled in the lower part of the cavities. During maturation and specialization these cells move to the top of the villi where they finally shed off into the lumen of the intestine.

Professor Clevers demonstrated that if the Wnt signaling pathway is blocked, the supply of fresh specialized cells ceases and stem cells disappear from the intestine. The converse is true for the development of cancer. In almost every case of colon carcinoma, activating mutations of the Wnt signaling pathway are found, mostly within the APC gene. He was able to show that mutations in this gene result in permanent activation of the Wnt signal, putting cells into a dividing stem cell like state. In this diseased state they escape differentiation and cell death resulting in the accumulation of dividing non-functional cells. Accumulation of additional mutations leads to a metastatic tumor. Ever since the lab of Hans Clevers identified the Wnt pathway as the major player in the onset of cancer, it has become n important target for the development of new therapies against cancer.

A recent breakthrough from Professor Clevers’ group was the recent identification of a Wnt pathway target gene, the membrane protein Lgr5 that is unique in that it marks small cycling cells at crypt bottoms. Subsequently, he was able to identify that the cells are stem cells of the small intestine and colon, the hair follicle, the stomach, the liver and the pancreas.

The study of these stem cells revealed that given the right growth conditions mimicking in vivo physiological requirements, we could establish an in vitro culture of healthy and diseased human tissue with virtually unlimited expansion capacity. More importantly and in contrast to all previous attempts, the organoids maintain histologically and genetically normal characteristics. Therefore the cells represent a unique new source of cells for regenerative medicine as well as a source of cells for drug development.

“A better understanding of cancer developement is vital to the quest for new treatment methods. Clevers’ research makes the possibility of regenerative medicine more realistic,” Ms. Sweerman proudly adds.

In February 2013, Professor Clevers became one of eleven recipients of the Breakthrough Prize in Life Sciences for his work on Wnt signaling in tissue stem cells and cancer. Silicon Valley aristocrats Mark Zuckerberg, Sergey Brin and Yuri Milner jointly established this most lucrative annual prize to recognize excellence in research aimed at curing intractable diseases and extending human life.

Crippling Osteoarthritis

A revolutionary jab made from stem cells found in tummy fat could soon stop osteoarthritis in its tracks. The breakthrough provides hope for millions of people around the world who suffer from the incurable condition and could potentially save thousands from needing joint replacement surgery. Dutch and French researchers found that injecting stem cells harvested from a patient’s own waistline protects joints against crippling damage. It appears to be the closest experts have come to halting the disease using stem cells.

The therapy works by stopping destruction of cartilage – the ‘shock absorber’ tissue inside which gets ground down by osteoarthritis – and by protecting ligaments.

A single dose of stem cells extracted from adipose tissue – fat which accumulates around the stomach – more than halved damage to knee joints in mice. The findings, revealed at the American College of Rheumatology in Chicago, could mark a turning point in the search for a treatment.

Many sufferers rely on anti-inflammatory painkillers to ease their suffering, but these can damage the stomach if used long-term. About 60,000 people a year end up needing a knee replacement.

Significantly, adipose tissue is relatively easy to access and is thought to be the most abundant source of adult stem cells in the body. According to some estimates, it contains 40 times more stem cells than bone marrow. Scientists are already using these fat cells in the search for cures for cancer, heart disease and spinal injuries.

Researchers at Radboud University in the Netherlands and the National Institute of Health and Medical Research in France injected adipose stem cells into the joints of mice with arthritic knees. The cells, known as mesenchymal cells, have the capacity to grow into a variety of body tissues. Some mice received the jab seven days after osteoarthritis first set in, others 14 days after – which would translate into a few weeks or months in humans.

When it was given sooner, the jab cut destruction of cartilage by 54% compared with those injected with a dummy jab. After six weeks, they had half the amount of ligament damage. The jab also slowed a process called synovial activation, where the soft membrane around the joint becomes inflamed, in some cases by as much as 30%.

Treating Burn Victims

Traditional non-communicable diseases like diabetes, cancer and cardiovascular diseases continue to receive much attention from the international community and have seen developments all across the globe, albeit more extensively by the Dutch. However, the Dutch have gone beyond the traditional definition of non-communicable diseases to include the plight of burn victims.
Four students from the Dutch University of Leiden have pioneered an award-winning concept for the treatment of burns victims: 3D printed skin. Their project ‘SkinPrint’ has already won the largest student entrepreneurship award in the Netherlands and looks set to revolutionize the treatment of burns patients.

Skin grafts are a painful but necessary part of the current treatment of burns. However, harvesting skin from suitable sites on the body is painful, time-consuming and not always possible. SkinPrint hopes to answer these shortcomings by combining a 3DBioprinter with the advanced technology of induced Pluripotent Stem Cell (iPS), which enables the creation of stem cells from specialized cells, such as hair or skin cells. These cells are then used as the ‘ink’ for the bioprinter.

The printed cells eventually go on to form all the layers of the skin. With the use of iPS personalized medicine is achieved: the patient is treated with material derived from his or her own cells. The team is working with renowned Swiss skin expert Ernst Reichmann and hope to gain necessary approvals from the European Medicines Agency for their process.

Hospitals should be able to offer printed skin treatments within five years.

A Promising Future

Although promising, stem-cell research remains at a very early stage and few human trials have taken place. But scientists are already excited about its potential impact on regenerative medicine. There is growing evidence that stem cells can be used to treat currently untreatable diseases or offer a viable solution to the limited availability of donor material for whole organ transplantation. An important challenge for the near future is to establish safe production protocol and efficient transplantation technologies to translate stem cell research to an effective therapy.

Medical researchers believe that in the future it will be possible to use stem cells to treat diseases such as diabetes, heart disease, HIV/AIDS, hepatitis, arthritis and cancer that are problematic in the developing world.

About the NFIA

The NFIA (Netherlands Foreign Investment Agency) is an operational unit of the Ministry of Economic Affairs. The NFIA helps and advises foreign companies on the establishment, rolling out and/or expansion of their international activities in the Netherlands. The NFIA was established more than 35 years ago, and has since then supported more than 3,300 companies from nearly 0 countries in the establishment or expansion of their international activities in the Netherlands. Besides its headquarters in The Hague, the NFIA has its own offices in the United Kingdom, Turkey, North America, Asia and the Middle East, as well as a representative office in Brazil. Additionally, the NFIA works together with Dutch embassies, consulates-general, and other organizations representing the Dutch government abroad, as well as with a broad network of domestic partners.

For more information on stem cell research and investment opportunities in the Netherlands, contact the Netherlands Foreign Investment Agency: Ms Suzanne Sweerman, Executive Director, South East Asia at Tel: +65 67391135, Email: sweerman@nfia-singapore.com / Ms Adeline Tan, Senior Project Manager at Tel: +65 67391137, Email: tan@nfia-singapore.com or visit www.nfia-singapore.com

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