Regenerative Medicine at Harvard

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Medical Milestone: Doug Melton, co-director of the Harvard Stem Cell Institute, says that distributing induced pluripotent stem cells to researchers around the world will advance the study of degenerative diseases like Parkinson’s and diabetes.
Credit: B. D. Colen/ADIOL

Biologist Doug Melton talks about how disease-specific stem cells will reshape medicine, in a stem-cell revolution

MIT Technology Review, Fall 2008, by Emily Singer — Scientists at Harvard University recently announced a much anticipated milestone in regenerative medicine: the creation of stem cells from patients with a variety of diseases. The cells, which can be encouraged to develop into cell types damaged by disease, such as the insulin-producing cells in diabetes or neurons in Parkinson’s, are poised to give scientists an unprecedented view of disease.

Scientists have hoped to create such cells for more than a decade, initially attempting the feat through human cloning. But cloning proved more challenging than expected, and it wasn’t until the introduction of a novel technique, developed recently in Japan, that they succeeded. By exposing a patient’s skin cells to four genetic factors found in the developing embryo, scientists can turn back the clock, triggering the cells to look and behave like embryonic stem cells. Known as induced pluripotent stem cells (iPS), they eliminate the need for human eggs or the creation or destruction of embryos, thus bypassing major ethical and technical hurdles that have plagued the field of embryonic stem-cell research.

The scientists who created the cells at the Harvard Stem Cell Institute, including George Daley and Kevin Eggan, now plan to distribute them to colleagues around the world. Doug Melton, codirector of the institute and a longtime champion of stem-cell research, talks with Technology Review about the future of the field.

Technology Review: Why are disease-specific cell lines so important?

Doug Melton: If a patient has Parkinson’s disease, their dopamine-producing cells are gone. We don’t understand anything about what makes those cells go away–the field is kind of stuck because you can’t watch the progression of the disease.

Stem cells can make neurons in a dish. Imagine you have iPS cells from a healthy person and from a Parkinson’s patient. If you make dopamine neurons from both sets of cells in separate dishes, you can look at what went wrong with the diseased stem cell. The same approach will work with different degenerative diseases, such as diabetes or ALS [amyotrophic lateral sclerosis, a motor-neuron disease].

TR: How long will it take to get insight into these diseases?

DM: For ALS, Kevin Eggan published a paper on mice showing he could see a defect in cell survival in motor neurons [made from cells derived from an animal model of the disease]. He is now looking for that defect in human cells. The next step would be to determine if that defect is the same in all patients.

TR: Where will this field go in the future?

DM: I think it will change the way degenerative diseases are studied–we’ll reduce the whole process of disease to a petri dish. Within a few years, researchers the world over should have access to disease-specific cells that can be turned into cell types defective in a particular disease.

We can also start to study environmental factors. We know sun is important for skin cancer, and smoking is important for lung cancer. But what do we know about Parkinson’s, Alzheimer’s, ALS, and diabetes? That’s hard to study in people because there is a long time between the proximal cause and effect.

Now, scientists can start to think more about how to look at environmental factors in a dish. Let’s take food, oxidative insults, pesticides, and extracts and ask how they affect the cells. Scientists can also screen for drugs that slow or stop degeneration of those cells. If that were successful–and now we’re talking about a decade-long project–you could make a drug that would slow or stop disease progression.

TR: The Harvard Stem Cell Institute is planning to distribute these cell lines to scientists. Why?

DM: Science clearly works best when you have a lot of bright, motivated people working on these problems. The institute has sent thousands of human embryonic stem-cell lines to hundreds of labs all over the world. We like to think that has been helpful in encouraging basic research on embryonic stem cells. The new cells reported by George Daley and his colleagues may be in some instances even more helpful. They are more than just iPS cells; they are disease-specific stem cells.

TR: Do Harvard scientists plan to make more cell lines?

DM: Yes. These first lines are just the beginning.

TR: Why do you plan to make multiple lines for a single disease?

DM: To continue with the Parkinson’s example, suppose you have 50 people with Parkinson’s disease. We know that when they have the disease, dopamine neurons are gone. But we don’t know how many different ways their neurons are destroyed. Are there 50 different ways those neurons go kaput? It’s possible that in every case genetics and the environment conspire to make the same defect in the life of those neurons. If we’re going to watch the cells become defective, we want to make 50 dishes from 50 different patients. I hope they all get defective in the same way; that would make it much easier. If not, each variation might require its own strategy for treatment.

TR: How much will the cells cost?

DM: There will be a nominal cost for academics. We don’t have a plan for industry yet.

FDE426CC-04C8-42E9-A41D-A3EEBB3896A9.jpgUntil the end of September 2007, Prof. Dr. Nils Haberland was chief physician of the neurosurgery and neurotraumatology department at the Berufsgenossenschaftliche Unfallsklinik in Frankfurt am Main. Since October 2007, he has assumed an internationally recognized position as the Chairman of the International Spine Center Cairo (ISCC) at the Egypt Air Hospital in Cairo. In addition, he is working for the International Neuroscience Institute (INI) in Hannover. The stem cell concentrates applied by him are prepared in a patented process in cooperation with the XCell-Center.

Dr. Haberland, as a neurosurgeon you have been working until now mainly with the help of highly precise, computer supported operative procedures.

What moved you to dedicate yourself to adult stem cells as a treatment vehicle?
Because of high tech neurosurgery, we are today in the position of operating on many diseases of the spinal column and the brain with minimal intrusion and with excellent clinical results. Injuries and damage to the spinal cord or to the brain require, however, the additional processes that regenerative medicine can provide in order to, for example, repair the spinal cord of paraplegics. Which diseases have treated with adult stem cells so far? We have applied these modern and new therapies in the first instance in the case of incomplete paraplegic syndromes. We also have experience with stroke patients and are developing initial experience with multiple sclerosis patients.

Can you describe the course of treatment? How do you apply the stem cells?
Operative interventions are minimally invasive procedures. Initially approx. 200ml of bone marrow is harvested under local anesthesia from the rear iliac crest from which the stem cells are isolated in a special laboratory. The prepared stem cells are then applied in the patient either in a lumbar punction or through a direct injection in the damaged region of the central nervous system.

How are the results? Could you mention one or two examples?
In the case of incomplete paraplegia – even in high level cases – we have seen significant clinical improvements already three months after treatment in spasms, bladder-colon disturbances, sensitivity, and motor functions. Not all deteriorations improve. However, this therapy can be repeated after six months or a year thus allowing for further progress. We also saw an excellent result immediately with the first treated patient, a forty year man, who came to us with incomplete traumatic cervical hemiplegic symptoms. After treatment with his stem cells prepared from his own body, a complete regression of his symptoms was indicated. He now works full-time as a businessman. Another patient, a 53 year old man with high level, but still incomplete cervical symptoms of paraplegia, also showed after treatment significant results in the form of a restored bladder functions and a partial restoration of sensory and motor deterioration and spastics.

What risks do you see in the application of adult stem cells?
Until now we saw no specific complications regarding adult stem cell therapy, because we have been removing stem cells from the patient’s own body. The known risks with embryonic stem cell therapy do not exist in this case.

What can you say about the effectiveness of stem cell therapies?
Stem cell therapy takes advantage of the ability to develop stem cells in dependence on the application location in various highly specialized tissues, such as the spinal cord and the brain similar to the processes in embryonic development.

PRESS RELEASE

— Award Places VistaGen among First Group of Companies to Receive Funding —

SOUTH SAN FRANCISCO, Calif., Dec 16, 2008 (BUSINESS WIRE) — VistaGen Therapeutics announced today that the California Institute for Regenerative Medicine (CIRM), the State’s stem cell agency, has awarded a major grant to the Company to expand ongoing development and commercialization of its leading-edge stem cell-based technologies designed to predict clinical safety and efficacy of new drugs in ways never before possible.

VistaGen is among the first group of for-profit stem cell companies to secure CIRM funding as part of the Institute’s new “Tools and Technologies” research and development program.

Ralph Snodgrass, Ph.D., VistaGen’s CEO, explained that this timely new CIRM grant, valued at nearly $1 million, “will allow us to expand our core stem cell technologies for producing human liver cells into more advanced biological research tools to enable the pharmaceutical industry to identify and develop safer drugs more efficiently. Liver toxicity is very costly to the pharmaceutical industry, and is one of the two most common causes of drug failures.” VistaGen Senior Scientist, Dr. Kristina Bonham, will serve as principal investigator for the CIRM-funded study program.

Established in California in 1998, VistaGen is one of the world’s leading companies focused on using the power of stem cell technologies to transform the ways new drugs are discovered and tested. CIRM is the California state stem cell agency that administers $3 billion in voter-approved funding for stem cell research in California. The new grant funding awarded to VistaGen is an example of the direct entry into CIRM-funded initiatives by the commercial sector of California’s biotech industry. All prior CIRM research grants were awarded to academic groups studying the biology of stem cells.

CIRM’s Tools and Technologies Awards are intended to support work that either creates new reagents and methods for stem cell research, or that scales up existing technologies — all designed to accelerate the development of critical therapies for patients with chronic diseases or injury.

“This funding is another critical step in our strategy to become a ‘one-stop-shop’ for the world’s premier stem cell differentiation systems,” Dr. Snodgrass said. “It will enhance our fundamental expertise for capturing the value of stem cell biology for predictive toxicology, drug discovery screening and drug development.”

VistaGen Therapeutics is a biotechnology company based in South San Francisco, California. In 2009, VistaGen expects to launch a new era of R&D productivity in the pharmaceutical industry, an era driven by clinically relevant, commercially scalable, human biology-based screening systems capable of predicting the safety and efficacy of new drugs in ways never before possible. By using predictive information from its stem cell-based “Clinical Trials in a Test Tube(TM)” to increase the efficiency of identifying effective drug candidates and reduce clinical trial failures, especially failures due to heart or liver toxicity, VistaGen expects its next-generation stem cell-based human systems biology platform to enhance dramatically the pharmaceutical industry’s ability to deliver innovative drugs for some of the world’s most challenging diseases and conditions.

SOURCE: VistaGen Therapeutics

XCell Center, Cologne, Germany — No matter how big a human becomes, it all began with an ovum and a sperm cell. This means that cells exist which have the potential to form a complete human. The first cells to arise from a fertilized ovum are described as totipotent (“potent for everything”). After a few days in the womb, the blastocyst forms. The cells contained in it are called embryonic stem cells. They are still very unspecialized and have the ability to divide endlessly and to develop into all of the 220 human cell types. However, a whole human cannot arise from these few cells. They have lost their toti-virility and are described as pluripotent (“potent for a lot”). As soon as the human’s development is completed, these former all-arounders will have changed into mature, differentiated cells taking over a specific function in our body, for example neurocytes which conduct electric impulses, muscle cells which contract and the ß-cells of the pancreas which produce insulin.

However, skin renews itself throughout adulthood, injuries heal and hair grows. Right to the end of our lives, we have cells which are very unspecialized, can divide often and help the organism to regenerate and repair itself. These cells are called adult stem cells. To date, adult stem cells have been found in nearly every body tissue, for example in the skin, the brain, the blood, the liver and the bone marrow.

Biological function of adult stem cells

If body tissue is damaged, stem cells head for the damaged area and advance the process of healing. However, day-to-day processes in the human body also rely on stem cells: our erythrocytes only live for about 120 to 130 days, by which time they have become too old, cannot transport enough oxygen and have to be replaced. This task is taken over by the hematopoietic stem cells that can be found in the bone marrow. According to theoretical calculations, about 350 million new erythrocytes are formed every minute. Most of the other somatic cells are also replaced regularly: liver cells after 10 to 15 days, white blood cells after 1 to 3 days.

In theory, the body has its own repair system. So why do people still become terminally ill? And why does the organism age if it has the ability to regenerate itself?

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Limits of regeneration

One established theory is that special messengers lure adult stem cells to the damaged area; However, they often do not arrive in sufficient numbers, or may even fail to arrive at all because the artery is blocked. The damaged area then only heals very slowly, or may not heal at all if the cause of the disease is not eradicated. It might also be possible that some diseases develop covertly and are not recognized as being in need of repair. Another problem: adult stem cells also age. They have much higher regeneration potential than differentiated somatic cells, but it seems that this potential is exhausted after 130 years at the latest. Up to now, the oldest woman in the world lived in France and reached 122 years of age. The process of aging cannot be stopped. However, with the help of modern medicine, it is possible to abstract stem cells from the body, to clean them, concentrate them and then apply them to the diseased area. In many cases, the physiological healing process can be enhanced.

Stem cells from cord blood

Nowadays, a lot of parents have their newborns’ cord blood frozen in order to give their children the chance to resort to their own adult stem cells in the event of a serious disease. In principle, this does make sense, because these cells seem to be less differentiated than the cells in the blood of adult organism, and they have higher potential for changing into different types of cells. These stem cells are also less immunological and therefore might be suited to use in foreigners. But nevertheless, certain restrictions have to be taken into consideration. Problems are inevitable if providers do not obtain and store the stem cells in compliance with the globally valid “Good Manufacturing Practice” quality standards, or if the stem cells are not isolated from the cord blood and the blood bottle is frozen throughout. While no hospital is allowed to use the cells in the first case, the cells suffer damage through the use of anti-freezers and the comparatively long time needed for unfreezing. In both cases, the stem cells are rendered practically worthless.

There are some further aspects that have to be considered when extracting stem cells from cord blood. Predispositions to diseases such as Alzheimer’s or Parkinson’s, leukemia or other types of cancer can be saved in one’s own stem cells, thus making it possible to transmit the disease further. Moreover, only a limited number of stem cells remain in the cord blood. However, as a certain minimum of cells is needed for therapy, researchers are today working on the increase of adult stem cells outside the body; the XCell-Center is also taking part in this research. If the breakthrough comes, it might be assumed that the disposal of stem cell depots will soon become common practice. An article from the professional journal “The Lancet” shows that the unique possibility of obtaining stem cells from cord blood is already realistic. It says that since 1989, more than 7,000 transplantations have been carried out worldwide using stem cells from cord blood.

Institute For Regenerative Medicine, Cologne, GE

The use of endogenous adult stem cells is ethical and legally straightforward. Under German law, the extracted stem cells are categorized as drugs. Because they are exclusively for personal use, they are individual drugs, and under German law do not require the same governmental approval as other drugs. Despite this, the clinic still has to obtain a manufacturing license from the surveillance authority. At the XCell-Center, it is guaranteed that the processes of extraction, cleaning and transplantation are all carried out in compliance with Good Manufacturing Practice (GMP) standards, thus guaranteeing maximum quality and safety for the patient.

For the last few years, attempts at therapy with adult stem cells from bone marrow have been carried out at university hospitals. This means that unlike animal testing with embryonic stem cells, adult stem cells are in-part, already being clinically tested. The well-documented success of the cardiologist Prof. Dr. Bodo Strauer from Düsseldorf can be seen as an example. He treated a patient suffering from a series of heart attacks for whom common therapies could not assure any chance of survival with the patient’s own bone marrow stem cells. Nine days after the stem cells had been injected into the diseased area, the patient was able to leave the intensive care unit. Up to now, more than 300 patients have been treated in Düsseldorf using this procedure – most of them successfully.

The XCell-Center’s treatment is based on the therapy experiences of more than 400 patients, treated both in the XCell-Center directly and in cooperation with other universities and research institutes (standing: October 2007). At present, the results of treating diabetes mellitus and stroke with stem cell therapy are looking particularly auspicious. Initial results have also been obtained from the treatment of patients with Parkinson’s, Alzheimer’s or Multiple Sclerosis.

Curing leukemia

The use of adult stem cells is by no means completely new. Stem cells have been used for the therapy of blood cancer (leukemia) for more than 40 years now. Normally this is done by allogenic bone marrow transplantation, i.e. bone marrow is taken from suitable donors. In this respect, the treatment differs from that which is offered by the XCell-Center because we use the patient’s own bone marrow stem cells. The hematopoietic stem cells contained in the bone marrow settle into the recipient’s body and produce fresh blood cells there. At this point the original bone marrow and thus, the patient’s leukemia cells have already been previously destroyed by chemotherapy. One problem is the rejection of foreign cells. The patient has to take medicine to suppress this reaction. Of special interest is the relatively new knowledge that these defensive reactions are in part beneficial: the cancer cells are destroyed more effectively by activating the immune system. One can speak of an anti-leukemic effect that helps to destroy the sick leukemia cells. In contrast to other diseases, the use of exogenous stem cells is desirable for leukemia.

Further methods of use under investigation

The spectrum of applications for the use of adult stem cells is wide. Examples include the use of adult stem cells for rebuilding cartilage and destroyed wrist, skin or bone tissue (keyword: Tissue Engineering). No studies have yet examined the well-documented research on human beings, proving this scientifically. Two studies published in professional journals in 2007 showed for the first time that endogenous insulin production in type 1 and type 2 diabetics is activated through therapy with adult stem cells. The questions of whether new insulin-producing cells are formed or whether existing cells are regenerated have not yet been clarified. The XCell-Center is conducting its own clinical studies parallel to the treatment of patients with different diseases using autologous adult stem cells.

The field of neurology is being examined very intensively. The use of adult stem cells offers a new treatment strategy for previously incurable diseases such as Alzheimer’s, Parkinson’s or Multiple Sclerosis. Here the defined aim is either to replace the damaged neurocytes with stem cells or to regenerate them. One approach that is of special interest for stroke patients: researchers from the “Fraunhofer-Institut für Zelltherapie und Immunologie” in Leipzig were able to show curative successes in animal testing with adult stem cells.

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XCell-Center, Regenerative Institute, Cologne, GE

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It is not yet absolutely clear how bone marrow stem cells participate in healing processes. For a long time, it was assumed that stem cells simply replace the damaged cells. This seems to be the case to some extent, but in recent years, research has shown that stem cells more often stimulate the healing of the damaged tissue rather than replacing it completely. The adult stem cells discharge messengers that stimulate both damaged and healthy cells, thus strengthening the whole tissue – for example a myocardial muscle.

Scientists assume that the redundant messengers give a starting signal for endogenous regeneration. These cells start processes with an anti-inflammatory and circulation-enhancing action, for example stimulating the growth of new arteries.

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Some patients see a marked improvement after treatment with adult stem cells, but the same treatment will have no effect on others. Thus, there is a need for further research: What is the mechanism that causes the stem cells to work? Which messengers implement the healing process? How great is the potential of adult stem cells to integrate into the tissue? And what does this transformation into different cell types depend on?

Stem cell quality

Great importance is attached to the quality of the bone marrow used. In older humans, there is a decrease in stem cells’ viability and their ability to divide. The question –from what point have the bone marrow stem cells exhausted their healing potential– is especially important for diseases that appear in a later period of life. Many researchers believe that research results will lead to the conclusion that the preventative withdrawal of stem cells is necessary.

Embryonic stem cell controversy

The discussions in the field of stem cell therapy being held nowadays usually refer to embryonic stem cells. To obtain these, embryos, i.e. fertilized ovum from which a whole human can develop, must be killed. Many people understandably oppose the idea of using embryos as spare parts stores. Regardless of these discussions, the use of embryonic stem cells is still far from being clinically viable because embryonic stem cells have an amplificatory effect and may therefore accelerate the growth of tumors. This is also why many doctors see adult stem cells as the silver bullet of regenerative medicine.

The XCell-Center uses only adult stem cells for treatment and research.

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Motor neurons: Scientists generated motor neurons (cell nuclei shown here in red), which are destroyed in amyotrophic lateral sclerosis (ALS), from stem cells created from a patient with the disease. The newly created cells should allow scientists to study the disease and screen new drugs. All neurons are marked in green.
Credit: Kit Rodolfa and John Dimos at Harvard University

Scientists have created stem cells from an ALS patient using a new reprogramming method.

MIT Technology Review, by Emily Singer — Stem cells derived from the skin of an 82-year-old patient with amyotrophic lateral sclerosis (ALS) could provide a novel model for studying the degenerative motor disease and for screening new treatment drugs; eventually, it could pave the way for cell-replacement therapies. The findings, published today online in Science, were made possible by new techniques to reprogram adult cells to become pluripotent–able to become any type of cell in the body.

Researchers have long wanted to make stem cells from actual patients to better understand the diseases from which they suffer. “Because the cells harbor genes that led to the disease in that patient, we might be able to use them in the laboratory to understand certain aspects of disease,” says Kevin Eggan, a stem-cell scientist at the Harvard Stem Cell Institute, who led part of the research.

To create the stem cells, researchers used a novel technique, recently developed by scientists in Japan, that doesn’t require human eggs or the creation or destruction of embryos, and thus bypasses major ethical and technical hurdles that have plagued the field of embryonic stem-cell research. Eggan’s team exposed the patient’s skin cells to four genetic factors found in the developing embryo. The procedure turned back the clock on the cells, triggering them to look and behave like embryonic stem cells.

While scientists had already used these reprogramming techniques to create stem cells from skin cells, this is the first time that these cells–called induced pluripotent stem cells, or IPS cells–have been generated from a patient. The ability to do so is key to creating models for studying complex genetic diseases, such as Alzheimer’s. The findings also confirm that it’s possible to use reprogramming techniques in older people and in those with a serious disease. “It was unclear if the fact that the patient had been sick for many years would interfere with our ability to reprogram [the cells],” says Eggan.

The researchers prodded the stem cells to differentiate into motor neurons by exposing them to another series of chemicals. Motor neurons are the primary cell type destroyed in ALS, a progressive neurodegenerative disease. While animal models of the disease exist, they can’t capture the complexity of human biology.

The new research allows scientists to generate an endless supply of motor neurons that are genetically identical to those of the cell donor, which should allow them to study the molecular events that trigger the disease. “Now we can see if they behave in a manner that mimics the disease,” says Chris Henderson, codirector of the Motor Neuron Center at Columbia University, in New York, who led part of the research. “For example, do they tend to die and degenerate in the culture dish? If so, we can try to understand more about the mechanism of degeneration.” Scientists also hope to use the cells to screen for new drugs that protect against neurodegeneration in ALS.

“It is likely that this will be one of the most important uses of stem cells during the next 10 to 20 years,” said Ian Wilmut, director of the Scottish Centre for Regenerative Medicine, in Edinburgh, in an e-mail. Wilmut, best known for the cloning research that produced Dolly the sheep, was not involved in the current project but is pursuing a similar path.

Because the cells were created using genetic engineering, they are not suitable for therapeutic use. Scientists are now working on ways to reprogram cells using drugs rather than genes. However, therapies using IPS cells to replace the cells damaged in disease are likely years, if not decades, away.

The researchers haven’t yet studied the new motor neurons for signs of disease, but similar experiments in mice hint at the cells’ promise: mouse cells with a mutation in the same gene as that in the ALS patient seemed to reflect the disease. When differentiated into neurons and compared with neurons made from normal stem cells, those that carried the mutation didn’t survive as well as those that did not carry it, says Eggan, who is now using the cells to screen potential new drugs for ALS. “These approaches would be much more powerful if we could do them with actual patient cells,” he says.

The cells should also allow scientists to test specific theories of ALS. For example, in the mouse experiments, the researchers found that another type of neural cell, known as an astrocyte, seemed to produce a toxin that harmed motor neurons. “We’re curious to see if we can make astrocytes from stem cells and if they also have this toxic effect,” says Eggan.

The cell donor in this research has a rare, familial form of ALS linked to a specific genetic variation. Scientists are now trying to derive stem cells from a patient with the more-common sporadic form of ALS, as well as from a healthy control donor, in order to compare healthy and diseased cells.

Eggan first set out to create patient-specific stem cells more than two years ago using therapeutic cloning. In that technique, DNA from an adult cell is inserted into an egg whose DNA has been removed. The egg begins to develop as a normal embryo would, and scientists harvest stem cells after a few days. However, human eggs proved extremely hard to find: Eggan’s group, which is still pursuing cloning, has received eggs from only one donor to date. No one has yet produced stem cells from human therapeutic cloning.

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Press Release – Carlsbad, Ca and Madison, Wis., – Invitrogen Corporation (NASDAQ: IVGN), a provider of essential life science technologies for research, production and diagnostics, and the Wisconsin Alumni Research Foundation (WARF), the private, non-profit patenting and licensing organization for the University of Wisconsin-Madison, announced today that they have signed a license for human embryonic stem cell (hESC) patents for the development of research tools.

Under the terms of the agreement, Invitrogen will have the right to work with karyotypically normal hESCs to develop novel research and drug discovery tools.

“Invitrogen’s goal is the development of research tools that enhance the ability of scientists to work with embryonic stem cells and to enhance the utility of these cells for research and drug discovery,” said Joydeep Goswami, Vice President, Stem Cells and Regenerative Medicine. “Having the ability to work with karyotypically normal hESCs through our license with WARF allows us to develop better technologies for research, such as more defined media and engineered stem cell lines. This agreement is another step in our strategy of pursuing advances in the high-growth area of regenerative medicine.”

“We are pleased to have a signed license with Invitrogen,” said Carl E. Gulbrandsen, managing director of WARF. “Invitrogen’s market penetration and knowledge of cell biology research tools will help support and nurture the growth of the burgeoning hES cell industry.”

WARF officials note the licensing agreement with Invitrogen demonstrates that commercial interest in human embryonic stem cells remains strong. With this agreement, WARF now has completed 24 licensing agreements for stem cell technologies with 18 companies.

About Invitrogen
Invitrogen Corporation (NASDAQ:IVGN) provides products and services that support academic and government research institutions and pharmaceutical and biotech companies worldwide in their efforts to improve the human condition. The company provides essential life science technologies for disease research, drug discovery, and commercial bioproduction. Invitrogen’s own research and development efforts are focused on breakthrough innovation in all major areas of biological discovery including functional genomics, proteomics, stem cells, cell therapy and cell biology — placing Invitrogen’s products in nearly every major laboratory in the world. Founded in 1987, Invitrogen is headquartered in Carlsbad, California, and conducts business in more than 70 countries around the world. The company employs approximately 4,700 scientists and other professionals and had revenues of approximately $1.3 billion in 2007. For more information, visit www.invitrogen.com.

About the Wisconsin Alumni Research Foundation
The Wisconsin Alumni Research Foundation supports world class research at the University of Wisconsin-Madison by protecting the intellectual property of University faculty, staff and students, and licensing inventions resulting from their work. WARF was established in 1925 as the world’s first university-based technology transfer office.

Safe Harbor Statement
Certain statements contained in this press release are considered “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, and it is Invitrogen’s intent that such statements be protected by the safe harbor created thereby. Forward-looking statements include, but are not limited to 1) Invitrogen’s work with karyotypically normal hESCs through the license with WARF allows the development of better technologies for research; 2) Invitrogen’s market penetration and knowledge of cell biology research tools will help support and nurture the growth of the hESC industry. Potential risks and uncertainties include, but are not limited to, a) Invitrogen’s development of research tools may or may not enhance the ability of scientists to work with embryonic stem cells nor enhance the utility of these cells for research and drug discovery; b) commercial interest in hESCs may or may not remain strong; as well as other risks and uncertainties detailed from time to time in Invitrogen’s Securities and Exchange Commission filings.

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Christopher Henderson PhD
Co-Director, Motor Neuron Center
Professor of Pathology and Cell Biology in Neurology

RESEARCH THEME:
One of the major challenges facing researchers who wish to develop therapeutic strategies for ALS and SMA is to better understand the molecular and cellular mechanisms underlying motor neuron degeneration and loss. Such mechanisms constitute potential therapeutic targets – steps that can be controlled so as to enhance motor neuron survival or prevent degeneration. In practice, it is difficult to gain such insight by direct study of patients or animal models of disease. Work in my laboratory therefore focuses on the study of motor neuron development as an important area in its own right, but also as an approach to understanding and analyzing mechanisms underlying SMA and ALS.

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This has been successful in several ways. For example, by studying the motor neuron cell death process that occurs naturally during fetal development, we discovered a novel degenerative mechanism that we now believe to be involved in ALS. Similarly, the techniques we developed for culturing purified motor neurons allow us to screen large numbers of agents for their ability to promote motor neuron survival and growth. This has led to identification not only of natural survival-promoting polypeptides called neurotrophic factors, but also of chemical compounds with similar properties. The latter provide new insights into mechanisms involved and can also serve as the basis for subsequent drug development.

By providing an environment in which we can interact with both basic and clinical researchers at the highest level, the Motor Neuron Center will significantly reinforce our efforts toward effective therapy for motor neuron diseases. In collaboration with other MNC members, we will develop new cell models that more closely mimic ALS and SMA and use high-throughput screening techniques to identify genes and chemical compounds that influence the disease mechanisms. By further studying the differences between groups of motor neurons that innervate different muscles during development, we will better be able to analyze the process of selective motor neuron loss in animal models of each disease. Lastly, by creating mouse models in which genes that affect motor neuron death, survival or growth are either absent or over-expressed, we will be able to test the role of these potential therapeutic targets in models of both SMA and ALS. Our aim is to move each project forward to the stage where it not only provides new biological insights but also, when appropriate, can serve as the basis for future development of new therapeutic strategies.

BACKGROUND AND EDUCATION: Christopher Henderson is Co-Director of the Columbia University Center for Motor Neuron Biology and Disease. He holds a joint appointment as Professor in the Departments of Pathology and Cell Biology and Neurology, and is on the faculty of the Center for Neurobiology and Behavior. Henderson obtained his Ph.D. from the University of Cambridge (UK) in 1979. He subsequently spent much of his career in France, first at the Pasteur Institute in Paris with Jean-Pierre Changeux, then as CNRS Director of Research in Montpellier and Marseille, where he directed the INSERM research unit on Neuronal Development and Pathology. Henderson’s interest in translational neuroscience led him to spend time as a Visiting Scientist with Genentech, Inc. (San Francisco, CA) and to become co-founder of Trophos, S.A. (Marseille, France), a drug discovery biotech focused on neurodegenerative disease, including ALS and SMA. He moved to Columbia in May, 2005.

Fall 2008

Prof.Dr. Lombardi, Eye Clinic Rome/ XCell-Center Cologne

Case Report

Patient age: 45

An extremely myopic patient (around -7/ -8 diopters) previously treated in 2001 with refractive PRK laser surgery came to our clinic on March 3rd 2007.

In October 2005, she was treated at the University Clinic of Rome for a left eye maculopathy. She had undergone several photodynamic laser macula treatments and two “lucentis” intra vitreo injections with a disastrous clinical result. Her clinical condition continued to worsen.

When she arrived she had a central scotoma on the left eye and she could not count her fingers.

In the right eye we observed the onset of macula degeneration with macula epiteliopathy and 9/10 corrected visual acuity that we have been able to preserve until the present.

After some detoxification treatments the patient was sent to the XCell-Clinic on April 25, 2008 for a bilateral autologous stem cell retrobulbar implantation.

Just two weeks after the treatment, during an objective, standardized examination, this patient shows significant improvement.

Even an untrained observer can clearly see this improvement in the graphics and the numerical variation of retinal sensitivity clearly expressed in the Visual Fields and Threshold Fovea Maps.

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Until treating this patient with stem cells, we had never observed such improvement, especially considering the severity of the disease and the iatrogenic damage.

We believe that the retrobulbar injection of stem cells might first prevent the progression of dry and wet macular degeneration by reducing the Drusen deposits in the retinal pigment epithelium beneath the macula. It might also prevent the destruction of the photoreceptors in both the dry and wet type, by reactivating proper micro-vessel activity and reducing the abnormal blood vessel growth beneath.

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The XCell-Center teams up with reputed eye specialist

January 15, 2008

The XCell-Center in Cologne has concluded a cooperation agreement with the Italian physician and ophthalmic microsurgery specialist, Dr. Massimo Lombardi. Lombardi will be treating patients at his clinic in Rome with autologous adult stem cells prepared in a patented process at the XCell-Center’s laboratory. He will also be providing stem cell therapy to patients with eye diseases at the XCell-Center. The cooperation between the XCell-Center and Lombardi covers the treatment of degenerative eye diseases such as retinitis pigmentosa, diabetic retinopathy, Leber’s optic atrophy and macular degeneration.

Dr. Lombardi first performed surgery on keratoconus patients using symmetrical incisions in 1984, and he is the physician who made a breakthrough with this technique in the treatment of keratoconus.

The XCell-Center is located in Cologne, Germany at Eduardus Hospital’s Institute of Regenerative Medicine. Bringing together therapeutical use of autologous adult stem cells and medical research, it is our mission to:

· Provide therapeutic application of autologous adult stem cells to patients at the highest medical standard;

· Extend existing knowledge on the effects of autologous adult stem cells by supporting pre-clinical and clinical research.

We offer patients with degenerative diseases the opportunity to undergo an innovative and promising stem cell treatment.

Since the start in January 2007, more than 750 patients have safely undergone our various stem cell treatments.

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Therapeutic use

The XCell-Center treats patients with their own autologous adult stem cells. It is the first private institute worldwide to hold an official license for the extraction and approval of stem cell material for autologous treatment.

Therapy focuses on the treatment of diabetes mellitus (types 1 and 2 as well as sequelae) and stroke. Further indications comprise neurological diseases, in particular spinal injuries, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson’s and Alzheimer’s disease as well as arthritis, heart disease, eye disease, neuropathy and incontinence.

Clinical data

Beside therapeutic applications that take place at the institute, the XCell-Center also spearheads research on the medical use of adult stem cells. Two phase II studies are submitted and are scheduled to start in the second half of 2008.

Advisory board

Learn more about the XCell-Center’s Medical and Scientific Advisory Board.

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