20091124-3

Northwestern University researcher Dr. Douglas Losordo using Baxter process to rebuild weak hearts

GoogleNews.com, ChicagoTribune.com, November 23, 2009, by Bruce Japsen —  A treatment that uses adult stem cells to rebuild failing hearts reduced chest pain and improved activity levels for severely ill patients one year after injection, a Northwestern University researcher working with a Chicago-area device-maker reported.

Though still in early development stages, the work of Dr. Douglas Losordo, using technology developed by Baxter International Inc., is being watched closely by the stem cell research community. The trial data, presented Tuesday at the American Heart Association scientific conference in Orlando, Fla., is also important in the study of heart disease.

Because the group receiving therapy continues to show reduced angina and improved activity a year after being injected with their purified stem cells, Losordo sees that as progress. In early stage clinical trials, it is critical for researchers to show differences between treatment and control groups to warrant further study.

“In this study, the treatment groups are separating so there is further improvement in the treatment group,” said Losordo in a telephone interview from the meeting. “The curves are separating as we go. We take that as a good sign.”

The trial of 167 patients, mostly men, showed a range of improvement in a population that has exhausted most other conventional treatments. Many are home-bound or unable to do normal daily activity such as walking up stairs or shop for groceries.

“We are not talking that they can do mountain climbing, but some who had stopped playing golf can do so again,” Losordo said.

Many of these patients have had so-called balloon angioplasty or open-heart surgery and are so weak such treatments are no longer an option.

The stem cell treatment in the trial uses Baxter’s Isolex cell separation and collection system to extract stem cells in bone marrow. Once isolated, the cells are injected into the heart via catheter in hopes of regenerating damaged areas.

Stem cells are building blocks that theoretically can be manipulated to perform the work of other cell types.

The latest trial is considered the second of three phases needed before Baxter would submit the data to the U.S. Food and Drug Administration for approval. Final, or Phase III, trials generally involve several hundred patients.

It’s unclear when Baxter and Losordo would begin a next phase. Baxter’s Isolex is approved by the FDA for use in cancer therapy.

20091124-1

Howard Hughes Medical Institute, November 23, 2009  —  A protein found in the saliva of ticks may prove to be an attractive target for a new type of Lyme disease vaccine. In studies in mice, Howard Hughes Medical Institute researchers at Yale University produced an antiserum against a protein in tick saliva that significantly reduced the likelihood that mice could be infected with the tick-borne bacterium that causes Lyme disease.

Lyme disease first manifests in humans as a rash that may pass unnoticed. As the infection worsens, symptoms may include fever and chills, joint swelling, numbness, weakness, and even heart problems. The findings suggest a new way forward for Lyme disease vaccine development.


“For vector-borne diseases, where the bacteria are transmitted by a tick or a mosquito, we wanted to know: Is it possible there is something that is not pathogen-based that can be targeted?”
Erol Fikrig

Vaccines have traditionally targeted unique proteins found on the surface of pathogens. In the new studies, published in the November 19, 2009, issue of Cell Host & Microbe, the researchers show that it is possible to target molecules carried by a disease vector – not the pathogen itself. This could be an effective strategy to prevent Lyme disease, as well as malaria, dengue fever, and other diseases carried by arthropods such as ticks and mosquitoes, said senior author Erol Fikrig, a Howard Hughes Medical Institute investigator at Yale University.

When the bacterium that causes Lyme disease is transmitted to a mammal via a tick’s bite, the bacterium wraps itself in a protein cloak that makes it invisible to the host’s immune system. That cloak is made from a protein found in tick saliva, which the Lyme bacterium, Borrelia burgdorferi, causes the tick to produce in excess. In Cell Host & Microbe, Fikrig and his colleagues describe a way to turn this cloak of invisibility into a vulnerability.

Fikrig, who is chief of infectious diseases at the Yale School of Medicine, said vaccine development – even as far back as Louis Pasteur’s discoveries in the 1880s – has historically relied on using a weakened form of the pathogen, or a component of it, to evoke an immune response that would protect against later encounters with the same microbe.

“For vector-borne diseases, where the bacteria are transmitted by a tick or a mosquito, we wanted to know: Is it possible there is something that is not pathogen-based that can be targeted?” Fikrig said.

“The tick isn’t just a syringe,” Fikrig said. Tick saliva contains a variety of unsavory ingredients that help the insect’s five- or six-day blood meal proceed unnoticed by the host, and the presence of the pathogen actually changes the composition of the tick’s saliva. For example, the saliva contains anesthetics that keep the bite from stinging and blood thinners to prevent clotting.

In 2005, Fikrig and his colleagues found that tick saliva also harbors Salp15, a protein that shields the tick from mammalian immune cells known as T-cells. The Lyme disease bacterium drives the tick to overproduce Salp15, so that it can use that protein to remain invisible to the host’s immune system.

“For us, a central question was, if the spirochete requires the tick protein for infection, and it’s coated with it, can we actually target this protein?” Fikrig said. To test the efficacy of Salp15 as an immunizing agent, researchers injected a few mice with an antiserum against Salp15. Other mice, to be used as controls, were injected with an inactive serum. The following day, both groups of mice were injected with B. burgdorferi coated by the cloaking Salp15 protein.

When the mice were examined a week later, all of the control mice showed signs of Lyme disease, but only half of the mice treated with the Salp15-antiserum were sick. When infection did occur in Salp15-injected mice, the antiserum was still protective: It helped to reduce the total amount of Borrelia burgdorferi bacteria in the body compared to control mice. After three weeks, 40 percent of the mice given Salp15 antiserum remained Lyme-free. Those that showed infection had lower levels of the Lyme bacteria in their hearts and joints than control mice.

One value of creating a vaccine against a protein produced by the vector, Fikrig said, is that it might enhance the effectiveness of a traditional pathogen-based vaccine. “Take a disease like dengue virus or malaria, for which there is no highly efficacious vaccine,” he said. The vaccines that do exist follow the traditional model — that is, they are based on components of the pathogen that infects the host. Fikrig suspects that including a vector protein like Salp15 in a vaccine that also targets a pathogen component could boost the vaccine’s ability to prevent disease. “Let’s say the vector targets are 50 percent efficacious and some pathogen components 40 to 50 percent. Combine the two and you might have a very good vaccine.”

To test that idea, Fikrig’s team combined the Salp15 antiserum with an existing pathogen-based vaccine against Lyme disease. That vaccine, which Fikrig helped develop in the early 1990s, promotes immunity to a protein on the surface of the Borrelia burgdorferi pathogen called outer-surface protein A, or OspA. The vaccine was on the U.S. market from 1998 to 2002, when the manufacturer, GlaxoSmithKline, withdrew it, blaming poor sales. In an article that Fikrig wrote earlier this year for the journal Future Microbiology, he noted that concerns about potential side effects may have been a factor in the drug company’s decision to withdraw the Lyme disease vaccine.

In another set of experiments reported in Cell Host & Microbe, Fikrig and his colleagues combined low-dose Salp15 antiserum with a lower-than-effective dose of OspA monoclonal antibody and administered the mix to one group of mice. Other mice received either protective doses or low doses of just one of the two vaccine components. Each mouse was then exposed to 10 ticks carrying the Lyme-disease bacteria.

Mice treated with a combination of low-dose OspA and Salp15 fared better than mice treated with either agent alone at low dose. Only 25 percent of mice treated with both agents showed signs of Lyme infection. In addition, only 20 percent developed signs of arthritis, and their inflammation was low compared to the inflammation of controls. These mice also showed the lowest spirochete burden.

In contrast, 90 percent of mice treated with low-dose OspA alone and 100 percent of untreated mice were infected with Borrelia burgdorferi.

These results eased one of the researchers’ concerns about combining the two approaches, Fikrig said. Since Salp15 normally mutes the body’s immune response to the spirochete invader, there was concern that it might blunt the immune response to OspA, and fail to produce any combined benefit. But their experiments ruled out that possibility. “We immunized with both together and found out that wasn’t the case,” he said.

In additional tests, mice were inoculated with a form of Salp15 that the researchers produced in the lab. These mice developed antibodies that protected them against infection when they were exposed to Lyme-carrying ticks. Three weeks after tick exposure, 40 percent of the inoculated mice showed no signs of infection, while 95 to 100 percent of controls were infected. Further research suggested that Salp15 probably protected the mice from infection by flagging the cloaked Borrelia burgdorferi spirochetes, which led immune cells to ingest the invaders, Fikrig said. Mice inoculated with both Salp15 and OspA fared even better- 80 percent remained uninfected. The combined impact of the two vaccines suggests other areas of research, and Fikrig says his group has already begun investigating whether a similar vaccine strategy might be effective in preventing malaria.

 

About the Research Scientist

Erol Fikrig, M.D.

20091124-2

As a medical student at Cornell University, Erol Fikrig spent time in Brazil studying a disease called leishmaniasis, which sand flies transmit to humans. That experience piqued an interest in vector-borne diseases that Fikrig has pursued ever since. His research has led to a new understanding of the relationship between the pathogens that transmit the diseases, the vectors that carry the pathogens, and the hosts they infect. Information from his studies is suggesting new strategies to prevent and treat Lyme disease, West Nile encephalitis, and other infections by interrupting these relationships.

In 1988, Fikrig came to Yale University School of Medicine on a fellowship and was immediately attracted to research on Lyme disease. Named after the town in Connecticut where a cluster of cases was described in the 1970s, Lyme disease is caused by a bacterium transmitted to humans through tick bites. “I thought to myself that it was a vector-borne disease, a local disease, with a lot of research going on-I’d like to look at that,” he said.

His first project was developing and testing a Lyme disease vaccine with HHMI investigator Richard Flavell, who remains a frequent collaborator. The Food and Drug Administration eventually approved the Lyme vaccine for use, though its manufacturer later withdrew it from the market, citing poor sales. While the vaccine was being developed, Fikrig made the first of a series of remarkable discoveries about the life cycle of the bacterium. He demonstrated that, in moving between the tick and humans, the bacterium covers itself with a protein drawn from the tick’s saliva. That protein helps the bacterium avoid attack by the human immune system.

Fikrig also discovered that the bacterium has a way of inducing the tick to make more of the protective saliva protein. “That set us thinking,” said Fikrig. “Why did the bacterium do that? It needed to protect itself. But it also needed to interact with things in the local environment if it was going to survive.”

That insight has led Fikrig to investigate the ways human pathogens interact with their environments, often by manipulating the biological mechanisms of their hosts. In particular, his laboratory focuses on tick-borne diseases like Lyme disease and human granulocytic anaplasmosis, as well as the West Nile virus, which is transmitted by mosquitoes. Through those studies, he has uncovered new ways to disrupt pathogens at various stages in their life cycles, not just when they are infecting humans.

Lyme disease, which Fikrig often sees in some of the patients he treats, provides a good example, he said. The bacterium uses the tick’s biochemistry to full advantage in infecting humans. “A tick is like a little pharmacological factory,” Fikrig said. Unlike a mosquito, whose stinging bite immediately draws swats, a tick has to remain unnoticed for three to five days while it feeds on the blood of its host. To do that, it manipulates the host organism by generating anticoagulants that keep the blood flowing and proteins that prevent inflammation and protect it against the host’s immune response.

In fact, the bacterium cannot survive in the tick without hijacking proteins from it. Fikrig discovered that the bacterium has a protein on its surface that binds to a receptor in the tick’s gut. When the receptor in the tick is blocked by antibodies or RNA interference, the bacterium cannot gain a foothold.

Fikrig’s work is suggesting innovative ways to use vaccines to combat infectious agents by disrupting a pathogen’s environment. “We’d like to explore whether it’s possible to make vaccines that don’t target the pathogens per se but the molecules the pathogens require,” Fikrig said.

Fikrig’s work suggests that the same tactic may work with other diseases. For example, he discovered that the bacterium that causes an illness called tick anaplasmosis lives within human cells known as neutrophils, which kill bacteria. The bacterium turns on genes in the neutrophil that it needs to survive and turns off others, suggesting that altering the biochemistry of the neutrophil may block the disease.

Fikrig also has been studying the inflammatory process caused by infection with the West Nile virus. In most people, the virus causes only a fever, but in the elderly and the immunosuppressed, it may cause severe inflammatory reactions that can lead to death. Fikrig is now studying the receptors on human cells that trigger this inflammation. “There is a constant battle in the host between pathogen control and excessive inflammation,” he said. It’s a battle Fikrig would like to turn in our favor.

Dr. Fikrig is also Professor of Internal Medicine, Microbial Pathogenesis, Epidemiology, and Public Health at Yale School of Medicine.
RESEARCH ABSTRACT SUMMARY:

Erol Fikrig is studying the relationship between pathogens, the vectors that carry them, and the hosts they infect, and looking for ways to interrupt those relationships to prevent or treat disease

Technique used in mice may offer hope to burn patients awaiting grafts

 

USNews.com,  (HealthDay News), November 23, 2009 — Embryonic stem cells, which can turn into a variety of cells in the body, can produce temporary skin that could help burn victims while they’re waiting for skin grafts, new research from France suggests.

 

The findings, reported in the Nov. 20 issue of The Lancet, could lead to treatments that build on the existing use of cell therapy to help burn patients recover from injuries.

In existing cell therapy, a person’s own skin cells are grown in the laboratory to provide replacement skin. But it takes weeks for the process to occur, and burn patients can suffer from a variety of complications while they wait for skin grafts.

In a new study on mice, stem cells produced skin cells, and the skin grafts appeared to be similar to human skin, the researchers reported.

They wrote that the new skin cells “could have clinical relevance as an unlimited resource for temporary skin replacement in patients with large burns awaiting autologous grafts.”

In a commentary, Australian doctors said the finding “takes research into regenerative skin stem cells to the next level.”

Researchers Say Seasonal Flu Provides Some Cross-Immunity Against H1N1 Swine Flu

By Daniel J. DeNoon
Reviewed by Louise Chang, MD

GoogleNews.com, WebMD.com, November 23, 2009 – People who got last year’s seasonal flu vaccine are at lower risk of H1N1 swine flu illness — particularly severe disease, a study of U.S. military personnel shows.

Overall, getting a seasonal flu shot or sniff cut the risk of swine flu by 45%. It cut the risk of getting a normal case of swine flu by 42%, and cut the risk of being hospitalized with swine flu by 62%.

Oddly, not everyone was protected. The vaccine was not effective in personnel age 25 to 39. But it was 50% effective in those under age 25 and 55% effective in those over age 39, find Jose Luis Sanchez, MD, MPH, influenza team leader at the Armed Forces Health Surveillance Center in Silver Spring, Md., and colleagues.

“This strongly suggests that prior vaccination with seasonal influenza vaccine confers some degree of cross-immunity against H1N1 swine flu,” Sanchez tells WebMD. “It’s probably not conferring protection against H1N1 infections, but probably is protecting against disease and hospitalization once you are infected.”

How can this be? CDC studies show that people who got the seasonal flu vaccine do not have antibodies in their blood that neutralize the H1N1 swine flu.

But antibodies are only one arm of the immune system. Another arm is cell-mediated immunity, in which T cells learn to recognize pathogens. The next time they see these pathogens, these “memory” T cells marshall various defenses that kill off infected cells to limit the spread of infection.

Just this week, Jason A. Greenbaum, PhD, of the La Jolla Institute for Allergy and Immunology and colleagues, reported that T cells primed to recognize seasonal H1N1 flu bugs trigger immune defenses when they see 2009 H1N1 swine flu bugs.

That, Sanchez says, is his best guess to explain why seasonal flu vaccines protect against severe disease, but not against infection. But why aren’t people age 25 to 39 protected?

It may take at least two exposures — either two seasonal flu shots given at different times, or exposure to the flu plus one later flu shot — to be primed to fight off a new flu bug.

Because H1N1 viruses did not circulate from 1958 through 1978, it’s possible that people born around that time had less chance to be primed by H1N1 infection during childhood, when people are most likely to catch the flu. The years don’t exactly match, but Sanchez finds the coincidence quite interesting.

“So now, 30 years later, you are 32, 35, and get the seasonal vaccine and whoa! It didn’t protect you against the H1N1 swine flu, because you were not primed by an H1N1-like strain,” he suggests.

What all this means, Sanchez says, is that getting the flu vaccine every year offers extra benefits.

GoogleNews.com, ScienceDaily.com, November 23, 2009  –  For the first time, scientists have demonstrated that stem cells found in amniotic fluid meet an important test of potential to become specialized cell types, which suggests they may be useful for treating a wider array of diseases and conditions than scientists originally thought.

Reporting in Oncogene, a publication of Nature Publishing Group, the research teams of Anthony Atala, M.D., director of the Wake Forest Institute for Regenerative Medicine, and Markus Hengstchläger, Ph.D., from the Medical University of Vienna, have shown that these amnion stem cells can form three-dimensional aggregates of cells known as embryoid bodies (EBs). It is believed that cells at this stage of development can be directed to become virtually any cell in the human body.

“This finding suggests that the amnion cells have greater potential than we originally thought and may be able to form many cell types,” said Atala. “This could expand the number for diseases and conditions that they may be helpful for.”

Atala’s team is currently evaluating the cells for their potential to treat diabetes and kidney disease. They were the first to report success (Nature Biotechnology, Jan. 2007) in isolating stem cells from placenta and amniotic fluid, which surrounds the developing fetus. The current research is one of several projects designed to determine the potential of this new type of stem cell.

For the study, scientists generated two additional lines of stem cells from amniotic fluid using the same protocol developed by Atala’s lab. They then investigated the incidence of EB formation in all three lines.

“Performing many independent experiments using different approaches, we demonstrate in the report that human amnion stem cells … can indeed form embryoid bodies,” write the researchers in Oncogene. “Amnion cells are on the way to become an important source for both basic science and regenerative medicine.”

In addition to the finding about EBs, the scientists identified a protein found inside cells (mTOR) as the regulator of EB formation. Hengstshläger, whose team was the first to provide evidence for the existence of stem cells in amniotic fluid, said that this finding may allow for new insights into the molecular mechanism of EB formation.

He said the cells may be a useful source for generating disease-specific stem cell lines for studying the differentiation process to determine what goes wrong in genetic diseases.

“These stem cells allow for studying the effects of mutations causing human genetic diseases on specific cell differentiation processes,” he said.

Other potential advantages of the cells are that they can be grown in large quantities and are readily available during gestation and at the time of birth. “Whether these cells are as versatile as embryonic stem cells remains to be determined,” said Atala, “but the current finding is certainly encouraging.”

Atala stopped short of calling the cells pluripotent, which means the ability to form many cell types. He said while the cells meet some of the characteristics of pluripotency, such as versatility, they do not form tumors when implanted in animals, which is also considered a characteristic. The fact that the amnion cells are less likely to form tumors may be one advantage that they have over embryonic stem cells in their potential for clinical use.

Co-researchers were Alessandro Valli, Ph.D., Margit Rosner, student, Christiane Fuchs, MSc., Nicol Siegel, MSc., and Helmut Dolznig, Ph.D., from the Medical University of Vienna, Colin E. Bishop, Ph.D., from Wake Forest, and Ulrike Mädel, student, and Wilfried Feichtinger, M.D., from Wunschbaby Zentrum, in Vienna, Austria.

ScienceDaily  –  A new study has found that transplantation of stem cells from the lining of the spinal cord, called ependymal stem cells, reverses paralysis associated with spinal cord injuries in laboratory tests. The findings show that the population of these cells after spinal cord injury was many times greater than comparable cells from healthy animal subjects. The results open a new window on spinal cord regenerative strategies.

The transplanted cells were found to proliferate after spinal cord injury and were recruited by the specific injured area. When these cells were transplanted into animals with spinal cord injury, they regenerated ten times faster while in the transplant subject than similar cells derived from healthy control animals.

Spinal cord injury is a major cause of paralysis, and the associated trauma destroys numerous cell types, including the neurons that carry messages between the brain and the rest of the body. In many spinal injuries, the cord is not actually severed, and at least some of the signal-carrying nerve cells remain intact. However, the surviving nerve cells may no longer carry messages because oligodendrocytes, which comprise the insulating sheath of the spinal cord, are lost.

The regenerative mechanism discovered was activated when a lesion formed in the injured area. After a lesion formed in the transplant subject, the stem cells were found to have a more effective ability to differentiate into oligodendrocytes and other cell types needed to restore neuronal function.

Currently, there are no effective therapies to reverse this disabling condition in humans. However, the presence of these stem cells in the adult human spinal cords suggests that stem cell-associated mechanisms might be exploited to repair human spinal cord injuries.

Given the serious social and health problems presented by diseases and accidents that destroy neuronal function, there is an ever-increasing interest in determining whether adult stem cells might be utilized as a basis of regenerative therapies.

“The human body contains the tools to repair damaged spinal cords. Our work clearly demonstrates that we need both adult and embryonic stem cells to understand our body and apply this knowledge in regenerative medicine,” says Miodrag Stojkovic, co-author of the study. “There are mechanisms in our body which need to be studied in more detail since they could be mobilized to cure spinal cord injuries.”

 

Cloning Expert Quits Country in Row with Partner

 

Sarah-Kate Templeton, Medical Correspondent

TimesOnline.co.uk 

The scientist who cloned Britain’s first human embryo has accused his partner of breaching good scientific practice. 

Miodrag Stojkovic says the dispute played a “significant part” in his decision to quit Newcastle University to take up a post this month in Spain.

His departure is a setback for therapeutic cloning in Britain. Newcastle University has admitted that its human cloning programme is now on hold, but said it was assembling a new scientific team.

Stojkovic, who was professor of embryology and stem cell biology at Newcastle, has accused Professor Alison Murdoch, his former collaborator, of ignoring good scientific practice by arranging to announce the breakthrough at a press conference.

Stojkovic, who is now deputy director of regenerative medicine at the Prince Felipe research centre in Valencia, also accuses Murdoch of trying to take the credit for his research team’s work.

He says he was so unhappy with the way Murdoch behaved that he has not spoken to her since shortly after their research was published last summer.

The Newcastle team breached convention by publicising the work before a full account had been reviewed by experts and published in full in a scientific journal. At that point only a summary of the findings had been submitted to the online journal Reproductive BioMedicine Online.

Murdoch timed the announcement to coincide with the publication of a scientific paper by a South Korean team led by the now disgraced Professor Woo-suk Hwang, which declared the creation of human stem cells from cloned embryos. The research was faked.

Stojkovic claims Murdoch planned the announcement when he was out of Newcastle. He said he was angry that arrangements had been made to announce his work in an “unprofessional” way and that he took part only because it was too late to prevent the press conference taking place.

“I was upset with the strategy to inform the press before our manuscript was accepted,” said Stojkovic. “Especially to know that the media were invited (to participate in a telephone briefing) without my agreement and knowledge. Other team members were also unaware of this development.” Newcastle insists the decision to go to the media was taken jointly.

Nature, the scientific journal, was also critical. It wrote: “The premature release of this incomplete information . . . is contrary to good scientific practice.”

Although Murdoch is widely described as the leader of Britain’s cloning team, Stojkovic insists her contribution was limited to providing human eggs from her fertility clinic for the experiments. “There are plenty of people dissatisfied with Professor Murdoch taking the publicity,” he said. “The laboratory scientists do not need someone who has been doing nothing in the laboratory and who knows nothing about the work, to represent them.”

Newcastle University insists Murdoch’s contribution was important. Professor Michael Whitaker, dean of research at its faculty of medical sciences, said: “This work was a team effort. You cannot clone an embryo without an egg and you cannot get eggs without a clinic. Professor Murdoch has had to deal with all the ethical and regulatory issues (of using patients’ eggs) and that is a huge contribution.”

A spokesman for Newcastle University admitted that Murdoch had asked Reproductive BioMedicine Online, without the agreement of Stojkovic, to delay publication of the summary until the day the Koreans published their research. But he claimed Stojkovic had approved the statements released to the media.

Miodrag Stojković (Serbian: Миодраг Стојковић) (born on July 5, 1964 in Leskovac, Serbia, then Yugoslavia) is a Serbian researcher in genetics with the Institute of Human Genetics at Newcastle University. He holds a PhD from the Ludwig-Maximilians University in Munich. As of January 2006, he is serving as a Deputy Director and Head of Cellular Reprogramming Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain.

According to the TIME magazine, Stojković caused a controversy when he tried to create human embryos by injecting a patient’s own DNA into an egg from which the genetic material has been removed. He then hopes to harvest stem cells-which can develop into almost any organ-and coax them to produce insulin in diabetics. The research could lead to cure of Alzheimer’s, Parkinson’s and heart diseases.

In a German TV show “Menschen bei Maischberger ” (ARD;6/6/2006) he claimed that due to stem cell therapy paraplegic patients will be able to walk in the upcoming three years.

Biografía Prof. Miodrag Stojković

1984-1990 Veterinary Medicine Degree, University of Belgrade, Serbia & Montenegro. 1993-1995 Veterinary Medicine Equivalency, LMU, Munich. Sept. 1995 Post-Doctoral Fellow, Responsible for in vitro production of bovine embryos, Dept. of Molecular Animal Breeding & Biotechnology, LMU, Munich. Nov. 1998 C1 position, Post Doctoral Fellow, Head of the IVF Laboratory, Dept. of Molecular Animal Breeding & Biotechnology, LMU, Munich. June 2000 Winner of the International ARTA award in Jena. Jan. 2001 Founding Diplomat of the European College for Animal Reproduction (ECAR). Jan 2001 Scientific Advisor, Therapeutic Human Polyclonals, Tyscon, USA and Agrobiogen GmbH, Laretzhausen, Germany. July 2002 C2 position, Private Docent, Head of the UVF Laboratory, Dept. of Molecular Animal Breeding & Biotechnology, LMU, Munich. Oct. 2002 Senior Research Embryonologist and Senior Research Associate. Apr. 2003 Honorary Research Associate of the School of Surgical & Reproductive Sciences, Faculty of Medical Sciences, University of Newcastle. Dec. 2003 University Reader in Embryology & Stem Cell Biology, Medical School, Institute of Human Genetics, University of Newcastle. Aug. 2004 First licence granted to use nuclear transfer embryos to derive human embryonic stem cells in Europe. Sept. 2004 Deputy Director of the Centre for Stem Cell Biology and Developmental Genetics, University of Newcastle. Dec. 2004 Honorary citizen of Leskovac, Serbia and Montenegro. Jul. 2005 Visiting Professor, Medical Faculty, University of Kragujevac, Serbia and Montenegro. Aug. 2005 Chair in Embryology and Stem Cell Biology, Centre for Stem Cell Biology and Developmental Genetics, University of Newcastle, Newcastle upon Tyne, UK. Jan. 2006 Deputy Director and Head of Cellular Reprogramming Laboratory, Centro de Investigación Príncipe Felipe,