 Thank you and good morning. Before Dame Julia Pollock was appointed Dame Commander of the British Empire by Queen Elizabeth II in 2003, she was Dr. Julia Pollock, a young physician who moved with her family to London from her home in Argentina in 1968. She had obtained her medical degrees in early training in histopathology, the microscopic study of diseased tissue at the University of Buenos Aires. In England, she planned to pursue additional postgraduate studies in histopathology and after several years returned to Argentina. A permanent move back to Argentina never occurred though as her remarkable scientific career took off. As a member of the Department of Histochemistry at the Hammersmith Hospital, Dame Pollock developed immunocytochemical techniques to identify and localize the production of peptide hormones at the cellular level. By the early 1990s, she had been promoted to professor and chair of the Hammersmith Hospital, Department of Histochemistry, and refocused her research on nitric oxide regulation of normal and diseased states, particularly this molecule's role in bone and lung tissue. In a bizarre life twist, Dame Pollock was diagnosed with pulmonary hypertension, one of the diseases she was studying, requiring her to undergo a life-saving heart and lung transplant in 1995. This experience on the care-receiving side of the doctor-patient relationship spurred her into a new field, the field of tissue regeneration and engineering. The lack of appropriate donor organs for patient transplant led her to investigate new solutions that utilize our own cells to generate needed tissues and organs, work that she continues to this day. Since 1997, she has served as professor and director of the Tissue Engineering and Regenerative Medicine Center at Imperial College London, overseeing a diverse group of researchers in areas such as biomaterial science and stem cell research. This work has generated a number of patents and resulted in the establishment of the biotech company Novathera to develop and commercialize the center's discoveries. The extent of Dame Pollock's research accomplishments is evidenced by her approximately 1,000 published papers, positioning her as one of the most published and also cited scientists of the last two decades, also by her appointment to numerous editorial boards, and by the international recognition and awards she has garnered from her professional colleagues in pathology and endocrinology, culminating in her receipt of that title, Dame Commander of the British Empire. Please join me in welcoming Professor Dame Julia Pollock, who will speak to us this morning on her work with stem cells and regenerative medicine. Thank you, and thank you ladies and gentlemen, and thank you for the invitation to see these wonderful autumn colors of your country. It's really very, very nice, but I really didn't expect to talk to a few 5,000 people. I thought I was coming to give a lecture of 50 or 70 people, but the most surprising event was the prior to my lecture, a jazz band. It never happened to me. I'd like to tell you a bit about what we do at Imperial College, and the work on tissue engineering and regenerative medicine. I think I'm doing the right thing. So Imperial College is located in quite a trendy area of London. So if you are coming to visit London, try to avoid it because it's horribly expensive. But Imperial College is in an area where Prince Albert, the Prince Concert Queen Victoria, wanted to develop science and arts in that area. And they developed, they showed a tower, a queen tower, that you can see depicted here. And this has a preservation order, so it cannot be built. So Imperial College was built all around the tower. And it's located in a nice area where the Albert Hall is. And in summer there are the summer concerts, which the area of the grand floor is the promenade concert. They remove the seats and all the young people are standing there cheering, listening to the most wonderful classical music. And there are a number of associated hospitals that are part of Imperial College. So what is regenerative medicine? Well, it's really, they have many terms, like tissue engineering, biomedical engineering, bioengineering. And it's the application of the principles and methods of life sciences, medicine and engineering, toward the development of biological substitutes to restore, maintain and improve body functions. So what is not regenerative medicine? I wish it would be, but it's not. This is me, and it's not Ida, as my children already are preparing for inheritance money. And it's not what the papers wanted us to believe, that it's in the air, on the back of a mouse. So really what it is, it is about living a long healthy life for everybody, if we can repair damaged tissue. And in fact, it's divided into several segments, which I will go through in the lecture. But if we are able to create a tissue in a test tube, with the aid of specially designed materials and cells, we can have tissue engineering. We can also use cells differentiated into a particular lineage to cure a particular disease organ by the name of cell therapy, or we can stimulate the regeneration of our own body. So it's helping the body to heal itself, so we can replace by tissue engineering if we are able to create an organ in a test tube using cells and materials, as illustrated here. Or we can have cells prepared in a test tube that will be able to regenerate a particular organ of the body. Or we can stimulate cells which are in our body, stem cells in our body, that will tend to go to the sides of injury. And we can then, if we learn what are the chemicals that these cells contain that allows regeneration, maybe one day we will have a regenerative pill. We'll tell the patient, take this, and your lungs will regenerate. I don't think it'll be my lifetime, but it may happen. But it is possible to regenerate because other mammals and other species can regenerate. And what's happening? Have we lost the genes that these animals have? For instance, a deer can regenerate easily when it breaks, or other animals. Or we have containing in our body genes that they are suppressing our ability to regenerate. But in order to succeed, regenerative medicine has to combine. We need to come out of our boxes and collaborate between cell biologists, material scientists, geneticists, and all others because we need to learn how from one cell we become one individual. So it's needed because we need to create good health and wealth. And by doing so, perhaps one day we could have aging, the natural aging, but not in an unpleasant way like osteoporosis or Alzheimer's disease or unable to hear or to see. Nobody is extending life, but to make it very pleasant and painless. Or trauma. We can really help to regenerate. And of course we lost the champion of regeneration with a continuous with a real urban research center. So there are a medium, every disease you can think of could help by this field in the future. Just a few examples, a smoker's lung, or a heart attack, or damaged liver, or many others. And we need that because in many terminal diseases, organ transplantation is the only solution. And there are no sufficient number of organs. Every 18 minutes there is the need for an organ and most of the patients that need an organ will die before they get a chance. And we need to create cutting in the healthcare and commercialize and we will have wealth and health in the country. So we move to different stages of regenerative medicine. We need to learn which is the best cell source, how we encourage the differentiation to a different lineage, to a different tissue type, how we get sufficient number of cells, how we combine with materials, how can we expand the cells that we have them in a petri dish, how we know that these cells perform the function that we are hoping they will perform, how we develop appropriate animal models to test, and how we move to clinical trials. So, although this looks very simple that can be done by tomorrow, we face mega challenges in every single aspect of regenerative medicine. We need to do more and more research. But we are getting there, as I'll show you later on. So what are the challenges we have on the cell type which will be the most appropriate? So first we need to decide which cell we want to use. So, if we want to use a stem cell, a stem cell is a cell that divides and produce another stem cell. So we have the ability to have stem cells in our body to regenerate and the sister cell will be of the type of tissue. For instance, if we cut our skin, we can heal, obviously we can regenerate, a baby will leave no scars, the older we get we have more protracted regeneration, but it is due to the fact that we have stem cells in our skin and the cell needs to remain as a stem cell and divide to make a skin cell. So the older we get we lose more and more of the stem cells, so the ability to regenerate when we age is more protracted. So we can have within the stem cells the famous or infamous embryonic stem cells and we can have other cells which are a little bit mature within the development like there are plenty of cells in the bone marrow stem cells and be like a cord of a good source of stem cells. There are niche specific like I explained to you in the skin and every organ fat has a number of cells. Do we know which best? No. Nobody has done a systematic study comparing in a single identical circumstances different cell types. It's a mega study, should be done, but it hasn't been done as yet. In terms of human embryonic stem cells, these cells come from the very early embryo on the program of in vitro fertilization and in the UK once it's a successful fertilization the eggs are stored but they cannot be stored for more than eight years. After eight years when they are frozen and it was implanted and the family has the family two or three children or whatever they want they are asked whether this, the rest can be destroyed, they cannot be kept forever or they can be used for research and if the patient doesn't want to allow research they are destroyed so one way or the other these very early embryos are destroyed. In the UK we can use imported cells, we can derive embryonic stem cells and the license and the ethical approval, we can use therapeutic cloning and the license and reproductive cloning is illegal, is a criminal offence. So where are the cells? Any cell from the development can be used. Here is depicted a fallopian tube and on day four there is a collection of cells and on day five between four and five a little cell is taken for the prenatal genetic diagnosis routinely and you must have read in this country the work of Robert Lanza that is able to derive embryonic stem cells from there. Normally they are obtained a little later on of the pre-implantation, these are the kind of implanted from the inner cell mass on day six. And then continues, so you have a fertilized egg, then a totipotent stem cell will produce even placenta, these are to use for in vitro fertilization but not for human cloning, it cannot be done, it's forbidden, then when it's a hollow ball of cells, the blastocyst, cells can be obtained and the embryonic stem cells, when they continue the development they become a little bit more differentiated than like the cells in the bone marrow and then totally differentiated like a neural cell, so the examples are illustrated there. So from the bone marrow plenty of stem cells that are not embryonic are obtained and transplantation is routine clinical procedure for blood disorders. So this may be the best cell for clinical applications in the early days, then when we learn more about embryonic stem cells that could be done later on. Ambilical cord contain a burst of embryonic stem cells and this can also be used for regenerative medicine, fat tissue which is not an ethical to take and at least in the UK. And cells are located in each organ as I explained to you about the skin. So again we don't know the stem cells, the adult stem cells from the bone marrow or the tissue, it's useful because transplantation is in routine clinical practice, it's from the same person, so are autologous, they will not produce tumors and there are clinical trials, but they have a more limited development, they are in low numbers and they all get even less and compared with embryonic, these cells can produce all cell types, they can self renew, they can easily be available and grow very rapidly, but if you implant these undifferentiated cells, you can produce a malignant tumor, so they have to be differentiated, it's dangerous, there are huge clinical hurdles, there are ethical problems that the world yet has not settled down and because they are not from the same patient can produce rejection and immune rejection. The niche specific can be from the same person, they will not produce tumors, have a limited development, they are sometimes difficult to access, to access stem cells from the brain to operate the patient, take a bit of the brain and then put it back, maybe quite difficult and they are present in low number. Once we have the cells, we need to learn how we differentiate the cells for the tissue we are interested in and there are normally the embryonic stem cells will tend to differentiate spontaneously into different types, but to coach them to a particular lineage, one needs to do experiments and it could be by giving growth factors to the soup where you are having your cells in the dish and other ways which I'll go through. So using that at Imperial College we were able to obtain pieces of bone both from mouse embryonic stem cells and from human embryonic stem cells and we were able to characterize the little pieces of bone and we were able to obtain peripheral lung cells. There are two types of peripheral lung cells, one that is called type 2, that one can use a marker to distinguish and these cells can give rise to the type 1 cells which are flat and they are in contact with the blood vessels and they produce gas exchange and these pluripotent embryonic stem cells can give rise to these cells which ultimately will be functioning type 1 cells able to gas exchange because we have the marker. There are other tricks that one can do, this is an illustration, we can permeabilize the membrane and then we culture with for instance lung extracts if we are interested in lung or any other extract then we reseal the membrane and we can obtain differentiated cells and doing so we are able to obtain a shorter time differentiation because these procedures are cumbersome and take a long time and it does not produce a pure large amount of desired cell types but we are getting slowly there by having 17 days instead of 33 a little larger yield like we were having before. So can we introduce a collection of precursor cells, young cells but not pluripotent and allow the microenvironment to do the job that we want in the body. So there is an interesting aspect, we co-culture, we put it in a dish, in a petri dish pluripotent embryonic stem cells with pieces of lung and the cells became lung by contrast if we put it with cartilage the cells became cartilage so the microenvironment obviously is playing an important role here is a diagrammatic illustration how we can unwrap the cells with the tissue we are interested for instance in this case was lung and then we see whether the cells differentiate and this could be very relevant for cell therapy maybe we don't need to struggle to produce a whole organ to repair somebody's damaged tissue maybe if we have the cells to worse a differentiation pathway then allow the microenvironment to do the job for us but we still have a mixture of cells when we are in a petri dish so how can we have pure cells how we can have a collection of cells and we can use markers if the markers are on the surface of the cells if it's a protein on the surface of the cell we can label it with the color and with the machine we can pull them out and have a collection so we have to have a specific surface marker and it's non-invasive at real time and it's called fluorescent activated cell sorting to purify the cells prior to implantation we need also materials so cell biologists alone can provide certain degree of contribution but not the entirety and why we need materials we need them for carriers if we are going to do cell therapy or providing tissue engineering per se an organ in a test tube so these materials are combined with the cells this is a three-dimensional scaffold with the cells and eventually can be implanted into a living organism and we have enormous amount of materials and of course Dr. Jennifer West is a world expert on that so I'm only a cell biologist but there is a great quantity of very suitable materials this is one bioglass created by your fellow countryman Professor Larry Hench and creates an interfacial bone between implant and host tissue and it was important to know what were the molecular events that took place in the cells the cells needs to attach to the material sometimes they repel so had to be man-made material but they need to attach they need to grow nicely and demonstrate that with the material they grow better like demonstrated here they need to differentiate the lineage you are interested in in this case was bone lineage and it can be done three-dimensionally to have a little three-dimensional organ in a petri dish so three-dimension configuration to regenerate the tissue material should stimulate cell growth and differentiation attachment the position of extracellular matrix act as a template for tissue growth for implantation be reservable one doesn't want it all the time for pharma be insoluble because we can test drugs in a petri dish and here we can test for pharma bioterrorists household chemicals a variety if we have a three-dimensional composite of cells and materials in a petri dish but we still are struggling with a number of cells even if we beautify even if we have put them with the material we need to bulk up the number of cells in a three-dimensional configuration so we need to use machines that will permit fluids to come in because if you grow the cells without nutrients the middle will die so we need to rotate them we need to introduce fluids we need to monitor what is happening so this is another aspect of the research so one illustration is to be ready for preclinical applications so here is an illustration that these pluripotent embryonic stem cells if they are conditioned in a special way by grown for a short period of time with a particular medium they will produce lots of bone if the cells are cultured for a bit longer with the same misotherm medium they will produce heart we can have customized lineages which will be very useful for cell therapy but ideally we want to have a closed system that is fully automated where we encapsulate the cells and we put them in there and we will have control, reproducibility, automation, validation and safety and it won't have the handling the human error it will be fully automated machine and we will have a non-invasive sensor that will tell us the amount of sugar we have there the amount of metabolites, the amount of oxygen whether we need to put more or less and they will be very useful for three dimensional constructs and to use for clinical application I seem to talk like this and it comes but it never mind and an illustration is putting pluripotent stem cells encapsulated in a bead, in a little bead and then you can differentiate it into bone you put it in this rotating bioreactor and you get lots and lots and lots of bone nodules and ideally you want to have a closed system that you can give to the clinic and they can treat a heart patient or a bone fracture or whatever is the clinical need so another illustration, cells maintain their pluripotency when they are encapsulated and the alginate beads are biocompatible, FDA approved, can be soluble and injectable and they maintain their pluripotency for at least 116 days and here it shows how the cells are alive because we are giving nutrients so the cells are alive and they stay undifferentiated then you take them out of the bead and they are still undifferentiated then you can put differentiated factors to have large collection of cells so how do we move from all this experimental work to preclinical phase the animal models where there is good variety of very reliable models we put embryonic stem cells into animals which didn't have an immune system and we were able to produce bone pieces of bone and others are doing different animal models so we need purification to homogeneity, we need to characterize the cells we need to see that genetically they are normal and they are good for clinical applications and the animal models will provide us to analyze the cell fate and engrassment and how they are functioning in bed before we go to clinical applications and illustration is an animal model for regenerative medicine for cardiac disease the heart was injured by ligation of the coronary artery and the stem cells allegedly because it's very controversial were able to repair the heart muscle so currently at Imperial we are trying to repair lungs and we characterize the cells as peripheral lung cells by various means including protein expression and gene expression and then we see that the cells become flattened and they are in contact with blood vessels because they are exchanging gas and on this we publish the series of papers and now currently we are putting them on animal models of major septicemia or smoking lungs to see whether the cells will repair currently we mark the cells with a substance that we can visualize we see they go to the lung and now we need to find out whether they perform a function in the lung before moving to appropriate clinical trials there are clinical trials, early clinical trials were a proof of concept that putting bone marrow stem cells can correct children brittle bone disease or they can correct heart failure or they have engineered skin as early clinical trials but the criteria should be robust, we need to use large numbers double blind randomize we don't need to know to avoid bias and it needs to be confirmed by many other workers but then feel this moving, when I am asked when do you think we will have an organ in a dish I used to say well it will take another five or six years but now you see recently Tony Attala produced functioning bladders for children and lasted for eight years so we are moving faster than I would have thought so the field of stem cells, tissue engineering, gene therapy, nanotechnology are all converging to produce clinical applications to cure human beings so a revolutionary medical discipline with enormous implications for therapy and economic impact I think the future is here but I don't see it but I hope it will be seen soon so Imperial College is very multidisciplinary with enormous amount of departments during different aspects of regenerative medicine my own little team contributes with cell biology thank you