Cell Fate: Journeys to specialisation

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Cell Fate: Journeys to specialisation

we know medicine and biology have helped cure many diseases what we hope now is to go even further as we begin to understand how cells are made in the body how stem cells work and how DNA controls them we expect to make new and better treatments Thomas Graf has devoted his career to understanding cells his team investigates how DNA control cells and whether it is ever possible to convert one cell type into another this could have implications beyond the laboratory it could mean that we could take diseased cells and change them to become healthy cells or if we lose brain cells take cells from our muscles and turn them into what we lack but first of all we need to understand exactly how different sales are made in the body and the cells we know most about are in blood the blood cell system is comprised of different types of specialized cells each blood cell type has a specific function for example the red blood cells carry hemoglobin to the different parts in our body which bring the oxygen which our cells need the macrophages eat and engulf bacteria and dead cells and B cells or B lymphocytes are the cells which produced the antibodies which attack invading pathogens the question is what makes the cells what they are what controls their identity we already know that each different blood cell is produced from the same original blood or Hamato poetic stem cell hematopoietic stem cells are the cells that produce all the different slot cell types in the body they’re extremely rare there’s only about 1 in 10,000 in the bone marrow where they actually live what makes stem cells unique is that they cannot only produce the different types of specialized cells but they can also make more of themselves they can self-renew the metabolic stem cells they live in little nests or niches surrounded by other cells which are called stroma cells and by the blood flow which provides nutrients and signals which will activate mechanisms within the stem cells last time cells are able to give rise to all the differentiated cell type in the blood one way to help us imagine this is to see a model that shows plows themselves as a pool on top of the mountain itself in the pool as the potential to become any cell type in the blood when an event happens like an injury the stem cells are pushed over the bridge of the mountain and they begin their path downwards as it progresses downhill various paths diverge the cell loses some potential and gains specific properties this process is tightly controlled to make sure the sub becomes the one the body needs when the cell finally reaches the bottom of the mountain it does acquire its final event so the first pool immediately downstream of the hematopoietic stem cells these are like parent cells that can make all the different types of cells are still multipotent they can form the different blood cell types but they have lost the

ability to self renew therefore they are no longer stem cells this system is so robust in the body that we can take stem cells from one person and transplant them into someone whose blood system is faulty or damaged and the repair will be for life blood stem cell transplants have been used since the 1950s but it’s only now that we understand the mechanism cassia who is 3 was born without B and T cells in his blood gosh yeah but if it feels he accompanied us a Vera case we infer me that the original red otário y lo que pasa es que no tiene not not any elephants a la sangre pro tanto el a vulnerable a a qualcare infección pudiera tener s cows our program Ottaviano chromosome ax e in show caso particular note any lymphocyte or stay he lost him force it was be no food theorem correctamente y el déficit during a protein l not only is the system i’m owner s the ther source Esposito’s Terran pharaoh una vez en dos de kado de la enfermedad pues nos dijeron que el único tratamiento que habia aaron transplant a de de meadow la esperanza a vida que NOS dieron era de dos años en un ambiente un poquito sterile see no no podría as a proverbial once the donors healthy stem cells produce a new blood system it functions in the same ordered way as it would in any healthy person to make sure the right numbers of all the different blood cells are made in the body throughout life what happens after transplantation is that the whole blood cell system has been replaced we have injected the patient with him idiotic stem cells from a donor which now find their niche in the bone marrow and you can imagine in this mountain analogy that again there are healthy stem cells sitting on the top of a mountain which now can form the whole blood cell system and builds up a healthy new blood cell system within the patient the question is how does this work how do stem cells know what to become how do they know to make red blood cells macrophages lymphocytes etc the answer lies in her genes in the DNA in the nucleus of the cell are switched on and off each DNA strand consists of four small tiny ring light molecules which in an abbreviated form are called ACGT adenine cytosine thymine and guanine and these four building blocks exists in different combinations and sequences like letters in an alphabet which can form sentences paragraphs articles and entire books so the nucleus of each cell contains DNA this famous molecule which consists of two intertwined strands that contain the genetic information which is then packed in 23 chromosomes in human cells if you would isolate the DNA from a single cell and would pull the ends apart it would actually form a rod of 2 meters length which is enormous in comparison to the size of a cell this is because each DNA strand contains a huge amount of information packaged up into genes each gene is a section of a DNA strand the DNA can do two things you can self-replicate and produce more releases or it encode for proteins each cell containing 25,000 genes and each genes code for a specific protein all the different proteins have different functions in the body to all specialized cells like neurons

blood cells muscle cells etc have the same amount of DNA and the same number of genes which is about 25 thousands of mammals but they only use the information for a subset of these genes which are important for their functions so the difference is between let’s say lymphocyte and the macrophage is not that they contain different genes but which genes are active it turns out that there are still a lot that we have to learn how these proteins are made how they function how they are stabilized the key is to understand how the right set of genes for each cell type get switched on and off for Casilla who was lacking the right genes to create functional BMT cells the only way was to find blood from a donor whose DNA was intact and so whose stem cells were capable of creating every sort of blood cell empathy renacer la busca de dante in nose and control indignant a vivo digamos compatible canal in the destined path Allah busca and Los Blancos the Sangre de coeur umbilical desirous Madre de todo el mundo y finalmente poison control un cordon compatible a americano URI soul transplant a meadow la vida free patterns of mesquita like a nucleus a patterns mr. C’s measures color podium say Caputo tiene que ver compatible Adad our Maximus a voy a hacer sarah hace important ntral durante receptor debido a que puede ver enrich a foe and su casa Erin a compatibility way over the death varam is most ah ah stayin recuperación immunological pero el principio está bien está not even a normal valise kwela a Coheed infección espero las normal s de los ninos Esplanade DNA lymphocytosis Eldon and a llama la mayoría porque la reine capaz de fabric carlos para tener un pequeño % ah hay de Delon fuzzy toes Vasu yos km principio nono funcionan Ariston estudiando CCENT en den los de los del de Nantes estos lymphocytosis Aaron capacités de de general Paz la CIMA no Globo Lina’s que parece que también que si por que hace una noche know Lebanon tratamiento y él está bien kasia’s transplant has rebuilt his blood system from the original cell the stem cell by doing experiments with two types of blood cell the B cell and the macrophage Thomas grafts group together with colleagues around the world using DIF our systems have helped uncover mechanisms hidden inside the nucleus that control the final blood cells fixed identity in each cell nucleus swimming around the chromosomes are a class of molecules which are called transcription factors there are actually quite abundant and they are characterized by their ability to find sites on the DNA to which they can bind they can talk to them in every cell there are a lot of different transcription factors transcription factors are protein able to recognize a specific sequence within the DNA the binding of transcription factor to the DNA cannot switch genes on and off after the binding of the transcription factor to the DNA onions I’m called RNA polymerase is needed to produce RNA molecules the codes for proteins to proteins are responsible for the different types of cell types so they are the proteins which instructs the cell fate it seemed that cell identity is set by

transcription factors macrophage transcription factors control genes needed in macrophages B cell transcription factors control genes needed in B cells and so on thomas grafts laboratory isolated different transcription factors that were present only in b cells or macrophages graphs experiment tested what would happen if he puts the macrophage transcription factor into B cells could these cells that have reached their final identity still change different specialized cell types in the body are actually very stable the macrophage is always a macrophage a b cell is always a b cell but with the mechanisms that we have learned we can now use these transcription factors to change cell identity we can now introduce them into cells in which they are not normally expressed and we can force the cells to change and make for example a b cell into a mcafee basically what we do is we use a virus to deliver the protein that we want to be expressed into the B cells and together with the protein we use as a reporter gene another protein that is green so once the cells will be infected with this virus they will turn into green and after two to three days if this protein is over expressing the B cells they will be converted into macrophages which is what we see here after three days from the induction of the b-cells they convert into rapidly moving macrophages we can recognize them because they aggregate and then begin to eat all the bacteria in the culture we can put a piece of DNA which corresponds to the gene of the transcription factor CP alpha which is normally active in macrophages into a b-cell it’s like putting a troy and Horus into this P cell and now this transcription factor activates macrophage specific genes violate at the same time it represses b-cells specific genes this coordinate activation of the macrophage program and the extinction of the visa program results in a complete conversion of this to SATA this experiment is shown that it is after all possible to change a cell’s fate we call it transdifferentiation following the steps of the first transdifferentiation experiments done by harold Weintraub’s lab in the 1980s thomas was able to produce macrophages from b-cells by changing a single transcription factor the B cell has been pushed out of its pool and propelled across to a different pool to understand what’s going on at the molecular level we have to go back to the multipotent progenitors these cells which are the parent cells for many different types of cells these cells contain actually in their nucleus a mixture of different transcription factors each of them having a different specificity in each of them regulating a different subset of genes and so there is a battle of dominance which has to be resolved transcription factor dominance is regulated by external signals by the micro environment by the niche and it’s consists in the binding of small molecules also called cytokines to receptors that are on the surface of these cells or the interaction of these receptors with molecules on other cell types and these signals have an effect on the balance of the transcription factors inside the cell the way they do it is they lead to the increase in the amounts of one particular transcription factor which now becomes dominant and reduces the amount of all the other transcription factors that are important for other cell types these transcription factors that are now abundantly expressed in this cell dictate the cells

fate for example they produce a lot of lysozyme in a cell that becomes a macrophage and they produce a lot of antibodies in a cell that becomes a B cell and other transcription factors that in principle could have made other cell types are now repressed in these cells and therefore we have now a locked state Thomas’s theory is that transcription factor dominance may explain how cells find their roots down the mountain scientists are testing this at the moment what we do know is that these transitions often require several transcription factors not just one I understanding our genes control cell fate we hope to apply this knowledge to the clinic and improve a patient specific treatments we are working on that and that’s our hope for the future Thomas Graf has shown that blood cells can be converted and how this is done Francesca and Alessandro and Brunner and others will take this forward even though it sounds like science fiction we might be able to create cells Alucard by taking a biopsy from a patient and making any cell type that we would like to produce to replace a cell that is defective in the body by generating patient specific cells immune rejection can be avoided with the rapid progress in the transfer NC Asian research fields in recent years and months it seems possible that we will eventually learn what transcription factor combinations are required to specify all the different cell types in the body graph and his team have shown how some blood cells can have their identity changed it seems this principle could be true for all the cell’s by unlocking these biological secrets we may be able to create new and even personalized medicines these are the challenges for the next generation of science explorers