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Thread: A new lecture of stem cell biology that I have been giving

  1. #1

    A new lecture of stem cell biology that I have been giving

    Here is the substance of a lecture that I have been giving about stem cells.

    Something has been bothering me. Every time I open up a newspaper, I hear journalists call stem cells "primitive". Scientists call stem cells "undifferentiated" which is a more nuanced way of saying the same thing. I want argue here that stem cells are neither primitive nor undifferentiated, in the same way an egg is not primitive or undifferentiated. Let me explain. An egg is possibly the most specialized cell in the body and at the same time is omnipotent. The egg is exquisitely designed to perform a very important task, to receive the overtures of many millions of sperms but select only one to fuse with, and then execute the most complicated program in biology, the creation of an organism. At the same time, the egg is the only truly omnipotent cell (i.e it can produce *any* cell of the body) whereas embryonic stem cells are merely pluripotent (i.e. it can produce *many* cells of the body).

    I believe that stem cells are highly specialized cells, designed to execute the most difficult task of our body and that is to make and repair tissues. Think about what a stem cell must do. First, it must create a cell that is not like itself, and it must also be able to create more stem cells. That is no mean feat. Yes, any old cell can reproduce itself but very few cells can create many other kinds of cell and also reproduce itself. Second, a stem cell must produce the right type and the right number of cells in any given tissue, as well as cells the respect the boundaries of the tissue. If it does not, it would be a tumor cell. In fact, isn't that the definition of a tumor cell, a cell that produce the wrong type and numbers of cells, and also does not respect the tissue boundaries? Third, stem cells seem to know where to go. Recent studies suggest that stem cells gather around areas of injury, like firetrucks gather around a fire.

    How do stem cells do what they do? We don't know. Not only do we not understand how stem cells do what they do but, as we study stem cells, they appear to break the three cardinal rules of cell biology:
    • Differentiation is a one-way street
    • Cells cannot produce cells other than themselves
    • Cells don't fuse with each other and other cells except under very special circumstances.

    For centuries, biologists thought cell differentiation is a one way street, that once a cell differentiates, it can't go backwards. Superficially, the evidence appears to be overwhelming in favor of this rule. Cells indeed seem to stay on their differentiation path, come hell or high water. If a cell does go backwards or dedifferentiate, we would call it a tumor cell. There must be extraordinarily strong regulatory controls of dedifferentiation. What would our body be like if our cells were to de-differentiate routinely? We would not be able to function. However, there is no doubt that cells do de-differentiate in culture. Every scientist who has grown cells in the laboratory knows this. In fact, it is extraordinary hard to grow primary cells that keep their original characteristics. Over time, most cells transform in culture.

    The concept of a cell producing a cell other than itself is rather extraordinary. For example, it would surprise me enormously if one of my nipples grew into an eyeball. In fact, this would be so unbelievable that the Guiness Book of World Records would suspect me of trickery, such as transplanting an eyeball. Why is this so shocking? After all, we have long known that there are cells that make many kinds of cells during development and that bone marrow cells can make many different kinds of blood cells. Furthermore, if we had only differentiated cells in our bodies, we would have to keep in reserve an enormous army of many different types of cells to repair tissue injury. It is far more efficient to have cells that can make many different types of cells and send them to injury sites.

    it may be a quintessentially western belief that cells are individuals and they interact with each other by exchanging molecules through receptors, cell adhesion molecules, cytokines, and neurotransmitters, rather than by melding into their neighbors. Several years ago, biologists were shocked to find that stem cells fused readily with other cells. But, why should we be so surprised that stem cells fuse with other cells? We know that some cells do fuse with each other. For example, a sperm fuses with the egg and muscle cells fuse with each other. The more interesting and unanswered question is why stem cells have the ability to fuse with other cells. What purpose does it serve? We don't know.

    Stem cell research is shaking the foundations of biology in much the same way the discovery of nuclear physics shook the foundations of Newton's world. In the last few years, stem cells have broken almost every rule of cell behavior that I was taught as a graduate student. It didn't seem so long ago that I wrote in a article that the neurons are extraordinary long-lived cells because they cannot replace themselves. Of course, I did not think at the time that there could be adult stem cells in the brain that produced new neurons. I believe that Nature has more surprises in store for us.

    Where have adult stem cells have been? After all, we have been studying cells for over a century and the only "adult stem cell" that we knew about a decade ago were in the bone marrow because they can produce many types of red and white blood cells. The discovery of stem cells in the brain was particularly shocking. Neuroscientists have been looking at the brain for a long time and have always assumed that the neurons we die with are the same neurons that we were born with. Why weren't adult stem cells discovered earlier?

    The answer to this question is stranger than fiction. We have been looking for the wrong types of cells. Recent studies by my friend Arnold Kreigstein really changed the way I thought. A special cell called radial glia populates the developing cerebral cortex. Their cell bodies reside next to the ventricles and they send long processes all the way to the surface of the cortex. Ramon y Cajal and neuroanatomists described radial glia and knew that neurons migrated on their processes. Little did they or we suspect that radial glia not only guided neurons but also produced them.

    Radial glia however disappear with the conclusion of brain development. So, what do adult neural stem cells look like? Well, it turns out that they are astrocyte! Arturo Alvarez-Buylla showed recently, that astrocytes located in the subventricular zone (SVZ) of the brain produce neurons. Even more interesting, the progency of these adult neural stem cells migrate from the SVZ into two streams, one of which goes to the hippocampus and the other ones of which goes to the olfactory bulb. It turns out that one of the best places to get adult neural stem cells is the olfactory bulb.

    Curioser and curioser, as the saying goes. The radial glial cell is very specialized. It has a morphology like no other cell, performed an unique and essential function of guiding neurons to their destination in the cortex. Yet, nature endowed this tall, thin, gangly glial cell with the responsibility of making the neurons of the developing cerebral cortex. My colleague Marty Grumet has been studying this cell and find that it not only produces neurons but also astrocytes and oligodendroglia. Then came the shocker that adult neural stem cells are astrocytes. We should think twice about the cutting out glial scars, don't you think?

    I started this discourse hoping to dissuade people from thinking that stem cells are primitive and undifferentiated cells. Let me continue. Diana Bianchi recently gave a wonderful lecture at Rutgers this past summer. It turns out that we were in the same medical school class but we didn't know each other. In 1996, she reported that millions (perhaps billions) of fetal stem cells escape from the fetus and crosses the maternal-placental barrier, cruise in the blood of the mother, settling down in all sorts of tissues including brain, forming tissue-specific clusters cells that stayed in the mother for the rest of her life.

    When she first reported this, I think that many scientists sort of dismissed this as a cute story about how mothers carried the cells of their children in their bodies. However, upon reflection, her discovery turned my thinking concerning stem cells upside down. How do stem cells know what to do? Imagine yourself to be a stem cell cruising in the bloodstream of a foreign body (your mother's) and you end up in the liver. How do you know that you are in the liver and what cells to make? There are many thousands of tissue factors, cell adhesion molecules, growth factors, all strangers to you. Yet, you nestle in there and make the right type and the right number of cells that do not transgress the boundaries of the tissue.

    Think about it. The ability of embryonic and fetal stem cells to respond appropriately to any kind of tissue is truly amazing. We are asking these cells to perform miracles when we place them into different kinds of tissues and expect them to make the correct type and number of cells that are needed, and to respect the boundaries of the tissue. If they transgress these bounds, we call them tumor cells. How do stem cells know that they should form neurons or oligodendroglia when they are put into the spinal cord? Why should they know that they should make insulin-secreting cells when we plop them into the pancreas of somebody with diabetes. How can a cell, any cell, be so responsive to so many different kinds of tissues? Stem cells must be bristling with receptors to every kind of tissue factor.

    The behavior of stem cells must be evolutionarily highly selected. I was saying to the Open House on Friday that the evidence of fetal stem stems escaping into the mother has extraordinary implications. If we think about it, the only difference between a stem cell and a tumor cell is that stem cells respond appropriately to tissue factors and do not grow the wrong type of cells or too many cells. As soon as a cell grows inappropriately, too much, and invade across the tissue boundaries, it would be a tumor cell and not a stem cell. We would not survive as a species if embryonic and fetal cells do not respond appropriately to tissues because all mothers would be riddled with tumors after a pregnancy. This does not happen.

    All of the above have convinced me that stem cells are not primitive and undifferentiated cells. On the contrary, I think that they are not just pluripotent but highly specialized cells that can respond appropriately to a multitude of tissue signals, to produce the appropriate types and numbers of cells that respect boundaries of all tissues. Understanding how stem cells do what they do will revolutionize biology. It is simply the most exciting time in biology that I can remember. We will be the first generation to apply a radically new biology to curing diseases.

    The current stem cell debate is unfortunately slowing down science at a very crucial juncture. It is prolonging our need to collect cells from embryos, fetuses, umbilical cord blood, bone marrow, and other sources. If we understand what makes a stem cells do what they do, we will be able to produce blood and all the different cells of body. Let us move beyond harvesting and transplanting cells. Let us take the next stage of producing cells. We should be able to make any cell into a stem cell. After all, what is a stem cell but simply a cell that is expressing certain genes.

    We must move forward. Stopping now only prolongs the agony of incomplete technology. As my good friend Alan Roses (who discovered one of the genes responsible for Alzheimer's disease) once testified to Congress, finding a diagnostic tool that predicts disease and death but not having treatments to do something about the diagnosis is unacceptable. Likewise, knowing that there is a cure and not moving forward to make it a reality is unacceptable. It is so important that we not slow science down now when we are on the verge of most incredible discoveries of our lifetimes.

  2. #2
    Banned Faye's Avatar
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    Originally posted by Wise Young:

    All of the above have convinced me that stem cells are not primitive and undifferentiated cells. On the contrary, I think that they are not just pluripotent but highly specialized cells that can respond appropriately to a multitude of tissue signals, to produce the appropriate types and numbers of cells that respect boundaries of all tissues. Understanding how stem cells do what they do will revolutionize biology. It is simply the most exciting time in biology that I can remember. We will be the first generation to apply a radically new biology to curing diseases.
    I have always liked the phrase "a stem cell is the mother of all cells", or even the term used in the UK referring to stem cells as the master cell. ( a master who can adjust to circumstances )

    The current stem cell debate is unfortunately slowing down science at a very crucial juncture. It is prolonging our need to collect cells from embryos, fetuses, umbilical cord blood, bone marrow, and other sources. If we understand what makes a stem cells do what they do, we will be able to produce blood and all the different cells of body. Let us move beyond harvesting and transplanting cells. Let us take the next stage of producing cells. We should be able to make any cell into a stem cell. After all, what is a stem cell but simply a cell that is expressing certain genes.
    I agree, except that I feel that in the interim it is appropriate to use readily available ESC derived cells. If we only focus on determining the gene expression to make a desired stem cell and wait until we can produce those cells for treatment, we may be delaying application of viable treatment options with ESC derived cell therapies, which may be ready for application sooner. Both these avenues need to be pursued concurrently.

    We must move forward. Stopping now only prolongs the agony of incomplete technology. As my good friend Alan Roses (who discovered one of the genes responsible for Alzheimer's disease) once testified to Congress, finding a diagnostic tool that predicts disease and death but not having treatments to do something about the diagnosis is unacceptable. Likewise, knowing that there is a cure and not moving forward to make it a reality is unacceptable. It is so important that we not slow science down now when we are on the verge of most incredible discoveries of our lifetimes.
    I have always said that neurologists on the whole can only diagnose but not really treat, which must be so frustrating. It must be far more rewarding to be a neurosurgeon or interventional neuro-radiologist!

    ~It's troubling that exit polls and vote totals were so far out of whack. "I've spent my whole life in marketing. The difference is clearly beyond any sampling variability. ... The community of statisticians and media experts need to not let this be dropped"~ Bill Hawkes, a retired A.C. Nielsen Co. statistician.

  3. #3
    where are the answers ??????????????? 2008
    Han: "We are all ready to win, just as we are born knowing only life. It is defeat that you must learn to prepare for"

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    Senior Member cypresss's Avatar
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    many thx
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    Senior Member patd's Avatar
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    Very interesting Wise,

    Altough I'm still looking up the definitions of many of your words, I detect a core component neccessary for me to take this seriously; questions. When folks start talking about having all the questions answered, I tend to call bunk!

    Thanks for your work.

    Pat

  6. #6
    Quote Originally Posted by Wise Young
    We will be the first generation to apply a radically new biology to curing diseases.
    Do you really believe this generation will be the ones to apply stem cells with the rate that things are moving? I personally don't. stem cells seem like a next generation thing. I dont think science is aggressive enough to put stem cells to beneficial use because of both contraversey and scientific conservatism.

  7. #7
    Quote Originally Posted by Eric.S
    Do you really believe this generation will be the ones to apply stem cells with the rate that things are moving? I personally don't. stem cells seem like a next generation thing. I dont think science is aggressive enough to put stem cells to beneficial use because of both contraversey and scientific conservatism.
    Eric,

    Clinicians are the ones who will apply the clinical trials, not "scientists". Most scientists have never run a clinical trial. There are a few "clinician-scientists" who have crossed the line between the laboratory and clinic.

    Scientists are cautious because they are trained to be critical and, as I have pointed out, they aren't the ones who have to apply the therapies in clinical trlals. Clinicians are intrinsically conservative, particularly in fields such as spinal cord injury where clinical trials are rare and very few clinicians have any experience, for example, transplanting cells.

    There is the very difficult and crucial step of transferring the technology from animal studies (preclinical) to human (clinical). It is a lot of work, as I think the Geron example is showing people, especially when the therapy is controversial.

    Finally, there is the crucial ingredient of funding. Even the scientists and doctors want to, and the technology is available to be applied to humans, there many not be funding to do so. It always amazes me that people expect clinical trials to happen without money. By the way, it is illegal and unethical for patients to pay for experimental therapies.

    To do the above, what is needed is a clinical trial network, the purpose of which is to do clinical trials, where groups of clinicians are trained to apply experimental therapies and to measure outcomes. There must be companies or grants (from government and foundations) to sponsor the trials. There must be experienced trialists to help design and plan the trials. There must be clinical commitment to do clinical trials.

    Wise.

  8. #8
    Quote Originally Posted by Wise Young
    By the way, it is illegal and unethical for patients to pay for experimental therapies.

    I can't argue with the legality but ethics is subjective and depends on perspective. I personally feel its unethical to have what you believe is a cure and deny it to the public to help people who are suffering all to jump through the million hurdles placed in front of you by regulators. Once safety is established why not move it to the poeple? I may not be a seasoned scholar but i do understand how many fields get bogged down by the status quo and stallworths way of doing things.

    and I dont mean "you" personally I'm talking about the system in general.

  9. #9
    Informing phase, complete. It's time to persuade.

    "We choose to [cure spinal cord injury]

    We choose to [cure spinal cord injury] in this decade, not because it is easy, but because it is hard, because that goal will serve to organize and measure the best of our energies and skills, because that challenge is one that we are willing to accept, one we are unwilling to postpone, and one which we intend to win."

    This should be the aim of the lectures these days. Think JFK.

    f
    ight

  10. #10
    Quote Originally Posted by donz
    Informing phase, complete. It's time to persuade.

    "We choose to [cure spinal cord injury]

    We choose to [cure spinal cord injury] in this decade, not because it is easy, but because it is hard, because that goal will serve to organize and measure the best of our energies and skills, because that challenge is one that we are willing to accept, one we are unwilling to postpone, and one which we intend to win."

    This should be the aim of the lectures these days. Think JFK.
    Bravo. Well-spoken. I agree. Wise.

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