Q&A: Is stem cell research misguided?

Searching for a set of molecular characteristics common to all stem cells is, at best, a quixotic quest, argues a systems biologist in an opinion linkurl:piece;http://jbiol.com/content/8/8/70 recently published in the __Journal of Biology__. This overly-simplified view of stem cells, the article notes, may be leading science down unfruitful paths and holding back clinical research. Instead, the author of the review, University of California, Irvine, researcher linkurl:Arthur Lander;http://lan

By | September 29, 2009

Searching for a set of molecular characteristics common to all stem cells is, at best, a quixotic quest, argues a systems biologist in an opinion linkurl:piece;http://jbiol.com/content/8/8/70 recently published in the __Journal of Biology__. This overly-simplified view of stem cells, the article notes, may be leading science down unfruitful paths and holding back clinical research. Instead, the author of the review, University of California, Irvine, researcher linkurl:Arthur Lander;http://lander-office.bio.uci.edu/landerfacts.html advocates a change in mindset. "It is perhaps curious that, after 45 years, we have been unable to place the general notion of 'stemness' on a purely molecular footing," he writes in the article. He posits that the time has come to consider stem cells in broader physiological contexts, studying their role in complex networks of molecular and cellular interactions rather than examining the function and genetic makeup of stem cells in isolation. Lander took time to chat with __The Scientist__ about reframing stem cell research to emphasize this systems-level perspective and the intricate feedback loops that spur stem cells into action in vivo. __The Scientist__: Can you start by enunciating your main point about the fallacy of the stem cell concept? __Arthur Lander__: It's a little easy to get carried away and think that I'm trying to say there's no such thing as stem cells, which I'm certainly not. The main point I'm trying to make is that the most prevalent conception of stem cells within the scientific community is of the sort of thing you would expect to have a unique defining molecular signature...[and] we shouldn't necessarily expect that there will be some unique molecular signature of what it means to be a stem cell. __TS__: Are you saying that we should abandon the almost 50-year-long effort to define the concept of 'stemness' and change how we think about it? __AL__: We want to nail down the concept, but we need to nail it down in a different way. So if this is really a network property -- that is, a property at a higher level than the cell itself -- then nailing down the concept means knowing something about molecular properties of the cell and molecular properties of cell types it produces, the molecular properties of things that they produce that then feed back on the stem cells? It's a system level property, so we need to have information about a whole system. The [essential] pieces...may be more about the dynamics of responses. For example, you could have one system in which a particular factor is used for the feedback loop and another system in which a different factor is used for the feedback loop. Exact molecular details of what it is -- whether is a TGFbeta family member or notch signaling or a hormone -- those may not at all be defining characteristics of a stem cell system. Those may be peculiarities of each individual case of stem cells.

Download Flash player to listen to an interview with Arthur Lander.

__TS__: How do you reconcile the fact that adult cells are capable of being reprogrammed using a very small number of genes? Wouldn't those genes be molecular descriptors of 'stemness?' __AL__: I would disagree. Those sorts of experiments are really not addressing the issue of 'stemness.' They're addressing the issue of potency. They're saying you have cells which appear to be unipotent, and you can put in a few genes, and you can make them pluripotent. So I suspect that certain degrees of potency, by themselves, are concepts that can be reduced to particular patterns of gene expression. Whether one needs the same cocktail of genes in every different cell type to get to the same stage of potency remains to be seen. There may be many routes. In a sense, by saying, 'Let's be careful about how we use stem cells,' I'm trying to advocate that people, when they study potency, say that they're studying potency and not 'stemness.' __TS__: In your article, you drew the comparison to phlogiston -- the disproved 17th century idea that a common and mysterious substance is released from all burning materials. That surprised me, because phlogiston was something that science found to not exist. What is your comparison between the concept of stem cells or 'stemness' and the mistaken phlogiston theory? __AL__: There, the point I'm trying to make is that the concept can have a perfectly good operational definition and still refer to nothing that actually exists. Later on in the article, I bring up the concept of the rate-limiting enzyme as probably the most similar sort of concept to stem cell. So like phlogiston, rate-limiting enzyme is defined by an operation: You look at a pathway, and if you take this thing and change its levels, the levels [of metabolic product] coming out of the pathway change. We can point to all kinds of rate limiting enzymes, and we can purify them, we can characterize them, they have molecular properties. But what they don't have is a single distinctive set of molecular properties that defines what it means to be a rate limiting enzyme. And that's because the concept of rate limiting enzyme is entirely contextual. Ditto for stem cells: You take them out of their context, which people like to refer to as 'niche' -- and they never behave the way they do in vivo. __TS__: You seem to say that the concept of rate-limiting enzymes, as an operational definition, is useful in some ways. Do you feel the same way about stem cell as an operational definition? __AL__: Absolutely. Clearly one can define the behavior of being the stem cell in a system. And so operationally, you can talk about, 'Can I transplant some cells that will behave this way?' or 'Within cancer, are there some cells that are behaving in this manner?' The tricky part is if then you jump from that to say, 'Well great, so since there are cells behaving in that manner, I should be able to define a network of gene expression that tells us what it means to behave in that manner.' That would be like saying that I should be able to find a type of fold or a type of amino acid that defines being a rate-limiting enzyme. That, of course, is nonsense. __TS__: What is the damage or the danger in perpetuating this mistaken concept of stem cells or 'stemness?' Are there any false paths that we've been led down? __AL__: I shudder a little bit about being too critical about false paths, because I think the natural course of science is that we go down lots of false paths. I think we have to. If we try to be so clever that we never went down anything that might be a blind alley, we'd never get any work done. [Cancer therapy research is] a case that has a certain clinical immediacy to it. You don't want people jumping in and making assumptions about how therapy would work that would lead them to explore some therapies and not others that would perhaps hold back the course of finding better therapies for a certain amount of time. That has real impact on people and their lives. Whether those of us who are doing research on animals or doing theory get held back by a little bit...I'm not sure that that's the end of the world. __TS__: Do you think that by shifting the framework away from a single cell to a broader system, there's a danger of the concept of 'stemness' becoming too diffuse? Would we be losing some level of detail by pulling the microscope back from the cell to consider the system? __AL__: We might be. I think that just remains to be seen. It remains to be seen how many different ways there are to achieve stem cell behavior within a lineage. If there are 100 different ways and [that number] keeps growing, then there might be a sense in which the concept is a nice concept, but it refers to so many phenomena that it's not that helpful. On the other hand, we might find that there really are a very limited number of tricks that are used, and so the concept might be quite useful, just having been bumped up to a slightly higher level. __TS__: Have you presented your ideas to any colleagues or stem cell researchers and gauged their reactions? __AL__: I have presented it to some colleagues, and I haven't had anybody yell at me yet. There are others who have been sounding this note for a while now. What's different here is that in the work of others they've tried to argue that stem cell is a condition rather than a character based largely on some of the difficulties that have been obtained in trying to pin down 'stemness.' I come at it by saying that in addition to that, we now know, because of our understanding of feedback control, that we shouldn't expect to be able to pin down stemness. It's just not going to happen unless we treat it at a network level. So I'm trying to add to the chorus here rather than be the lone voice. When I present this, it's not as radical as it might seem, and I hope I don't come across as though I'm trying to take credit for being the only person in this camp.
**__Related stories:__***linkurl:One step to human pluripotency;http://www.the-scientist.com/blog/display/55949/
[28th August 2009]*linkurl:Stem cell therapy triggers tumor;http://www.the-scientist.com/blog/display/55430/
[18th February 2009]*linkurl:Identifying the niche;http://www.the-scientist.com/article/display/53227/
[June 2007]

Comments

Avatar of: anonymous poster

anonymous poster

Posts: 20

September 29, 2009

Some researchers believe in a stem cell niche that provides a favorable environment for stem cells. I would be curious what Dr. Lander thinks about this concept.
Avatar of: anonymous poster

anonymous poster

Posts: 125

September 29, 2009

Trying to find the most basic answer to how stem cells "know" to differentiate to different cells in an organism is probably as difficult as how molecules combine to form a living organism. Both are holy grails of life science.

September 29, 2009

\nExciting the previous poster on the stem cell niche. Yes, I would also like to hear Dr Lander on it. I know little on the subject but you brought to my mind the ecological niche, where integration and adaptation seem to occur by virtue of the ?place? and ?function? of a particular organism within a larger and more complex biological context. It somehow helped me understand better the ?network? framework that Dr Lander is presenting. Thanks.
Avatar of: Alexey Bersenev

Alexey Bersenev

Posts: 3

September 29, 2009

If we can not pin down "stemness" it doesn't mean it's not exist. I don't think that many modern researchers consider that stem cell must have one stable distinguishable molecular signature or one stem cell must definitely represent whole population. We know, for instance, that even very pure hematopoietic stem cells could have 40-90% of quiescent fraction but engraft differently or in similar rate - different pathways working and different molecular signature. I don't think this paper and Dr. Lander's thoughts somethings radical. Many scientists will agree at some point (for example me at extrapolation to cancer stem cell, which are evolve), some will disagree at some point. \nBut it's good essay, we really need discussions like this.\nAlso read comments on FriendFeed - http://ff.im/8vhPF
Avatar of: Dov Henis

Dov Henis

Posts: 97

September 30, 2009

Cell And Life Research Are Misguided\nNot Just Stem Cell research\n\n\nA. From "Is stem cell research misguided?"\nhttp://www.the-scientist.com/blog/display/56024/\n\n- Considers "reframing stem cell research to emphasize...systems-level perspective and the intricate feedback loops that spur stem cells into action."\n\n- We shouldn't necessarily expect that there will be some unique molecular signature of what it means to be a stem cell... It's a system level property, so we need to have information about a whole system.\n\n- Whether one needs the same cocktail of genes in every different cell type to get to the same stage of potency remains to be seen. \n\n- Because of our understanding of feedback control...we shouldn't expect to be able to pin down stemness. It's just not going to happen unless we treat it at a network level. \n\n\nB. It is not just stem cell research that is misguided; it is that generally cell research and life research are misguided\n\nI humbly suggest, again and again:\n\n"Genostemness Induction, More On The Lifehood Of Genes", that makes each and all organisms alive\n\nhttp://www.the-scientist.com/community/posts/list/160/122.page\n\n\nDov Henis\n(Comments From The 22nd Century)\nUpdated Life's Manifest May 2009 \nhttp://www.the-scientist.com/community/posts/list/140/122.page#2321\nImplications Of E=Total[m(1 + D)] \nhttp://www.the-scientist.com/community/posts/list/180/122.page#3108
Avatar of: Jian-Xin Gao

Jian-Xin Gao

Posts: 28

September 30, 2009

\nLet us take an enzyme as an example:\n\nAmino acid consisting of the enzyme: stemness? No!\n\nBinding sites and catalytic sites of the enzyme: stemness? Yes!\n\nSubstratum of the enzyme: potency of stem cells? likely!\n\nReaction temperature for the enzyme and concentration of substratum of the enzyme: Niche? Yes!\n\nStemness: looking for amino acids? Yes, misguided!\n\nStemness: looking for binding and catalytic sites on the enzyme? Yes, right way?!\n\nGene signature of stemness: mimicking functional sites of the enzymes? Right way! \n\nGene signature of stemness: mimicking amino acids consisting of the enzyme? Wrong way or misguided!\n\nReaction system of the enzyme: equivalent to ecological system of stem cells? Yes. It includes stem cells, niche cells and surrounding metabolites, etc. \n\nBiological system: empahsize cell intinsic network.\n\nEcological system: emphasize environmental effects on biological system. \n\nEcological system of stem cells: emphasize interactions of stem cells with environmental niches. A eclogical system of stem cells consists of various types of biological systems of stem cells and subeclogical systems of stem cells. \n\nSo do cancer cells!\n\nImmature idea for critical comments.\n\n

September 30, 2009

\n\nHey Jian-Xin,\n\nI like your inmature ideas a lot !!!\n\nAre you, by any chance, a new "inmature" investigator ?. I wish I had an ARRA. I would hire you right away.\n\nThanks !!! \n\nRafaela
Avatar of: Jian-Xin Gao

Jian-Xin Gao

Posts: 28

October 1, 2009

I have my own laboratory. However, I would keep in touch with you. Are you at University of Pennsylvania Medical Center?\n\nBest!\n\nJian-Xin

October 2, 2009

\n\nHi Jian-Xin, \n\nYOU "immature" investigator with luck (lab) and IDEAS !!!\n\nI am very glad that you have your own lab !. May I apply for a position with you ?. Just kidding.\n\nSorry Jian-Xin, I closed my "little kiosk" in July 2007 and decided to look for new adventures. I, however, keep an eye on you guys doing creative science. I would like to be one of your advocates.\n\nThis is how Jazz singer Louis Amrstrong expresses my feeling:\n\nWhen I am dancing with you CREATIVE CLASS,\nI get ideas, I get ideas,\nI wish you kept going on doing brilliant science\nspreading it to the young and senior folks.\n\nAnd don't forget the undergraduate boys,\n'cause their 'hip hop' might make great sense,\njust try to push them to their creative mood\nand INNOVATION will be WITH YOUUUUUUUU !!!!!!!

October 2, 2009

\n\nSorry Jian-Xin,\n\nThe original lyrics is to be corrected\n\n"And don't forget the undergraduate girls and boys".\n\nLouis said that fits much better the musical space and rythm
Avatar of: Jian-Xin Gao

Jian-Xin Gao

Posts: 28

October 2, 2009

Dear Rafaela: \n\nThank you for sharing the beautiful lyric with me! Science and mucsic are more or so the same in creativeness except for not being lyrical!\n\nHowever, life is always lytical whether successuful or frustrated! World is always moving on and many paths toward Rome!\nThe destination of "Immature" is "mature"!\n\nJian-Xin\n

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