Is the study of stem cells moving there?

Recently, The Journal of Biology published a review (The 'stem cell' concept: is it holding us back?) Systems biologist from the University of California (Irvine) According to Arthur Lander, the search for a complex of molecular characteristics that are universal for all stem cells is, at best, a quixotic endeavor. Lander believes that such an overly simplistic view of stem cells can lead the development of science in the wrong direction and slow down clinical research.

Instead, the author recommends looking at the problem with different eyes. In his article, he writes that the fact that until now, after 45 years of research, we cannot formulate a general concept of "stemness" on a purely molecular basis looks very strange. He argues that it is time to start considering stem cells in broader physiological contexts, studying their role in complex systems of molecular and cellular interactions, leaving behind the evaluation of the functions and genetic characteristics of isolated stem cells.

Lander took the time to talk with a representative of The Scientist, dedicated to shifting the focus of stem cell research to the study of complex feedback loops that make stem cells function in a living organism (in vivo), and the need to consider these cells at the systemic level.

– Could you start with the formulation of your main idea concerning the fallacy of the concept of stem cells. – It is very easy to get carried away with the idea and interpret my words as a denial of the existence of stem cells, which I do not mean at all.

The essence of the main idea that I am trying to prove is that, according to the currently dominant concept in the scientific community, stem cells have a unique set of molecular markers that characterize them… [and] we should not expect that in reality a real stem cell has the same unique molecular characteristics.

– Are you saying that we should abandon the results of almost 50 years of work devoted to the formulation of the concept of "stemness" and change our attitude to this issue? – We want to develop a final concept, but we should do it in a different way.

So, if this is really a characteristic of the system, that is, a characteristic belonging to a higher level than the cell itself, does the formulation of the concept mean having information about the molecular characteristics of the cell itself and its daughter cells, as well as about the molecular characteristics of the substances produced by them that affect stem cells through a feedback mechanism? All this is related to the system level, so we need information about the system as a whole.

[The main] fragments... may be relevant to the dynamics of reactions. For example, you may have one system in which a certain factor is used in a feedback mechanism, and another system in which a different factor is used in a feedback mechanism. The exact molecular characteristics of this factor (whether it belongs to the family of transforming growth factor beta – TGF-beta, whether it is a link in the signaling mechanism mediated by the notch protein, or has a hormonal nature) may have no relation to the defining characteristics of the stem cell system. They may be features of each individual variety of stem cells.

– What do you think about the fact that adult stem cells can be reprogrammed using a very small number of genes? Are these genes molecular identifiers of "stemness"? – I do not agree with this assumption.

Such experiments do not affect the issue of "stemness" in any way. Their goal is to study the potency of cells. Their results say: you have cells that look unipotent, you can embed several genes into their genome and they will become pluripotent. Therefore, I suspect that certain levels of potency are concepts in themselves that can be reduced to certain variants of gene expression. It is still necessary to find out whether the same gene complex is suitable for the return of different cell types to the same level of potency. Many options are possible. In a sense, when I say, "Let's be careful about using stem cells," I'm trying to convince people who study cell potency to say that they are studying potency, and not "stemness" in any way.

– In your article, you resorted to comparison with phlogiston – the debunked idea of the XVII century, according to which all substances emit the same mystical substance during gorenje. This surprised me, because science has proven that phlogiston does not exist. What do you find in common between the concept of "stemness" and the erroneous theory of the existence of phlogiston?

– The idea that I am trying to convey by this is that a concept can have quite a good functional definition and still refer to something that does not really exist. Later in my article, I mention the concept of enzymes that limit the reaction rate as perhaps the most similar to the concept of stem cells. Like phlogiston, the enzyme that limits the reaction rate is determined by the function: you look at the process and if you take the component in question and change its concentration, in each case the concentration of the final resulting [metabolic product] changes. We can isolate any enzyme that limits the reaction rate, purify it and study its molecular characteristics.

However, what the rate–limiting enzymes do not have is a set of distinctive molecular characteristics that determine what it means to be a rate–limiting enzyme. This is due to the fact that the concept of enzymes limiting the reaction rate is determined solely by the context. The same goes for stem cells: you take them out of the context that people like to call a "niche", and under no circumstances will they behave the way they behave in a living organism.

– It sounds as if you want to say that the concept of rate-limiting enzymes, as a functional definition, makes some sense. Do you think the same about the concept of stem cells as a functional definition?

– Absolutely. It is quite obvious that in the conditions of the system it is absolutely possible to determine the real characteristics of a stem cell. And as for practice, in this case you can reason like this: "Can I transplant cells that behave in a similar way?" or "Are there cells with similar characteristics inside a malignant tumor?" However, in this case there is a risk to jump to: "Great, because there are cells that behave in this way In this way, I can identify a gene expression model corresponding to this behavior." This is equivalent to saying that you are able to determine the shape of a protein molecule or a characteristic amino acid that determines whether it belongs to the enzymes that limit the reaction rate. Which is obviously absurd.

– What is the harm or danger of further following this erroneous concept of stem cells, or "stemness"? And in what wrong directions has it possibly already led us?

– I'm a little worried about my criticality regarding the wrong directions, because I personally believe that following a lot of erroneous directions is the natural course of development of science. I am of the opinion that this is how it should be. If we were so smart that we would never have started moving in a dead-end direction, we would never have completed any work.

[Research in the field of antitumor therapy is] a case, from a clinical point of view, of an urgent nature. You would not want people to make hasty assumptions about how a particular therapeutic approach will work, which will lead them to study some specific methods from a variety of possible ones, which will probably delay the emergence of optimal treatment methods for some time. Such a narrow approach can have a real impact on people and their lives. If those of us who conduct experiments on animals or engage in theoretical research have lost a little time… I don't think it's the end of the world.

– Don't you think that shifting the focus of research from the study of an isolated cell to the study of a larger system carries the danger that the concept of "stemness" will become too vague? Won't we lose the level of detail if we stop looking at the cell through a microscope in order to better understand the system?

– It can happen. I think it will be seen over time. It remains to be seen how many different methods exist for studying the behavior of a cell within its biological lineage. If there are 100 different methods and [this figure] continues to grow, then there may be a feeling that the concept being studied is interesting, but it combines so many different phenomena that it itself loses meaning. On the other hand, we may find that we use a very limited number of techniques, which indicates the usefulness of the concept and raises it to a slightly higher level.

– Have you presented your idea to colleagues or researchers studying stem cells, and what was their reaction? – I discussed it with some colleagues and no one has yelled at me yet.

There are other specialists who have already begun to express similar opinions in some ways some time ago. Their main difference is that in their works they try to prove that the "stemness" of a cell is rather a condition than a special characteristic. This opinion is based for the most part on the difficulties that attempts to formulate the final concept of "stemness" have broken down. I categorically disagree with this and claim that, in addition to these difficulties, we now know, thanks to our understanding of the feedback principle, that we cannot formulate the concept of "stemness". This will not happen until we begin to consider this issue at the system level. So in this question, I'm trying to join the chorus and not be a lone voice. When I present my idea, it's not as radical as it might seem, and I hope it doesn't look like I'm trying to attract attention by being the only person in my camp.

Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of The Scientist – Q&A: Is stem cell research misguided? 

05.10.2009