Skin stem cells are constantly replacing and repairing the body's surface. Fuchs says figuring out how this happens is a delight

Elaine Fuchs of Rockefeller University in New York City studies how stem cells in the skin maintain their orderly but complicated cycle of skin renewal, how they adjust so effectively to heal wounds and what goes wrong in disease. She is also a leader in the stem cell field and an advocate of women in science. Nature Reports Stem Cells spoke to her about the progress of stem cell science and scientists.

What's the best advice you've received as a scientist?

The best advice was from my graduate mentor teaching me how to do a well-controlled experiment. It's easy to come up with controls for what you think is going be the answer in your experiment. It's much more difficult to think more broadly about what could be the possible outcomes if you don't get the result you're expecting. My mentor taught me to set up the controls to be able to interpret an unexpected finding.

What does the stem cell field need to move forward?

There's always the need for the basic scientist to recognize the importance of translating the basic research to clinical practice. That's always been a barrier. Medical doctors tend not to jump into the science and scientists tend not to jump into the medicine. This has changed dramatically in the last thirty years, but it still has a ways to go. It should be our goal to see that the science we do becomes useful to mankind.

In order to accomplish this goal, it is essential to have scientific issues taken out of the political arena and the religious arena and placed more squarely within the scientific arena. One of the major hurdles of stem cell biology is that the guidelines to research with stem cells have gotten tied up too much in religious and political arguments. The argument which I find fallacious is that if NIH is left to make the decisions that ethics won't be followed. I think that's nonsense.

You protested the Vietnam War, almost joined the United States Peace Corps and have participated in other socially conscious activities. How does that influence your science?

My father would take me to the Museum of Science and Industry and then drive through the poor neighbourhoods of Chicago, wanting me to see that there are people who need help. What prompted me to go into biochemistry in the first place was the desire to work at the interface between basic science and medicine. And even though I was ultimately doing very basic biochemical research, I was excited that I was learning how antibiotics worked through their actions on bacterial cell walls.

And then you moved closer to medicine in your postdoc.

I chose to work with Howard Green at MIT because he was a quintessential cell biologist and I thought if I was going to take the plunge into more medically oriented research, I should work with someone who was a pure cell biologist, and I wanted to work on humans as a model system. I was looking for a system where I could study normal cells. I felt that if I wanted to understand what was abnormal, I had to first understand what was normal. Howard had developed the methods of [culturing] epidermal stem cells straight from human skin. It was really the ability to maintain and propagate these stem cells as normal cells in culture that inspired me to become a skin biologist.

A recent paper showed that keratinocytes [skin cells from the upper, ectodermal layer] reprogram much more efficiently than fibroblasts [skin cells from the lower, mesenchymal layer] and you have worked in nuclear transfer with skin cells. Does it make sense that these cell types would convert to pluripotency more readily?

To me it makes perfect sense. Embryonic stem cells share many more similarities with epidermal stem cells than with fibroblasts [a mesenchymal cell]. To give you an example, Fiona Watt has shown [in the epidermis] that cMyc is necessary to drive epidermal stem cells to a transient amplifying state that then differentiates. My lab showed that Klf4 is necessary for epidermal stem cells to differentiate. So here are two of the four genes necessary to reprogram adult cells into induced pluripotent stem cells that are naturally expressed at some point in the epidermal cell lineage.

The counter argument is that in the epidermis, these two genes drive differentiation, not stemness. Yet there is beautiful work by Rick Young's lab that has demonstrated that genes expressed in a lineage are often poised to be expressed before they actually switch on. Genes can often display certain activating chromatin marks, but they await one last factor before they can trigger transcription. So my own feeling is that even though Klf4 and cMyc are utilized by the epidermis to drive differentiation, their ability to be activated in the epidermal lineage may make it easier for them to be induced by an epidermal stem cell than by a fibroblast where genes such as Klf4 are never naturally expressed.

There are all these different places in the skin where stem cells can live. Tell me about that.

In the skin, there are stem cells that exist within the bulge of the hair follicle and also in the basal layer of the epidermis. We still don't know whether all of the cells within the basal layer can behave as stem cells or whether only a few stem cells exist that are scattered within this layer. It's an open question of where along the lineage to differentiation is the point of no return where a stem cell becomes irreversibly committed to terminally differentiate. In the skin the point of no return has definitely passed in the dead hair cells or in the enucleated squames [squamous cells] that are sloughed off the skin. But can an epidermal cell that has exited the basal layer and begun its journey to the body surface go backwards under certain circumstances and become a stem cell again?

To answer this question, we need to have a firmer grasp of the key features of a stem cell that determine stemness.

How much of an advantage is it that the stem cells in the skin are all found in neatly defined places?

Epithelial tissues differ from the haematopoietic system where cells leave the bone marrow and you really don't know who came from where. With epithelia, such as the intestine and mammary gland and skin epidermis and hair follicle, you can conduct lineage tracing and really follow the fate of the stem cell and its progeny.

One thing that fascinates me about the hair follicle is its cyclical bouts of growth, destruction and regeneration. During the growth phase, the stem cells have to be activated to regrow the hair, but then in the destructive phase, when the lower two-thirds of the hair follicle completely self-destructs, and in the ensuing resting period, the stem cell compartment is dormant. Other tissues don't have this neatly defined stage where there's a period of destruction and rest and then stem cells must be called into action again to regrow the hair.

From reading your review [in the February issue of Nature Reviews Molecular Cell Biology ] it seems like normally in the hair follicles all the types of stem cells have very set roles but if there's an injury any stem cell will do whatever is needed.

[Laughs] All of the tissues have to be able to repair themselves for the sake of the organism.

If you don't touch it, the tissue is pretty much all laid out, and to keep things this way, the tissue could be using very primitive mechanisms that are characteristic of the skin of a fruitfly or worm, but mammals have to sustain the epidermis over a much longer term and they must to be able to repair it rapidly upon injury. Mammals may have evolved backup systems to maintain and repair the epidermis more efficiently, and as such, they may use more diverse combinations of mechanisms than lower eukaryotic organisms.

You were the first woman in the biochemistry department at the University of Chicago. Tell me about breaking the gender barrier.

My older sister applied to graduate school at the University of Michigan but was turned down because she was female. They told her that they thought women were risks because they would just get pregnant and quit, so they didn't accept her. She ended up going to MIT.

I didn't have an experience like this, and in fact didn't feel that I was experiencing any kind of gender discrimination. It wasn't until I really reflected upon the topic as a young assistant professor that I started to realize that I had in fact experienced a gender barrier on multiple occasions. One was when I first arrived at the University of Chicago and walked into the elevator. One of my colleagues introduced me as the "prettiest member of the department". And I remember having an argument at a faculty meeting and one of my colleagues said, "I can understand why you would have that point of view because women tend to like knitting". Things like that wouldn't happen today.

One of the most disconcerting experiences occurred after I was a tenured faculty member. In a discussion with a colleague one day, I realized that assistant professor recruitment candidates were being offered a salary higher than my own. In follow up conversations with my chairman and the associate dean, I was told that the administration had realized for some time that my salary was low. Their excuse was that I had an NIH career development award and the university did not want to supplement it. Upon a threat to leave, my salary was raised, although no one ever offered to provide any compensation for all the years it had been too low.

What are the barriers now?

I don't think that there are such kinds of salary disparities at Rockefeller, but if you look at Nancy Hopkins' MIT report, then there is or has been a major gender salary issue at universities across the United States. Salary equality is something that people are much more cognizant of now, and they try to avoid serious disparities. But there are other areas that are still of concern, for instance in terms of honours and awards. There are many women senior to myself who still haven't gotten into the National Academies of Science and yet have done very original work and are very deserving.

Even with regards to more subtle things like getting articles published in journals, there is more discrimination than meets the surface. Quite frankly, I think it is starting to fade. The younger generation doesn't view gender as an issue like the older generation has. As the older generation is replaced, the gender discrimination will be less.

Now the greater issues are those of ethnic minority bias. If one looks at the number of blacks who go into science, there are very few. And as a community, we need to be more proactive about this.

Your Howard Hughes Medical Institute profile relates how you used to like doing crossword puzzles but how they sort of fell flat after puzzling out the skin.

I'm sure it's an unfair comparison, since I only have my undergraduate youth to go on for experience. When I was [working] in physical chemistry, I felt that problems had solutions, and I got an enormous sense of joy in solving equations. If there are an appropriate number of variables, the problems were challenging but solvable. But in biology there are far too many variables and you can't possibly solve the equation.

At the height of my excitement for crossword puzzles, [I was] feeling a sense of delight in taking physical chemistry exams. In making the transition to biology, I struggled with [the field's] uncertainty; I found it very frustrating that I could never solve the problem. But that's the excitement for me now, that you can't solve the problem, that every time you come close, there's some new dimension, some new twist, and every new twist becomes an avenue for exploration.

You have to be a passionate scientist to crave the uncertainty of science.

 
Source:  Nature

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