Geoff Gurtner, Stanford University School of Medicine Credit: Geoff_95

[Editor's note: This is part of a series of interviews conducted to accompany Nature Insight Regenerative Medicine .]

Wound healing in adults often leaves a scar where functional tissue once was. In a review in Nature, Geoff Gurtner of Stanford University, in California, explains how in other organisms, as well as in early human foetuses, injured tissues can be completely restored1. Here, Gurtner explains how studying the molecular processes of healing could spur medical techniques to prompt regeneration.

What's the difference between scarring and regeneration?

When a scar is formed, you have an area where tissue is missing or has been damaged. You essentially fill in that defect with disorganized cement that is scar tissue; you don't ever get the architecture you had before, and so that tissue never behaves in the way [it did] before there was the scar. In regeneration, the architecture of the organ or tissue is completely recreated, and so you have complete functionality of the area.

You write that organs like liver, heart or skin all regenerate in about the same way. Should that be surprising?

The lesson of molecular biology is [that when] you go deeper and deeper into the complexity of life, there are similarities you don't see at the whole-animal physiology level that become clear. It's not all that surprising that the same pathways are involved in the healing and response to injury. We are trying to understand what the fundamental and primordial stimuli are.

What can you learn about regeneration from other organisms?

The overarching interest in my lab is: Why are we no longer able to regenerate? It is conceivable that if we tried to recapitulate that ability, maybe there would be malignant transformation or uncontrolled growth. Until we understand better why in some organisms it's the way to heal and in others it's not, we're not able to move forward.

In certain organisms, regeneration is the default. In mammalian systems it's certainly not. The sponge is about as simple a multicellular organism as one can imagine, but it's clear that there's a fair degree of complexity in terms of control of patterning. But when you reach a certain point in terms of organismal complexity, you start to lose the ability for tissue regeneration. So why was the ability selected for, and why was losing that ability selected for?

Why doesn't regeneration cause cancer?

It's a little perplexing. One would predict that there would be more propensity to have malignant transformation where you have very rapid growth, but I guess the hand-waving answer is that the growth is controlled in the same way that development is controlled. Development is a very complex process; as you go through a zygote to a whole organism, it's really rare to have a developmental cancer that ends up malignant.

And what are the pathways that are involved across tissues?

It's a really fertile ground for research. Wound healing research has lagged behind others because it's been phenomenological. You make a defect and you see something happen, but why that happens and whether it's inevitable, those are questions that are just now starting to be asked.

Wound healing research has lagged behind others because it's been phenomenological. You make a defect and you see something happen, but why that happens and whether it's inevitable, those are questions that are just now starting to be asked. , . Geoff Gurtner, Stanford University School of Medicine

You talked about three stages of repair: inflammation, new tissue and remodelling. How important are stem cells among all the hordes of migrating cells?

Wound healing research has lagged behind others because it's been phenomenological. You make a defect and you see something happen, but why that happens and whether it's inevitable, those are questions that are just now starting to be asked.

It's a surprisingly open question right now. Clearly there are well-described epidermal stem cells within the hair follicle, and those are known to be involved for keratinocytes [epidermal skin cells] of the healing skin. Whether or not stem cells exist in the fibroblast dermis part of the skin is unclear; whether or not there are blood-borne reparative cells is an area of open controversy.

Many factors involved in regeneration are well known in different contexts.

Anything that has been involved in other systems we find changes in gene expression in wound healing. It's been hard to sort through in a reductionist way because you have so many cell types interacting: some are resident; some are migratory. They interact, expressing secreted molecules that change behaviour of the cells.

When you focus on a single growth factor or single molecule among thousands that are changing, it's not surprising that single-growth-factor therapies have been unsuccessful in changing how wounds heal, so to me that's why there's so much promise in cell-based therapies where you can potentially change the balance of a number of factors.

There are so many things to keep track of.

It's an area where a systems biology approach might really be necessary to encompass the data. It's the kind of thing that can only be studied in an in vivo system, so a lot of the precision and rigor needed to make a systems biology approach work hasn't been there.

The most tractable models are not the most representative of the clinical situation, and it's proven difficult for us to figure out how to find studyable systems that have predictable effects in humans.

If you were writing a review called “Wound repair and regeneration” in 15 years, what challenges and accomplishments would you be describing?

We would know what the early events are in inflammation. We would have a better idea of what is the match that really sets off the conflagration, what sets all these events off cartwheeling.

I think the best way to treat most of those problems [is to deal with] them extremely early, before they have momentum and are out of control. I think we now have the tools to study what happens really early. We're pretty well equipped to study the end stages. It's important to look at the whole spectrum to figure out what the low-hanging fruit is.

What about for stem cells?

We need a better understanding of what the importance of stem cells in wound healing [is] at normal physiologic levels and then ask: Is there any benefit of having more? It may be that there is no benefit. And the other piece is [discovering] what is the most receptive soil for tissue regeneration.

Complexity of wound healing is really hard to wrap your arms around. It's difficult to study in a reductionist way, so you have to study it in vivo, warts and all. And that's the challenge, to tackle all that complexity.