A study conducted by Nathaniel P. Hoyle, Ph.D. — from the MRC Laboratory of Molecular Biology in Cambridge in the United Kingdom — and his colleagues and published on Wednesday in the journal Science Translational Medicine reports that some of the cells resident in our skin are under the influence of circadian rhythms.
As part of the work, the team analyzed data from the International Burn Injury Database to see whether or not the same applies to healing times in human burns.
They report that in a subset of burn cases, those sustained between 8 p.m. and 8 a.m. took 60 percent longer to heal than burns that occurred between 8 a.m and 8 p.m.
The story has been picked up by other news outlets, but I think these claims are unsubstantiated and misleading. Here is why.
Burn patient data
Dr. Hoyle and his colleagues used data from major burn units in England and Wales from 2012 to 2015.
The inclusion criteria were people aged 18 to 60 with a body mass index (BMI) between 20 and 30, who had been admitted to the emergency room because of their burn injury. Data from patients with any previous diseases or those who had received a skin graft were excluded.
In this subset of patients, Dr. Hoyle found a significant difference in the time it took for 95 percent of each burn to heal when he compared 75 daytime burns with 43 night-time ones.
"We observed an about 60 percent decrease in healing time when burns occurred during the night compared with during the day," he writes in the paper.
Senior study author John O'Neill, Ph.D., comments on the significance of the findings in a press release. "It may be," he says, "that healing time could be improved by resetting the cells' clocks prior to surgery, perhaps by applying drugs that can reset the biological clock to the time of best healing in the operation site."
The main issue is that burns occur in individuals of all ages, all sizes, and those with underlying conditions. The burns themselves also come in all different shapes and sizes, and there are no data here to indicate the size of each burn. But size matters when it comes to wound healing times.
The other problem is the exclusion of burns that received skin grafts.
Deep vs. superficial burns
Skin grafts are used when a burn is not likely to heal by itself. This is the case for deep burns and large burns.
I asked Dr. Hoyle why he and his team decided to leave out data from patients with skin grafts. He said, "[W]e excluded skin grafts because it would affect how well the wound heals dramatically and we wanted the burns to have been treated, more or less, in the similar way. Including both grafted and ungrafted wounds would have massively increased variability."
Here is the crux of the problem: by looking at a subset of the available data, it is impossible to make a sweeping statement about burns or wounds in general.
I spoke to Dr. Baljit Dheansa — who is Lead Surgeon for Burns at Queen Victoria Hospital in East Grinstead in the U.K. — about the study.
In his opinion, "[S]ome of the data relating to burns in humans is not detailed enough to make any conclusion, as the variation in burn size or depth is too great [...] we cannot say if we really are comparing like with like.
"I advise caution in interpreting such data and suggest that much more detailed analysis is performed before making any conclusions," he added.
So, what exactly did the study find, and what are the implications on wound healing?
Cell behavior influenced by circadian clock
The fact that fibroblasts — or the main cell type in the dermis, the deeper layer in our skin — are influenced by circadian rhythms is not new. The big question is whether or not this control is exerted by the cells themselves, and how this affects their behavior.
Dr. Hoyle and colleagues therefore started with a proteomics screen, using fibroblasts from mice genetically engineered to carry reporters for the circadian clock. This allowed the researchers to synchronize the cells to a 24-hour rhythm.
The results showed that actin dynamics were under the control of the circadian clock.
Actin is a key component of the cytoskeleton, which maintains a cell's structural integrity. Actin is also essential for cell movement, which, in turn, is essential for wound healing.
Dr. Hoyle summarized the team's approach, saying, "Our work built up from molecular biological foundations — a hypothesis-free proteomics screen in fibroblasts."
"So incrementally we could make clear predictions at each step as we moved up the complexity scale. First, actin would be rhythmic due to rhythmic actin regulator abundance, second that cells would therefore have rhythmic motility, and finally that wound healing would be rhythmic."
Nathaniel P. Hoyle, Ph.D.
Fibroblasts in wound healing
After an injury to the skin, fibroblasts multiply and migrate to the injury site to fill the void left by the lost tissue. Here, they produce collagen to make new connective tissue.
Using their cell model, Dr. Hoyle shows that wounds made to a layer of fibroblasts in a petri dish, by scratching away a corridor of cells, heal faster when the cells are in their active circadian state. This is a classic wound healing experiment called a scratch assay.
When I say that the wounds healed faster, what I mean is that the cell migrated to close the empty corridor more quickly. But there is a big difference between how an artificial wound behaves in a petri dish and what happens in the human body.
To test his findings in living organisms, Dr. Hoyle used mice. Here, he saw that fibroblasts migrated faster during the first 2 days after wounds were made.
These results are very interesting and clearly show that the circadian clock plays a role in how fibroblasts behave in the laboratory and in mice during the early stages of wound healing.
But does this really indicate that human wounds heal faster when they occur during the day?
From cells and mice to humans
It's hard to say whether the short-term effect on cell migration that Dr. Hoyle sees in mouse wounds has a long-term effect on the complex process outcomes of wound healing.
Wounds, and especially burn wounds, can take a long time to heal. A wound is considered "closed" when the top skin layer, or the epithelium, has been re-established. But underneath the epidermis, fibroblasts can continue to make and remodel new connective tissue for months, even years.
"Although this [...] analysis cannot prove that human wound healing is under clock control, we note that the time of day associated with optimal healing for human burns patients is consistent with our results from rodent and cellular models," Dr. Hoyle writes in the paper.
But he also told me, "I should stress that further study is required before any change to clinical practice should be considered."
Finally, I want to address the impact that Dr. Hoyle's findings may have on scarring. In the study, he found increased deposits of collagen in daytime wounds in mice 14 days after injury.
He explained to me that he and his team are "not really sure how time-of-wounding relates to scarring but increased aberrant collagen deposition is a major hallmark of scarring so it could be that daytime wounds heal faster but with more scarring. This is something we're not sure of yet but we'd like look into it."
Scars are a significant problem, especially in burn injuries. As Dr. Hoyle said, wounds that occur during the day may close faster, but the scars may be worse — not a desirable clinical outcome.
Dr. Hoyle's findings are fascinating and a real scientific breakthrough in the study of cell behavior. But what the long-term implications on human wound healing and burn care will be remains to be seen.
"This paper puts forward an interesting hypothesis which relates circadian rhythms to wound healing," Dr. Dheansa commented. "As we discover more about the very complex mechanisms within the human body we may be able to find many potential areas where we can make things better for our patients and I would encourage such research but we have to accept that we have a very long way to go."
"It may be decades before we can identify the most important factors for wound healing and so we must be patient and engage in research at all levels to benefit future society."
Dr. Baljit Dheansa