Why can’t we heal perfectly?
You slice your finger open while dicing onions. You fall over running in the playground and graze your knee. You take a pot out of the oven to cool on the stove, immediately forget it’s 220 degrees, and burn your palm as you grab the handle...
Whether big or small, throughout our lives we all accumulate injuries. If we’re lucky, the bleeding finger or the scraped elbow will heal quickly and efficiently, with no infection and - even luckier - no scar. If we’re not so lucky, we might end up with a serious wound needing immediate medical attention. But why? From salamanders to starfish, there are many animals who are not just excellent at healing when wounded, but can even regenerate entire limbs if the damage is severe enough. As humans, we don’t have that luxury.
Successful skin wound healing
So what occurs in our skin when we cut ourselves? “The first thing that happens is platelets in your blood come together to form a clot - that stops you bleeding to death” described Professor Matthew Hardman of the University of Hull, where he is Chair of Wound Healing, “then immune cells are recruited from your circulation to the sites of injury”. The immune cells help remove any debris or bacteria left behind to prevent infection. Then, stem cells in the nearby skin start dividing to make more cells to plug the void left by the gash, “and the key thing is that the void has to be filled,” explains Hardman. The filler in this case is a matrix, “kind of like a biological poly-filler. And the way that that is sculpted is what causes the scar.”
It turns out that this rapid response to injury is key when considering why we scar in the first place. “It's evolutionarily programmed, so we've developed over thousands of years to actually heal in in a dirty environment,” says Hardman. In the bacteria-ridden habitat our ancestors lived in it was important to close a wound as quickly as possible to prevent infection. “If you have a really exuberant immune response, that releases loads of factors which actually activate the scarring response. But actually these days most injuries happen deliberately in operating theatres - a much cleaner environment. So you don't necessarily need to heal so quickly and with such a prominent scar.”
Essentially, it looks like an evolutionary battle took place between healing rapidly without infection, but with a scar, or healing slowly with a less prominent scare but a much greater risk of infection. In the end, the fast-healing, life-saving scarring won. Evolution, after all, doesn’t care much about aesthetics if you’re dying of infection. This can be seen in how our wound healing abilities change as we age, too. Older people tend to heal with less scarring as the immune response is dampened in elderly people, making the healing process occur more slowly. However, there’s also a much greater risk of chronic wounds in older people for this same reason - the slow healing process makes a wound more likely to get infected or never heal properly.
On the other end of the spectrum, most mammals - including humans - don’t scar in the womb1. This is thought to be down to the immune system again, as “when you’re in the womb, you have a less developed immune system,” says Hardman. Plenty of scientists are interested in understanding if we could somehow replicate the same process used by a foetus in an adult to allow scarless wound healing, but there’s still a long way to go before new technologies will be ready1. Similarly, according to Hardman, “there are lots of groups around the world who are actually looking at understanding regenerative healing in less developed animals, to be able to implement that in humans.”
Regeneration and regrowth - the liver leads the way
There’s one organ, however, which proves that we are capable of regenerating in the right circumstances, and that is the liver.
“The liver is one of those organs that has a remarkable ability to regenerate which is very nice for us,” says Auinash Kalsotra of the University of Illinois. A healthy liver is essential for healthy human life, as the liver not only produces a lot of important molecules - like albumin, a component of our blood - but also detoxifies our blood, too. For example, when we take paracetamol or drink alcohol, it’s the liver that metabolises those chemicals so their constituent components, which are toxic, don’t cause us harm. Removing these toxins does require a trade-off, however, as "when the liver tries to get rid of them, some of those liver cells die," explains Kalsotra.
It is for this reason that the liver has to be able to regenerate when damaged, and how it manages this is a question of great interest to many scientists. “If you compare the liver to other tissues in our body that can regenerate, like our skin cells or the cells of our intestines, they go through a normal cycle where the stem cells in these organs give rise to new cells which can replace the old dead cells.” The liver, however, doesn’t have any stem cells, so how does it regenerate?
“The existing, fully differentiated cells of the liver - called hepatocytes - are normally dormant, so they are not dividing,” Kalsotra continues. “Now, if there is an injury to the liver, these cells can re-enter the cell cycle and start to divide and give rise to new cells.” This means that the liver cells are almost recapitulating the same mechanism that our bodies used to grow a liver in the first place, when we were in the womb. It’s thanks to this remarkable ability that live liver transplants - where people can donate up to 70% of their liver to a patient with liver disease - are possible, as the what’s left of the donor’s liver will simply grow back to its original size. How it knows when to stop growing is another fascinating question and, as Auinash’s lab have discovered, this is also likely a replication of the same mechanisms that determined the original size of our liver as we were growing in the womb and as children.
Despite its excellent regenerative capabilities scar tissue can form on the liver in certain conditions. Alcoholic liver disease, for example, is caused by repeated injury to the liver from drinking too much alcohol, and eventually the liver can’t keep up. The liver cells stop regenerating properly and become non-functional. So for humans, even the organ that wins first place in the regeneration olympics can be pushed beyond the point of healing.
The regeneration rockstars
Despite our livers’ regenerative abilities, most of our other organs are fairly hopeless at regrowing new tissue if they get injured. So, scientists have turned to the animal kingdom to understand how other animals regenerate so well.
Many of us will remember hearing on the playground that if you cut the worm you found in the flowerbeds in half, it would grow into two new worms. To the great disappointment of school children everywhere this isn’t actually true (the half with the head may be able to regrow its tail but the tail end can’t regrow a head), but there are other types of worms that really do show us up when it comes to regenerative capacity.
Planarians are a type of very small flatworm (just 2-20mm in size) that can regrow any body part after injury - eyes, muscle, skin, even a brain. Scientists all over the world are interested in understanding just how planarians manage this, with a goal to try and use that knowledge to inform medical treatments someday. A key development by Northwestern University scientist Christian Petersen from 20112 showed that an ancient cell communication pathway called Wnt helps planarian cells regenerate the correct body parts when injured. It’s also understood that planarians keep a large reservoir of adult stem cells which they use to replenish and regenerate whole structures after injury. This is a popular technique in the world of highly regenerative creatures - Hydractinia, sometimes called ‘living hair’, are tiny marine animals capable of regenerating their heads in less than a week, achieving this feat by handily keeping around embryonic stem cells throughout their lives3. Embryonic stem cells could be considered the holy grail of healing, as they have the capacity to become any type of cell required - muscle, skin, brain, connective tissue, you name it.
As humans we maintain populations of tissue-specific stem cells in our bodies, like our skin and our bone marrow, which is necessary for us to keep producing things like blood and new skin throughout our lives. However, in most of our tissues - including our hearts and brains - we either have very few or zero stem cells waiting around to be used in the case of injury. This means we might be better off taking lessons from animals like zebrafish, which don’t have large reservoirs of stem cells but can still regenerate limbs and organs to an enviable degree4. Zebrafish hearts can regrow after injury because the heart cells that are still there can undergo a process called dedifferentiation - this means they revert back to a more primitive state in which they can divide and produce new cells. Salamanders can regrow their tails without a pool of ready stem cells by taking advantage of this method, too - cells near the tail start dividing again and slowly the tail grows back4.
A lot of this research points towards the same thing - if we can enable healthy cells left behind in the heart after a heart attack, for example, or in the brain after a stroke, to start dividing and then become functional, we might be able to encourage regeneration in organs that currently don’t perform well after injury. It’s important to note that some prerequisites might be beyond our reach - the regeneration gene Prod1 is crucial for salamanders and hasn’t been found in any other species so far4, and it’s also possible that there are genes which promote regeneration in some contexts and some species but perform a different job in others. It’s generally understood by scientists that at some point, long ago in our evolutionary history, we also had the capacity to regenerate whole organs and limbs. This is a feature that seems to have been lost during the evolution of more sophisticated animals like mammals for reasons that we just don’t know (although it is suspected to be because we have such complex biological systems it could be hard to regulate. A worm brain is much simpler than a human brain, after all). That said, many scientists are hopeful that with better understanding of how other animals regenerate, we can improve treatments for humans in the future.
The future of regeneration
Our bodies are always trying to heal us when we’re injured - from our skin, to our liver, to our muscles after we hit the gym too hard, even if we are left with a scar. But, for those injuries that don’t heal so well, or for organs like our hearts or brains, which don’t have the capacity to heal as well as we would like, many scientists and doctors would love to find a way of regenerating the tissue that has been damaged.
Dr Tom Carmichael is a neurologist and stroke specialist at the University of California Los Angeles, and his lab have recently made significant progress towards this goal. “We've developed what's called a biopolymer hydrogel, basically a "jello"-like material that's made of naturally occurring molecules in the body, and that can promote regeneration of new tissue after stroke,” says Carmichael. His lab have used mice to show that new nerve cells can grow into the area of the brain that had been damaged by stroke, and these cells were able to restore function and enhance recovery, when the new hydrogel patch is applied to the area after the stroke injury. Carmichael hopes that this hydrogel might change the lives of stroke survivors in the future, as it could allow them to regain abilities like walking or talking that can be taken away by stroke even with the correct care.
For now, the dream of growing a new leg after amputation by replicating the salamander is still just a dream. That said, research to understand the techniques employed by the salamander and the flatworm is very much ongoing, and concurrent efforts to improve outcomes after injury continue alongside. Whether it’s a sliced open finger, a heart attack, or liver damage, the goal of being able to not just heal, but heal perfectly, is never far from the minds of the scientists who study regeneration.