2023-09-24 09:03:49
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Evolutionary biology is advancing to understand how the principle of evolution works in our organism.
Article informationAuthor, Sofia Quaglia Role, BBC Future
3 hours
When he was 20, Randolph Nesse wondered why we age. He couldn’t understand why natural selection had not eliminated aging completely. This laid the foundation for a completely new way of thinking about medicine.
Years later, friends at a local natural history museum pointed out to Nesse the theory that aging is simply a side effect of evolutionary pressure that selects some genes over others. If a condition only manifests itself after an organism passes its reproductive peak, then there will be no selective pressure to prevent it from being transmitted.
As a physician, Nesse realized that while he understood how these forces could shape species, he had no idea how natural selection worked within the human body.
“No one had ever talked about the importance of evolutionary biology (in medicine). I immediately began to wonder if there were similar explanations for genes that cause disease.”
Nesse is now credited with being the founding father of evolutionary medicine, sometimes also known as Darwinian medicine, a relatively new and growing discipline that applies evolutionary theory to questions of human health and disease.
While most modern medical research focuses on the physical and molecular causes of diseases, evolutionary medicine attempts to understand why we might have evolved to be susceptible to diseases in the first place, and how we can use evolution to combat them.
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Evolutionary medicine may help improve cancer treatments in the future.
“What we’re dealing with here is a completely new basic science that hasn’t been applied to medicine,” Nesse says.
It is a very big undertaking to completely change what we think about what the human body is and how it works. Their work is already beginning to change our understanding of how cancers and autoimmune diseases develop.
It is also revealing new strategies to address harmful healthcare problems, such as antimicrobial resistance.
“I was surprised that there have been so many practical implications in such a short time,” says Nesse.
A new way of understanding cancer
Cancers are themselves a demonstration of the evolutionary process in a microcosm. They are groups of cells that continually compete and cooperate with each other in a way that helps the tumor grow and flourish.
A recent study highlighted the almost “infinite” ability of cancer cells to evolve and survive.
When a patient receives drug therapy, for example, a new selective pressure is introduced that eliminates cells that are most vulnerable to the treatment. Those that are less vulnerable, or even immune to the effects of the treatment, survive to pass on their genetic traits to the cells that follow them.
That’s why even cancer therapies that have been successful over time will stop working for many patients: cancer cells develop resistance to the treatment and then grow uncontrollably.
“We could make a case for this being the immediate cause of death in most patients,” says Robert Gatenby, co-director of the Center of Excellence for Evolutionary Therapy at the Moffitt Cancer Center in Florida, USA.
Through the lens of evolutionary thinking, Gatenby’s lab is developing two different strategies to address cancer: adaptive therapy and extinction therapy.
Adaptive therapy aims to control the spread of cancer rather than trying to eliminate it completely.
The dogma for the last 50 years in cancer treatment has been that the same drug, or combination of drugs, is applied in cycles, until there is clear evidence of tumor progression (where the tumor begins to grow uncontrollably) or excess of toxicity, Gatenby says, which usually occurs long after the maximum response has been obtained.
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Adaptive therapy aims to control the spread of cancer rather than trying to eliminate it completely.
This is “useless”, he says, since most of the remaining cells are resistant to the drug and by continuing with the same therapy, the oncologist gives them the opportunity to proliferate so that their population is larger and more diverse.
His theory of adaptive therapy, by contrast, aims to adjust the dosage of drugs to achieve a personalized approach, giving enough treatment to keep the tumor as small as possible, without completely eliminating the sensitive population.
The therapy is then withdrawn. This allows treatment-sensitive cells to continue fighting for space within the tumor, preventing other drug-resistant cells from dominating due to an adaptive advantage.
“Since we can’t control tumor cells that are resistant to therapy, we need to recruit treatment-sensitive cells to do it for us,” says Gatenby, who has been developing the idea since he first published it in 1991.
The hope, he says, is that doctors can keep patients alive for a long period of time.
His research group, which is possibly the most advanced in this field, has already shown that this technique works in a small pilot trial involving patients with prostate cancer. Patients who received adaptive therapy also had 2.26 years longer overall survival than those who received standard treatment.
With the other therapy, extinction, Gatenby wants to go a step further and use what we know about how animal species become extinct to design curative therapies that cause the extinction of cancer populations.
The idea would be not to wait for the tumor to grow again after doctors apply the initial therapy, but rather to give the tumor an entirely different therapy before it can recover: catching the tumor cells by surprise with a rapid cycle of a different medicine.
Although there is only one mathematical model of this therapy so far, Gatenby’s team has proposed clinical trials against pancreatic cancer and breast cancer.
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Evolutionary medicine also seeks a solution to a growing problem: the resistance of bacteria to drugs.
The elephant in the room remains how research like this will move from clinical trials, if successful, to real-world acceptance, according to Michael E Hochberg, distinguished research director at the Center National de la Recherche Scientifique at the University of Montpellier, in France.
“What is its realistic use, in terms of utility?” he asks.
Perhaps evolutionary medicine really is the most likely scientific perspective to address big questions like these, according to Hochberg, but doctors still have to treat patients every day working with solutions they know, proven best practices, and little room for hypotheses:
“They have a duty to ‘first do no harm,'” he says, and at this point these findings are still too preliminary.
A solution to resistant bacteria
Evolutionary medicine is also applied in the search for a solution to one of the fastest growing problems in the modern world: antibacterial resistance.
The widespread use of antibiotics has inadvertently led bacteria to evolve and create resistance. In addition, bacteria also develop resistance in other ways, from exchanging genetic material to accumulating random mutations.
As a result, evolutionary scientists are trying several different approaches to breaking down these pathways.
“If we want to solve this problem, we need to understand evolution and then go after the weaknesses,” says Andrew Read, director of the Huck Institutes for Life Sciences at Penn State University.
Read’s team is developing “antibiotic drugs” to help control the spread of antimicrobial resistance in places where the drugs can do more harm than good.
For example, antimicrobial resistance often occurs because some of the powerful antibiotics that patients receive intravenously reach the patient’s digestive system, changing the balance of the microbiota there, and as a result, drug resistance is created.
Inactivating drugs, in themselves, do nothing clinically, but they prevent the drug from acting in the intestine and could reduce this harmful effect.
His lab has already shown that this mechanism works well in mice to prevent the spread of the superbug Enterococcus faecium after antibiotic treatment.
But this is a general solution that does not inhibit resistance in case bacteria and drugs are found.
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Seeing under what conditions bacteria mutate or not may be key to curbing their resistance.
One of the reasons bacterial resistance is so difficult to address is that it doesn’t simply occur through the typical chance-driven evolutionary route: when a random mutation makes some bacteria stronger and able to resist drugs.
It also occurs thanks to horizontal gene transfer, something that happens both within the same species of bacteria and between species. This process allows mutations that transmit drug resistance to spread much more quickly.
Anne Farewell’s research group at the University of Gothenburg, Sweden, is trying to stop one of the mechanisms bacteria use to share DNA horizontally, known as “conjugation,” where cells come into direct contact, often through a tube that runs between them.
In their research, scientists look at which pairs of bacterial species mix and whether there are specific environmental conditions, such as pesticides or heavy metal pollution, that make this easier or more difficult.
They have already shown that Escherichia coli, a common bacteria that can cause food poisoning and a wide range of other infections, could stop conjugation upon contact with copper, reducing its conjugation capacity almost 100-fold.
“Understanding which molecules ruin conjugation could help develop effective ‘anti-conjugation drugs,’ but the research here is still preliminary, and there are still many other ways DNA can be shared between bacteria that this approach won’t affect.” , Farewell admits.
Bacteria are incredibly intelligent, he says. “I don’t think there’s going to be one solution. There’s going to be a lot of approaches.”
A dilemma between academics and doctors
While the fields of cancer research and bacterial resistance are the most advanced in the field of evolutionary medicine, there is still a long way to go.
Critics argue that despite understanding more about the theory of evolutionary medicine, it is unclear to what extent this new knowledge can be used in practice.
“I have rarely seen conversations that really focus on the issue of logistics and the benefits of moving from bench to clinic,” Hochberg says.
There is also friction between intellectuals and between what Darwinian academics and doctors think.
“The main challenge is to close the gap between academics working in evolutionary biology, the training of doctors and the mentality of the doctor in the context of the entire establishment of the big pharmaceutical companies,” says Bernard Crespi, evolutionary biologist at the Simon Fraser University.
It also remains a big question how evolutionary medicine will find a way to collaborate with the pharmaceutical industry.
But Nesse – the man who started it all – says evolutionary medicine still has the power to provide new questions and new answers about diseases:
“There is a chasm between evolutionary biology and medicine and it is actually harming human health,” Nesse says. “It’s a slow process, but science always wins.”
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