2023-11-16 18:00:05
Understanding how the human pancreas develops is crucial to allowing scientists to produce insulin-producing beta cells in the quest to cure type 1 diabetes. Now, a study published in ‘Nature Genetics‘ presents a unique and surprising discovery: a gene that is essential for producing the pancreas in humans is not present in almost all other animals.
The beta cells of the pancreas produce insulin that regulates blood sugar. Every mammal needs pancreatic beta cells to survive. In type 1 diabetes, there are very few or no functional beta cells.
But this new finding challenges ideas about how developmental regulation evolves.
Until now, it was assumed that genes essential for the development of key organs and functions were highly conserved throughout evolution, meaning that the genetic pathway remains the same between different species, from fish to humans.
However, the gene ZNF808 is only found in humans, other apes such as chimpanzees and gorillas, and in some monkeys, such as macaques.
The research carried out by researchers from the University of Exeter School of Medicinethe University of Cambridge (United Kingdom) and the University of Helsinki (Finland) shows how different humans can be from other animals often used in research, such as mice, and emphasizes the importance of studying the human pancreas.
«It is the only example we know of where a gene that is essential for the development of an organ in humans and primates is not present in other animals. A gene found only in primates would be expected to regulate a primate-specific characteristic, such as brain size, but this is not the case for ZNF808, which instead participates in the development of an organ shared by all vertebrates. We believe this shows that there must have been a evolutionary change in higher primates to fulfill a purpose,” says lead author Elisa De Franco of the University of Exeter.
It is the only example we know of where a gene that is essential for the development of an organ in humans and primates is not present in other animals.
Elisa De Franco
University of Exeter
Among the hypotheses that are being explored, he assures Andrew Hattersley, is that the evolutionary benefit is for the pancreas of the fetus. “Human babies are born through the pelvis, so they cannot stay in the womb for long as they would grow too big to be born. Instead of facing being born prematurely and needing to survive without continuous feeding, they need to be born with more fat than any other animal. This fat is deposited when the fetus’s pancreas produces more insulin. Our research has shown that human fetuses have greater insulin-related growth than other animals».
Many different
The work emphasizes the importance of studying the human pancreas to understand and find new treatments for diabetes. «Research with animals is important -Nick Owens-, but it can only provide certain information. We know that there are fundamental differences between humans and other animals, such as mice, that are often the subject of research in this field. The human pancreas is different in its appearance, function and development.
ZNF808 belongs to a family of recently evolved proteins that bind and “deactivate” specific regions of DNA that have also evolved recently in evolutionary terms. These DNA regions were among the regions considered junk DNA without any significant purpose for decades, but recently new technology has allowed us to discover its functions. The results confirm that these regions of our DNA play important functions during human development.
As he emphasizes Michael Imbeault, from the University of Cambridge, “the findings show that genes like ZNF808, even if relatively ‘recent’ in evolution, may play a crucial role in human development. ZNF808 is a member of the largest, but also least studied, family of proteins that regulate our genome. “There are hundreds of genes like ZNF808 in our DNA, many of them specific to primates or even humans, and our results demonstrate how these may be key players in human health.”
The identification of ZNF808 as being involved in the development of the human pancreas came after researchers at the University of Exeter examined genetic samples from patients recruited around the world who were born without a pancreas and found that they all had genetic changes that resulted in loss of pancreas. ZNF808.
The partners subsequently studied the effect of loss of ZNF808 using stem cells in the laboratory. The results showed that ZNF808 plays an important role in the early stages of human development, when cells need to “decide” whether to become pancreas or liver.
Tania
Among those who shared their genetic samples was the girl Tania Bashir, 12 years old. «We have always wanted why and now we know. My dream is that one day scientists will be able to genetically modify a stem cell and grow a human pancreas, implant it in Tania and potentially cure her. I don’t know if that will ever be possible, but I do know that this understanding is a crucial step forward,” says her father, Imran Bashir.
The contribution of people born without a pancreas was fundamental for this discovery
Timo Otonkoski
University of Helsinki
Tania Bashir, twin 2, weighed just 1.1kg when she was born, via emergency caesarean section, five weeks early, without a pancreas.
Tania with her twin
«Tania weighed approximately as much as a sack of sugar; you could easily fit it in the palm of your hand. They immediately realized that she had neonatal diabetes, but she was not growing or gaining weight either. It took eight weeks of investigations, tests and scans to discover that she did not have a pancreas,” says Imran.
Tania does not produce the enzymes that break down fats, proteins and carbohydrates into smaller molecules
In addition to not producing insulin to control your blood sugar, Tania does not produce the enzymes that break down fats, proteins, and carbohydrates into smaller molecules, such as triglycerides, amino acids, and sugars, so they can pass through the intestine. into the bloodstream. Today, with the support of her parents, she leads a relatively normal life, although she still requires a special liquid tube feeding at night and constantly uses an insulin pump.
A decade later, by sequencing all of Tania’s DNA genes (a technique called whole-exome sequencing), the Exeter team has identified a gene crucial to the development of the human pancreas that is only present in humans and some. monkeys, but not in other mammals.
«The contribution of people born without a pancreas was fundamental for this discovery. No one would have ever thought that ZNF808 played a role in pancreatic development if we had not found the changes in this gene in these patients. The ultimate goal of our research is for this knowledge to translate into the ability to manipulate stem cells to produce beta cells that can produce insulin in the laboratory. “That could be the key to curing type 1 diabetes. Our finding is an important step in understanding what makes the human pancreas unique,” he emphasizes. Timo Otonkoskifrom the University of Helsinki.
“Our findings really show the importance of studying the DNA of people with rare diseases to understand how organs develop and function. We are immensely grateful to people like Tania and her family, without them none of this would be possible,” he concludes. Elisa de Franco.
#essential #gene #human #pancreas #key #curing #diabetes