Rare Genetic Change Provides Clues to Pancreas Development

|| Tuesday: April 30: 2019: University of Exeter News || ά. Researchers have discovered a key clue into the development of the pancreas and brain by studying rare patients born without a pancreas. Published on April 18 in the American Journal of Human Genetics, the Study showed that all three patients without a pancreas and with abnormal brain development had an identical change in the CNOT1 gene.

The research team went onto show how this genetic change kept stem cells in their original state, preventing them from developing into pancreatic cells. The Study from the Wellcome Sanger Institute, the University of Exeter and other researchers, also, identified a previously unexpected pathway, involved in the development of the human pancreas and confirmed this in mice. Understanding how the human pancreas forms could help researchers develop replacement cells to treat patients with Type One Diabetes in the future.

The pancreas is part of the digestive system and makes various hormones, including, insulin, that controls the amount of sugar in the blood. Problems with the insulin producing cells in the pancreas can cause Type One Diabetes, which affects over 10 million people worldwide.

Type One Diabetes develops when insulin-making cells in the pancreas, called, beta cells, are attacked by the immune system. People with this disease need daily injections of insulin to control their blood sugar levels. Replacing the damaged pancreatic cells with cells derived from stem cells could treat the disease but, the pancreatic development pathways are not yet fully known.

In very rare cases, the pancreas fails to develop, which is called Pancreatic Agenesis and babies born with this condition need immediate and life-long treatment with insulin and other hormones to survive.

To learn more about the development of the pancreas, researchers from the University of Exeter studied the genetics of 107 international patients with Pancreatic Agenesis. They discovered that three unrelated patients with very similar clinical features, including, a possible neurological disorder, had an identical mutation in the CNOT1 gene. This gene had never been implicated in pancreatic or brain development before. 

The Wellcome Sanger Institute researchers, then, bred mice with this mutation in the mouse version of the gene to see how it affected development. They found the mouse embryos with the mutation in CNOT1 had a much smaller upper pancreas than usual, directly linking the CNOT1 gene with pancreas development. They, also, saw changes in the mouse brain development.

Dr Elisa De Franco, the Co-first Author from the University of Exeter Medical School, said, “We found that three patients with Pancreatic Agenesis had an identical spelling mistake in the CNOT1 gene. This was the first time that anyone had realised that CNOT1 was important in pancreatic and neurological development and has revealed a new genetic cause for Pancreatic Agenesis.”

Dr Inês Barroso, Co-senior Author on the Paper from the Wellcome Sanger Institute and University of Cambridge, said, “Through a great collaboration between clinical and mouse research disciplines, we have provided compelling evidence that the CNOT1 gene is involved in the formation of the pancreas in both humans and mice. We are now able to investigate the developmental mechanism, to understand how the pancreas develops.”

The CNOT1 gene had, previously, been implicated in keeping human and mice embryonic stem cells in a state where they can develop into any type of cell, known as, pluripotency. Studying which genes were active in the developing mouse pancreas, the researchers discovered that the CNOT1 mutation changed the levels of a key developmental factor, preventing the stem cells from developing.

Dr Rachel Watson, a Joint First Author from the Wellcome Sanger Institute, said, “Once we knew the CNOT1 gene was involved in pancreatic development, we wanted to find out how it worked. Changes in some developmental factors in CNOT1 mutant mice indicated that the stem cells remained as stem cells, rather than developing into pancreatic cells. This suggested an entirely new mechanism for Pancreatic Agenesis, which involved maintaining stem cells in a pluripotent state.”

Professor Andrew Hattersley, Co-senior Author on the Paper from the University of Exeter Medical School, said, “In the future, therapies, that created new pancreatic beta cells, could end the need for insulin injections for millions of people with Type One Diabetes. This type of therapy would require a very good understanding of how the pancreas develops. Our multi-disciplinary collaboration has allowed us to unravel a new gene and mechanism involved in pancreas development and revealed further avenues for investigation."

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The Genetics of the Scent of Flowers

|| February 24: 2019: Lund University News || ά. A research team has discovered that the scent of flowers of the same species can be completely different, despite growing only some 10 kilometres apart.  Researchers have studied floral scents for eight years in 94 populations of woodland star plants of the genus Lithophragma, on the west coast of the USA. When the researchers studied the floral scent of the entire plant genus, they discovered that the scent varies widely, even, over relatively small geographical distances.

Sometimes, the scent of individual plants of the same species, that are growing some 10 kilometres from each other are completely different. The local scent attracts moths of the genus Greya for pollination and the plant populations and moths have co-evolved over a long period. The evolutionary process has resulted in the flowers evolving a unique scent within a small area and that the moths in the same area, in turn, evolved into local specialists attracted by the specific local scent, not recognising woodland star scents from other species and populations than the local one.

“At one location it, may be, a pinewood scent, in another root beer and a little further south perhaps perfume.” says Mr Magne Friberg, Senior lecturer at the Department of Biology at Lund University. The floral scent differences are genetic and not due to factors, such as, degree of humidity, soil type or nutrient levels.  “We know this because the differences remain when we grow plants from different populations of the same species in a greenhouse environment.”, says Mr Magne Friberg.

According to the researchers, the discovery is important when implementing measures, if, a population or species of plant is endangered, a scenario, that, may, occur more frequently when the climate changes. Co-author Mr John Thompson, whose laboratory has long studied co-evolution between plants and animals argues that these are the kinds of studies we need, if, we are to make scientifically informed plans for conserving the earth’s many highly co-evolved interactions at a time when environments are changing quickly.

‘’These results tell us that species co-evolve as a geographic mosaic, in which, each local interaction between species, may, include unique evolutionary solutions. If, we are to conserve species in a world in which environments are changing rapidly, we need to conserve as many of these links as possible.”

“In this case, it is probably not possible to move plants with a root beer scent to an area where endangered populations of the same plant have a pinewood scent and believe that it can help. There is a considerable risk that the pollinators will not recognise the root beer scent and that the plant population does not recover.” said Mr Magne Friberg.  

Conversely, the moths are completely dependent on finding the flower, in which, they specialise. They mate on the flower, drink nectar and lay eggs in the flowers and will not survive in an environment where they can not identify their host and nectar plants.

The work began eight years ago, when Mr Magne Friberg was a post-doctoral associate in John Thompson’s laboratory at UC Santa Cruz. Mr Friberg, who is now at the faculty at Lund University and the Leader on this Project, has continued to collaborate with Mr Thompson since then.

Mr Christopher Schwind helped find plants in many remote eco-systems throughout far western USA. Mr Robert Raguso from Cornell University is a specialist in chemical ecology and plant-insect interactions and brought expertise not only the methods needed for analysis of these complex floral bouquets but, also, on interpretation of the wide range of bio-chemical pathways, used by woodland stars.

Mr Paulo Guimarães, Junior from University of São Paulo, who is a specialist in ecological and evolutionary network theory, brought expertise on how to interpret the complexity of these floral scents. It is the kind of collaborative research, that is the hallmark of most modern science.

The Paper: Extreme diversification of floral volatiles within and among species of Lithophragma: Saxifragaceae: Friberg M, Schwind C, Guimarães Jr PR, Raguso RA, Thompson: Published in Proceedings of the National Academy of Sciences:::ω.

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Preventing the Production of Toxic Mitochondrial Proteins Opens Up Promising Therapeutic Target

|| February 22: 2019: University of Helsinki News || ά. Researchers at the University of Helsinki uncovered the mechanisms for a cellular stress response, arising from the toxicity of newly synthesised proteins. Activation of the stress response is at the epicentre of the molecular events, generated by genetic mutations, that cause a complex neurological syndrome. In humans, mitochondrial DNA is only inherited from the mother and which encodes only 13 proteins, essential for energy metabolism.

Defects in the faithful synthesis of these 13 proteins represents the largest group of inherited human mitochondrial disorders, which display exceptional clinical heterogeneity, in terms of presentation and severity. Disruptions to energy metabolism alone do not explain the disease mechanism. “The ability to treat patients has been stymied because of the fragmented understanding of the molecular pathogenesis and, thus, bridging this knowledge gap is critical.” says Research Director Mr Brendan Battersby from the Insitute of Biotechnology, University of Helsinki.

AFG3L2 genes act as mitochondrial quality control regulator, preventing the accumulation of toxic translation products and, thereby, keeping the organelle and cell healthy. Mutations in the genes AFG3L2 and paraplegin cause a remodelling of mitochondrial shape and function, which are one of the earliest known cellular phenotypes in the disease.

However, the mechanism, by which, these events arose was, so far, unknown. The research group of Mr Brendan Battersby, at the Institute of Biotechnology, University of Helsinki, have now solved a molecular puzzle, associated with genetic mutations, linked to a multi-faceted neurological syndrome.

A recently published research of Battersby’s Group showed that the etiology for the cellular effects was due to a proteo-toxicity, arising during the synthesis of new mitochondrial proteins. The group showed how this proteo-toxicity was a trigger for a progressive cascade of molecular events as part of a stress response, that, ultimately, remodels mitochondrial form and function.

Excitingly, a clinically approved drug, that can cross the blood-brain barrier was, also, found to block the production of the toxic proteins and the ensuing stress response. “Since the mitochondrial proteo-toxicity lays at the epicentre of the molecular pathogenesis, preventing the production of toxic mitochondrial proteins, opens up a promising treatment paradigm to pursue for patients.” says Mr Battersby.

Next step in the research is to test the efficacy of the drug in a double-blind pre-clinical trial in animal models of these diseases.:::ω.

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Having Discovered a New Disease We Have Bumped Onto Ways That May Lead Us to New Diabetes Treatment: See Why Must We Keep on Seeking and Learning

|| February 17: 2019: Karolinska Institutet News || ά. Knowledge of a newly discovered genetic disorder, which means that a person can not produce the protein  thioredoxin interacting protein:TXNIP in their cells, can open up the possibility of developing new diabetes drugs. This is shown in a Study from Karolinska Institutet, published in the journal Diabetes. With modern techniques more and more previously unknown genetic diseases are being discovered, which can lead to new knowledge about human biology and contribute to the development of new drugs.

Researchers at Karolinska Institutet have recently been using gene sequencing or genome analysis to investigate a family, in which three of the children had excessively high levels of lactic acid and, simultaneously, low levels of the amino acid methionine in the blood, which is an unusual. If, left untreated, elevated lactate levels can cause tissue damage, respiratory effects and, even, can have fatal outcome but, the children are being given continuous medical treatment and are otherwise well. TXNIP is active in the thioredoxin system, which is found in all living cells. The system is of great importance in terms of the ability to make new genetic material and to protect cells from reactive radicals.

In the current Study, the researchers examined cells from the children, using more detailed methods and analyses of both the thioredoxin system and sugar metabolism. They, also, investigated how the mitochondria, which are the cells’ energy factories, functioned. "We discovered that the children's symptoms were due to a mutation in the gene, that encodes the protein thioredoxin interacting protein:TXNIP, which had, never, previously, been described in humans.

Based on the results in animal models, this protein has been suggested as a possible target for new Diabetes drugs, since, over-expressing TXNIP in mice induces Diabetes, while a lack of TXNIP protects against Diabetes.” says Professor Anna Wedell, Consultant at the Department of Molecular Medicine and Surgery at Karolinska Institutet and SciLifeLab.

"We found that the TXNIP protein was completely absent from the cells from these patients. The result is that the mitochondria are unable to use pyruvate, resulting from the break-down of glucose, as is, usually, the case when cells use sugar to make energy. Instead, they only produced lactate from pyruvate. However, the cells were able to use another substance as fuel for the mitochondria: malate.

This can explain much of the patients’ symptoms and, also, shows that a complete absence of TXNIP is compatible with human life.” says Professor Elias Arnér, at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, who led the Study, together with Professor Anna Wedell and Mr Alfredo Giménez-Cassina at the Universidad Autónoma de Madrid.

It has not, previously, been known what happens in humans, if, TXNIP is absent. The results of the new Study provide important insights into the significance of TXNIP and strengthen the hypothesis for TXNIP being a potential target for drug treatment in Diabetes, provided that any high lactate levels as a result of such treatment can be managed.

"Studying patients, in whom this protein is entirely absent can give some idea of the potential effects of a drug, that inhibits the protein, though, more studies are needed because these children do not have Diabetes." says Professor Elias Arnér.

The researchers now want to conduct further research in order to understand why the children, also, have low levels of methionine in their blood and how the metabolism of methionine, might be, linked to sugar metabolism.

The Study was funded with the support of Karolinska Institutet, the Swedish Research Council, the Swedish Cancer Society, the Knut and Alice Wallenberg Foundation, Region Stockholm, the Spanish Ministry of Economy and Competitiveness, the Ramón y Cajal Fellowship, the Swedish Diabetes Fund, the Alicia Koplowitz Foundation and the Ragnar Söderberg Foundation.

The Paper: Absence of TXNIP in human gives lactic acidosis and low serum methionine linked to deficient respiration on pyruvate: Yurika Katsu-Jiménez, Carmela Vázquez-Calvo, Camilla Maffezzini, Maria Halldin, Xiaoxiao Peng, Christoph Freyer, Anna Wredenberg, Alfredo Giménez-Cassina, Anna Wedell and Elias S.J. Arnér: Diabetes: Online: February 12: 2019

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