Decode ME: The Largest Ever DNA Study Into
Myalgic Encephalomyelitis Awarded £03.2 Million Funding |
 |
||
Wednesday: July 01: 2020 || ά.
New funding has been announced for the world’s largest
genetic study into Myalgic Encephalomyelitis:ME, led by a
partnership of patients and scientists. Despite its high
cost to patients, the economy, the NHS and society, very
little is known about the causes of ME, also, diagnosed as
Chronic Fatigue Syndrome:CFS or ME:CFS, including, how to
treat it effectively.
The £03.2 million funding, awarded jointly by the Medical Research Council
and National Institute for Health Research, will allow work to begin on
Decode ME, the ME:CFS DNA study, that hopes to reveal the tiny differences
in a person’s DNA, that, may, affect their risk of developing ME:CFS and the
underlying causes of the condition. Decode ME
will look at samples from 20,000 people with ME:CFS, in the hope that the
knowledge discovered will aid development of diagnostic tests and targeted
treatments.
Co-Principal Investigator Dr Luis Nacul, Cure ME Biobank at the London
School of Hygiene and Tropical Medicine, says, “Unlocking the genetic
susceptibility to ME:CFS is a key part of understanding what causes ME:CFS
and the disease mechanisms involved. This, in conjunction with other
bio-medical research into ME:CFS, should finally pave the way to better
diagnosis and the development of specific treatments for this debilitating
disease.”
ME:CFS affects an estimated 250,000 people in the UK, of all ages and from
all social and economic backgrounds. Post-exertional malaise, an adverse
reaction to levels of exertion, that many might consider trivial, is, often,
considered to be the defining symptom. This can leave patients suffering
from symptoms, including, extreme levels of fatigue, pain, inability to
process information and light and noise sensitivities. One in four people
with this condition are so severely affected that they are house and,
frequently, bed-bound.
Partnering with the MRC Human Genetics Unit at the University of Edinburgh
and the London School of Hygiene and Tropical Medicine, the Study is being
led by the ME:CFS Bio-medical Partnership. This collaboration of
researchers, people with ME:CFS, carers and advocates has grown out of the
UK CFS:ME Research Collaborative:CMRC.
People with ME:CFS across the UK will be asked to volunteer to take part in
Decode ME Study, which they can do from home, confirming they meet the
selection criteria via a patient questionnaire already being used by the
Cure ME Bio-bank. Participants will be mailed a collection kit and asked to
send back a saliva sample. These will be compared with samples from healthy
controls.
The samples will enable the Partnership to undertake the world’s largest
genome-wide association study:GWAS of ME:CFS. Such studies have already
helped to uncover the biological roots of many other complex diseases,
including, the identity of genes, involved in Type Two Diabetes and the
microglia, immune cells of the brain, that play a key role in Alzheimer’s
Disease.
Mr
Andy Devereux-Cooke, one of the patients, leading Decode ME, says, “As
someone living with ME:CFS, I'm well aware that the patient community has
waited a long time for a study, such as, this one, that has such a strong,
genuine element of patient involvement. All of us involved with this
research project hope that it can start to address the totally unwarranted
stigma and lack of understanding that so many patients with ME:CFS face on a
daily basis."
Principal Investigator Professor Chris Ponting, MRC Human Genetics Unit,
University of Edinburgh, says, “Our focus will be on DNA differences, that
increase a person’s risk of becoming ill with ME:CFS. We chose to study DNA
because significant differences between people with and without, ME:CFS must
reflect a biological cause of the illness. It is our hope that this Study
will transform ME:CFS research by injecting much-needed robust evidence into
the field.”
The Study is scheduled to begin in September, with recruitment of
participants from March 2021. Anyone with ME:CFS, aged 16 years or over, who
wants to take part in the Decode ME Study can register online https://www.decodeme.org.uk/home/#get-involved-form.
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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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Readmore || 010519 || Up ||
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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Readmore || 250219 || Up ||
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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230219 ||
Up ||
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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