Researchers have spent decades trying to replace the insulin-producing
pancreatic cells, called beta cells, that are lost in diabetes. Now a
team of researchers, reporting Feb. 18, 2016 in Cell Stem Cell,
have discovered that tissue from the lower stomach has the greatest
potential to be reprogrammed into a beta-cell state. The researchers
took samples of this tissue from mice and grew them into “mini-organs”
that produced insulin when transplanted back into the animals. The
mini-organs’ stem cells also continued to replenish the
insulin-producing cell population, giving the tissue a sustainable
Caption: A section of the gastric mini-organ engineered to
produce insulin-secreting cells, with immunofluorescent staining. This
image shows many induced insulin-producing cells (red) present in the
mini-organ. Gastric stem and progenitor cells (green) are detected at
the base of the glands. Cell nuclei labeled in blue. Credit: Chaiyaboot Ariyachet
The immune system is not immune to mistakes. In type 1 diabetes, it wrongly identifies beta cells (large, green) within the pancreas as pathogens. It attacks and destroys these cells, while leaving other cells in the pancreas (small, blue) untouched. Beta cells produce a hormone, called insulin, which controls the levels of sugar in the blood. Insulin stimulates our body’s cells to absorb sugar by opening up shuttles, called transport proteins (red), on the cells’ edge. Diabetic patients can manage their sugar levels with injections of insulin, but may suffer complications. If doctors could diagnose and treat the condition earlier, they could reduce such complications and extend a patient’s life. Scientists at the MRC’s Clinical Sciences Centre have shown that when beta cells die, they release large quantities of a molecule, called microRNA 375, into the blood. A simple blood test could detect this molecule years before symptoms develop.
The research, published today in the journal Cell Metabolism, provides further insights on how the insulin-producing beta cells are formed in the pancreas. The team discovered that mutations in two specific genes which are important for development of the pancreas can cause the disease. These findings increase the number of known genetic causes of neonatal diabetes to 20. The study was funded by the Wellcome Trust, Diabetes UK, European Community’s Seventh Framework Programme, with some of the authors supported by the National Institute for Health Research (NIHR).
Dr Sarah Flanagan, lead author on the paper, said: “We are very proud to be able to give answers to the families involved on why their child has diabetes. Neonatal diabetes is diagnosed when a child is less than six months old, and some of these patients have added complications such as muscle weakness and learning difficulties with or without epilepsy.
“Our genetic discovery is critical to the advancement of knowledge on how insulin-producing beta cells are formed in the pancreas, which has implications for research into manipulating stem cells, which could one day lead to a cure.”
Dr Alasdair Rankin, Diabetes UK Director of Research, said: “As well as shedding further light on the genetic causes of neonatal diabetes and providing answers for parents of children with this rare condition, this work helps us understand how the pancreas develops. Many people with diabetes can no longer make insulin and would benefit from therapies that replace the insulin producing beta cells of the pancreas. The results of this study are critical to bringing the day closer when this type of treatment is possible.”
Neonatal diabetes is caused by a change in a gene which affects insulin production. This means that levels of blood glucose (sugar) in the body rise dangerously high.
The Exeter team is the leading centre for neonatal diabetes having recruited over 1200 patients from more than 80 countries. This specific study focussed on 147 young people with neonatal diabetes, a rare condition which affects approximately 1 in 100,000 births. Following a systematic screen, 110 patients received a genetic diagnosis. For the remaining 37 patients, mutations in genes important for human pancreatic development were screened. Mutations were found in 11 patients, four of which were in one of two genes not previously known to cause neonatal diabetes (NKX2-2 and MNX1).
For many of the 121 (82%) patients who received a genetic diagnosis, knowing the cause of the diabetes will result in improved treatment, and for all the patients it will provide important information on risk of neonatal diabetes in future pregnancies. These patients also provide important scientific insights into pancreatic development.
For the first time, researchers have converted induced pluripotent stem cells - cells capable of turning into any other type of cell - into fully functioning pancreatic beta cells, and when transplanted into diabetic mice, they blocked the disease altogether.
While the process has yet to be tested in humans, the results are exciting, because the hallmark of diabetes is a loss of functioning beta cells. If we can figure out how to transplant new, healthy beta cells into diabetes patients, we’re looking at an actual cure, not just a treatment. “This discovery will enable us to produce potentially unlimited supplies of transplantable cells derived from a patient’s own cells,” lead researcher Ronald Evans told ABC News.
Diabetes, simply put, involves the loss of functioning beta cells in the pancreas: either these cells die (type I diabetes) or they don’t do as they’re told (type II diabetes), and in both cases, it leads to a lack of insulin to regulate the glucose levels in the blood. For a long time, scientists have been trying to replace these damaged or dead beta cells with healthy ones, and it finally looks as though they might have cracked it (in mice, at least).
Diabetes in a Dish With NIH grant, UC San Diego researchers hope to build bits of miniature pancreas
Although type 1 diabetes can be controlled with insulin injections and lifestyle modifications, major advances in treating the disease have not been made in more than two decades and there remain fundamental gaps in what is understood about its causes and how to halt its progression.
The team’s goal is to bioengineer a miniature pancreas in a dish, not the whole pancreas but the organ’s irregularly shaped patches – called Islets of Langerhans – that regulate the body’s blood sugar levels.
“The bottleneck to new cures for type 1 diabetes is that we don’t have a way to study human beta cells outside of the human body,” said Maike Sander, MD, professor in the departments of Pediatrics and Cellular and Molecular Medicine and director of the Pediatric Diabetes Research Center at UC San Diego and Rady Children’s Hospital-San Diego. “If we are successful, we will for the first time be able to study the events that trigger beta cell destruction.”
Beta cells in islets secrete the hormone insulin. In patients with type 1 diabetes, the beta cells are destroyed and the body loses its ability to regulate blood sugar levels. Researchers, however, are unsure of the mechanism by which beta cells are lost. Some researchers believe that the disease may be triggered by beta cell apoptosis (self-destruction); others believe that the body’s immune system initiates attacks on these cells.
To actually bioengineer the pancreas’ endocrine system, researchers plan to induce human stem cells to develop into beta cells and alpha cells, as well as other cells in the islet that produce hormones important for controlling blood sugar levels. These cells will then be co-mingled with cells that make blood vessels and the cellular mass will be placed within a collagen matrix mimicking the pancreas. The matrix was developed by Karen Christman, PhD, associate professor of bioengineering at the Jacobs School of Engineering.
“Our previous work with heart disease has shown that organ-specific matrices help to create more mature heart cells in a dish,” Christman said. “I am really excited to apply the technology to diabetes research.”
If the pancreatic islets can be successfully bioengineered, researchers could conduct mechanistic studies of beta cell maturation, replication, reprogramming, failure and survival. They say new drug therapies could be tested in the 3D culture. It would also be possible to compare beta cells from people with and without the disease to better understand the disease’s genetic component. Such work might eventually lead to treatments for protecting or replacing beta cells in patients.
For Type 1 diabetes sufferers, eating a chocolate bar can be deadly. This is because they lack a protein called insulin, which removes sugar from the blood preventing dangerously high concentrations occurring. The irreversible destruction of the pancreas’ beta cells that produce insulin is to blame, and often means enduring a lifetime of injections to keep sugar levels in check. However, switching off one particular gene can transform different cells into these vital insulin factories. With this gene inactivated, new beta cells (here coloured green) have begun to re-emerge, only four days after they were completely eliminated from this mouse pancreas. In the midst of a global diabetes epidemic that has seen the number of sufferers rise seven-fold over the last 20 years, this new avenue of exploration for potential treatment methods is most welcome.
Penicillin, the wonder drug discovered in 1928, works in ways that are still mysterious almost a century later. One of the oldest and most widely used antibiotics, it attacks enzymes that build the bacterial cell wall, a mesh that surrounds the bacterial membrane and gives the cells their integrity and shape. Once that wall is breached, bacteria die – allowing us to recover from infection.
That would be the end of the story, if resistance to penicillin and other antibiotics hadn’t emerged over recent decades as a serious threat to human health. While scientists continue to search for new antibiotics, they still don’t understand very much about how the old ones work.
Now Thomas Bernhardt, associate professor of microbiology and immunobiology at Harvard Medical School, and his colleagues have added another chapter to the story.
Their findings, published Dec. 4 in Cell, reveal how penicillin deals bacteria a devastating blow – which may lead to new ways to thwart drug resistance.
Hongbaek Cho, Tsuyoshi Uehara, Thomas G. Bernhardt. Beta-Lactam Antibiotics Induce a Lethal Malfunctioning of the Bacterial Cell Wall Synthesis Machinery. Cell, 2014; 159 (6): 1300 DOI: 10.1016/j.cell.2014.11.017
Bacteria in the plate on the left are susceptible to antibiotics but show resistance in the plate on the right. Credit: James Gathany/CDC
These incredible images have revealed insights into how the kidney develops from a tiny cluster of cells into a complex organ.
The time-lapse pictures of growing mouse kidneys are helping scientists to understand the early stages of development in mammals.
They identified a key molecule called beta-catenin that instructs cells to form specialised structures within the kidney. These structures – called nephrons –are responsible for filtering waste products from the blood to generate urine.
If nephrons don’t work properly, it can cause a wide range of health problems — from abnormal water and salt loss, to dangerously high blood pressure. The findings will help scientists to grow nephrons in the lab that can be used to study how kidneys function.
Using the time-lapse technique also means that the same mice can be studied over time, at different developmental stages. This significantly reduces the number of animals needed
for this type of research.
The research was funded by the
National Centre for the Replacement, Refinement and Reduction of Animals in
Despite therapeutic advances, mortality rates for neonatal
meningitis have remained the same over the last two decades. Addressing this
requires better understanding of how the disease is caused at a cellular and
molecular level. Here we see the re-distribution of the protein beta-catenin
(blue) in brain endothelial cells after infection by the bacteria Escherichia coli K1. This bacterium (the
small, rod-like cells seen in the grayscale image) has been shown to cause
Led by principal investigator Prasadarao
Nemani, PhD, researchers in the Microbial Pathogenesis Research Lab at
Children’s Hospital Los Angeles generated this image to better understand the
cellular and molecular events that occur when these bacteria pass through the
blood-brain barrier as occurs in cases of neonatal meningitis. Beta-catenin
helps coordinate adhesion between cells and, in cases of neonatal meningitis,
the adhesion between brain endothelial cells is disrupted, leading to brain
edema or swelling where fluid accumulates in the brain.
“This helped us
identify that re-distribution of beta-catenin helps the bacteria invade the
brain endothelium and may serve as a critical step in causing neonatal
meningitis,” say Subramanian Krishnan, post-doctoral fellow at Children’s
Hospital Los Angeles, who was first author on the study
published in Cellular Microbiology.
Image courtesy of Subramanian
Krishnan, Prasadarao Nemani, PhD, and Esteban Fernandez, PhD, The Saban
Research Institute, Children’s Hospital Los Angeles.
Researchers at the University of California, San Diego School of Medicine have identified a gene variant that may be used to predict people most likely to respond to an investigational therapy under development for Alzheimer’s disease (AD). The study, published March 12 in Cell Stem Cell, is based on experiments with cultured neurons derived from adult stem cells.
“Our results suggest that certain gene variants allow us to reduce the amount of beta amyloid produced by neurons,” said senior author Lawrence Goldstein, PhD, director of UC San Diego Sanford Stem Cell Clinical Center and UC San Diego Stem Cell Program. “This is potentially significant for slowing the progression of Alzheimer’s disease.” AD is the most common cause of dementia in the United States, afflicting one in nine people age 65 and older.
The genetic risk factor investigated are variants of the SORL1 gene. The gene codes for a protein that affects the processing and subsequent accumulation of beta amyloid peptides, small bits of sticky protein that build up in the spaces between neurons. These plaques are linked to neuronal death and related dementia.
Previous studies have shown that certain variants of the SORL1 gene confer some protection from AD, while other variants are associated with about a 30 percent higher likelihood of developing the disease. Approximately one-third of the U.S. adult population is believed to carry the non-protective gene variants.
The study’s primary finding is that variants in the SORL1 gene may also be associated with how neurons respond to a natural compound in the brain that normally acts to protect nerve cell health. The protective compound, called BDNF, short for brain-derived neurotrophic factor, is currently being investigated as a potential therapy for a number of neurological diseases, including AD, because of its role in promoting neuronal survival.
For the study, UC San Diego researchers took skin cells from 13 people, seven of whom had AD and six of whom were healthy control subjects, and reprogrammed the skin cells into stem cells. These stem cells were coaxed to differentiate into neurons, and the neurons were cultured and then treated with BDNF.
The experiments revealed that neurons that carried disease-protective SORL1 variants responded to the therapy by reducing their baseline rate of beta amyloid peptide production by, on average, 20 percent. In contrast, the neurons carrying the risk variants of the gene, showed no change in baseline beta amyloid production.
“BDNF is found in everyone’s brain,” said first author Jessica Young, PhD, a postdoctoral fellow in the Goldstein laboratory. “What we found is that if you add more BDNF to neurons that carry a genetic risk factor for the disease, the neurons don’t respond. Those with the protective genetic profile do.”
“The value of this kind of stem cell study is that it lets us probe the uniquely human aspects of disease and identify how a person’s DNA might determine their drug response, in this case to a potential treatment for Alzheimer’s,” Young said. “Future clinical trials on BDNF should consider stratifying patients based on their SORL1 risk factor and likelihood of benefiting from the therapy.”
Memory and as well as connections between brain cells were restored in mice with a model of Alzheimer’s given an experimental cancer drug, Yale School of Medicine researchers reported in the journal Annals of Neurology.
The drug, AZD05030, developed by Astra Zeneca proved disappointing in treating solid tumors but appears to block damage triggered during the formation of amyloid-beta plaques, a hallmark of
Alzheimer’s disease. The new study, funded by an innovative National
Institutes of Health (NIH) program to test failed drugs on different
diseases, has led to the launch of human trials to test the efficacy of
AZD05030 in Alzheimer’s patients.
“With this treatment, cells
under bombardment by beta amyloid plaques show restored synaptic
connections and reduced inflammation, and the animal’s memory, which was
lost during the course of the disease, comes back,” said Stephen M.
Strittmatter, the Vincent Coates Professor of Neurology and senior
author of the study.
In the last five years, scientists have
developed a more complete understanding of the complex chain of events
that leads to Alzheimer’s disease. The new drug blocks one of those
molecular steps, activation of the enzyme FYN, which leads to the loss
of synaptic connections between brain cells. Several other steps in the
disease process have the potential to be targets for new drugs,
“The speed with which this compound moved to
human trials validates our New Therapeutic Uses program model and serves
our mission to deliver more treatments to more patients more quickly,”
said Dr. Christopher P. Austin, director of NIH’s National Center for
Advancing Translational Sciences (NCATS), which funded the work.
Yale’s Christopher H. van Dyck, a co-author of the paper, and Strittmatter have initiated a multi-site clinical trial to determine
whether the drug can also benefit Alzheimer’s patients. For more
information on this trial being directed by van Dyck, visit http://www.adcs.org/studies/Connect.aspx or https://clinicaltrials.gov (NCT02167256 and NCT01864655).
5kg of skin care right here! Carrots deliver high doses of vitamin A and beta carotene into the cells to promote skin healing, anti ageing and cell rejuvenation giving you that healthy golden glow. Carrots also assist in the prevention of acne, eczema and skin dryness. Carrots are know for there cancer fighting benefits and are an all over body tonic. 👍
Nearly 15 months ago on August 26, 2013, I decided to see how long it would take me to fill up a Spaghettios can with test strips. Since then I have pricked my fingers approximately 2,010 times. In the 4 years and 11 months I’ve had type 1 diabetes, I have pricked my fingers an estimated 8,068 times. Not counting finger pricks, I have pierced my skin with a needle around 1,600 times. But it’s not just me. There are as many as 3 million Americans with type 1 diabetes. 80 people get diagnosed each day. We must do these things to stay alive. Type 1 diabetes is not “Diabeetus.” We didn’t ask for this, just like we didn’t do anything to cause it. It’s an autoimmune disease in which the insulin-producing beta cells are killed off. That means we have to take artificial insulin to stay alive, whether that be through shots or an insulin pump. There is NO CURE. Type 1 diabetics can’t “just exercise and eat right” to get rid of this disease. It is an everyday struggle for us to maintain a healthy blood sugar level. Some days we cry in defeat. Other days we smile in triumph. To all my fellow diabuddies: you may have diabetes, but remember that it will NEVER have you.
(Image caption: Production of APPsα in the brain: The nerve cells that encounter viral
gene shuttles produce the therapeutic APPsα protein (orange) along with a
green fluorescent protein. Brain region: hippocampus, important for
learning and memory. Credit: S. Weyer, IPMB)
In laboratory experiments on the basic mechanisms that cause
Alzheimer’s dementia, an international research team led by Heidelberg
neurobiologist Prof. Dr. Ulrike Müller and a team of French scientists
have succeeded in largely “repairing” the nerve cell damage typical in
this disease. The researchers took a closer look at a key protein in
Alzheimer’s pathogenesis, APP, and one of its cleavage products APPsα.
Prof. Müller of Heidelberg University’s Institute of Pharmacy and
Molecular Biotechnology explains that viral gene shuttles were used to
drive the delivery of APPsα into the brains of Alzheimer´s mouse models.
The protein APPsα in turn elicited repair effects and clearly improved
memory. The researchers hope to use these findings to explore new
approaches in the development of gene therapy for Alzheimer’s. Their
results were published in the journal “Acta Neuropathologica”.
Alzheimer’s is the most frequent cause of dementia in the elderly. It
particularly affects regions of the brain that are fundamental for
memory and learning. The junctions through which the nerve cells
communicate, the synapses, disappear long before the nerve cells die,
damage that impairs both learning and memory. “While dead nerve cells
are irretrievably lost, damaged synapses can be regenerated in the
elderly,” Prof. Müller emphasises.
The brains of Alzheimer’s patients show plaque deposits, she explains. The deposits
thwart the communication between the nerve cells and cause them to
eventually die. The main component of the plaque is a short protein
fragment known as the beta amyloid peptide. It is generated when the
considerably larger amyloid precursor protein, or APP, is cleaved.
“Until now, scientists believed that the overproduction of beta amyloid
peptides was the main cause of Alzheimer’s. More recent investigations,
however, have demonstrated that another APP cleavage product, the APPsα
protein, also diminishes over the course of the disease,” Ulrike Müller
continues. The protein cleaving enzymes, called secretases, play a key
role in this process. The scissor-like secretases cut the APP cell
surface protein at various positions. “These cleaving processes produce
beta amyloid peptides that are toxic to the nerve cells, but also
produce the protective APPsα cleavage product, which counteracts the
toxic peptide,” says Prof. Müller. “Research over the last few years
indicates that a misregulation of the secretase cleavage in Alzheimer’s
results in inadequate production of protective APPsα.”
Earlier studies by Müller’s research group had already shown that
APPsα has an essential function in the nervous system, particularly
because it regulates the formation and function of synaptic junctions
and spatial memory. These findings were used to investigate a new
approach for a possible gene therapy for Alzheimer’s. The international
research team used viral gene shuttles to introduce APPsα into the
brains of mouse models with plaque deposits like those in Alzheimer’s.
“After introducing the APPsα, we saw that the nerve cell damage could be
repaired. The number of synaptic junctions increased, and spatial
memory began to function again,” reports Ulrike Müller. “Our research
results show the therapeutic effectiveness of APPsα in the animal model
and open up new perspectives for the treatment of Alzheimer’s.”