New research tries to ‘calm down’ stressed B-cells in-order to treat diabetes

The cycle of inflammation. B cells communicate via cytokines with other inflammatory cells, such as T cells and macrophages, to maintain and amplify the cycle of inflammation (http://www.roche.com/pages/downloads/photosel/061106/html/detail_3.html)

Diabetes is a major global health problem. In the USA alone there are some 25.8 million people living with the disease. Diabetes costs the US healthcare system more than $200 billion dollars each year. It’s a problem that is likely to further explode in the next few years. Consequently new treatments are of the upmost importance.

There are two types of diabetes: type 1 and 2. The hormone insulin is a major player in the development of the disease. Insulin has an important role in the body and works alongside glucagon to regulate blood sugar.  The most common is type of diabetes is type 2 (90-95% of cases). It is caused by insulin insensitivity and eventual loss of insulin production in the pancreas.

Diabetes is highly related to stress. New research has discovered a key molecule that works to amplify this stress early on the diabetes process. This molecule is called thioredoxin-interacting protein (TXNIP). It is central to the inflammation process and leads to the death of insulin secreting B cells in the pancreas.

B cells can be thought of as the factories of the pancreas producing vast amounts of insulin every minute. Great fact:

“There are a billion or so beta cells in the average healthy pancreas. These cells will make more copies of insulin every year than there are grains of sand on every beach and in every desert in the world”

 B cells and every other cell rely on an organelle called the endoplasmic reticulum (ER). This organelle works to package, tag and dispatch all the proteins, including insulin, from the cell. Diabetes comes about when the ER becomes stressed and faulty (maybe due to the need to overproduce insulin). When this occurs proteins are not packaged properly and accumulate within the B cell. The body’s response to this malfunction is drastic; it effectively destroys the cell. It does this by activating the interlukin-1 (IL-1) pathway and therefore inducing apoptosis.

This in its self is not as bad as it sounds, because our bodies have B cells in reserve. However when it does occur, our B cells will have to work harder and become more stressed. Therefore the problem propagates and the chance of developing diabetes is increased.

TXNIP is involved in the exacerbation of the IL-1 pathway and cell apoptosis. Current studies are looking into IL-1 targeting, however new research has shown that TXNIP is a very central player in the stimulation of the IL-1 pathway. Therefore if you remove TXNIP from the equation you will save B-cells from apoptosis and in theory protect the body form developing diabetes. This has been shown by the researchers to occur in mouse models. Consequently this idea is being translated and tested in up coming clinical trails. The hope is that by shutting down TXNIP we will prevent cell stress and hopefully delay or stop the onset of diabetes. However my question is surely TXNIP has a natural role in the body, by shutting it off are we not in danger of loosing its benefits? What do you think about this new development?

Success for gene therapy in treating spinal muscular atrophy

Spinal Muscular atrophy (SMA) is the leading genetic cause of infantile death in the world. It is a rare genetic disease, which occurs in 1 in 6000 children. These children often die young because there is currently no cure for SMA. Children with SMA are missing a protein called Survival motor neuron-1 (SMN1). SMN1 directs nerves in the spine and gives commands to muscles.

A study at the university of Missouri recently found that SMA could be treated using gene therapy. The team used a viral vector, expressing full length SMN1 cDNA, to introduce the missing gene into a mouse’s nervous system. Therefore allowing SMN1 to be expressed within the nervous system and restore ‘normal’ function.

The introduction of the missing gene increased the mouse’s lifespan to 10-25 days when compared to 5 or 6 days for untreated mice. The researchers admit the system is far from perfect but say the experiment shows promising results in our ability to rescue the nervous system in SMA.

Importantly this treatment has a real application for human patients suffering from SMA. Clinical trials for SMA gene therapy are likely to begin within the next 12-18 months. Hopefully researchers can build on the success of this study and refine and develop the gene therapy process so it is more effective. This is a positive step in the field of gene therapy and offers a window of hope for those suffering from various genetic disorders. What do you think? How could this research be used for other genetic disorders? What are the major barriers to gene therapy?

Hope for Huntington’s

Huntington’s Disease affects key areas of the brain

Two recently identified regulatory proteins may hold the key to success for the treatment of Huntington’s disease (HD) and other neurodegenerative diseases. These proteins appear to play a critical role by clearing away misfolded proteins, which accumulate in neurons affected by HD. The findings help to explain some of the fundamental causes of this untreatable disease. The study also provides ‘clear’ therapeutic targets, which cold be utilised to treat HD.

HD is a genetic disorder that occurs in 6-7 persons per 100,000. It is characterised by progressive deterioration of: involuntary movement control, cognitive decline and psychological problems. This is all caused by a mutation in the htt gene. This mutation results in the accumulation of the misfolded htt protein within certain cells of the nervous system. Currently there is no cure or effective treatments. Consequently these results are hugely encouraging.

The first of these regulatory proteins is PGC-1alpha. This protein helps regulate the creation and operation of mitochondria. It does this by regulating mitochondrial transcription factors. This regulation is important because neurons are ‘all about energy’. This is because they have such a huge demand for it. It has been previously shown that the mutant htt gene interfered with normal levels of PGC-1alpha. This study went onto to show this to be correct. It also showed, in a mouse HD model, elevated PGC-1alpha levels virtually eliminated problematic misfolded htt proteins.

Specifically PGC-1alpha is vital in mitochondrial autophagy. Autophagy is essential because neurons must last a lifetime. Therefore recycling old and dangerous parts of the neuron limits dangerous oxidative molecules, produced during metabolism. PGC-1alpha drives this autophagy pathway through transcription factors EB or TFEB. TFEB is a relatively newly discovered player, however it is emerging as a leading actor in HD. It was shown that even without the induction of PGC-1alpha, TFEB could prevent the aggregation of htt and subsequent neurotoxicity.

 In their experiments the scientists crossbred HD mice with mice that produced elevated levels of PGC-1alpha. The offspring consequently showed a dramatic improvement in their HD progression. Neuronal degeneration was not observed and neurons did not die, like they would under normal circumstances. These two regulatory proteins, PGC-1alpha and TFEB, provide 2 new therapeutic targets for HD. They utilise two key areas bioenergetics and protein quality control to allow neurons to function properly. By utilising these regulatory proteins neuronal function can be maintained and accumulation of misfolded proteins prevented. This is great news for HD because it has so often been seen as a lost cause. The next important steps will be to develop ways to exploit these molecules further and develop therapeutic options utilising these molecules in humans. What do you think about this topic? Are we going to see a breakthrough in HD treatment? How long would it take to develop?

Live Stem Cell Regeneration

Great new research is now allowing scientists to watch and manipulate stem cells regenerating tissue in real time. This can all happen without injuring the animal. In order to do this researcher have developed a new sophisticated imaging technique. This new technique has allowed a greater insight into how the tissue regeneration process works.

This study focused on stem cell behaviour within the hair follicles of mice. Due to the accessibility of these stem cells, the researchers were able to view the process in real time. The study used a 2-photon intravital microscopy. This new techniques works by using transgenic mice and near infrared light, to allow deeper penetration with less damage to the tissue.

Using this technique the study was able to observe the interactions between stem cells and their progeny. It showed that different stem cells were creating different cell types within the tissue. Further the interaction between these cells and their immediate environment determines how they will divide, where they will migrate too and in what way they will specialise. I hear you saying we already knew this. I agree, but the ability to visualise this in a uninjured animal, in real time, really bring the whole process to life and after all that’s what biology is about; real life.

The real ‘discovery’ in this project was in terms of mouse hair follicles. The study found that hair growth would not occur in the absence of the connective tissue mesenchyme, which appears early on in embryonic development. Stem cells are very important and as our understanding grows, they are only going to get more important. This is due to their ability to regenerate many other types of tissue in mammals. This study really highlights the importance of the microenvironment in determining stem cell behaviour. Armed with this knowledge we can uncover the mechanisms that go wrong in the cases of cancer and other diseases. This same technique has the potential to shed light on multiple different areas: what stimuli is required to trigger repairs in a variety of organs and how stem cells interact with other cells.

Is it a Jellyrat, no it’s a Medusoid…

An amazing new development has come out of Harvard University. A synthetic jellyfish made from heart cells derived from a rat. This “medusoid” can swim like a jellyfish and will pulse when subjected to an electrical field. Check out the video:

This was built by first mapping the cellular structure of moon jellies. Then recreating this structure by placing heart cells on a sheet of polydimethylsiloxane. This approach to synthetic life is different from normal, because the scientist did not modulate the animal’s genetic composition. This study used the pre-existing genes to create a jellyfish’s morphology and function, whereas usually genes are added to produce changes in morphology and function.

Apart from being a scientist new ’must have’ lab pet. The hope for this medusoid is to improve testing of new drugs. For example you have just developed a new heart drug, all you need to do is test it upon the jellyfish and see how it’s pumping changes.

The whole thing for me is mind blowing. It is a true example of how powerful of our understanding of life systems is. How are we going to move on from here? If you’d asked me if this were possible I would of said no, however this has adjusted the playing field. What new synthetic animals are going to be able to create? How will this effect our ability to test different hypothesis and garner further information on how the human body works. However, you could also say, it is just scientists having fun and it doesn’t actually add any ‘real value’ to science? But it is probably the coolest thing I’ve ever seen in science? Has anyone else seen anything better? I would love to know, please let me know!