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Researchers at the University of Illinois (U of I) have identified a new method of synthesising a wide range of medicines using a small number of building blocks.

Thousands of compounds in a class known as polyenes – many of which could be used to develop new drugs – can be constructed simply and economically from a dozen different building blocks.

"We want to understand how these molecules work, and synthesis is a very powerful engine to drive experiments that enable understanding," said Martin Burke, a chemistry professor at the U of I and the Howard Hughes Medical Institute. "We think this is a really powerful road map for getting there."

One simple reaction is used to bind the chemical building blocks, in the same way in which plastic building blocks fit together because they have a simple connector. Scientists thus have greater freedom to construct molecules that may be difficult to extract from their natural source or to synthesise in a laboratory.

Researchers are able to omit or substitute parts of substances in order to create products that may have therapeutic potential. 

Recently, Professor Burke's group synthesised a derivative of the anti-fungal medication amphotericin and gained an insight into how this clinically vital but highly toxic medicine works. They were also able to create a derivative which is an effective fungicide but is nontoxic to human cells.

The team moved on to focus on polyenes and discovered that many elements are common across numerous compounds. They calculated that more than three-quarters of all natural polyene frameworks could be made with only 12 different blocks.

In order to demonstrate their findings, they synthesised a number of compounds representing a wide variety of polyene molecules using only the dozen designated building blocks. 

It is hoped that the identification of the building blocks and their widespread availability will lead to a greater understanding of polyene natural products and their potential as pharmaceuticals, particularly compounds that have hitherto proved to be too costly or time-consuming to make.

Researchers have uncovered direct proof of a long-suspected cause of multiple HIV-related health complications, supporting the use of complementary therapies to antiretroviral drugs to significantly slow HIV progression.

Scientists at the University of Pittsburgh Center for Vaccine Research (CVR) found that a drug often administered to patients undergoing kidney dialysis significantly reduces the levels of bacteria that escape the gut and reduces health complications in non-human primates infected with the simian form of HIV.

Inflammation and chronic activation of the immune system are major determinants of progression of HIV infection to AIDS. They also play a key role in inducing excessive blood clotting and heart disease in HIV patients.

It was theorised that microbial translocation, which occurs when bacteria in the gut escapes into the body through intestinal lining damaged by HIV, lay behind these findings – but no direct proof of the mechanism existed.

The University of Pittsburgh researchers gave the drug Sevelamer, which is used to treat elevated levels of phosphate in the blood of patients with chronic kidney disease, to monkeys infected with simian immunodeficiency virus, or SIV, the primate form of HIV.

Gut bacteria bind to Sevelamer and this makes it more difficult for them to escape into the body and cause serious problems, such as heart disease, while further weakening the immune system and allowing HIV to progress to full-blown AIDS.

Levels of a protein which indicates microbial translocation remained low in SIV-infected monkeys treated with Sevelamer, while it increased nearly four-fold a week after infection in untreated monkeys.

In treated monkeys, lower levels of a biomarker associated with excessive blood clotting were recorded, demonstrating that heart attacks and stroke in HIV patients are more likely associated with chronic immune system activation and inflammation, rather than HIV drugs.

"These findings clearly demonstrate that stopping bacteria from leaving the gut reduces the rates of many HIV comorbidities," said Dr Ivona Pandrea, professor of pathology at Pitt's CVR.

"Our study points to the importance of early and sustained drug treatment in people infected with HIV."

New stem cell research suggests indicators of schizophrenia are present in early neuron differences, supporting the theory that the risk of developing the disease may begin in the womb.

Scientists at the Salk Institute have uncovered evidence of strange behaviour in the early development stages of neurons generated from the skin cells of people suffering from schizophrenia.

The findings of the study, published in Molecular Psychiatry, suggest the origins of the disorder may lie in the brains of babies still in the womb.

Studying schizophrenia has until recently proved very difficult for scientists, as they have had to examine the brains of patients after death. However, the brains of these patients had often been damaged by age, stress, medication or drug use.

Stem cell technology enabled the Salk scientists to overcome these hurdles. They took skin cells from patients, encouraged them to revert back to an earlier form and then prompted them to grow into very early-stage neurons (dubbed neural progenitor cells or NPCs), which are similar to the cells in the brain of a developing fetus.

The researchers carried out tests on NPCs from the skin cells of four patients with schizophrenia and six people without the disease. 

In one test, they looked at how far the cells moved and interacted with particular surfaces; in the other, they looked at stress in the cells by imaging mitochondria.

The results of both tests demonstrated that NPCs from people with schizophrenia differed in significant ways from those taken from unaffected people.

Unusual activity was detected in two major classes of proteins in cells predisposed to schizophrenia: those involved in adhesion and connectivity and those involved in oxidative stress.

Cells derived from patients with schizophrenia tended to have aberrant migration (which may result in the poor connectivity seen later in the brain) and increased levels of oxidative stress (which can lead to cell death).

These results appear to support the theory that events occurring during pregnancy can contribute to schizophrenia, even though the disorder does not tend to manifest until early adulthood.

"The study hints that there may be opportunities to create diagnostic tests for schizophrenia at an early stage," said Fred Gage, Salk professor of genetics.

Researchers have made a breakthrough in the field of personalised medicine by growing functioning human heart tissue carrying an inherited cardiovascular disease.

The advance comes as the result of a collaborative effort between scientists from the Harvard Stem Cell Institute, the Wyss Institute for Biologically Inspired Engineering, Boston Children's Hospital, the Harvard School of Engineering and Applied Sciences, and Harvard Medical School.

Scientists modelled the cardiovascular disease Barth syndrome, a rare X-linked cardiac disorder caused by mutation of a single gene called Tafazzin, or TAZ.

Skin cells were taken from two Barth patients; these were manipulated to become stem cells that carried the patients' TAZ mutations.

Rather than being used to generate single heart cells in a dish, the cells were tricked into joining together in the way they would if they were forming a diseased human heart. This was achieved by growing them on chips lined with human extracellular matrix proteins that mimic their natural environment.

The tissue thus created contracted very weakly, as would the heart muscle seen in Barth syndrome patients.

Genome editing was then used to mutate TAZ in normal cells, confirming that this mutation is sufficient to cause weak contraction in the engineered tissue.

"You don't really understand the meaning of a single cell's genetic mutation until you build a huge chunk of organ and see how it functions or doesn't function," said Dr Kevin Parker.

"In the case of the cells grown out of patients with Barth syndrome, we saw much weaker contractions and irregular tissue assembly."

The scientists also found that the TAZ mutation works in such a way to disrupt the normal activity of mitochondria, which produce energy – although the overall energy supply of the cells appeared to be unaffected by the mutation.

They describe a direct link between mitochondrial function and a heart cell's ability to build itself in a way that allows it to contract – a newly identified function for mitochondria.

Barth syndrome cells produce an excess amount of reactive oxygen species or ROS as a result of the TAZ mutation. In the laboratory, quenching ROS production restores contractile function, but the scientists have yet to ascertain whether this could be replicated in human or animal models.

A new study challenges the efficacy of using stem cells to regenerate damaged heart tissue.

Researchers at Cincinnati Childrens Hospital Medical Center and the Howard Hughes Medical Institute (HHMI) claim that cardiac stem cells used in ongoing clinical trials – which express a protein marker called c-kit – do not achieve high enough regeneration rates to justify their use.

Many patients have already been treated using c-kit positive stem cells, which are removed from healthy regions in a damaged heart, processed in a laboratory and then re-injected into the patients' hearts.

This is an experimental treatment based on preclinical studies in rats and mice which have indicated that c-kit-positive stem cells completely regenerate myocardial cells and heart muscle.

However, the researchers have pointed out that this does not accurately reflect the situation in the heart following an injury, as regenerative capacity is almost non-existent.

Combined data from a range of clinical studies reveals patients experienced around a three to five per cent improvement in heart ejection fraction – a measurement of how forcefully the heart pumps blood.

Dr Jeffery Molkentin, study principal investigator and a cardiovascular molecular biologist and HHMI investigator at the Cincinnati Children's Heart Institute, said this effect is unlikely to be due to the generation of new contractile cells, known as cardiomyocytes. In fact, it is probably because injecting these cells stimulates the growth of new capillaries.

The research team conducted studies on mouse models to see how efficiently c-kit-positive cardiac progenitor cells regenerate cardiomyocytes. Regeneration rates were measured during embryonic development, ageing and after myocardial infarction (heart attack).

A fluorescent marker was used to track the specific types and volumes of any c-kit-positive cells being generated in the animals, including in their hearts.

It was found that c-kit-positive cells originating in the heart generated new cardiomyocytes at a percentage (from baseline) of 0.03 or less. This figure fell below 0.08 when considering a natural process called cellular fusion – where c-kit-positive cells from the bone marrow or circulating immune system cells fuse with cardiomyocytes in the heart. 

The team are conducting follow-up studies in an attempt to increase the rate of new cardiomyocyte generation from c-kit-positive stem cells.