Gene directs stem cells to build the heart

Researchers have shown that they can put mouse embryonic stem cells to work building the heart, potentially moving medical science a significant step closer to a new generation of heart disease treatments that use human stem cells.

Scientists at Washington University School of Medicine in St Louis, United States, report in the 3 July 2008 issue of Cell Stem Cell that the Mesp1 gene locks mouse embryonic stem cells into becoming heart parts and gets them moving to the area where the heart forms. Researchers are now testing if stem cells exposed to Mesp1 can help fix damaged mouse hearts.

“This isn’t the only gene we’ll need to get stem cells to repair damaged hearts, but it’s a key piece of the puzzle,” says senior author Kenneth Murphy, MD, PhD, professor of pathology and immunology and a Howard Hughes Medical Institute investigator. “This gene is like the first domino in a chain: the Mesp1 protein activates genes that make other important proteins, and these in turn activate other genes and so on. The end result of these falling genetic dominoes is your whole cardiovascular system.”

Embryonic stem cells have created considerable excitement because of their potential to become almost any specialised cell type. Scientists hope to use stem cells to create new tissue for treatment of a wide range of diseases and injuries. But first they have to learn how to coax them into becoming specialised tissue types such as nerve cells, skin cells or heart cells.

“That’s the challenge to realising the potential of stem cells,” says Prof Murphy. “We know some things about how the early embryo develops, but we need to learn a great deal more about how factors like Mesp1 control the roles that stem cells assume.”

Mesp1 was identified several years ago by other researchers, who found that it was essential for the development of the cardiovascular system but did not describe how the gene works in embryonic stem cells. Using mouse embryonic stem cells, Prof Murphy’s lab showed that Mesp1 starts the development of the cardiovascular system. They learned the gene’s protein helps generate an embryonic cell layer known as the mesoderm, from which the heart, blood and other tissues develop.

In addition, Mesp1 triggers the creation of a type of cell embryologists recently recognised as the heart’s precursor. They also found that stem cells exposed to the Mesp1 protein are locked into becoming one of three cardiovascular cell types: endothelial cells, which line the interior of blood vessels; smooth muscle cells, which are part of the walls of arteries and veins; or cardiac cells, which make up the heart. “After they are exposed to Mesp1, the stem cells don't make any decisions for several days as to which of the three cell types they're going to become,” Prof Murphy notes. “The cues that cause them to make those commitments come later, in the form of proteins from other genes.”

Take ethnicity into account, say breast cancer researchers

Breast cancer research needs to investigate how a person’s ethnicity influences their response to treatment and its outcome, according to a new Comment piece in the 18 July 2008 Lancet by researchers from Imperial College London.

Emerging evidence suggests that particular drugs may benefit people from one ethnic group more than others, because of differences in their genetic makeup. However, most key trials looking at treatments for breast cancer have been carried out in predominantly white populations in Europe, North America and Australasia.

Other populations might not respond to a drug in the same way as the white populations in these trials, argue the researchers. They suggest that clinical trials should record participants’ ethnicity and analyse whether there are differences in how patients from particular ethnic groups respond to a particular therapy.

The researchers highlight the example of a drug called trasztuzumab, which is commonly used to treat people with breast cancer that is HER-2 positive. Most studies of trasztuzumab have not reported the ethnicity of participants. However, a recent study showed that people with a particular genotype responded better than others to treatment with this drug.

The genotype in question is more common in some ethnic groups than in others, so the researchers argue that an individual’s ethnicity could be a key factor in determining which treatments are most likely to benefit them.

Dr Carlo Palmieri, from the Division of Surgery, Oncology, Reproductive Biology and Anaesthetics at Imperial College London and one of the authors of the piece, said: “Everyone responds differently to treatment and it’s often very difficult to predict how well someone will respond to a particular drug. However, evidence is now emerging that shows how your genes might influence whether or not a particular treatment can help you. Different ethnic groups have different incidences of different types of breast cancer “There are small genetic differences between people from different ethnic backgrounds and it is really important that we find out whether these genetic differences mean that certain drugs perform well in people from certain ethnic groups but not in others. It’s only by doing this that we can make sure each individual receives the best possible care,” added Dr Palmieri.

● “Ethnicity and breast cancer research”, The Lancet, 18 July 2008

21 new genes associated with Crohn’s disease

A consortium of researchers from the United States, Canada, and Europe has identified 21 new genes for Crohn’s disease, a chronic disease of the large and small intestines. This discovery brings the total number of known genes associated with Crohn’s disease to more than 30 and advances the understanding of causes and potential avenues to develop new treatments.

The results were reported 29 June 2008 in the advance online edition of Nature Genetics. To conduct the study, researchers combined and analyzed samples from three studies, totaling 3,230 people with Crohn’s and 4,829 unaffected individuals. Participants of the studies were all of European descent. The large sample size helped researchers implicate new genes in Crohn’s whose contributions to the disease were undetectable by previous small studies.

These findings make possible earlier predictions of which patients are at risk for the most serious forms of the disease, thereby permitting earlier treatment to prevent complications. As a result of the genomewide scan, the 21 new genes strongly associated with Crohn's were identified, including several functioning in biochemical pathways promoting inflammation, and others whose functions are still unknown.

Although the biochemical functions of these variants and how they trigger inflammation in the intestines requires further study, they all represent potential targets for the development of new medications.

First female human genome sequenced

The first full sequence of a female human genome is complete, this after four individual genomes, all of them male, had already been sequenced. The sequenced DNA belonged to Dr Marjolein Kriek, a clinical geneticist at Leiden University Medical Centre (LUMC), Netherlands, the university announced late June.

“If anyone could properly consider the ramifications of knowing his or her sequence, it is a clinical geneticist,” commented Professor Gert-Jan B van Ommen, leader of the LUMC team and director of the Center for Medical Systems Biology (CMSB) of the Netherlands Genomics Initiative. The decision to sequence the female DNA is timely, believes Professor van Ommen.

“While women don’t have a Y-chromosome, they have two X-chromosomes. As the X-chromosome is present as a single copy in half the population, the males, it has undergone a harsher selection in human evolution. This has made it less variable. We considered that sequencing only males, for ‘completeness’, shows insight into X-chromosome variability. So it was time, after sequencing four males, to balance the genders a bit.” Using the latest technology, approximately 22 billion base pairs – the ‘letters’ of the DNA language – were read.

That is approximately eight times the size of the human genome. “This high coverage is needed to prevent mistakes, connect the separate reads and reduce the chance of occasional uncovered gaps,” says Dr Johan den Dunnen, project leader at the Leiden Genome Technology Center.

“The sequencing itself took about six months. Partly since it was run as a 'side operation' filling the empty positions on the machine while running other projects. Would such a job be done in one go, it would take just ten weeks,” said Dr Dunnen. A further six months will be needed to analyse the DNA.

Researchers find gene that regulates ovulation

A group of Canadian and European researchers have unlocked the mystery of a gene with the potential to regulate and block ovulation.

The new study – a collaboration between the Universite de Montreal in Canada and the Institut de génetique et biologie moléculaire et cellulaire of the Université de Louis Pasteur, Strasbourg, France – is published in a recent issue of the journal Genes & Development.

“Our findings demonstrate that the Lrh1 gene is essential in regulating ovulation,” said Bruce D. Murphy, director the Animal Research Centre at the Faculty of Veterinary Medicine and an adjunct professor of obstetrics and gynaecology at the Faculty of Medicine of the Université de Montréal.

“Until this point, the role of Lrh1 in female fertility was unclear, but we have found the gene regulates multiple mechanisms of ovulation and may affect fertilisation.” To reach their conclusions, the research team developed a new type of genetically modified mouse whose Lrh1 gene was selectively blocked in the ovary. They found that deletion of the Lrh1 gene effectively stopped ovulation.

“This discovery means we can envision new contraceptives that selectively stop ovulation,” said Dr Murphy. “If created, these new contraceptives would be more effective and produce less side-effects than current steroid-based forms of birth control.” What’s more, the findings could lead to the development of pharmaceuticals that activate the Lrh1 gene, which may prove critical in giving infertile couples hope in producing children.

“This is an important development, since 15% of couples are infertile,” said Dr Murphy. “The widespread role of this gene in the ovary indicates that it may be targeted to stimulate ovulation and, eventually, conception.”

Gene profile for prostate cancer stem cells identified

Genetic changes during the initiation and progression of prostate cancer have eluded scientists to date. However, according to findings, published in BioMed Central’s open access journal Genome Biology, researchers have, for the first time, identified a specific gene expression profile of prostate cancer stem cells, with important implications for future treatments.

They revealed 581 genes that are differentially expressed in certain prostate cancer cells, highlighting several pathways important in the cancer stem-cells biology, and offering targets for new chemo preventative and chemotherapeutic approaches. The cells in the study represent less than 0.1% of prostate cancer tumours, and have properties that mark them out as cancer stem cells. The cells renew themselves, are highly invasive, and have a longer lifetime than normal stem cells.

They also feature a primitive epithelial phenotype and can differentiate to recapitulate phenotypes seen in prostate tumours. The cells are found in all stages and types of prostate cancer. Expression profiling of prostate cancers typically uses tumour cell mass samples to identify individual genes.

In this study, researchers harnessed advances in microarray and target labelling technologies to produce a functionally annotated expression profile of these prostate cancer stem cells.

The team, from the YCR Cancer Research Unit at the University of York and Procure Therapeutics, created a malignant stem cell signature by combining genes significantly overexpressed in stem cells with those significantly overexpressed in malignant stem cells. Quantitative RTPCR, flow cytometry and immunocytochemistry were used to validate the gene expression changes.

Genes associated with inflammation were prominent in the cancer stem cell expression profile. Potential therapeutic target NF B is known to promote cell survival. The researchers showed that an NF B inhibitor triggered programmed cell death in cancer stem cells, but spared normal stem cells.

This provides a potential therapeutic target for this rare group of cells, which are unlikely to be affected by current chemotherapy regimens. “For the first time we are looking at the subpopulation of cancer cells which actually initiate new tumours” explains Anne Collins, who coordinated the study.

“The genetic profiling we have carried out should stimulate new lines of research directed towards stem cell treatments for cancer." Gene expression profiling of human prostate cancer stem cells reveals a pro-inflammatory phenotype and the importance of extracellular matrix interactions

Study shows some people naturally resistant to HIV

Some people may be naturally resistant to infection with HIV, according to the results of a study conducted by Dr Nicole Bernard of the Research Institute of the McGill University Health Centre (MUHC), Canada.

Her study findings were published 16 July in the journal AIDS. The simultaneous expression of certain versions of two specific genes called KIR3DL1 and HLA-B*57 is thought to be at the root of some cases of this innate resistance to HIV infection. Depending on which versions of these two genes the patient has, he or she will resist HIV infection or develop AIDS at a slower rate.

These results were obtained by comparing the genetic profiles of people undergoing primary HIV infection (in their first year of infection) to those repeatedly exposed to HIV but non-infected. The group of exposed but noninfected patients came from a cohort studied by Dr Julie Bruneau of the Centre Hospitalier de l'Université de Montréal.

The cohort of primary HIV infected patients is studied by Dr Jean-Pierre Routy, from the MUHC. Analyses show that the “good” versions of both genes were  present in 12.2% of exposed but non-infected subjects versus only 2.7% in patients in primary HIV infection. As of yet, no study has clearly described the mechanism of this protection.

The KIR3DL1 gene codes for a receptor on the surface of the immune system’s natural killer (NK) cells, which when activated destroy infected cells in the body.

The HLA-B*57 gene codes for a protein normally found on the surface of all body cells that binds the KIR3DL1 and dampens NK cell activity. The most likely hypothesis is that HIV prevents the HLAB* 57-encoded protein from being expressed on the surface of the infected cells, making it unavailable to bind KIR3DL1. As a consequence, the NK cells retain their activity and destroy the virus-infected cells.

As this mechanism can occur very soon after the virus has started to infect the body cells, people carrying those versions of the 2 genes may be able to destroy more efficiently the infected cells following exposure to HIV, thus lowering their chances of developing AIDS.

“More research is needed to determine the exact mechanism behind the protection we have observed, but these findings have revealed a promising avenue,” says Dr Bernard.

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