For the first time, researchers have linked autism in a mouse model of the disease with abnormalities in specific regions of the animals’ chromosomes. The regions contain genes associated with aberrant brain development and activity.
‘These discoveries in mice may eventually pave the way towards understanding autism in human patients and devising new treatments,’ said co-senior author, Elliott H. Sherr, MD, PhD, a pediatric neurologist at UCSF Benioff Children’s Hospital and professor of neurology at UC San Francisco (UCSF).
The scientists bred a group of normal mice with a line of genetically modified mice that exhibit behaviours which are the mouse equivalent of autism. The 400 descendants of that crossbreeding, explained Sherr, ‘had a random assortment of genetics – some normal and healthy, some aberrant.’
The scientists exhaustively observed and recorded the behaviour of each descendant mouse. Since each animal’s genetic makeup was already known, the researchers were able to pinpoint associations between specific autistic behaviours and specific chromosomal regions.
‘This allowed us to say which regions we think contain the genes that contribute to which behaviour,’ said Sherr.
Sherr noted that those regions ‘contain genes that are already known to cause autism in humans, or are involved in brain development in such a way that makes it likely that they can cause autism.’
To test for autistic behaviour, the mice were put in the middle chamber of an enclosure with three chambers. In the chamber on one side was another mouse; in the other, an inanimate object. ‘Mice are social animals, so a normal mouse would spend much more time in the chamber with the other mouse,’ said Sherr. ‘An autistic mouse would spend more time with the object, or equal time with the object and the other mouse, because it didn’t care.’
The researchers also observed what the mice did when they were in a chamber together. ‘A healthy mouse will spend a lot of time sniffing or interacting with the other mouse, while an autistic mouse will roam around the chamber ignoring the other mouse as if it was inanimate,’ said Sherr.
The research will have a number of potential benefits, he said, particularly once researchers pinpoint the exact locations of the genes on the chromosomes. ‘Having the genes means that you can begin to pick apart the connection between the genes and the actual behaviour, and look at how the mutation on a gene might result in aberrant behaviour. Having an animal model means that you can look at the anatomy in a more careful way, study the cells in a tissue culture dish and manipulate them in other ways.’
Scientists will also be able to test the effects of exposure to toxins and other substances on the development of autism, he said.
Eventually, said Sherr, ‘Having an animal model will let us test potential drugs to treat autism.’ University of California – San Francisco

Scientists from The University of Manchester have identified 14 new genes which could have important consequences for future treatments of childhood arthritis.
Scientists Dr Anne Hinks, Dr Joanna Cobb and Professor Wendy Thomson, from the University’s Arthritis Research UK Epidemiology Unit looked at DNA extracted from blood and saliva samples of 2,000 children with childhood arthritis and compared these to healthy people.
Principal Investigator Professor Thomson, who also leads the Inflammatory Arthritis in Children theme at the National Institute for Health Research (NIHR) Manchester Musculoskeletal Biomedical Research Unit, said: ‘This study brought together an international group of scientists from around the world and is the largest investigation into the genetics of childhood arthritis to date.’
Childhood arthritis affects one in 1,000 in the UK. It is caused by a combination of genetic and environmental risk factors, however until recently very little was known about the genes that are important in developing this disease – only three were previously known.
Dr Hinks, joint lead author of the study, said the findings were a significant breakthrough for understanding more about the biology of the disease and this might help identify novel therapies for the disease. ‘Childhood arthritis, also known as juvenile idiopathic arthritis (JIA), is a specific type of arthritis quite separate from types found in adults and there’s been only a limited amount of research into this area in the past,’ she said. ‘This study set out to look for specific risk factors. To identify these 14 genetic risk factors is quite a big breakthrough. It will help us to understand what’s causing the condition, how it progresses and then to potentially develop new therapies.’
The study may help to predict which children need specific treatment earlier and allow health workers to better control their pain management, quality of life and long-term outcome. Currently 30 per cent of children with the disease continue to suffer from arthritis in adulthood.
Dr Cobb, joint lead author, added: ‘There are lots of different forms of childhood arthritis so identifying the markers will help us understand a little bit more about the disease process. It will also help to categorise children with JIA into sub-types dependent on which genes they have and allow us to determine the best course of treatment.’ Manchester University

For the first time, scientists from the German Cancer Research Center (DKFZ) and the National Center for Tumor Diseases (NCT) Heidelberg have characterised cancer cells that can initiate metastasis in the blood of breast cancer patients. These cells have properties of cancer stem cells and are characterised by three surface proteins. Patients with large numbers of these cells found in their blood show a rather unfavourable disease progression. The pattern of the three molecules may therefore be used as a biomarker for disease progression. The scientists plan to investigate whether the characteristic surface molecules may be used as targets for specific therapies for patients with advanced breast cancer.
Individual cancer cells that break away from the original tumour and circulate through the blood stream are considered responsible for the development of metastases. These dreaded secondary tumours are the main cause of cancer-related deaths. Circulating tumour cells (CTCs) detectable in a patient’s blood are associated with a poorer prognosis. However, up until now, experimental evidence was lacking as to whether ‘stem cells’ that lead to metastases can be found among CTCs.
‘We were convinced that only a very few of the various circulating tumour cells are capable of forming a secondary tumour in a different organ,’ says Prof. Andreas Trumpp, a stem cell expert. ‘Many patients do not develop metastases even though they have cancer cells circulating through their blood.’ Trumpp is head of DKFZ’s Division of Stem Cells and Cancer and director of the Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM) at DKFZ. ‘Metastasis is a complex process and cancer cells need to have very specific properties for it,’ he says. ‘Our hypothesis was that the characteristics of cancer stem cells, which are resistant to therapy and very mobile, are best suited.’

Irène Baccelli from Trumpp’s team developed a transplantation test for the experimental detection of metastasis-initiating cells. In collaboration with Prof. Andreas Schneeweiss from the National Center for Tumor Diseases (NCT) Heidelberg, along with colleagues from the Institute of Tumor Biology in Hamburg and the Institute of Pathology of Heidelberg University Hospitals, the researchers analysed the blood of more than 350 breast cancer patients. Using specific surface molecules, Baccelli isolated circulating tumour cells from the blood and directly transplanted them into the bone marrow of mice with defective immune systems. ‘Bone marrow is a perfect niche for tumour sells to colonise,’ Trumpp explains. After more than one hundred transplantations, metastases started forming in the bones, lungs and livers of some of the animals.

This proved that CTCs do contain metastasis stem cells – even though their frequency is apparently low. What characterises these cells? To define their molecular properties, the researchers analysed the surface molecules of the CTCs that had led to metastases after transplantation.

Three molecules characterise the metastasis stem cell
In a systematic screening process, Baccelli first isolated cells carrying a typical breast cancer stem cell protein (CD44) on their surface from the CTCs. This protein helps the cell to settle in bone marrow. Next, the researchers screened this cell population for specific surface markers which help the cells to survive in foreign tissue. These include, for example, a signalling molecule (CD47) that protects them from attacks by the immune system, and a surface receptor that enhances the cells’ migratory and invasive capabilities (MET).

Using a cell sorter, the researchers were then able to isolate CTCs which simultaneously exhibit all three characteristic molecules (CD44, CD47, MET). Another round of transplantation tests showed that these were in fact the cells from which the metastases originated.

Depending on the patient, cells exhibiting all three surface molecules (‘triple-positive’ cells) made up between 0.6 and 33 percent of all CTCs. ‘It is interesting that only cells with the stem cell marker CD44 carry the combination of the other two surface molecules,’ said Irène Baccelli. ‘It looks like the triple-positive cells are a specialized subtype of breast cancer stem cells circulating in the blood.’

Triple-positive cells as prognostic biomarkers

Are the triple-positive cells a more precise biomarker of breast cancer progression than the number of CTCs alone? In a small patient group, the researchers observed that as the disease advances, the number of triple-positive cells increases, but the total number of CTCs does not. In addition, patients with very high numbers of triple-positive cells had particularly high numbers of metastases and a much poorer prognosis than women in whom only a few metastasis-inducing cells were detected. ‘On the whole, triple-positive cells seem to have a substantially higher biological relevance for disease progression than previously studied CTCs,’ Andreas Schneeweiss explains. The researchers plan to confirm these new results in a large study.

Andreas Trumpp considers it good news that metastasis-initiating cells are characterised by the two proteins CD47 and MET. Therapeutic antibodies that target CD47 and inhibit its functions are already being developed. A substance inhibiting the activity of the MET receptor has already been approved and shows good effectiveness in treating a type of lung cancer. The substance may also help breast cancer patients with detectable metastasis-inducing cells. ‘The triple-positive cells we have found turn out to be not only a promising biomarker of disease progression in breast cancer but also a prospect for potential new therapeutic approaches for treating advanced breast cancer,’ says Andreas Trumpp. German Cancer Research Center

Cancer is typically thought to develop after genes gradually mutate over time, finally overwhelming the ability of a cell to control growth. But a new closer look at genomes in prostate cancer by an international team of researchers reveals that, in fact, genetic mutations occur in abrupt, periodic bursts, causing complex, large scale reshuffling of DNA driving the development of prostate cancer.
The scientists, led by researchers from Weill Cornell Medical College, the Broad Institute, Dana-Farber Cancer Institute and the University of Trento in Italy, dub this process ‘punctuated cancer evolution,’ akin to the theory of human evolution that states changes in a species occur in abrupt intervals. After discovering how DNA abnormalities arise in a highly interdependent manner, the researchers named these periodic disruptions in cancer cells that lead to complex genome restructuring ‘chromoplexy.’
‘We believe chromoplexy occurs in the majority of prostate cancers, and these DNA shuffling events appear to simultaneously inactivate genes that could help protect against cancer,’ says the study’s co-lead investigator Dr. Mark Rubin, who is director of the recently-established Institute for Precision Medicine at Weill Cornell Medical College and NewYork-Presbyterian Hospital/Weill Cornell Medical Center.
‘Knowing what actually happens over time to the genome in cancer may lead to more accurate diagnosis of disease and, hopefully, more effective treatment in the future,’ says Dr. Rubin, also the Homer T. Hirst III Professor of Oncology, professor of pathology and laboratory medicine and professor of pathology in urology at Weill Cornell and a pathologist at NewYork-Presbyterian/Weill Cornell. ‘Our findings represent a new way to think about cancer genomics as well as treatment in prostate and, potentially, other cancers.’
The discovery of ‘chromoplexy’ came after the research team worked collaboratively to sequence the entire genomes of 57 prostate tumours and compare those findings to sequences in matched normal tissue.
Co-lead investigator Dr. Levi Garraway, of the Broad Institute and Dana-Farber Cancer Institute, and his collaborators then tracked how genetic alterations accumulated during cancer development and progression. They used advanced computer techniques to identify periodic bursts of genetic derangements.
‘We have, for the first time, mapped the genetic landscape of prostate cancer as it changes over time,’ says Dr. Garraway, a senior associate member of the Broad Institute and associate professor at the Dana–Farber Cancer Institute and Harvard Medical School. ‘The complex genomic restructuring we discovered, which occurs at discrete times during tumour development, is a unique and important model of carcinogenesis which likely has relevance for other tumour types.’
Co-senior author Dr. Francesca Demichelis, assistant professor at the Centre for Integrative Biology at the University of Trento who also serves as adjunct assistant professor of computational biomedicine at Weill Cornell, worked with her collaborators to understand how widespread the DNA mutations and alterations seen in the tumours were across the cancer samples, and what that might mean in terms of cancer progression and, potentially, treatment. ‘Information about what alterations are common, and which aren’t, will most likely help guide us in terms of cancer drug use and patient response,’ says Dr. Demichelis.
The researchers also report that future targeted cancer therapy may depend on identifying complex sets of genetic mutations and rearrangements in each patient.
‘Every cancer patient may have individual patterns of genetic dysfunction that will need to be understood in order to provide precise treatment. Multiple drugs may be needed to shut down these genetic derangements,’ says Dr. Rubin. ‘Providing those tests now on every patient isn’t possible, but our study suggests that punctuated cancer evolution may occur to provide a subset of genes that offer a selective advantage for tumor growth. If that is true, we may be able to zero in on a limited number of genetic drivers responsible for an individual’s prostate cancer.’ Weill Cornell Medical College

One of 100,000 children is born with Menkes disease, a genetic disorder that affects the body’s ability to properly absorb copper from food and leads to neurodegeneration, seizures, impaired movement, stunted growth and, often, death before age 3. Now, a team of biochemistry researchers at the University of Missouri has published conclusive scientific evidence that the gene ATP7A is essential for the dietary absorption of the nutrient copper. Their work with laboratory mice also provides a greater understanding of how this gene impacts Menkes disease as scientists search for a treatment.

Humans cannot survive if their bodies are lacking the ATP7A gene, yet children can develop Menkes disease when the gene is mutated or missing. Previously, scientists did not have a good model to test the gene’s function or develop an understanding of the underlying causes of the disease symptoms. In his new study, Michael Petris, associate professor of biochemistry, was able to modify mice so that they were missing the ATP7A gene in certain areas of the body, specifically the intestinal track where nutrient absorption takes place.

‘These findings help us to understand where in the body the function of this gene is vital and how the loss of the gene in certain tissues can give rise to Menke’s disease,’ said Petris, who is a researcher in the Bond Life Sciences Center and holds an appointment in the Department of Nutrition and Exercise Physiology. ‘We want to continue to explore the underlying biology of Menke’s disease to determine where we should focus our research efforts in the future. If we know which organs or tissues are most responsible for transporting copper throughout the body, we can focus on making sure the gene is expressed in those areas. This disease is ideal for gene therapy down the road.’

Petris found that young mice missing the ATP7A gene in their intestinal cells were unable to absorb copper from food, resulting in an overall copper deficiency that mimics symptoms of Menkes disease in children. Petris says it’s vital to ensure that the developing newborns absorb enough copper during the neonatal period when the demand for the mineral is highest.

‘Copper is a little-appreciated but essential trace mineral in all body tissues,’ Petris said. ‘Cells cannot properly use oxygen without copper; it helps in the formation of red blood cells, and it helps keep the blood vessels, nerves, skin, immune system and bones healthy. Normally, people absorb enough copper through their food. However, in the bodies of those with Menkes disease, copper begins to accumulate at abnormally low levels in the liver and brain and at higher than normal levels in the kidney and intestinal lining.’

Newborn screening for this disorder is not routine, and early detection is infrequent because it can arise spontaneously in families, Petris said. Many times, the disease is not detected until the symptoms are noticed, and by that time, it can be too late for any aggressive treatments.

‘The clinical signs of Menkes disease are subtle in the beginning, so the disease is rarely treated early enough to make a significant difference,’ he said. ‘However, a single dose of copper injected into mice within a few days of birth restored normal growth and life expectancy. Early intervention was critical because treatment that began after symptoms developed wasn’t successful.’

Petris says that understanding the roles of copper in biology may have far-reaching health implications for the general population because copper underpins many facets of biology, including the growth of cancer tumours and the formation of toxic proteins in Alzheimer’s disease.

The development of these mice provides a novel experimental system in which to test treatments for patients with this disease. The early-stage results of this research are promising, but additional studies are needed. University of Missouri