Scientists have developed an ultra-sensitive test that should enable them to detect signs of a disease in its earliest stages.
The scientists, from Imperial College London and the University of Vigo, have created a test to detect particular molecules that indicate the presence of disease, even when these are in very low concentrations. There are already tests available for some diseases that look for such biomarkers using biological sensors or ’biosensors’. However, existing biosensors become less sensitive and predictable at detecting biomarkers when they are in very low concentrations, as occurs when a disease is in its early stages.
In this study, the researchers demonstrated that the new biosensor test can find a biomarker associated with prostate cancer, called Prostate Specific Antigen (PSA). However, the team say that the biosensor can be easily reconfigured to test for other diseases or viruses where the related biomarker is known.
Professor Molly Stevens, senior author of the study from the Departments of Materials and Bioengineering at Imperial College London, said: ‘It is vital to detect diseases at an early stage if we want people to have the best possible outcomes – diseases are usually easier to treat at this stage, and early diagnosis can give us the chance to halt a disease before symptoms worsen. However, for many diseases, using current technology to look for early signs of disease can be like finding the proverbial needle in a haystack. Our new test can actually find that needle. We only looked at the biomarker for one disease in this study, but we’re confident that the test can be adapted to identify many other diseases at an early stage.’
The team demonstrated the effectiveness of their biosensor by testing PSA biomarker samples in solutions containing a complex mixture of blood derived serum proteins. Monitoring the levels of PSA at ultralow concentrations can be crucial in the early diagnosis of the reoccurrence of prostate cancer, but classic detection approaches are not sensitive enough to carry out this analysis with a high degree of accuracy. The new test could enable more reliable diagnosis, but more research will need to be done to further explore its potential.
In their study, the team detected PSA at 0.000000000000000001 grams per millilitre, which is at the limits of current biosensor performance. By comparison, an existing test called an Enzyme-Linked Immunosorbent Assay (ELISA) test can detect PSA at 0.000000001 grams per millilitre, which is nine orders of magnitude more concentrated.
The biosensors used in today’s study consist of nanoscopic-sized gold stars floating in a solution containing other blood derived proteins. Attached to the surface of these gold stars are antibodies, which latch onto PSA when they detect it in a sample. A secondary antibody, which has an enzyme called glucose oxidase attached to it, recognises the PSA and creates a distinctive silver crystal coating on the gold stars, which is more apparent when the PSA biomarkers are in low concentrations. This silver coating acts like a signal that PSA is present, and it can be easily detected by scientists using optical microscopes.
The next stage of the research will see the team carrying out further clinical testing to assess the efficacy of the biosensor in detecting a range of different biomarkers associated with conditions such as HIV and other infections. They will also explore ways of commercialising their product. Imperial College London

Researchers at the IMIM (Institut de Recerca Hospital del Mar) have proven that the absence of the 14-3-3 protein sigma in breast cancer cells is directly associated with these cells’ capacity to activate the signalling of a protein complex called NF-kB, which is related to tumour progression. The activation of NF-kB in tumours was also identified as the best indicator for relapse in breast cancer patients, compared to other parameters currently used, such as the presence of affected ganglions or the tumour’s size and degree. The investigators have also described a group of genes that are activated in breast cancer cells and that are also associated with a poor prognosis in other types of tumours.
Previous studies had detected that the 14-3-3 protein sigma was not present in the tumours of many breast cancer patients. They have now discovered that ‘the lack of this protein does not in itself establish a prognosis factor for these types of cancer, although the NF-kB complex is an essential requirement for it to remain active chronically, as it is associated with tumour invasion and metastasis or, stated differently, the progression of the tumour’, comments Lluís Espinosa, study co-ordinator and researcher in the IMIM stem cells and cancer research group.
Breast cancer is most common among women in Western countries and relapse and metastasis are the fatal consequences of this disease. Identifying the mechanisms involved in the survival of breast cancer cells and their ability to colonise other tissues are crucial issues for improving treatment. With the participation of some 100 patients, this study analysed the possible usefulness of determining the lack of the 14-3-3 sigma and/or the activation of NF-kB in tumour cells as a factor in prognosis and diagnosis, as well as for future clinical and therapeutic applications.
The results obtained from this project have opened up new roads of investigation that will have to centre on identifying the pharmaceuticals that induce the expression of the 14-3-3 protein sigma in breast tumours and characterise their effect on tumour cells. They also hope to define which genes activated by the NF-kB complex are important for tumour progression in this group of patients and to study their potential as possible therapeutic targets.
According to Espinosa ‘This opens up the possibility of researching and employing specific therapeutic strategies for this concrete group of patients who, in principle, have bad prognoses and an especially high risk of relapse’. IMIM (Hospital del Mar Research Institute)

There is little argument among experts that autism spectrum disorders (ASD), complex developmental disabilities that vary widely in their severity, are caused by both genetic and environmental factors. Advances in genome sequencing now permit scientists to uncover specific mutations in DNA that are associated with ASD at unprecedented resolution. Such data are vital to understanding the genetic basis of the disorder.

A new study co-authored by UCLA researchers has led to a better understanding of the genetic contribution to autism using this new approach. By comparing siblings with and without ASD, the researchers have discovered a single instance in the affected siblings in which two independent mutations disrupt a gene called SCN2A.

Dr. Daniel Geschwind, a UCLA professor of neurology and psychiatry, and colleagues from Yale University, Carnegie Mellon University and the University of Pittsburgh completed ‘whole-exome sequencing’ of 238 parent-child quartets. A quartet is defined as two parents and one child without ASD and one child with ASD.

Instead of the time-consuming process of searching the entire genome of an individual, the researchers turned to the newer technology of whole-exome sequencing, which searches only the protein-coding regions of the genome to pinpoint the mutation that causes a particular disorder.

The researchers compared mutation rates between unaffected individuals and those with ASD within a family, then compared the ASD mutations to the entire cohort. They found multiple variations between the unaffected and affected groups. Specifically, among a total of 279 coding mutations, they identified a single instance in individual children with ASD — and not in siblings — in which two independent mutations disrupt the gene SCN2A. That same mutation was found in all the unrelated children with ASD, confirming its importance.

In addition, the researchers found many other genes with similar mutations occurring only once — these also make promising new candidates for autism susceptibility. Finally, they were able to estimate that there are likely about 1,000 or more genes that contribute to autism risk.

‘This work demonstrates that autism, in most cases, has a contribution from several genes, as the average risk imparted by one mutation is typically not sufficient,’ said Geschwind, who holds UCLA’s Gordon and Virginia MacDonald Distinguished Chair in Human Genetics and directs the UCLA Center for Autism Research and Treatment. ‘Overall, these results substantially clarify the genomic architecture of ASD, and this is an important step in attempting to better understand the genetic basis of these disorders.’ UCLA

A study of almost 3,800 pregnancies has provided the most accurate and direct evidence to date that malaria infection reduces early foetal growth. Low birth weight is the most important risk factor for neonatal mortality in developing countries. The research highlights the importance of preventing malaria in pregnancy.
According to the World Malaria Report 2011, malaria killed an estimated 655,000 people in 2010. The disease is one of the most common parasitic infections to affect pregnancy. Previous studies have suggested that infection with both P. falciparum and P. vivax malaria during pregnancy reduces birth weight whether or not maternal symptoms are present. However, these studies have been hampered by difficulties in estimating gestational age accurately and diagnosing malaria infection in early pregnancy.
Now researchers at the Shoklo Malaria Research Unit on the border of Thailand and Myanmar, part of the Wellcome Trust-Mahidol University-Oxford University Tropical Medicine Research Programme, have used ultrasound scans to provide the first direct evidence of the effect of malaria on foetal growth in pregnancy. Antenatal ultrasound, which is essential for dating pregnancy accurately, is becoming more widely available in developing countries. The technology also allows the diameter of the foetus’s head to be measured. For infections that occur in early pregnancy, the researchers believe that the size of the head may be the most appropriate indicator of growth restriction.
The ultrasound scans revealed that the diameter of the average foetus’s head was significantly smaller when malaria infection occurred in the first half of pregnancy when compared to pregnancies unaffected by malaria. On average, at the mid-pregnancy ultrasound scan the foetuses’ heads were 2% smaller when affected by malaria. Even a single infection of treated P. falciparum or P. vivax malaria was associated with reduced foetal head diameter, irrespective of whether the woman had shown symptoms or not.
However, although a single early detected and well-treated malaria episode had an effect on foetal head size at mid-trimester, this was not seen at delivery, suggesting that early treatment with effective drugs may allow for growth to recover later in pregnancy.
Strategies to prevent malaria in pregnancy have focused on the second half of pregnancy, when most of the foetal weight gain takes place, but this works suggests that focus should be on the first trimester too. Pregnant woman need to be educated about the risks of malaria in pregnancy and where possible in areas of high risk, offered preventative medication from early pregnancy onwards.

Researchers studying the genetic roots of the most common malignant childhood brain tumour have discovered missteps in three of the four subtypes of the cancer that involve genes already targeted for drug development.
The most significant gene alterations are linked to subtypes of medulloblastoma that currently have the best and worst prognosis. They were among 41 genes associated for the first time to medulloblastoma by the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project.
‘This study provides new direction for understanding what drives these tumours and uncovers totally unexpected new drug targets. There are drugs already in development against these targets aimed at treating adult cancers and other diseases,’ said Richard Gilbertson, M.D., Ph.D., St. Jude Comprehensive Cancer Center director. Gilbertson and Jinghui Zhang, Ph.D., an associate member of the St. Jude Department of Computational Biology, are the study’s corresponding authors.
The results mark progress toward more targeted therapies against medulloblastoma and other cancers. While better use of existing drugs and improved supportive care have helped push long-term survival rates for childhood cancer to about 80 percent, drug development efforts have largely stalled for more than two decades, particularly against pediatric brain tumours.
‘This study is a great example of the way whole-genome sequencing of cancer patients allows us to dig deep into the biology of certain tumors and catch a glimpse of their Achilles heel,’ said co-author Richard K. Wilson, Ph.D., director of The Genome Institute at Washington University School of Medicine in St. Louis. ‘These results help us better understand the disease and, as a result, we will be able to more effectively diagnose and treat these kids.’
This study involved sequencing the complete normal and cancer genomes of 37 young patients with medulloblastoma, making it the largest such effort to date involving the cancer. Researchers then checked tumours from an additional 56 patients for the same alterations.
The findings are part of the Pediatric Cancer Genome Project, which launched in 2010 as a three-year effort to decipher the complete normal and tumour genomes of 600 young cancer patients with some of the most challenging tumours. The endeavour has already yielded important clues into the origin, spread and treatment response in childhood cancers of the blood, brain, eye and nervous system.
Medulloblastoma is diagnosed in about 400 U.S. children and adolescents annually. Their outcome varies widely based on the subtype they have. While nearly all patients with the wingless (WNT) subtype survive, just 60 percent of those with subtype 3 medulloblastoma are alive three years after diagnosis. WNT medulloblastoma is named for the pathway disrupted in the tumor subtype.
This study found a high percentage of patients with WNT-subtype medulloblastoma had mutations in the DDX3X gene. The investigators found evidence that mutated DDX3X is required to sustain the brain cells where WNT subtype tumours develop. The research also found evidence linking alterations in other genes, including CDH1 and PIK3CA, to the development and spread of the WNT subtype. ‘It is particularly exciting that these genes, or the pathways in which they work, are already the focus of drug development efforts. This opens up the possibility of using these drugs to treat medulloblastoma in new ways,’ said Giles Robinson, M.D., St. Jude Department of Oncology research associate and one of the study’s first authors.
Investigators demonstrated that subtype three and four medulloblastoma often had alterations in genes that impact cell maturation. The genes carry instructions for proteins that add or remove the chemical group methyl to the H3K27 protein. H3K27 is part of the chromatin structure that packages DNA to fit inside cells. That packaging helps determine if genes are switched on or off. The addition of methyl to H3K27 permits less specialised cells to keep dividing and blocks activity of genes that would prompt cells to stop dividing, differentiate and take on more specialised roles.
Some subgroup 3 and 4 tumours were characterised by a gain in EZH2, which adds methyl to H3K27. EZH2 is also associated with adult cancers and the focus of ongoing drug development. St. Jude has begun screening those and other compounds for evidence of effectiveness against medulloblastoma.
In other subtype 3 and 4 tumours a different gene, KDM6A, was inactivated by mutations. KDM6A works to remove methyl groups from H3K27, thus eliminating this gene’s function could keep cells in an immature dividing state. The results suggest the genes possibly work together to promote medulloblastoma development.
The EZH2 and KDM6A alterations were found only in the subgroup three and four tumours, which also had higher levels of H3K27 methylation than other medulloblastoma subtypes. ‘With this research we have ‘lifted the lid’ on the most aggressive and challenging form of medulloblastoma, subtype 3, which was really a black box in terms of our understanding, and revealed a major driver of the disease,’ Gilbertson said.
The findings add to mounting evidence from the Pediatric Cancer Genome Project that epigenetic changes play a pivotal role in fueling childhood cancer. Epigenetic mechanisms can serve as on-off switches, altering gene activity without changing the makeup of the gene. Such changes can lead to the unlimited cell growth of cancer. St. Jude Children’s Research Hospital