Many diseases, including cancers, leave genetic clues in the body just as criminals leave DNA at the scene of a crime. But tools to detect the DNA-like sickness clues known as miRNAs, tend to be slow and expensive. Now a chemist and a biologist from University of Copenhagen have invented a method that promises to shave days off the lab work done to reveal diseases, using cheap methods and easy to use analytical apparatuses.
Chemistry researcher Tom Vosch and plant molecular biologist Seong Wook Yang invented a DNA sensor, coupling genetic material to a luminous molecule which goes dark only in the presence of a specific target. Details on their invention,
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It’s an unusually quick and elegant method for screening
‘We invented a probe that emits light only as long as the sample is clean. That is an unusually elegant and easy way to screen for a particular genetic target’, says Vosch of the Department of Chemistry’s Nano Science Centre.
You could say that the inventors took their cue from crime detection. In murder cases police technicians use DNA to identify the killer. Similarly Individuals with disease are likely to have a unique miRNA profile. Any disease that is attacking a patient leaves this genetic clue all over the victim. And because the profiles of miRNAs vary by type of cancer, finding it proves beyond a reasonable doubt what made the patient sick.
The new detection method exploits a natural quality of genetic material. A single DNA strand is made up of molecules, so called bases, ordered in a unique combination. When two strands join to form their famous double helix, they do so by sticking to complementary copies of themselves. Likewise strands tailored to match particular miRNAs will stick to the real thing with uncanny precision. But detecting this union of the strands was only made possible when Vosch and Yang paired their skills.
Tom Vosch is specialised in studying molecules that light up. Seong Wook Yang is specialised in miRNA. Together they figured out how to attach the light emitting molecules to DNA sensors for miRNA detection. Vosch and Yang discovered, that when these luminous DNA-strands stick with microRNA-strands, their light is snuffed out, giving a very visible indication that the target miRNA is present in the sample. In other words: When the light goes out, the killer is in the house.
Vosch and Yang tested their Silver Nano Cluster DNA probes with eight different types of genetic material and found that they work outright with six of them. But more importantly, they figured out how to fix the ones that didn’t. This indicates that their method will work in the detection of almost all types of miRNAs, also in all likelihood for cancer related miRNAs. The most widespread current miRNA detection method requires some 48 hours of lab work from raw samples. The new method can do the same job of detection within a maximum of 6 hours. University of Copenhagen

Although placebos have played a critical role in medicine and clinical research for more than 70 years, it has been a mystery why these inactive treatments help to alleviate symptoms in some patients – and not others. Now researchers have for the first time identified genetic differences between placebo responders and non-responders, providing an important new clue to what has come to be known as ‘the placebo effect.’
Led by investigators at Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School (HMS), the new findings demonstrate that genetic differences that account for variations in the brain’s dopamine levels help to determine the extent of a person’s placebo response, a discovery that not only has important implications for patient care, but could also prove to be of significant benefit to researchers in designing and conducting clinical trials to help determine a drug’s effectiveness.
‘There has been increasing evidence that the neurotransmitter dopamine is activated when people anticipate and respond to placebos, ‘ explains the study’s first author Kathryn Hall, PhD, a research fellow in the Division of General Medicine and Primary Care and member of the Program in Placebo Studies and Therapeutic Encounter (PiPS) at BIDMC. ‘With this new research, we may now be able to use a person’s genetic makeup to predict whether or not they will respond to a placebo.’
The placebo effect occurs when patients show improvement from treatments that contain no active ingredients. For investigators conducting clinical trials of new drugs — which require that new treatments be tested against a placebo control to determine their efficacy– placebo responses can pose a particularly difficult challenge, requiring investigators to recruit additional patients in order to acquire statistically significant data, and substantially adding to the overall cost of the trial.
Because dopamine is known to be important to both reward and pain, the investigators began their search for a genetic placebo marker in the dopamine pathway. Their focus soon turned to the catechol-O-methyltransferase (COMT) gene.
‘COMT made for an excellent candidate because it’s been implicated in the cause and treatment of many conditions, including pain and Parkinson’s disease,’ says Hall. ‘It’s also been found in behavioural genetic models of reward responsiveness and confirmation bias, the tendency to confirm new information based on your beliefs.’
Polymorphisms are gene variations, and in the case of the COMT val158met polymorphism, the changes in the COMT gene result in people having either two copies of the methionine (met) allele, two copies of the valine (val) allele, or one copy of each.
‘People with two copies of met, the ‘met/mets,’ have three to four times more dopamine available in their prefrontal cortex [the brain area associated with cognition, personality expression, decision making and social behaviour] than the people with two copies of val,’ explains Hall. The scientists hypothesised that if dopamine was indeed involved in the placebo response, they would see a difference between how met/met, val/val and met/val genotypes responded to placebo treatments, with the met/met individuals showing a higher response.
To test this hypothesis, the researchers took advantage of a unique opportunity, revisiting a 2008 clinical trial led by PiPS Director Ted Kaptchuk, designed to study the placebo effect in patients with irritable bowel syndrome (IBS). ‘In our original work, IBS patients were assigned to one of three treatment arms and we explored the placebo response in relation to the patient-provider experience and the clinical environment in which the placebo is administered,’ explains Kaptchuk, Associate Professor of Medicine at HMS and the study’s senior author. The treatment conditions included either being ‘waitlisted’ and receiving no treatment, receiving placebo acupuncture in a business-like clinical manner, or receiving placebo acupuncture treatment from a warm supportive health care provider.
Armed with this original data, the scientists genotyped blood samples from patients from the earlier study, using a statistical method known as regression analysis to analyse the effects of a person’s genotype and the type of treatment received. ‘Our regression analysis found that as the copies of met increased, placebo responses increased in a linear fashion, presumably because more dopamine was available,’ Hall explains. The findings showed that among the IBS patients who had been in the waitlist treatment arm there was no difference in treatment responses between met/met, val/val and met/val genotypes as determined by the IBS-Symptom Severity Scale and Adequate Relief. Among those in the group that received a placebo administered in a businesslike manner, the met/met genotypes showed a small improvement over their val/val and met/val counterparts.
But, says Hall, among the individuals who had received placebo treatment from the warm supportive health care providers, there was a striking difference: the ‘met/mets’ demonstrated a six-fold greater improvement in their IBS symptoms relative to the ‘val/vals.’
‘These findings suggest that it is possible that met/met is a genetic marker for the placebo response and val/val is a marker for non-response,’ says Hall. ‘In addition, our findings underscore differences in placebo response based on the patient’s experience of the clinical environment. In the case of the met/met individuals, you can really see the advantage of a positive doctor-patient relationship. Conversely, our findings suggest that the val/val patients are less influenced by placebo treatment and this sheds light on a clinical challenge faced by many health care providers, whose empathic care helps some people, but makes no difference to others.’ Beth Israel Deaconess Medical Center

Blood hormone tests can predict a woman’s risk for developing postmenopausal breast cancer for up to 20 years, according to a study led by Xuehong Zhang, MD, Channing Division of Network Medicine, Brigham and Women’s Hospital (BWH) Department of Medicine.
Using data from the Nurses’ Health Study, Zhang , Susan Hankinson, ScD, Channing Division of Network Medicine, BWH Department of Medicine and colleagues analysed 796 patients with postmenopausal breast cancer who had not received hormone therapy.
They conducted blood hormone tests at two time points: between 1989 and 1990 and between 2000 and 2002. Researchers matched each patient with two controls who were not diagnosed with breast cancer.
‘We found that a single hormone level was associated with breast cancer risk for at least 16 to 20 years among postmenopausal women not using postmenopausal hormones,’ said Zhang. ‘We, and others, are now evaluating if the addition of hormone levels to current risk prediction models can substantially improve our ability to identify high-risk women who would benefit from enhanced screening or chemoprevention-if so, the current data suggest that hormone levels would not need to be measured in the clinic more than once every 10, or possibly 20, years.’
Women with hormone levels in the highest 25 percent for estradiol, testosterone and DHEAS had a 50 percent to 107 percent greater chance for developing breast cancer compared with women in the lowest 25 percent. Relative risks for developing breast cancer were similar at one to 10 years vs. 11 to 20 years (also 16 to 20 years) after blood collection.
Researchers also investigated whether these higher levels were more closely linked to hormone-receptor positive breast cancers and if they predicted risk regardless of tumour aggressiveness.
In the first case, they found that elevated levels of estradiol increase a woman’s risk for hormone receptor-positive breast cancer, specifically oestrogen receptor-positive (ER+) and progesterone receptor-positive (PR+) tumours.
In general, increased hormone levels, except for DHEAS, tracked closely with increased risk for receptor-positive breast cancer. Data on receptor-negative cancers were inconclusive and need additional, large studies.
Significantly, elevated hormone levels were also associated with aggressive breast cancer, which the study defined as recurrent or fatal cancer.
‘The relationship was comparable or possibly stronger for recurrent and fatal breast cancer than it was for overall breast cancer risk although these results were based on relative small numbers of participants,’ said Zhang.
Researchers also confirmed the protective effect of sex hormone-binding globulin (SHBG), which seems to negate the cancer-causing effects of certain hormones. Women in the highest 25 percent of SHBG levels had a 30 percent lower risk for breast cancer compared with women in the lowest 25 percent for SHBG levels.
Zhang noted that the study had low case numbers for several cancer subgroups, including HER2, triple-negative and basal-like breast cancers. More research is necessary to determine the relationship between elevated hormone levels and these important breast cancer groups. Brigham and Women’s Hospital

High blood cholesterol, a serious hereditary disease, is far more common than previously recognised and not treated sufficiently. This is shown in new research from the University of Copenhagen and Herlev Hospital.
A group of scientists from the University of Copenhagen has recently shown that far more Danes than expected suffer from high blood cholesterol. The study also shows that the serious hereditary disease is not treated effectively.
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Dr Børge Nordestgaard, clinical professor at the Faculty of Health and Medical Sciences, University of Copenhagen, and senior physician at Herlev Hospital is surprised at the findings.

‘We have now investigated 69,000 Danes to see how many have hereditary high blood cholesterol and have undergone sufficient treatment for the disease. We can see that out of 137 people in Denmark 1 has hereditary high blood cholesterol. That corresponds to 40,000 people with the disease in the Danish population of 5.5 million,’ states Børge Nordestgaard.
The study also shows that very few families and individuals with this serious disease have been identified and treated effectively with statins, a type of drug for treating high cholesterol. In Holland, by comparison, early detection of patients and their families has almost eliminated the increased risk of coronary disease, because effective treatment to reduce cholesterol levels was implemented quickly.
‘Never before anywhere in the world has the ordinary population been studied to see how many people and families with hereditary high blood cholesterol there actually are. It was previously assumed that only 1 out of every 500 people had it, so it was quite a surprise for us suddenly to find 3 ½ times as many people with this serious disease. At the same time, it was also startling to discover that a disease that can easily be prevented by treatment to reduce blood cholesterol has not been treated sufficiently,’ says Dr. Marianne Benn, senior physician, also from the University of Copenhagen.
Of those Danes shown to have hereditary high blood cholesterol, one-third already had coronary disease, and only half were being treated with statins. People with hereditary high blood cholesterol not undergoing treatment with statins have a 1,200 per cent higher risk of developing coronary disease. Even more surprising: people with hereditary high blood cholesterol who are being treated with statins still have a 900 per cent higher risk of incurring coronary disease. In total, the study documents massive underdiagnosis and undertreatment of these high-risk individuals and their families in Denmark.
Researchers used the internationally recognised Dutch criteria for hereditary high blood cholesterol based on very high blood cholesterol level and early-onset coronary disease in the test person and his/her family, and on the finding of mutations that directly lead to hereditary high blood cholesterol. The increased risks appear even when figures are adjusted for several other factors that also contribute to coronary disease. Researchers use this method to eliminate biased results.
These new figures mean that there are about 50 million people worldwide with hereditary high blood cholesterol. Today most of these people are undiagnosed, untreated and therefore at serious risk of dying early from coronary disease. According to the World Health Organization (WHO), coronary disease is the most common cause of death in adults worldwide. WHO estimates that at least 17 million people die from coronary disease annually. A considerable number of these deaths are due to hereditary high blood cholesterol.
‘We have known for decades about high blood cholesterol and how to prevent it. Nonetheless the disease is massively underdiagnosed and undertreated. This means that many people unnecessarily develop early-onset coronary disease and die far earlier than normal,’ says Børge Nordestgaard. University of Copenhagen

Measuring blood levels of high-sensitive C-reactive protein, an important marker of inflammation, in apparently cancer-free men could potentially help identify those at increased risk for death from cancer, in particular lung cancer.
‘Inflammation has been linked to the initiation and progression of several types of cancer, as well as to the progression of atherosclerosis and cardiovascular disease,’ said Minseon Park, M.D., Ph.D., M.P.H., assistant professor in the Department of Family Medicine at the Center for Health Promotion at Seoul National University Hospital in South Korea. ‘We wanted to determine whether there was a relationship between a well-established marker of inflammation, high-sensitive C-reactive protein (hs-CRP), and death from all causes, death from cancer or death from a site-specific cancer in Koreans.’
Park and colleagues retrospectively analysed data from 33,556 individuals who had completed medical check-ups, answered questions on cancer-related behavioural factors (like smoking status and exercise habits) and had been screened for blood hs-CRP at the health-screening centre at Seoul National University Hospital between May 1995 and December 2006. During an average follow-up of 9.4 years, 1,054 deaths from all causes and 506 deaths from cancer were recorded.
When the researchers adjusted for several variables, including age, diabetes, smoking status and exercise habits, men with the highest level of hs-CRP in their blood (3 mg per liter or more) were 38 percent more likely to have died from any cause compared with men with the lowest hs-CRP level (1 mg per liter or less). They were also 61 percent more likely to have died from cancer.
For women, after adjusting for a number of variables, no statistically significant association was observed for hs-CRP level and death from any cause or death from cancer.
Through analysis of associations between hs-CRP levels and site-specific cancers, the researchers found that a significant relationship existed only for lung cancer. After adjusting for multiple variables, individuals with the highest hs-CRP level were more than twice as likely to die from lung cancer compared with those with the lowest hs-CRP level.
The association between hs-CRP levels and all-cause mortality and cancer mortality was stronger in lean individuals compared with those who were overweight.
‘This was surprising,’ said Park. ‘Because obesity is a major risk factor for chronic diseases like cancer, physicians and the mass media often recommend eating less and exercising more. While an important public health message, some people are too concerned with these recommendations and they eat fewer calories than their body actually needs. It is important that we eat enough to meet the metabolic demands of our body to make sure our organs function adequately for a healthy life.’ EurekAlert