Recently, Dr. Cheryle Séguin, a musculoskeletal researcher at the Schulich School of Medicine & Dentistry, Western University who studies spinal disc development, made a scientific breakthrough that unintentionally provided the missing link researchers needed to study the genesis of chordoma
After years of work, Dr. Séguin and her colleagues succeeded in developing a one-of-a-kind genetically engineered mouse that enables researchers to observe and manipulate an embryonic tissue called the notochord. The notochord is important because during development it gives rise to the intervertebral disc, the degeneration of which is the primary cause of back pain afflicting hundreds of millions of people worldwide. In addition to forming the discs, some notochordal cells get lodged inside the developing vertebrae, and, in about 1 in 5 people, these notochordal cells form small benign tumours inside the spine. Occasionally, these benign notochordal cell tumours turn malignant and become a cancer known as chordoma.
Little is known about what causes notochordal cells to turn into chordoma, but now Dr. Séguin’s mouse makes it possible to study that transformation. To do so, Dr. Séguin needs to isolate notochordal cells from her mouse and turn them into a cell line – a constantly dividing family of cells grown in a petri-dish. Creating a notochordal cell line will give scientists a blank slate upon which to introduce genetic changes to see which cellular pathways are activating causing the cells to become cancerous. This could shed light on the cause of chordoma, and, in turn, could point to potential therapies that address the root cause of chordoma.
The Chordoma Foundation is pleased to award Dr. Séguin a $25,000 seed grant to support her attempts to develop the world’s first notochordal cell line. This grant was made possible by funds raised through the fourth annual Purple Aster Concert, an annual music event in Calgary, Canada, held in memory of chordoma patient Alison Laird. The concert is organized by Alison’s husband, Ian, and friend, Carolyn Harley. Chordoma Foundation board member, Dr. Ed Les, also of Calgary, matched donations by concertgoers to fully sponsor the grant. Schulich School of Medicine & Dentistry

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

An international team of researchers from 23 institutions across three continents has identified two genetic factors that are strongly associated with the most common form of non-syndromic craniosynostosis — premature closure of the bony plates of the skull. The team of geneticists, paediatricians, surgeons and epidemiologists includes Joan Richtsmeier, professor of anthropology at Penn State, and Yann Heuzé, a post-doc in the Richtsmeier lab.
During foetal and early childhood development, the skull is made of separate bony plates that allow for growth of the head. The borders between the plates do not normally fuse completely until a child is about two years old, leaving temporary ‘soft spots’ at the intersection of the seams.
If the bones fuse too early — the condition called craniosynostosis — a child will develop an abnormally shaped head. Left untreated the disorder can cause learning disabilities and other complications due to brain compression, such as neurologic and visual problems. Typically, craniosynostosis requires extensive neurosurgical correction.
About 20 percent of craniosynostosis cases previously have been linked to a number of different genetic syndromes, the researchers note, but the vast majority of cases (not associated with a syndrome involving other birth defects) arise without any known family history or cause. The most common form of non-syndromic craniosynostosis — affecting about 1 in 5,000 newborns — involves the sagittal suture, the main seam that runs down the centre of the top of the skull. These cases were the subject of the investigation.
Although the condition has long been thought to be partially determined by genes, since it is three times more common in boys than in girls, and identical twins are much more likely to both be affected than non-identical twins, the exact basis was unclear.
To help determine the cause, the researchers conducted the first genome-wide association study for the disorder, which involves scanning the entire genome of a group of people with craniosynostosis and comparing it to a control group of people without it. The study searched for single nucleotide polymorphisms (SNPs) that are associated with craniosynostosis. SNPs are DNA sequence variations in which a single nucleotide differs from the usual one at that position. There are some 3 billion nucleotides, the basic building blocks of DNA, in the human genome.
The study first evaluated the DNA, which was extracted from whole blood or oral samples, of 201 cases and both of their parents, who did not have the condition. After reviewing the morphological and ethnic details of each case, the researchers restricted their final analysis to a group of 130 non-Hispanic white case-parent trios. This approach reduced the genetic variability inherent to individuals from different ethnicities and the potential of mixing of patients with other diseases. Their results identified very strong associations to SNPs in two areas of the genome, coding for bone morphogenetic protein 2 (BMP2) and Bardet-Biedl syndrome 9 protein (BBS9). Both proteins are known to play a role in skeletal development.
Richtsmeier studies the processes of growth and development that translate genetic information into tissues of specific shapes and sizes, using computed tomography scans of patients with craniofacial diseases and animal models for those same conditions. Heuzé analysed the computed tomography data of cases in this genetic analysis, both qualitatively to establish the degree of suture closure and quantitatively to estimate the magnitude of dysmorphology, to guarantee that the individuals whose genes were analysed in the study showed physical traits of the disease and were not mixing the sample with outlier cases.
The findings were replicated in another population of 172 cases of children with the condition and 548 unrelated controls. The extensive international collaboration came about because of the desire to include as many cases as possible worldwide to strengthen the findings.
‘Our results provide strong evidence that non-syndromic sagittal craniosynostosis has a major genetic component and identifies where the problem is likely to originate,’ said Simeon Boyadjiev, a researcher affiliated with the University of California Davis MIND Institute. ‘The genetic changes we discovered could provide important clues for explaining how craniosynostosis occurs. This will be a critical first step in determining how it might be prevented.’
He added that the genetic differences do not fully explain the development of the condition and that other genes and environmental factors are also likely important. Further research is planned. Penn State

A research team from King’s College London and the University of Exeter Medical School has identified how a genetic mutation acts during the development of nerves responsible for controlling eye muscles, resulting in movement disorders such as Duane Syndrome, a form of squint.
The findings could provide the key to reversing the condition and unlocking the causes of movement disorders in other parts of the body.
As nerves develop in the womb they respond to signals that tell them in which direction to grow. Some signals encourage them to grow to a particular part of the body, while other signals tell them to avoid certain areas.
When the system works as it should, the right type of nerve grows to the appropriate part of the body.
The surface of growing nerves includes identification receptors that respond to signals from secreted proteins. The protein mutated in Duane Syndrome acts as a switch that weighs up incoming signals from the receptors – in this way the nerve knows whether it must grow towards a part of the body or be repulsed away.
In conditions such as Duane Syndrome, the signalling breaks down and the nerve cells are unable to distinguish between a signal of attraction or repulsion. As a result, the nerves that control eye movements grow to the wrong muscles causing limited or complete loss of eye movement. If not corrected surgically, this can lead to partial blindness in later life.
This recent research has provided new insights into how this ‘switch signal’ system works and how it has failed in cases of Duane Syndrome, causing the ‘wiring up’ of the wrong muscle or ‘overshooting’ of nerve development past the correct muscle.
The findings are likely to lead to further study which will identify how the ‘switch signal’ mechanism could be harnessed to selectively change nerve cell development behaviour, how the protein could be targeted to encourage damaged cells to re-grow, and how the ‘switch’ could be manipulated to reverse damage. EurekAlert