JUNE 2019 - Issue No.5
ISSN 7901-2398 innovations.kaimrc.med.sa
E-SKIN, THE NE X T PROS THE TICS FRONTIER NE W E L E C T RONIC S T R E T C H A BL E S E N S OR S C A N HE L P A L E R T BUR N V IC T IM S A G A IN S T D A NG E R S P. 3 0
PUT TING SAUDI A R A BI A ON THE CLINICA L TRI A L M A P K A IMRC ’ S NE W INI T I AT I V E W IL L K IC K S TA R T S A UDI A R A BI A’ S C L INIC A L T R I A L S E C ONOM Y P. 4 0
A BITTERSWEET PANDEMIC R E S E A RCHE R S TA K E A CL O S E R L OOK AT T HE A R R AY OF CHRONIC DI S E A S E S C A U S E D B Y UNHE A LT H Y L IF E S T Y L E S P.8, 18 & 6 4
Shared Enabling Platforms Shared enabling platforms is a key element to create a culture of cooperation. This approach is deeply engraved in KAIMRC to encourage collaborative environment between KAIMRC scientists and others to accelerate research outcomes and outputs. The Cord Blood Bank (CBB) at KAIMRC is a national non-profit project, responsible for recruiting, processing, testing, cryopreserving, storing, thawing and infusing cord blood units that will be used for patients in need of cord blood stem cell transplantation. The CBB activities are carried out within a quality control system up to international standards.
kaimrc-cbb@ngha.med.sa
TABLE OF CONTENTS
P.8 TRIMMING THE STOMACH LINING TO FIGHT FAT
P.10 BREAKTHROUGH IN BONE MARROW MAPPING
Research suggests that targeting the stomach lining may alleviate obesity.
New 3D imaging shows how cells, tissues and proteins are distributed within bone marrow.
FEATURE
P.11 A VITAL TEST FOR SPINAL MUSCULAR ATROPHY
P.12 CARDIOVASCULAR HEALTH: THE POWER OF MACHINE LEARNING
P.14 A YEAR OF BIOMEDICINE BREAKTHROUGHS
A new chip-based sensor could detect and monitor spinal muscular atrophy faster and more cheaply than current methods.
Machine learning accurately predicts the association between cardio-respiratory fitness and mortality.
The latest global innovations in the study of disease.
P.18 DANGEROUS TRENDS IN WORLDWIDE CHILDHOOD OBESITY
P.20 PROFILING THE EVOLUTION OF BREAST CANCER CELLS
There are more underweight than obese children in the world, but the balance could change in just five years.
Genetic profiling of breast cancer metastases provides insight that could help improve treatment.
innovations.kaimrc.med.sa
Issue No.5
3
TABLE OF CONTENTS
P.21 OBESITY AND DIABETES: HEADING FOR THE FAST BURN
P.22 MULTIPLE SCLEROSIS: AN EXERCISE IN BRAIN PROTECTION
Incorporating periods of fasting into diets shows potential as a means of halting the progression of metabolic diseases.
Exercise for people with multiple sclerosis protects against degeneration and improves physical function.
P.24 HEART DISEASE: LINK WITH AIR POLLUTION SPIKES IN CHINA
P.26 THE PSYCHOLOGICAL CHALLENGES OF EPILEPSY
A study covering 26 large cities in China links short-term exposure to air pollution with heart failure.
A common form of epilepsy is associated with emotional and behavioural problems in children.
FEATURE
P.28 PAYING HEED TO CHEST PAIN
Even without serious artery blockage, chest pain is often a harbinger of deadly heart disease.
4
June 2019
P.30 E-SKIN, THE NEXT PROSTHETICS FRONTIER
New electronic stretchable sensors can help alert burn victim and people using prosthetic limbs against dangers.
TABLE OF CONTENTS
P.34 UNCOVERING THE DRIVERS OF PRIMARY TUMOUR GROWTH
P.36 AN EFFECTIVE SOLUTION FOR MARROW TRANSPLANTATION
Key proteins could contribute to much earlier cancer progression than previously thought.
A combination of young and adult donor stem cells offers robust, safe treatment for lymphoma patients.
FEATURE
P.37 REVEALING THE MISSING HERITABILITY OF COLORECTAL CANCER
P.38 COLORECTAL CANCER: OVERWEIGHT YOUNG PEOPLE AT RISK
P.40 PUTTING SAUDI ARABIA ON THE CLINICAL TRIAL MAP
Diagnosis of colorectal cancer may improve following the discovery of two gene mutations.
Being overweight before the age of 30 may increase the chances of developing colon cancer later in life.
KAIMRC’s new initiative stands to kickstart Saudi Arabia’s clinical trials economy, and find treatments for its people.
P.42 NUCLEAR PROTEIN MODULATES CELL FATE AND IDENTITY
P.44 MUSCLE DISORDERS: STEM CELLS CREATE SKELETAL MUSCLE
A cellular protein that anchors chromosomal material to the nuclear membrane is important for determining a cell’s fate.
Stem cells from the placenta can form new skeletal muscle tissues that can treat muscular diseases.
innovations.kaimrc.med.sa
Issue No.5
5
TABLE OF CONTENTS
P.46 THE MANY FACES OF A MITOCHONDRIAL MUTATION
P.48 THE IMMUNE STING OF WASP
A rare gene mutation affecting a mitochondrial transporter could be more common than previously thought.
A protein implicated in a range of immune diseases proves essential for proper T-cell development.
FEATURE
P.50 MORE CASES OF A DEBILITATING GENETIC DISORDER
P.52 TRAIN EFFICIENTLY, NOT MORE
Mitochondrial DNA plays an essential role in human physiology, with devastating consequences when it is disrupted.
A new research suggests that 15 minutes of resistance training can have the same health benefits as longer sets.
P.56 A GRACIOUS HOST FOR MIDDLE EAST RESPIRATORY SYNDROME
P.58 WESTERN STRAIN OF HEPATITIS C ON THE RISE IN SAUDI ARABIA
Kidney tissues could support the growth of Middle East respiratory syndrome coronavirus.
National efforts to curb transmission are in place to limit the virus’s spread.
6
June 2019
TABLE OF CONTENTS
P.60 TARGETING HEPATITIS B VIRUS VULNERABILITIES
P.62 SAUDI ARABIA WORST HIT BY MERS
Metabolic pathways altered by chronic hepatitis B virus infection may give clues to novel treatment.
A study on MERS-CoV in the Gulf shows the virus has taken its greatest toll in Saudi Arabia.
P.64 OBESITY AND ANAEMIA RIFE AMONG SAUDI FEMALE ADOLESCENTS FEATURE
Study shows obesity and irondeficiency are common among young women in Riyadh.
KAIMRC Innovations is published for the King Abdullah International Medical Research Center (KAIMRC) by Nature Research Custom Media. King Abdullah International Medical Research Center (KAIMRC) P.O. Box 3660 Riyadh 11481 Mail Code 1515, Saudi Arabia Email: kaimrc@ngha.med.sa Web: kaimrc.med.sa
KAIMRC innovations Phone: +966 11 429 4516 Email: innovations@ngha.med.sa Web: innovations.kaimrc.med.sa
Springer Nature The Campus – 4 Crinan Street – London, N1 9XY, UK Email: nature@nature.com Web: www.nature.com
The Researcher Newsletter Phone: +966 11 429 4516 Email: theresearcher@ngha.med.sa Web: innovations.kaimrc.med.sa/en/newsletter
innovations.kaimrc.med.sa
Issue No.5
7
Removing the stomach lining, which secretes hormones that regulate our appetite and metabolism, could help treat obesity.
8
June 2019
Trimming the stomach lining to fight fat
T
he importance of the gastric mucosa in regulating metabolism and satiety has been overlooked, according to new research that highlights the stomach lining as a possible target in treating obesity and related disorders. Vivek Kumbhari of the Johns Hopkins Medical Institutions in the US, Andreas Oberbach of the Fraunhofer Institute for Cell Therapy and Immunology in Germany, and colleagues carried out the research in an effort to improve obesity treatment. Surgeries designed to treat obesity, known as bariatric surgeries, are invasive and expensive, making patients wary of them despite their efficacy. “As a clinician, it’s frustrating to have something that works but that’s not well received by patients,” says Kumbhari. Patients usually lose weight and experience rapid improvements in their metabolic profile after a bariatric procedure known as vertical sleeve gastrectomy (VSG), in which most of the stomach is removed. While the dominant view is that bariatric surgeries work
innovations.kaimrc.med.sa
by reducing the volume of the stomach, Kumbhari and Oberbach weren’t convinced. “Making the stomach smaller helps you lose weight,” says Kumbhari, “but it’s not achieving the real goal, which is improving your metabolic profile. When you’re treating a patient, what you care about is the metabolic profile. That’s why you want them to lose weight.” In other words, the real goal should be to improve patients’ insulin activity, cholesterol levels, blood sugar, and similar factors. Based on a survey of the surgical literature, Kumbhari hypothesized that VSG might work because it removes part of the stomach lining known as the gastric mucosa, which secretes hormones that regulate our appetite and metabolism. To test this hypothesis, Kumbhari and Oberbach fattened four-week-old rats by feeding them a high fat diet for eleven weeks before burning away their gastric mucosa. Measurements over the next eight weeks revealed decreased weight and appetite along with improved metabolic profiles in
rats subjected to the new procedure known as GMD. Remarkably, rats that underwent VSG and GMD had similar metabolic profiles, despite the GMD rats having no change made to the size of their stomach. “We think one of the big components making VSG effective is its removal of the gastric mucosa,” says Kumbhari, although he emphasizes that the results don’t mean that GMD should replace VSG, but rather that the less invasive alternative deserves further investigation. The team has since published a follow-up study in pigs, and human trials are scheduled to start this year. “The gastric mucosa is an overlooked organ,” says Kumbhari. “It has a role to play in obesity, food intake and metabolic profile, and it should no longer be ignored. Let’s see what it’s doing, how it’s doing it, and how treating it might be beneficial.” Oberbach, A., Schlichting, N., Heinrich, M.,
Kullnick, Y., Retschlag, U., et al. Gastric mucosal devitalization reduces adiposity
and improves lipid and glucose metabolism in obese rats. Gastrointestinal Endoscopy 87, 288–299 (2018).
Issue No.5
9
S EB AS T I A N K AULI T ZK I / A L A M Y S TOC K P H OTO
Research suggests that targeting the stomach lining may alleviate obesity.
Breakthrough in bone marrow mapping New 3D imaging shows how cells, tissues and proteins are distributed within bone marrow. A team of scientists in Switzerland have mapped a comprehensive atlas of the cells and structures that make up the microenvironment of bone marrow. Until now, conventional imaging methods, such as electron microscopy, have offered limited, two-dimensional glimpses of bone marrow cells. Due to the difficulty of keeping the tissue structure intact while preparing thin sections of bone for microscopic analysis, the spatial distribution of cells within the bone marrow has been unclear. To obtain a better view, Timm Schroeder, and colleagues at the Department of Biosystems Science and Engineering, ETH Zürich, developed a 3D multicolour mapping method that has enabled them to visualise the bone marrow in whole leg bones (femurs) of adult mice. The researchers first used a technique called immunostaining, which involves using antibodies that can identify specific markers in biological tissue. They were then able to selectively visualise those 10
June 2019
markers via fluorescent labelling. From an initial list of nearly 250 antibodies, 67 were extensively tested by the team to choose the ones that best selectively stained the cell types they were analysing. The researchers then used an imaging method called multicolour quantitative confocal imaging cytometry to generate an atlas of more than 40 molecules, including markers, which indicate the precise distribution of particular cells of interest. Specifically, they achieved state-of-theart imaging of osteoblastic cells (which produce bone), vascular and perivascular cells (related to or surrounding blood vessels), neuronal cells (linked to the nervous system), and stromal cells (found in connective tissue). They also detected several types of extracellular matrix proteins, which are thought to provide structural support to surrounding cells. Reporting their findings in Nature Biotechnology they state: “Although our results mainly confirm the conclusions of previous studies, they also extend some previous
observations and contradict others.” For example, a marker called Nes-GFP, which is known to indicate the presence of specialised nerve cells known as neuronal progenitors in the central nervous system, unexpectedly showed that those cells are also found in nerve fibres inside bone marrow. This is thought to be the first time that those cells have been identified outside the brain and spinal cord. The study also revealed that vascular cells, perivascular cells and stromal cells may be more diverse than previously thought. For example, a stromal cell marker called CD271 indicated stromal cell activity throughout the bone marrow, with the highest amount present in its central part. Using a stain called boron dipyrromethene, the researchers found that bone marrow adipocytes, a type of stromal cell needed for metabolism, were mainly found in the distal parts of the bone marrow, although their number and location vary with age. The researchers conclude that their observations “probably only scratch the surface of what can be gained from the data.” To enable the wider scientific community to delve deeper, they have made their imaging data freely available for download. Coutu, D.L., Kokkaliaris, K.D., Kunz, L. & Schroeder, T.
Three-dimensional map of nonhematopoietic bone and bone-marrow cells and molecules. Nature Bio-
technology 35 (2017).
S C I EN C E P H OTO LI B R A RY / A L A M Y S TOC K P H OTO
A new 3D imaging technique has allowed researchers to visualize the locations of various cells in bone marrow.
A new chip-based sensor could detect and monitor spinal muscular atrophy faster and more cheaply than current methods.
S
pinal muscular atrophy (SMA) is a hereditary disease that affects around 1 in 6,000 newborns, with symptoms including weakness, difficulty moving, bone problems and impaired breathing. The more severe forms of the illness are a cause of infant mortality, yet laboratories still lack a simplistic method to diagnose it. The disease results from a mutation to the ‘survival motor neurone’ (SMN) gene, causing a significant decrease in the expression of SMN protein. A Saudi research team led by Mohammed Zourob, of Alfaisal University and King Faisal Specialist Hospital and Research Center, has now developed a chip-based assay that has no moving parts, requires no reagents after construction, and can be screen-printed at low cost. Clinicians diagnose SMA through genetic testing, and investigations currently look for the illness by quantifying SMN protein levels in blood samples. However, these techniques are expensive, time-consuming, and involve complex steps and equipment. The chip produced by Zourob’s team consists of carbon nanomaterial electrodes, which are modified to enable the attachment of SMN-specific antibodies on the electrode surface. When a patient’s blood is applied to the sensor, the antibodies bind the protein of interest, which in turn produces an electrical signal that can be detected and recorded. The greater the concentration of SMN protein, the greater the magnitude of the signal’s peak. In developing the biosensor, the researchers first trialed six different kinds of carbon nanomaterials. “We were looking for the carbon nanomaterial that
innovations.kaimrc.med.sa
gives the best response signal and with the best selectivity for SMN protein,” explains Khalid Abu-Salah, co-author of the team’s Biosensors and Bioelectronics paper. Biosensors were produced from the six different candidates, and the response recorded after adding SMN protein to the electrodes. To check the specificity of the sensors, responses were also measured after adding other physiological proteins to the chips. Abu-Salah and his colleagues found carbon nanofibre to be the highest performing nanomaterial in their study, able to specifically detect SMN protein even at lower concentrations than a
“A Saudi research team has now developed a chip-based assay that has no moving parts, requires no reagents after construction, and can be screen-printed at low cost. “This technique will benefit the clinic by providing a highly sensitive biosensor for SMN protein detection and quantification,” he adds. Looking to the future, the team is looking for corporate partners to help move their biosensor from bench to business and into clinics, where it can provide vital assistance to those suffering from SMA. Eissa, S., Alshehri, N., Abdel-Rahman A. M., Dasouki, M.,
Abu-Salah, K. M., Zourob, M. Electrochemical immu-
nosensors for the detection of survival motor neuron (SMN) protein using different carbon nanomateri-
als-modified electrodes. Biosensors and Bioelectronics 101, 282–289 (2018).
With the advent of functionally-engineered carbon nanomaterials, biosensors to detect disease-related proteins may become a mainstay of diagnostic medicine
Issue No.5
11
LOL A BOU / A NA DOLU AG E NCY / G E T T Y I M AG E S
A vital test for spinal muscular atrophy
more complex, commercially available assay kit.
Cardiovascular health: The power of machine learning Machine learning accurately predicts the association between cardio-respiratory fitness and mortality.
12
June 2019
T
he ability of the circulatory and time of testing and who had a complete respiratory systems to sup10-year follow-up. ply oxygen to skeletal musThey found that a machine learning cles during sustained physical approach, involving computer algorithms activity is not only an objective measure that can learn from and make predictions of regular physical activity, but also a from complex data sets, was significantly useful diagnostic and prognostic health more accurate than conventional statistical indicator. Poor cardio-respiratory fitmethods at identifying the risk of death in ness has been linked to cardiovascular the patient cohort. The machine learning disease and death from any cause, with algorithm used data associated with 15 many studies highlighting the beneficial variables — including age, heart rate, blood effects of exercise. pressure, reason for the exercise test, and Statistical modelling is commonly used to family history — to predict the likelihood predict adverse clinical outcomes based on of death from any cause. The approach cardio-respiratory identified, with fitness. Previous over 90percent “They found that a work has shown c c u racy , t he machine learning approach aparticipants that this type of who was significantly more analysis can idenwere at high risk of accurate than conventional death. tify between 30 percent and 50 “Machine learnstatistical methods at percent of patients ing outperformed identifying the risk of death statistical tools in at high risk of in the patient cohort.“ death within an every aspect. This eight-year period. is partly due to the As the use of machine learning to analyse large sample size, which is known to be biomedical data expands, Mouaz Al-Malessential for machine learning to perform lah at KAIMRC’s Clinical Cardiovascular well,” explains Al-Mallah. Research Program and colleagues sought The team is now testing machine learnto determine whether it can be applied to ing on other outcomes and hopes it will predict the risk of death within 10 years of have a similar predictive power. Al-Malundergoing a physician-referred exercise lah expects that machine learning will treadmill stress test. “There is a lot of hype have a huge impact on medical diagnosis about machine learning, but we do not and prognosis thanks to its ability to anaknow if it is better than using conventional lyse images and recognize patterns. “In statistical tools,” says Al-Mallah. the future, the job of the radiographer will The authors used data from 34,212 be to confirm the machine learning findindividuals that took part in the Henry ings rather than to interpret the images,” Ford Exercise Testing Project, the largAl-Mallah says. est study of physical fitness to date. The project involved nearly 70,000 adults Al-Mallah, M. H., Elshawi, R., Ahmed, A. M., Qureshi, W. from Detroit, Michigan, who completed T., Brawner, C. A. et al. Using machine learning to define an exercise stress test between 1991 and the association between cardiorespiratory fitness and 2009. Al-Mallah and colleagues focused all-cause mortality (from the Henry Ford Exercise Teston patients that were free of coronary ing Project). American Journal of Cardiology 120, 2078– artery disease or heart failure at the 2084 (2017).
innovations.kaimrc.med.sa
Issue No.5
13
S UM ET EE T H EES UN G N E R N / E Y E E M / G E T T Y I M AG E S
A machine learning approach identified, with 90% accuracy, people at highest risk of death within ten years of conducting a treadmill cardio-respiratory fitness test.
FEATURE Tasuku Honjo of Kyoto University in Japan and James Allison of the University of Texas MD Anderson Cancer Center in Houston won the Nobel Prize in Physiology for Medicine in 2018 for their discovery of cancer therapy by inhibition of negative immune regulation.
A year of biomedicine breakthroughs
The latest global innovations in the study of disease
14
June 2019
A promising drug for Alzheimer’s
In a breakthrough for the study of Alzheimer’s disease, a group of scientists from the University of Cambridge, and Lund University, in Sweden have developed a systematic method to target the toxic particles believed to cause the deterioration of healthy brain cells. The study1 is the first method developed to target the pathogens behind Alzheimer’s, a form of dementia that affects between 60 to 70 percent of the 50 million dementia patients around the world. Drugs used to treat Alzheimer’s dealt only with the symptoms of the disease, but no treatment has yet been able to halt the onset or progression of the disease. The team behind the study hopes that their treatment can go into clinical trials at the end of 2020. “The Alzheimer’s field is making tremendous advances,” says Michele Vendruscolo, from the University of Cambridge and one of the lead researchers on the study. Until recently, scientists were not in agreement over the cause of the innovations.kaimrc.med.sa
disease, but recent findings identified the pathogens behind Alzheimer’s as small clumps of proteins called oligomers, allowing for potential target treatment. “The emergence of highly quantitative methods in drug discovery and diagnostics is very exciting,” says Vendruscolo. “It will likely transform the way in which we will deal with Alzheimer’s disease within a decade.”
Immunotherapy takes the spotlight
In October, 2018, James Allison of the University of Texas MD Anderson Cancer Center in Houston, and Tasuku Honjo of Kyoto University in Japan won the Nobel Prize in Physiology or Medicine for their discoveries in cancer immunotherapy. Immunotherapy, or the artificial stimulation of the immune system to target cancer cells, has recently been a focus of cancer treatment. “The past year was all about immunotherapy and how it works [combined with chemotherapy] against so many different types of cancer,” says Roy
This past year has seen major advancements in biomedicine with innovative methods that tackled diseases such as Alzheimer’s, and ventured into the exciting areas of artificial intelligence and digital imaging. Herbst, director of the Yale Center for Immuno-Oncology. The Nobel laureates showed how proteins on immune cells can be used to
manipulate the immune system to attack cancer cells, a technique upon which various therapies were based, extending the life of cancer patients and curing others. More recently, a group of researchers from Queen Mary University of London and St Bartholomew’s Hospital demonstrated how a combination of immunotherapy and chemotherapy can treat an aggressive form of breast cancer. The study2 showed that the treatment reduces the spread of the cancer by 40 percent, improving survival by 10 months. Immunotherapy has been proven to work on 20 percent of patients, according to Herbst. He adds that it is now time for collaboration between researchers and clinical personnel to determine why it works on some patients and not others, and how to make it beneficial for a larger group of people.
Revolutionary blood test for cancer screening
Early detection is often key to successful cancer treatment. Researchers at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins may have developed a way to screen for eight different types of cancers, as well as identify the location of the tumour. CancerSEEK3 is a simple, non-invasive blood test that examines the levels of proteins associated with the eight types of cancer and gene mutations that may emerge in the DNA circulating in the blood. It tests for the most common types of cancer, including lung, ovarian and breast. According to the study, the blood test detected cancer with a sensitivity of 69 to 98 percent and 99 percent specificity. The researchers estimated that would cost around $500 per patient. Issue No.5
15
© N OB EL M EDI A A B 20 1 8 / A L E X A NDE R M A HM OU D.
T
he biomedical field is always evolving as discoveries and new technologies reshape how scientists once thought of a disease or its cure. This past year has seen major advancements in biomedicine with innovative methods that tackled diseases such as Alzheimer’s, and ventured into the exciting areas of artificial intelligence and digital imaging. We look back on seven of the most significant discoveries of 2018. Along with researchers at KAIMRC, scientists around the world have been focused on diseases that affect millions around the world, including cancer, Alzheimer and cardiac diseases.
FEATURE AI that can predict disease
Refining 3D-imaging
Another technology trend reshaping the biomedical field is 3D imaging. In November, 2018, a device that took more than a decade to develop was finally released as the world’s first, full-body medical scanner. The EXPLORER captures a snapshot the full human body and produce a 3D image of it with just one scan in 20 to 30 seconds. The device was developed by a group of scientists from UC Davis and engineers from Shanghai-based United Imaging Healthcare, and is said to produce more detailed images than the regular x-ray, with less radiation. Madabhushi says that some radiology departments fear the new technology could make their role redundant, while others have reservations about trusting a machine. But he says, “but 16
June 2019
The past year has seen many advancements in studying Alzheimer’s, with researchers identifying a possible treatment that should go into clinical trials by 2020.
AI renders diagnosis faster and actually empowers us.”
Creating organs, digitally
Printing whole organs for transplantation may soon become a reality. Research into 3D bioprinting of organs such as the heart, kidney and liver has moved quickly in the past decade. In October 2018, a study6 at the University of Colorado Boulder developed a new printing method t to allow for the mimicking of blood vessels and arteries by controlling the printed object’s firmness, This could lead to more personalized treatments for hypertension and vascular disease patients. Another group of researchers at biotechnology company, BioLife4D is working on a process that could create a beating heart using a person’s own cells.
An evolution of the genes
Early trial phases of gene editing for use against genetic diseases are underway. In September, 2018, researchers from Sangamo Therapeutics in Richmond, California published a study on gene editing
for Hunter Syndrome and first trial results of the 16-week clinical study were promising. 1. Chia, S., Habchi, J., Michaels, T.C.T., Cohen, A.I.A, Linse,
S. et al. SAR by kinetics for drug discovery in protein misfolding diseases. PNAS 115, 10245-10250 (2019). 2. Schmid, P., Adams, S., Rugo, H.S., Schneeweiss, A.,
Barrios, C.H. et al. Atezolizumab and Nab-Paclitaxel in advanced triple-negative breast cancer. The New Eng-
land Journal of Medicine 379, 2108-2121 (2018). 3. Cohen, J.D., Li, L., Wang, Y., Thoburn, C., Asfari, B. et
al. Detection and localization of surgically resectable
cancers with a multi-analyte blood test. Science 359,
926-930 (2018).
4. Poplin, R. Varadarajan, A.V., Blumer, K., Liu, Y., McCon-
nell, M.V. Prediction of cardiovascular risk factors from retinal fundus photographs via deep learning. Nature
Biomedical Engineering 2, 158-164 (2018).
5. Ding, Y., Sohn, J.H., Kawczynski, M.G., Trivedi, H., Harnish, R. et al. A deep learning model to predict a diag-
nosis of Alzheimer Disease by Using 18F-FDG PET of the brain. Radiology 290, 456-464 (2018).
6. Yin, H., Ding, Y., Zhai, Y., Tan, W., Yin, X. Orthogonal programming of heterogeneous micro-mechano-environments and geometries in three-dimensional bio-stereolithography. Nature Communications 9 (2018).
PAS I EK A / S P L/ G ET T Y I M AG ES P LUS
The use of artificial intelligence as a tool in biomedicine could have a significant impact on the field. In 2018, Google announced an AI algorithm that can predict a person’s risk of heart disease by scanning their eyes. The research4, conducted by scientists at the Verily, formerly known as Google Life Sciences, and published in Nature Biomedical Engineering, details that through the scan, the machine would be able to identify a person’s age, blood pressure, and whether or not they smoke, without the need for a blood test. Another study5, by a team of researchers at the Department of Radiology & Biomedical Imaging at the University of California in San Francisco, has developed an AI system that predicts the risk of Alzheimer’s disease. The machine was trained to find irregularities in the brain’s metabolism, which could be indicative of Alzheimer’s. “[AI] is already reshaping medicine,” says Anant Madabhushi, professor of biomedical engineering at Case Western Reserve University in Cleveland and director of the university’s Center for Computational Imaging and Personalized Diagnostics, pointing to emerging technologies that are awaiting regulatory approval.
National Center for Stem Cell Technology With research partnerships spanning the globe, KACST is at the heart of the drive to reach innovative therapies for different diseases prevalent in Saudi Arabia, such as diabetes, through stem cells research. By establishing the National Center for Stem Cell Technology in April 2014, KACST is driving advances applied research in regenerative medicine and promoting technology transfer and localization. www.kacst.edu.sa
Obesity is rapidly outpacing underweight.
Dangerous trends in worldwide childhood obesity
There are more underweight than obese children in the world, but the balance could change in just five years.
A
n unprecedented worldwide analysis has shown that obesity in children and teenagers has risen tenfold in the past 40 years, and obese children could be more prevalent than underweight children within five years. Obesity is a leading risk factor for non-infectious diseases, also known
18
June 2019
as non-communicable diseases (NCD), such as type II diabetes. The NCD Risk Factor Collaboration (NCD-RisC), led by scientists from Imperial College London, in collaboration with the World Health Organization (WHO) and a network of more than 1,000 worldwide NCD experts, undertook more than 2,400 population-based studies. Overall, they pooled
data from almost 130 million individuals over five years of age, including 31.5 million young people between five and 19, to create worldwide trend models based on weight-to-height squared ratio (or body mass index, BMI). According to this analysis, the global number of underweight children peaked around the year 2000 and then stalled.
innovations.kaimrc.med.sa
about one third are overweight or obese, and 15 percent underweight,” explains KAIMRC’s Fadia AlBuhairan, Jeeluna’s principal investigator and contributor to the NCD-RisC global study. The researchers called for measures to shore up food security to ensure children had enough to eat, and for providing healthier nutrition and more physical activity to deal with obesity. Taxing unhealthy foods and drinks, as well as making whole grains, fruits and vegetables affordable for everybody could counteract the trend. “This research will continue over the coming years. We want to monitor how effective interventions from WHO and national governments are,” explains James Bentham, joint first author of this study. “We study diabetes, blood pressure and cholesterol as well, and in the next few years we will look at how many people have dangerous levels of a combination of these variables.” NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in body-mass index,
underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128.9 million children, adolescents, and adults. The Lancet 390 (2017).
Issue No.5
19
G ET T Y I M AGE S/ C A I AI M AGE /A DA M GAULT
From 1975 to 2016, the worldwide prevalence of underweight girls declined from 9.2 percent to 8.4 percent, and of boys from 14.8 percent to 12.4 percent. In 2016, 75 million girls and 117 million boys, mainly living in south Asia and in particular in India, were moderately or severely underweight. During the same timeframe, worldwide obesity rates soared from less than 1 percent to 5.6 percent in girls and 7.8 percent in boys. This translates to around 124 million obese kids around the globe. More than 30 percent of children and teenagers on Nauru, the Cook Islands and Palau, and more than one in five children in Polynesia, Micronesia, Egypt, Kuwait, Qatar, Saudi Arabia, Bermuda, Puerto Rico, and the United States are obese. Childhood obesity has recently stabilized at alarmingly high levels in rich countries, and it is still growing for kids in developing and emerging economies. As a consequence, several countries in East Asia, Latin America and the Caribbean have experienced a rapid shift from underweight to obesity issues. Problems at both ends of the scale are also present in Saudi Arabia. “The Jeeluna study, the Arabic term for ‘our generation’, showed that only 55 percent of adolescents have a healthy weight,
Profiling the evolution of breast cancer cells
Genetic profiling of breast cancer metastases provides insight that could help improve treatment. Genetic profiling has provided insight into the evolution of cells that are shed from primary breast tumours and go on to cause metastases in other parts of the body. The work validates current approaches to primary treatment, and identifies opportunities to develop more effective treatment for metastatic disease. Primary breast cancer can usually be treated with surgery and radiotherapy, but by the stage of diagnosis, the tumour might have shed cells that could cause metastases — new tumours in other parts of the body — which are usually fatal. Systemic treatment is needed to kill the shed cells and prevent metastases. Treatment is chosen according to the subtype of cancer, determined by which cancer-causing mutations are present in the tumour. However, relatively little is known about the genetics of metastatic 20
June 2019
breast cancer. Work led by Per Eystein Lønning from the University of Bergen, Norway, and Peter Campbell from the Wellcome Trust Sanger Institute, UK, has provided new insight, with implications for therapy. The researchers compared the mutations present in the cells of metastases with those in the original, or primary, breast tumours from the same patients. Almost all the mutations in the metastatic tumours were also present in the primary one, indicating that the metastatic cells were shed from the primary cancer late in the development of the tumour. Genetic profiling of the primary tumour is therefore likely to closely predict the genetic profile of any cells that have been recently shed, so systemic treatment chosen on the basis of mutations in the primary tumour is likely to be the most effective
at preventing metastases. Lønning, Campbell, and colleagues also investigated whether the main mutations that promote tumour growth—known as driver mutations—in metastatic tumour cells corresponded with those in the primary tumour cells. Metastases detected at the same time as the primary tumour mostly had the same driver mutations, supporting the selection of systemic treatment based on the profile of the primary tumour. However, metastases that were not detectable until later had accumulated additional driver mutations, meaning that therapy chosen on the basis of the primary tumour might be less effective. The researchers say that the ability of cancer cells to continue accumulating mutations over time means that the genetic profiles of metastatic tumours are likely to exhibit greater variation between patients than those of primary tumours. They conclude that large studies of patients with metastatic breast cancer are needed to determine the extent of this complexity and identify new therapeutic targets. Yates, L.R., Knappskog, S., Wedge, D., Farmery, J.H.R., Gonzalez, S. et al. Genomic evolution of breast cancer metastasis and relapse. Cancer Cell 32, 169–184 (2017).
Y. K H A LI L/N AT UR E
Researchers identified opportunities to develop more effective treatment for metastatic disease based on insight gathered from genetic profiling into the evolution of cells shed from primary breast tumours.
Incorporating periods of fasting into diets shows potential as a means of halting the progression of metabolic diseases.
An intermittent fasting regimen can reduce the size of white fat tissue cells (grey) and induce antiinflammatory immune cell activity (red).
Researchers in Canada have demonstrated how intermittent fasting can stimulate the metabolic system of mice to convert white fat tissue into energy-burning fat, thus reducing excess fat in the body. Their results could inform future treatments for type II diabetes and obesity. “The link between metabolic diseases, unhealthy lifestyles and eating habits is innovations.kaimrc.med.sa
clear,” says Hoon-Ki Sung at The Hospital for Sick Children and the University of Toronto, who led the international research team with his colleague Chi-chung Hui. “One possible intervention is intermittent fasting, which is already known to trigger a specific metabolic response.” Fasting kickstarts a process that transforms white fat tissue, which stores
Kim, K-H, Kim, Y.H., Son, J.E., Lee, J.H., Kim, S., et al. Intermittent fasting promotes adipose thermogenesis and metabolic homeostasis via VEGF-mediated alternative activation of macrophage. Cell Research (2017).
Issue No.5
21
JOE EUN S ON ( 2 0 1 7 )
Obesity and diabetes: Heading for the fast burn
energy and is present in excess in obese patients, into ‘beige’ fat, which fuels the body in lieu of food. Sung and Hui’s team wanted to find out exactly how this process works. Previous studies on mice used a ‘one day fast/one day normal diet’ form of intermittent fasting, but it was unclear whether reduced calories were responsible for weight loss. To address this, the researchers gave healthy, obese and diabetic mice a ‘one day fasting / two days normal eating’ regimen for 16 weeks, and compared the results with control groups. The animals in the intermittent fasting groups had the same overall calorie intake as control groups, fed with either a normal diet or 45% high fat diet, allowing accurate assessment of how fat tissues respond to fasting, regardless of calories. All mice on the intermittent fasting diet had lower body weight than those on a non-fasting diet. This effect was most significant for mice on a high fat diet. “We found that 2:1 intermittent fasting not only prevented obesity in mice, but also improved metabolic profiles of the diabetic animals by changing the quality of fat tissues,” says Sung. “The ‘stop-eating’ period stimulates anti-inflammatory immune cells found in fat tissues, and boosts levels of the VEGF gene, which is involved in blood vessel formation. These combine to transform white fat into energy-dissipating beige fat.” Further experiments on fasting mice in which the VEGF gene was disabled showed that the browning of white fat did not occur, indicating that VEGF expression is a vital part of the process. These findings suggest that the human metabolic condition may be significantly influenced by our daily eating cycle. “The next steps are to assess how our findings might be applied to the management and prevention of metabolic diseases,” says Sung.
Exercise may promote the protection of brain neurons in multiple sclerosis.
22
June 2019
Multiple sclerosis: An exercise in brain protection
A
combined exercise programme might promote nerve protection in people with multiple sclerosis (MS), according to new research. A combination of aerobic exercise and pilates boosted levels of an anti-neurodegeneration factor, and improved physical functions in patients with MS. MS is an autoimmune disease that causes inflammation and nerve degeneration. Some studies suggest that exercise is helpful in managing the symptoms of MS, but the reasons behind this benefit are unclear. Ceren Ozkul and colleagues from Gazi University in Turkey aimed to gain new insight into the ways in which exercise helps. The study involved 36 people with MS. Over a period of eight weeks, half of them took part in aerobic exercise and pilates training, while the other half only engaged in relaxation activities. The researchers assessed the effects by measuring blood levels of compounds that protect against MS, and by assessing the participants’ physical abilities at the beginning and end of the period. The exercise programme led to increases in blood levels of brain-derived neurotrophic factor (BDNF), a growth factor that protects neurons from degeneration. Blood levels of BDNF did not change
innovations.kaimrc.med.sa
over the same period in participants who engaged in the relaxation programme. The finding indicates that exercise has a neuroprotective effect by increasing levels of BDNF. The researchers also measured blood levels of SOCS1 and SOCS3, proteins that suppress cytokine signalling, modulating the effects of inflammation-promoting cytokines in MS. SOCS1 and SOCS3 levels did not change with exercise, but SOCS1 did increase in participants of the relaxation programme. The exercise programme was also associated with an improvement in balance, functional exercise capacity and fatigue. By contrast, fatigue worsened in patients who did not exercise, while other measures of physical ability did not change. The findings demonstrate that a combined exercise programme can improve physical function in patients with MS through increasing BDNF levels, thus protecting against neurodegeneration. The researchers say further studies are needed to understand their role and the effects of exercise on inflammation in MS. Ozkul, C., Guclu-Gunduz, A., Irkec, C., Fidin, I., Aydin, Y. et
al. Effect of combined exercise training on serum brain-derived neurotrophic factor, suppressors of
cytokine signalling 1 and 3 in patients with multiple scle-
rosis. Journal of Neuroimmunology 316, 121–129 (2018).
Issue No.5
23
W ES T EN D61
Exercise for people with multiple sclerosis protects against degeneration and improves physical function.
Heart disease: Link with air pollution spikes in China A study covering 26 large cities in China links shortterm exposure to air pollution with increased hospital admissions for heart failure.
A
growing body of evidence is showing a clear association between short-term exposure to air pollution, and hospital admissions and deaths due to heart failure. Despite developing countries experiencing some of the most severe air pollution, analyses in those countries have been sparse. Researchers in Beijing have addressed this gap by analysing data from 26 large cities across China. They believe the association they detected may have significant public health implications for preventing congestive heart failure in China, and suggest their results are relevant to other countries. The study, led by Yonghua Hu at the School of Public Health at Peking University, Beijing, looked for correlations between daily hospital admissions and changing air pollution levels in 2014 and 2015. The air pollution data covered the levels of several specific pollutants, including particulate matter, sulphur dioxide, nitrogen dioxide, carbon monoxide and ozone. This information was gathered daily from fixed-site air-monitoring stations in each city. These are an established part of the China National Air Pollution Monitoring System. After statistical analyses, the results showed that short-term increases in the
24
June 2019
levels of all of the pollutants analysed, with the exception of ozone, were associated with increased hospital admissions for congestive heart failure. The link was most notable in patients with diabetes or high blood pressure. The association identified in the study did not, however, vary significantly with age, history of other diseases, or the time of year. “To our knowledge, this is the first multi-city study in China, or in other developing countries, to examine the relation between air pollution and congestive heart failure mortality,� the authors say. A strength of this study is its capacity to detect increases in hospitalization linked to spikes in air pollution on a timescale of days, as opposed to the effects of more generalized chronic pollution levels. By revealing the significance of short-term pollution spikes, the study suggests that steps to avoid such transient increases could bring significant health benefits. The authors note that the significant detrimental health effects of air pollution cause widespread public concern in China, and the study validates that concern. Liu, H., Tian, Y., Song, J., Cao, Y., Xiang, X. et al. Effect of
ambient air pollution on hospitalization for heart failure
in 26 of China’s largest cities. The American Journal of
Cardiology 121, 628-633 (2018).
C U LT U RA R M EXC LUS I VE/C R A I G EAS TON C R EAT I VE/ G ET T Y I M AG ES
Air pollution in China has been linked to increased hospital admissions for heart failure.
innovations.kaimrc.med.sa
Issue No.5
25
Saudi children with epilepsy are more likely to experience depression.
The psychological challenges of epilepsy A common form of epilepsy is associated with emotional and behavioural problems in children. 26
June 2019
C
hildren in Saudi Arabia with idiopathic generalised epilepsy (IGE) experience depression, anxiety and behavioural problems more often than healthy children. The finding was published in the journal EC Neurology. Epilepsy affects approximately 50 million people worldwide. Patients experience recurrent seizures due to a surge in innovations.kaimrc.med.sa
electrical activity in the brain. More than 15 types of seizure and 30 different epilepsy syndromes have been described. IGE accounts for nearly a third of all epilepsies. Patients with IGE often have a family history of epilepsy and are genetically predisposed to the risk of seizures. The disease manifests in early childhood with seizures involving brief episodes of involuntary whole-body movement, and in some cases loss of consciousness and control of bowel or bladder function. Some patients outgrow their epilepsy during adolescence, but others require
Almutairi, A. A., Alrifai, M. T., Alturki, M. S., Alrashidi, Q. S., & Salama, M. M. Psychosocial problems in children with idiopathic epilepsy. EC Neurology 10, 91–97 (2018).
Issue No.5
27
K AT ERY N A KON /S C I EN C E P H OTO LI B R A RY /G ET T Y I M AG ES
lifelong medication and monitoring. Despite the variety of antiepileptic drugs on the market, current medications fail to control seizures in about a third of patients. Several studies have shown that children with any type of epilepsy have a higher risk of developing behavioural and emotional problems than children with other chronic diseases or healthy children. Muhammad Talal Alrifai and colleagues at King Abdullah Specialized Children Hospital and King Saud bin Abdulaziz University for Health Sciences in Riyadh explored the incidence of these problems in 44 children with IGE between the ages of five and 18 using a questionnaire-based survey. The parents of the 44 patients and those of 89 healthy children were asked to rate 35 items as ‘never’, ‘sometimes’ or ‘often’ present using a standard paediatric symptom checklist that screens children for common psychological and behavioural problems. They found that children with IGE experienced more trouble sleeping, and were more likely to fidget and more easily distracted than the healthy children. This could help explain why they tend to perform worse academically. They also felt unhappy and angry more often than the healthy children and were more likely to act younger than their age and blame others for their troubles, indicating a higher prevalence of depression, anxiety and behavioural problems. There were no differences between the results of the boys and the girls surveyed. “In light of these findings, we recommend referring all recently diagnosed patients to a psychiatrist, a psychologist and a social worker for support,” says Al Rifai. Although further research is required to determine whether the frequency of seizures, age and IQ are associated with emotional and behavioural problems, the possibility of identifying and treating them early will improve patients’ quality of life and perhaps their school performance.
People with chest pain who don’t have severe heart artery blockage should still be monitored for heart disease complications.
Paying heed to chest pain
Even without serious artery blockage, chest pain is often a harbinger of deadly heart disease.
C
hest pain can be a worrying sign of heart problems. It often prompts a check for cholesterol plaques blocking the arteries that feed the heart. Cardiologists had long assumed that, unless there were plaques causing substantial narrowing of the arteries, chest pain was nothing to worry about. But a new study involving KAIMRC researchers now refutes that idea. The findings have sparked a rethink about who should be considered at high risk for the complications of heart disease and might require more significant monitoring and medical treatment. The study, known as CONFIRM, included thousands of patients who received an imaging test for a suspected diagnosis of heart disease. Within this larger cohort, around 4,200 people had artery narrowing of less than
28
June 2019
Lee, J.H., Han, D., Hartaigh, B.Ó., Gransar, H., Lu, Y. et al. Influence of symptom typi-
cality for predicting MACE in patients without obstructive coronary artery disease: From the CONFIRM Registry (Coronary Computed Tomography Angiography Evalua-
tion for Clinical Outcomes: An International Multicenter Registry). Clinical Cardiology 41, 586–593 (2018).
innovations.kaimrc.med.sa
Issue No.5
29
ZOON A R G M B H / A L A M Y S TOC K P H OTO
50 percent. Within this subgroup, there were 312 cases of heart attacks, bypass surgeries or other severe heart-related issues. KAIMRC cardiologist, Mouaz Al-Mallah and collaborators from across North America, Europe and Asia dug into these numbers, looking for statistically meaningful associations between symptom severity and the risk of major complications in the group without substantial artery issues. Contrary to conventional wisdom, they found that chest pain was linked to worse outcomes. Patients with chest pain, men and women alike, were 1.6 times as likely to have serious heart problems than those without it. However, that was only the case among people with at least some degree of plaque build-up and artery narrowing, a condition known as atherosclerosis. For those without any evidence of atherosclerosis whatsoever, chest pain did not seem to portend a worse prognosis. Al-Mallah and his colleagues propose several explanations for why patients with chest pain and limited atherosclerosis may have a higher rate of adverse events. It’s possible, they note, that the imaging test may underestimate the extent of narrowing, or that some other feature of clogged arteries — such as the amount of plaque calcification — may be a more important driver of heart disease. The authors also speculate that chest pain in those without severe atherosclerosis may be a symptom of some other heart problem unrelated to artery narrowing — such as blood vessel dysfunction. Whatever the reasons, the findings from Al-Mallah’s team show that patients complaining of chest pain should be taken seriously by cardiologists, even when sophisticated imaging tests show only partial artery obstruction in the heart.
FEATURE
E-skin, the next prosthetics frontier
New electronic stretchable sensors can help alert burn victims and people using prosthetic limbs against dangers like fire.
30
June 2019
innovations.kaimrc.med.sa
Issue No.5
31
S OLS TOC K / E+ / G ET T Y I M AG E S
M
odern artificial limbs are stronger and lighter than ever, thanks to new materials and advanced plastics. They also provide improved control and capabilities through miniaturized electronics and greater computer power. Mechanical joints also adjust automatically, and pneumatic components and actuators generate realistic knee and ankle movements. Improved manoeuvrability is, however, only half of the picture. A team of mostly Arab researchers from the University of Connecticut and the University of Toronto is working on prosthetics that will be able to seamlessly make sense of their environment and interface with the brain to help people whose skin has been burned, and those using artificial limbs, regain the sense of feeling through electronic sensors. A key challenge for incorporating flexible, bio-compatible sensors into artificial skin or limbs is the need for power. A significant advance was the development of triboelectric nanogenerators (TENG). First demonstrated by Chinese scientists in 2012, TENGs generate an electrical current when two materials, one with positive polarity and the other with negative polarity, come into contact and then separate, or slide past each other. More usually used to convert mechanical energy into electrical energy, TENGs can also be used as sensors. Engineers at the University of Toronto, Canada, and chemists at the University of Connecticut in the US, created a flexible, waterproof sensor that can identify different forms of movement, pressure and various
FEATURE potential hazards.
Restoring senses
“We were initially trying to produce a skin sensor to restore a sense of feeling for those who lose limbs or those who have suffered burns,” said Islam Mosa, of the University of Connecticut. “Then we wanted to add extra functions that human skin does not have.” Mosa and his collaborators call their prototype the ferrofluid-based triboelectric nanogenerator (FO-TENG). Ferrofluids are liquids that contain nanoscale magnetic particles in suspension that become magnetic in the presence of a magnetic field. The FO-TENG consists of a liquid suspension of nanoscale iron oxide particles inside a silicon tube wrapped in a copper coil, all sealed into a silicone rubber gel. Stimuli like magnetic fields, acoustic waves and direct physical forces cause the silicone tube and ferroliquid to move with respect to each other, generating a positive charge in the tube and a negative charge in the ferroliquid. This creates an electric current which is picked up in the copper wire, activating the sensor. This electrical output varies based on the strength of the magnet and their proximity. This means it is able to produce different outputs for walking, running and jumping, with the signal strength varying according to movement intensity. Stretching the sensor to up three times its normal length, as well as repeated crumpling, bending and twisting, did not undermine its performance. Underwater simulations showed the sensor generated different electrical output patterns in response to different sizes and forms of wave. The researchers suggest the FO-TENG could even be used to track the performance of swimmers, and as an alarm in thre case of drowning. “A person who is drowning has a random style of motion that can be distinguished from the repetitive movements of a swimmer,” says Mosa. The researchers developed basic signal 32
June 2019
processing software to show it is possible to differentiate the outputs of the FO-TENG in different circumstances. They are investigating applications in prosthetics, robotics, artificial skin, remote healthcare monitoring and wearable hazard detection devices. Alex Chortos, a researcher who develops stretchable electronics at Stanford
“We were initially trying to produce a skin sensor to restore a sense of feeling for those who lose limbs or those who have suffered burns.“ University, and who is not involved in the FO-TENG project, says the sensor’s stretchability makes it especially useful for certain applications. “This type of tubular structure is advantageous because it can easily be integrated with biological structures,” says Chortos. “That’s not easy to do with a flat, flexible device that will wrinkle and move around.”
Advancing the field
Advances over recent years in flexible electronics are promising, however, components designed for advanced prosthetics and artificial skin must be able to interface smoothly with the human body. Chortos and co-workers in Professor Zhenan Bao’s group at Stanford University developed a stretchable circuit that can sense different degrees of pressure and transmit that information in signals the brain can recognize. “Because the information is encoded in the same way as the human body does it, we can directly input that signal into things like nerves,” says Chortos. In a 2018 paper, the group demonstrated the ability to recognize the direction and speed of an object moved across their pressure sensors. They were also able to identify braille characters pressed on an array of their sensors, and to control
muscles in a disconnected cockroach leg via electrical signals generated by applying pressure to their sensors. Chortos was part of the team that last year published details of technology designed to provide sensitivity to pressure comparable to humans. Their ‘e-skin’ contains arrays of capacitors that can measure the intensity and direction of forces simultaneously and in real time. The researchers showed how it could be used to allow a robot to handle delicate objects like raspberries without damaging them. Another major challenge is finding new ways to manufacture artificial skins and limbs so that new flexible sensors, actuators, computer chips and other components are integrated effectively. Last year, a group led by researchers at Harvard University, in the US, demonstrated the ability to integrate multiple features and materials within 3D printed soft robots, using a conductive organic ink they developed. They produced and tested a three-fingered soft robotic gripper that can sense light and deep touch, curvature and temperature. The complex systems that allow that allow human bodies to understand what is going on evolved over millions of years. Developing the next generation of artificial limbs and skin that can mimic this ability and communicate with biological systems, including the body is a major challenge. Like other complex problems, it becomes less daunting when broken up into smaller, more manageable parts. Recent evidence suggests that scientists are close to turning the theoretical vision of allowing prosthetics and man-made skin to sense their environments into a technological reality. Ahmed, A., Hassan, I. Mosa, I. M., Elsanadidy, E., Sharafel-
din, M., Rusling, J. F., Ren, S. An Ultra-Shapeable, Smart Sensing Platform Based on a Multimodal Ferrofluid-Infused Surface. Advanced Materials 31, (2019).
Boutry, C.M. Negre, M., O. Chortos, A. et al. Hierarchi-
cally patterned, bioinspired e-skin able to detect the direction of applied pressure for robotics. Science Robot-
ics 24, (2018).
Leading Reliable Healthcare An outstanding, timely and much awaited contribution to the healthcare sector in the Kingdom of Saudi Arabia and globally.
Edited by Bandar Al Knawy, MD, FRCPC CEO, Ministry of National Guard Health Affairs Foreword by Dr. Paul Rothman CEO, Johns Hopkins Medicine Published by CRC Press, 2017
FEATURES
Contains contributions from recognized healthcare leaders from the UK, USA, Canada and South Korea/Singapore.
Describes how leadership can ensure reliable standards of care for patients and how excellence can be achieved.
Focuses on a different aspect of building a reliable healthcare system.
Relevant to global healthcare systems with key themes such as effective clinical practice and crisis management being universal.
Cancer cells sometimes metastasize from a primary tumour to other sites in the body through the blood.
34
June 2019
Uncovering the drivers of primary tumour growth
I
t is widely known that metastases — cancer cells that have spread from a primary tumour to other parts of the body — are the main cause of cancer-related mortality. What triggers metastasis is a subject of intense investigation. Many studies have focused on the epithelial-to-mesenchymal transition (EMT), a process first described in chick embryos in the early 1980s, as a way to explore whether cancer cells might be hijacking this natural developmental process to spread. EMT involves the transformation of cells from an epithelial state, such as those found in the skin and intestine, to a mesenchymal state, such as those in bone, muscle and cartilage. Recently, attention has turned to various proteins that activate EMT, called EMT transcription factors. A research team in Spain has now uncovered further evidence pointing to the effects of two EMT transcription factors, named Snail and Serpent, on
innovations.kaimrc.med.sa
early tumour progression. The researchers observed that EMT transcription factors are often found in benign and in primary tumours — that is, before the onset of metastasis. “This observation motivated us to ask if they may play a role in driving primary tumour growth,” the team says in their paper, published in PLOS Genetics. The researchers studied the effects of Snail and Serpent on changes in wing disc size in fruit flies. Wing discs of fly larvae, which later develop into legs, wings and antennae, are commonly used as a model for studying cellular and genetic changes. Both Snail and Serpent led to uncontrolled proliferation of wing disc cells. However, Snail was also found to be associated with a decrease in cell size, as well as extensive cell death, which meant that on balance, the overall tissue size did not increase. In contrast, Serpent was associated with an increase in cell size, without cell death, which did
lead to an increase in wing disc size. Also, when the Serpent-induced tumour-like tissue was transplanted into the abdomen of adult fruit flies, the tissue continued to grow. These results suggest that Serpent induces tissue growth by “triggering cells to proliferate and grow indefinitely,” the researchers say. Based on previous findings, they say that Serpent might work by activating several tumour-promoting biological pathways at the same time. These pathways, including ones specifically known as the Yorkie signalling pathway and the Ras pathway, could “act cooperatively both in early stages of primary tumour growth and later in driving invasion and metastasis,” they conclude. Campbell, K., Lebreton, G., Franch-
Marro, X., & Casanova, J. Differential roles of the Drosophila EMT-inducing tran-
scription factors Snail and Serpent in driving primary tumour growth. PLOS
Genetics 14(2): e1007167 (2018).
Issue No.5
35
A N DR EAS F ÜLS C H ER S C H LI EM A N N / A L A M Y S TOC K P H OTO
Key proteins could contribute to much earlier cancer progression than previously thought.
An effective solution for marrow transplantation
A combination of young and adult donor stem cells offers robust, safe treatment for lymphoma patients lacking closely matching donors. Lymphoma patients who are ineligible for a commonly used stem cell transplantation regimen must typically resort to riskier and less effective treatment strategies. New research from a team led by Koen van Besien at Weill Cornell Medical College in New York presents an improved alternative for these patients, which can improve the likelihood of long-term remission. Autologous stem cell transplantation entails harvesting a patient’s marrow when their lymphoma is under control. If the cancer recurs, the patient is treated 36
June 2019
with chemotherapy to eradicate diseased blood cell precursors, which are then replaced with cells derived from the stockpiled, healthy marrow. However, many patients are not eligible for this treatment because of characteristics of their disease or their response to prior therapy. “Approximately 30 percent of our patients are in that group,” says van Besien. Individuals without closely matched donors can receive stem cells from a partially matched donor, which increases risk of relapse, or from umbilical
cord blood, which lowers the risk of rejection but greatly delays rebuilding of the immune system. Van Besien and colleagues showed that combining two approaches offers the best of both worlds. In this treatment, mature immune cells from partially matched donors temporarily protect the recipients until the immature umbilical cord-derived cells can catch up. Ultimately, these latter cells will become the majority of the immune cell population in most recipients. The researchers tracked outcomes for 42 lymphoma and chronic lymphoid leukaemia patients who received this combination treatment, and the outcomes were largely impressive. Three years after treatment, 65 percent of patients were still alive, and 53 percent of patients reached this stage without disease relapse or signs of graft-versus-host disease. Only 8 percent of patients were diagnosed with graft rejection. Van Besien found these results encouraging. “This was a group of patients who, until recently, lacked good alternatives,” he says. Most clinics still rely entirely on partially matched donor marrow when autologous transplant is not an option and when matching donors are not available. van Besien believes that faster recovery, reduced risk of relapse, and compatibility with less closely-matched donors of the combination approach offer significant advantage. Story summary: Many lymphoma patients are ineligible for a stem cell treatment that can lead to long-term remission, due to the absence of a closely matched donor. A treatment regimen that combines partially matched donor marrow with umbilical cord blood-derived stem cells can greatly benefit these patients, with minimal risk of graft rejection and years of relapse-free survival for a majority of recipients. Hsu, J., Artz, A., Mayer, S.A., Guarner, D., Bishop, M.R., ReichSlotky, R., Smith, S.M., Greenberg, J., Kline, J., Ferrante, R.
et al. Combined haploidentical and umbilical cord blood
allogeneic stem cell transplantation for high-risk lym-
phoma and chronic lymphoblastic leukemia. Biology of
Blood and Marrow Transplantation 24, 359–365 (2018).
P HA NI E / A L A M Y S TOCK P HOTO
A cocktail of young and adult stem cells could be a treatment option for some lymphoma patients.
The identification of new genetic risk factors for colorectal cancer offers hope for existing patients and a warning for those with the identified mutations.
Revealing the missing heritability of colorectal cancer
Diagnosis of colorectal cancer may improve following the discovery of two gene mutations.
T
hirty years of investigations into the genetic causes of colorectal cancer have identified 14 genes that, when mutated, are associated with an increased risk of the disease. Now, a Saudi-US research collaboration has found two more genes, greatly improving the ability of clinicians to identify at-risk individuals, while indicating potential therapeutic options for chemotherapy-resistant patients. innovations.kaimrc.med.sa
Colorectal cancer is a critical health concern in Saudi Arabia alongside much of the developed world. Despite a predicted 30 percent of colorectal cancer risk being attributable to inherited factors, the known genetic risk factors explain only five to ten percent of cases. “This is what’s known as ‘missing heritability,’” says Saud AlDubayan, who co-authored the collaboration’s study, published in The American Journal of
AlDubayan, S., Giannakis, M., Moore, N. D., Han, C., Rear-
don, B. et al. Inherited DNA-repair defects in colorectal cancer. The American Journal of Human Genetics 102,
401-414 (2018).
Issue No.5
37
JUA N G A E R T NE R / S CI E NCE P HOTO L I BR A RY / G E T T Y I M AG E S
Human Genetics. AlDubayan describes seeing many members of the same family developing colorectal cancer without having any of the known mutated genes that indicate hereditary risk. With a clear need to identify more sources of cancer heritability, AlDubayan’s team compared the DNA of almost 4,000 colorectal cancer patients to more than 27,000 healthy individuals. The results showed two heritable genetic mutations in the genes ATM and PALB2 that were more common in cancer patients, suggesting a causal link. “The diagnostic yield increased by 20 percent when we included these two genes in genetic screening for colorectal cancer risk. This is huge,” says AlDubayan. Not only does this discovery enable the identification of those at risk of colorectal cancer, but a positive result can also inform relatives of their own potential risk. Perhaps the most exciting revelation is that ATM and PALB2 are both involved in a biological pathway, known as homologous recombination (HR), that mediates the repair of double-stranded DNA breaks. “This particular pathway is very targetable,” explains AlDubayan. “We already have FDA-approved medications for chemo-resistant patients with mutations to genes involved in the HR pathway.” AlDubayan expects these particular patients to be “exceptionally responsive” to the drugs and that this will give some hope to people enrolling in clinical trials after initial chemotherapy has failed. AlDubayan credits the decreasing costs and increasing capabilities of genetic sequencing as driving forces behind the team’s discovery, alongside a global collaborative sharing of genetic data. The team now plans to use its methods to identify other pathogenic mutations within DNA pathways and are preparing to publish their discovery of a gene mutation that’s associated with a four-fold risk of developing egg or sperm cell cancers.
Colorectal cancer: Overweight young people at risk Being overweight before the age of 30 may increase the chances of developing colon cancer later in life.
P
oor diet, sedentary behaviour and obesity in adulthood have been linked to a higher risk of developing multiple cancers, including colon and rectal cancer. Now, scientists in China have shown that the risks of developing colon cancer may be related to being overweight before the age of 30. Colorectal cancer rates vary considerably from country to country, with the highest number of cases in Australia and New Zealand, and incidence rates rising in Asia, South America and Eastern Europe. Excess body fat in adulthood has long been
38
June 2019
associated with colorectal cancer risk, Shi. “However, it may be that difference possibly due to the associated hormonal in body composition between men and imbalances and inflammation, which have women, and possibly the protective influan impact on metabolic health. However, ence of oestrogen in hormone replacelittle is known about whether having a ment therapy in postmenopausal women, high body mass index (BMI) under the age could explain gender differences.” of 30 influences the chances of developing The team also found that excess body colorectal cancer later. fat at an early age is more strongly asso“It would be incredibly helpful to ciated with colon cancer risk than with know how body fatness affects the develrectal cancer risk. opment of colorectal cancer throughout Colorectal cancers can take many the human lifespan years to develop and to improve prevenspread, so it is pos“Scientists found a 17 tion strategies for sible that pre-canpercent higher risk of this cancer,” says cerous lesions may Khemayanto Hidayat start at a young age. developing colorectal at the First Affiliated Shi’s team calls for cancer in men and 8 Ho s pit a l o f S o o further internachow University in tional research into percent higher risk in Suzhou, China, who links of body fatness women for every 5 worked on the study with cancer to pinkilograms per square with co-workers point the times in life Chun-Mei Yang and meter increase in BMI.” where excess body fat Bi-Min Shi. is most detrimental. The team con “Our findings ducted a meta-analysis of data collected indicate that we should perhaps be during 15 studies from 1992 to 2016, coverintervening sooner than mid- and lateing 17,754 people under the age of 30 from adulthood,” says Shi. “Educating young predominantly Western countries. They people about the dangers related to weight found a 17 percent higher risk of developgain and obesity should be a global health ing colorectal cancer in men and 8 percent priority.” higher risk in women for every 5 kilograms per square meter increase in BMI. Hidayat, K., Yang, C-M., & Shi, B-M. Body fatness at an “The exact reasons for these sex-speearly age and risk of colorectal cancer. International Jourcific discrepancies remain unclear,” says nal of Cancer (2017). innovations.kaimrc.med.sa
Issue No.5
39
S EB AS T I A N K AULI T ZK I / A L A M Y S TOC K P H OTO
Researchers in China have conducted a meta-analysis of data indicating that people with excess body fat under the age of 30 are at high risk of developing colon cancer later in life.
FEATURE
Putting Saudi Arabia on the clinical trial map
KAIMRC’s new initiative stands to kickstart Saudi Arabia’s clinical trials economy, and find treatments for its people.
C
linical trials are a cornerstone of medical R&D, a wellspring of jobs, revenues and a way to provide more cutting-edge treatments to patients in desperate need. Yet, despite a population of nearly 33 million and an array of excellent research centres that attract academics from across the globe, Saudi Arabia doesn’t conduct nearly enough clinical trials. This represents a huge gap in the country’s burgeoning research portfolio, and a challenge that KAIMRC is rising to meet with its initiative: the Saudi Network for Clinical Trials 40
June 2019
(SNCT). Through increasing clinical trials around the country, researchers can also develop medicine for the specific genome of the Saudi population. The SNCT aims to increase the quality and quantity of clinical trials conducted within Saudi Arabia through two main projects; one aimed to develop the kingdom’s legal and regulatory framework to lessen the bureaucracy, and the other to train and retain the necessary talents. The SNCT prioritizes attracting and maintaining clinical trials expertise within the country through a training
programme and by bringing international experts to educate current and future Saudi clinical research personnel, says the project’s lead, Shuruq Al Yousef. The centre also wishes to transform the regulatory environment within Saudi Arabia to make the country an attractive destination for national and international partners. In trying to achieve this, the initiative also finds its greatest challenge: Clinical trials are very time-sensitive, and the biopharma industry will use locations which are best suited to the fast pace of trials. “It’s not open-ended,” says Abdelali Haoudi, KAIMRC’s head of strategy and business development. “We can’t just wait six, 12 or 18 months for a decision to be made — we won’t succeed unless our national framework adapts.” On this issue, KAIMRC is working collaboratively with the Saudi Food and Drug Authority, in efforts to foster understanding and raise interest in clinical trials. It’s envisaged that by laying the two foundations of skill development and regulatory amenability, Saudi Arabia can start to transform its clinical trials ecosystem. The team behind the initiative also hopes the SNCT can become a regional hub for drugs and therapies, and a coordinating centre for clinical trials.
Laying the foundations
KAIMRC is working to further clinical research by giving scientists more time. “Clinicians are known to be extremely busy, and allocating time for their patients is their number one priority,” says Haoudi, before explaining that some countries in Europe and North America designate protected time for clinicians so that they can afford to focus on research. “Unless we can provide that same opportunity here, they’ll never find the time to lead clinical trials,” he says. To try to mitigate, KAIMRC is pushing more funding towards clinicians, to reduce the time sink of applying for grants. This effort is already underway and making an impact: in September 2018, researchers funded by KAIMRC unveiled a wealth of new data on the prevalence of cancer-affiliated BRCA1/2 mutations in high-risk Saudi patients
with breast cancer. Haoudi wanted to make better use of KAIMRC’s experience, and help develop clinical trials across the kingdom. “I started thinking about taking a clinical trials initiative to a national level about two years ago,” recalls Haoudi. Noting the progress his own institution had taken in maintaining its own clinical trials, and their benefit to healthcare and the economy, Haoudi realized “that the resources of only one institution aren’t going to be enough.” Over about 15 months where Haoudi, Al Yousef and their team formulated a plan to take to the government. Their efforts paid off when the initiative was funded with SAR 55 million (more than $14.6 million) and was earmarked as one of the country’s top initiatives by Khalid al-Falih, the minister of Energy, Industry and Mineral Resources. Then in January 2019, the Crown Prince of Saudi Arabia, Mohammed bin Salman bin Abdulaziz Al Saud, announced the formation of the SNCT and signed a memorandum of understanding in support of the project.
Cross-border collaboration
The KAIMRC team is drawing inspiration and guidance from the clinical research success story of South Korea. In less than 10 years South Korea has transformed its unexceptional clinical trials profile into that of a world leader, explains Haoudi. KoNECT (the Korea National Enterprise for Clinical Trials) is now a close partner to the KAIMRC initiative, with the SNCT’s creators hoping that they can replicate South Korea’s exceptional growth in their own country. The architects of the Saudi-South Korea partnership hope their work will also deepen ties between the two countries. Following meetings in both South Korea and Saudi Arabia, representatives from both organizations signed an agreement in 2017 to jointly explore avenues of innovation in medical R&D. Now, they’re on the cusp of finalizing a new agreement to implement training courses for Saudi researchers. “I imagine there will be many more such agreements in the future,” says Al Yousef. Haoudi adds that “they’ll be our partner throughout innovations.kaimrc.med.sa
this whole initiative…We can learn from their success and hopefully improve our own practices here.” Following the signing of the agreement in June 2019, the SNCT hopes to formally start its activities in September. Houdi believes that a few main factors make KAIMRC the right institution to spearhead the country’s new clinical trials programme. “We conduct the largest
“The SNCT aims to
increase the quality
and quantity of clinical trials conducted
within Saudi Arabia.“ number of clinical trials in the country as an institution, averaging 70 per year,” he says, adding that KAIMRC’s sites spread around the country extends the institution’s reach to “the entire Saudi population.” In addition, KAIMRC already has its own clinical research organization (CRO), which brings with it key insights and experience to the business side of clinical research operations. The research centre’s deep ties with government and academia offer the support for many leading
institutions across the country, including the Saudi Health Council, King Faisal Specialist Hospital and Research Center, King Abdulaziz University, and Princess Nourah bint Abdulrahman University. KAIMRC is also the only intuition in Saudi Arabia constructing a Phase I clinical trials centre. “Phase I is the fundamental stage in clinical trials, and a good indicator of an institution’s capacity for innovation in medical R&D,” says Haoudi. As well the huge revenue potential of the SNCT and the boost to Saudi clinical trials it stands to offer, the initiative also provides direct support to the goal of Saudi Vision 2030 Perhaps the biggest benefactors of the SNCT, however, will be Saudi patients. With the current lack of high-quality clinical trials in the country, there remains a largely-underexploited opportunity to tailor treatments to conditions arising from Saudi-specific genetics. An investment in Saudi clinical trials will inevitably lead to new treatments and interventions able to transform the lives of Saudi citizens. There’s a long road ahead before this goal is realized, but KAIMRC is making daily progress. “Hopefully, this will set up the ecosystem that leads to facilitating local industrial drug development, manufacturing, and commercialization,” says Haoudi. “One step at a time.”
Issue No.5
41
Nuclear protein modulates cell fate and identity
A cellular protein involved in anchoring chromosomal material to the inside of the nuclear membrane is important for determining a cell’s fate.
A new study shows that beta-actin does play an essential role in regulating which gene programs are turned on in the nucleus during cell differentiation and development.
42
June 2019
T
he nucleus needs to be reprogrammed for cells to differentiate into new cell types. During this process, chromatin is seen to be re-organizing itself in a way that is thought to turn on new gene expression programs in the cell. A protein, called beta-actin, is implicated in this process of chromatin remodeling. Now, a new study shows that beta-actin does play an essential role in regulating which gene programs are turned on in the nucleus during cell differentiation and
development. It does this by bringing certain genes closer together at ‘docking stations’ on the inside of the nuclear membrane. A research team, including Bader Almuzzaini from King Abdullah International Medical Research Center, ‘turned off’ beta-actin in mice embryos to see how this affected fibre- and collagen-producing cells called fibroblasts. They found that densely packed chromosomal material, called heterochromatin, was not only localized to the inside of the nuclear membrane, as is the case in
beta-actin-containing cells, but was also present within the nuclear interior. This indicates that beta-actin plays a role in confining heterochromatin to the nuclear periphery. Beta-actin is an important component of the so-called ‘chromatin-remodelling complexes’; in particular the one known as Brahma–associated factor (BAF). Cells mobilize these complexes to hamper bonds in chromatin between proteins called histones and DNA. This reconfigures the DNA packaging structure and modifies innovations.kaimrc.med.sa
gene expression. There is evidence that BAF anchors heterochromatin to the nuclear periphery. The scientists suggest that actin is involved in the interaction between heterochromatin and the nuclear membrane, through the regulation of the Brahma-related gene 1 (BRG1) subunit of the BAF complex. Since the team measured a substantial loss of BRG1–chromatin binding in the absence of beta-actin, they suggest that BAF deprived of beta-actin is less efficient in binding and docking heterochromatin, which might explain why it
was found in the nuclear interior. The research sheds some light on the complex and still poorly-understood genetic reprogramming mechanism of cells, and suggests how beta-actin can act at the interplay between nuclear architecture, heterochromatin organization, and regulation of gene expression. Xie, X., Almuzzaini, B., Drou, N., Kremb, S., Yousif, A., et al. β-Actin–dependent global chromatin organization and gene expression programs control cellular identity.
The FASEB Journal (2018).
Issue No.5
43
HE IT I PAV ES / A L AM Y STO C K PH O TO
The researchers turned off beta-actin in fibreand collagen-producing cells called fibroblasts.
Uncovering the pivotal role of protein IGFBP-6 in the early stages of skeletal muscle differentiation could pave the way for stem cell therapies targeting muscle diseases.
Muscle disorders: Stem cells create skeletal muscle
Stem cells from the human placenta can form new skeletal muscle tissues and may be used for treating muscular diseases.
P
atients with degenerative diseases that attack skeletal muscle tissues, such as Duchenne muscular dystrophy, may soon benefit from novel stem cell therapies. A study has demonstrated how new skeletal muscle tissues can be grown from stem cells derived from the human placenta. The results give insights into the role of a protein that is crucial for correct skeletal muscle development.
44
June 2019
“Stem cell therapies that replace damaged cells or encourage renewed functioning of existing muscular tissues could transform the treatment of muscle diseases,” says KAIMRC’s Doaa Aboalola, who conducted the study with Victor Han at Western Ontario University in Canada. “Firstly, we needed to find a safe, abundant source of multipotent stem cells that would potentially be accepted by host immune systems. Placenta-derived
Aboalola, D. & Han, V.K.M. Insulin-like growth factor binding protein-6 alters skeletal muscle differentiation
of human mesenchymal stem cells. Stem Cells Interna-
tional (2017)
T E K I M AG E / S CI E NCE P HOTO L I BR A RY
mesenchymal stem cells, or PMSCs, showed great promise.” Previous investigations into PMSCs have shown that they can differentiate into bone, muscle, cartilage and fat cells. A collaboration with medical staff allowed Aboalola and Han access to fresh placenta tissue from healthy women, from which they isolated the PMSCs. They then incubated the stem cells in special cultures and confirmed that PMSCs can differentiate into skeletal muscle. The researchers then turned their attention to the role of one specific protein— insulin-like growth factor binding protein-6 (IGFBP-6)—in skeletal muscle differentiation. IGFBP-6 is part of a protein family that aids the activity of insulin-like growth factors: molecules that are vital to healthy muscle growth and development. The team knew that IGFBP-6 was highly expressed in developing muscle cells, but wanted to examine its role further. “We discovered that IGFBP-6 is expressed by PMSCs in the very early stages of differentiation, prior to commitment to a specific cell type,” says Aboalola. “In fact, the presence of IGFBP-6 is critical for the expression of ‘marker’ genes and proteins associated with muscle development and pluripotency. When we knocked out IGFBP-6, muscle marker expression reduced considerably, and this delayed the differentiation process.” These findings suggest that IGFBP-6 could potentially be used to help guide skeletal muscle regeneration for use in stem cell therapies. “We plan on using mouse models with muscle injury to test PMSCs and IGFBP-6 effects [in the living animal],” says Aboalola. “We are also expanding our research to include the insulin-like growth factor system and its signalling pathways to establish the best environment for the PMSCs to differentiate into skeletal muscle.”
Medical
BIOTECHNOLOGY Park The Medical Biotechnology Park, a new company at KAIMRC/MNG-HA is a strategic project of MNG-HA to contribute to the Saudi Vision 2030 through:
The development and commercialization of biomedical R&D products, technologies and services
The contribution to economic and health improvement through science and innovations in medical and health sectors
EMAIL: KAIMRC-KMBP@NGHA.MED.SA PHONE NUMBER: +966-11-429-4516 TWITTER: @MEDICALBIOTECH
The many faces of a mitochondrial mutation A rare gene mutation affecting a mitochondrial transporter could be more common than previously thought.
46
June 2019
A
team of Saudi researchers has found that a rare genetic mutation, mainly affecting the brain and muscles, may be more common than previously thought because it presents differently in people. The team studied 12 patients from Saudi Arabia and the US with a mutation in the gene SLC25A42. They found that each patient carried the same ‘founder mutation’ but that its clinical presentation varied. SLC25A42 codes for a protein that binds to and transports a crucial compound, called coenzyme A, across the membrane of mitochondria, the energy powerhouses of cells. Many enzymes need this compound to catalyse some of the most crucial reactions of metabolism. The disease associated with mutations in this gene is
innovations.kaimrc.med.sa
a form of ‘mitochondrial encephalomyopathy’, with a range of neurological and muscular problems as its most obvious clinical manifestations. The apparent absence of neurological problems in one child with the SLC25A42 mutation was the clue that led the research team to discover that the overall effects of the mutation can be more variable than previously supposed. The researchers identified twelve patients with the mutation by examining their medical histories. They then examined the protein-coding portions of their genomes. Their analysis revealed that the same mutation led to varied clinical manifestations, ranging from very mild, barely noticeable symptoms, to severe developmental impairment and epilepsy.
“Given the variable severity and non-specific presentation, this disorder is probably underestimated,” the researchers conclude in their study published in the journal Clinical Genetics. They suggest that clinicians should be more aware of the possibility that this disorder may lie behind any of a range of symptoms they have reported. They also suggest this should be considered “especially in patients of Arab descent,” given the prevalence of births from closely related parents in that population. Consanguinity was a common factor in the 12 cases examined in this study. Almannai, M., Alasmari, A., Alqasmi, A., Faqeih, E., Al Mutairi, F. et al. Expanding the phenotype of SLC25A42-associated mitochondrial encephalomyopathy. Clinical Genetics 93, 1097-1102 (2018).
Issue No.5
47
B SI P SA / A L AM Y S TOC K P H OTO
Mitochondria are the energy-supplying powerhouses of the cell, but are significantly disrupted by mutation in the SLC25A42 gene.
The immune sting of WASp
A protein implicated in a range of immune diseases proves essential for proper T-cell development.
T
48
June 2019
Deficiencies in WASp can cause Wiskott-Aldrich syndrome (pictured here) and a range of other immunological disorders.
They looked for sites where WASp bound to the genome in immature T-cells in the thymus and in more mature T-cells in the spleen. They pinpointed 15 genes and further investigated a few of them. Experiments in genetically modified mouse models confirmed that one gene in particular — tcf12, which encodes a protein called T-cell factor 12 — relied on interactions with WASp to properly regulate the activity of other genes. Further studies showed that WASp plays a similar role for another important regulator called tcf1. These findings place WASp in close proximity with these two factors, showing that “WASp is an essential regulator for the maturation of T-cells during development,” says Almuzzaini.
It is perhaps not surprising then that aberrations in T-cell development are a hallmark of diseases linked to WASp mutations. However, it remains unclear how different WASp deficiencies lead to different clinical symptoms. “This needs further investigation,” Almuzzaini says. With that knowledge it should be possible to devise immune-modulating treatments that overcome the aberrations in T-cell function induced in WASP-associated diseases. “That,” says Almuzzaini, “is the ultimate goal.” Kuznetsov, N. V., Almuzzaini, B., Kritikou, J. S., Baptista, M. A. P., Oliveira, M. M. S. et al. Nuclear Wiskott-Aldrich
syndrome protein co-regulates T cell factor 1-mediated transcription in T cells. Genome Medicine 9, 91 (2017).
M E D I S C AN / A L A M Y S TO C K P HO TO
he discovery of a protein’s contribution to the development of T-cells in the spleen and thymus could lead to new treatment strategies for immunodeficiency diseases. Despite its name, the Wiskott-Aldrich syndrome protein (WASp) is not only implicated in Wiskott-Aldrich syndrome, a rare genetic disease characterized by low platelet count, eczema and recurrent infections. Although mutations that abolish WASp expression can cause the namesake immunodeficiency disorder, other less disruptive DNA changes produce milder symptoms, such as low platelet counts, while mutations that put WASp activity into overdrive lead to low levels of infection-fighting white blood cells. KAIMRC molecular geneticist Bader Almuzzaini and his colleagues set out to determine why different WASp mutations elicit diverse effects on the immune system. They focused on one population of immune cells in particular: helper T-cells, which serve as master regulators of immune defence. The researchers used a method called ChIP-seq to find all the sites in the genome of mouse helper T-cells where WASp binds. They found that the protein interacted with both coding and non-coding stretches of DNA, and it was particularly prone to binding in or near genes involved in RNA synthesis. Almuzzaini and his colleagues — including scientists from the Karolinska Institute in Sweden and Harvard Medical School in the United States — next wanted to identify the genes that are consistently regulated by WASp throughout the full process of T-cell maturation.
Target Audience King Abdullah International Medical Research Center (KAIMRC) in collaboration with The Deanship of Postgraduate Education, KSAU-HS is pleased to invite you to attend the 9th Annual Forum for Medical Research with the theme “Achieving the National Vision through Medical Research”.
WEBSITE: FORUM.KAIMRC.MED.SA E-MAIL: RESFORUM-GENERAL@NGHA.MED.SA
• • • • •
Biomedical & health research experts, clinicians , faculty, students Pharmaceutical & Biotechnology industry experts Health Research funders Health government representatives R&D experts and administrators
In extremely rare cases, the mechanisms that maintain healthy mitochondria break down, with dire consequences for affected patients.
50
June 2019
More cases of a debilitating genetic disorder
U
ntil recently, ‘MPV17-related mitochondrial DNA preventing its proper function. maintenance defect’ had been identified in just 75 Looking at all 100 patients, the researchers found a bleak patpeople worldwide. The condition disrupts the functern of symptoms: the vast majority suffered severe, early-onset tioning of cellular energy producers known as mitodisease of the brain, nervous system and liver, with 87 progresschondria, leading to catastrophic dysfunction of the brain, liver ing to liver failure by early childhood. Other hallmark symptoms and nervous system. Now, a team of geneticists, pediatricians, included developmental delay, lack of muscle development, and and developmental biologists, led by Lee-Jun Wong of the Baya general failure to thrive. Of the patients with the disease, 75 lor College of Medicine in Texas, has combed medical databases have died, most in early childhood. There is no cure, and the to find new incidences of the disease. The management of the disease is largely team also collated and reviewed the medfocused on symptomatic relief and The vast majority suffered ical understanding of this extremely rare assessments of the patients’ affected and debilitating disorder. severe, early-onset diseases organs. 17 patients have undergone The vast majority of human genetic liver transplants; however, results of the brain, nervous material is contained within the nuclei of were largely unsatisfactory, with more cells; but a small amount of protein-enthan half dying from post-operative system and liver, with 87 coding DNA is found in mitochondria. complications. progressing to liver failure While containing just 37 genes, mitochonIt remains to be seen just why MPV17 by early childhood. drial DNA is critical to the maintenance of dysfunction particularly ravages the normal physiology, and its production is liver, brain and nervous system. In maintained, in part, by MPV17. This prohealthy individuals, these tissues tein is believed to form transmembrane channels for small molcontain high levels of the protein, suggesting a particular role ecules, allowing the building blocks of DNA to be transported in these organs. In their recently published Human Mutation into the interior of a mitochondrion. paper, the researchers note that cells taken from MPV17-defiThrough searches of the Baylor Genetics Laboratory datacient patients could be rescued with supplemental DNA compobases, Wong and his team were able to find 25 cases of nents, offering a potential avenue for further clinical exploration. MPV17-related mitochondrial DNA maintenance defect yet to be reported in medical literature, in addition to the 75 patients El-Hattab, A. W., Wang, J., Dai, H., Almannai, M., Staufner, C. et al. MPV17-related already known. These new patients also had nine previously mitochondrial DNA maintenance defect: New cases and review of clinical, bioundocumented pathogenic changes in the MPV17 gene, chemical, and molecular aspects. Human Mutation (2018). innovations.kaimrc.med.sa
Issue No.5
51
W I R 0 M A N / I S TOC K / G ET T Y I M AG ES P LUS
Mitochondrial DNA plays an essential role in human physiology, with devastating consequences when it is disrupted.
FEATURE
Train efficiently, not more
N
ew research published in Experimental Physiology suggests health benefits related to resistance training can be achieved in less time through single-set resistance training, which is good news for busy people seeking time-efficient solutions. The research found short-duration resistance training increased muscle mass and strength, and improved insulin sensitivity. The research was conducted by a team of researchers at the University of Glasgow led by Stuart Gray, lecturer in exercise and metabolic health. Low muscle strength is linked with a range of poor health outcomes, including cardiovascular disease, cancer, and higher diabetes 2 incidence. Previous work showed that maintenance of muscle strength through resistance training may improve metabolic health and insulin sensitivity in people with type 2 diabetes. The aim of this study was to investigate, in overweight healthy men, the effects of short-duration resistance training over a six-week period on insulin sensitivity and muscle adaptations, with a weekly time commitment of fewer than 60 minutes. Brad Schoenfeld, assistant professor at the Exercise Science Department, Lehman College at City University of New York who wasn’t involved in the study,
52
June 2019
points out one of the most unique aspects of the research is the fact that it was a low volume routine. “That means you don’t have to be at the gym a long period of time, and that’s one of the most known excuses why people don’t train,” he says.
Maximum effort, fewer reps
Nine exercises were selected based on equipment found at most gyms and that target most muscle groups. “The exercises we’re doing here are simple,” says Gray. Selected exercises were leg press, bench press, leg extension, shoulder press, leg flexion, seated row, calf raise, latissimus pulldown and biceps curl. The training programme consisted of a single set of each exercise three times a week. A training session lasted 15-20 minutes. Each set was performed at 80 percent of the one-repetition-maximum (1RM) to volitional fatigue. Volitional fatigue is the point at which you can’t move through with a full completion of an exercise, explains Richard Bracken, associate professor sports science at Swansea University. “Despite the best mental effort to will the body to move, the body is fatigued and can’t move. So that weight is taken as the 100 percent of your 1RM and that would occur for each exercise,” Bracken explains. “So by the end of that first
session you’ve got nine exercises with the maximum weight that you could lift.” To ensure participants achieved their maximum for the actual study, they were prepared in pre-training exercise sessions. “So what we do is we get people to start at a relatively light load not too heavy for them. They do a contraction, so maybe a bench press, and they manage it. Next time we make it a little bit heavier. They try it again until they can’t actually lift the weight,” explains Gray. Then it can be assumed they trained at 80 percent of their maximum.” Three weeks into the study, participants’ 1RM was reassessed and the weight was adjusted. Bracken, who wasn’t involved in the study, agrees with the method, explaining that “There’s a need to continually monitor how much you can lift maximally.” The six-week study resulted in increases in muscle strength and size and a 16 percent improvement in insulin sensitivity. “Insulin sensitivity is basically how sensitive that muscle is to that insulin,” explains Gray. “Somebody who is not insulin sensitive may require a lot of insulin to clear the blood.” “I often think the muscle is this sponge that soaks the sugar out of the blood,” says Gray. “So if you’ve got a bigger
Y. K H A LI L/N AT UR E
New research by the University of Glasgow suggests that 15 minutes of resistance training to the point of exhaustion three times a week can have the same health benefit as longer sets.
Going all out
Researchers conlcuded that 15 minutes of resistance training to the point of volitional fatigue three times a week can be just as efficient in improving insulin sensitivity and increasing muscle mass as longer periods of exercise at less effort.
15
Exercises
3
minutes of single-set resistance training
days a week
at an 80% of the one-repetition maximum
The exercises all consisted of a single set of each exercise performed to the point of volitional fatigue.
Leg Press
Bench Press
Seated Row
Leg Extension
Calf Raise
Shoulder Press
Latissimus Pulldown
Leg Flexion
Biceps Curl
This led to a 16% improvement in insulin sensitivity
innovations.kaimrc.med.sa
Issue No.5
53
sponge, it will soak out more sugar.” Gray explains, “Before and after this six-week period we carried out an oral glucose tolerance test, which gives a measure of how you’re handling your blood sugar, and what we found was that after the training people got rid of the blood sugar more quickly from the blood. Also, the amount of insulin required to take that sugar was also less.” Due to time limitations, the study only focused on overweight men, Gray explains, but future studies will include both genders. Gray also recognises the limitation of the small sample size and says they’re planning to expand in the future. Asked about the statistical significance of the results of the study, Bracken comments, “The study could 54
June 2019
“The six-week study resulted in increases in muscle strength and size and a 16 percent improvement in insulin sensitivity.“ have been strengthened if they had used the data and the magnitude of changes in the primary findings to work out the statistical power needed for showing a true statistical significance.” Furthermore, Bracken believes, “The study would have benefitted from the true revealing of the magnitudes of change in muscle mass or insulin sensitivity by
having a control arm which is something that the authors indicated in the limitations section.” Gray’s next steps include confirming the findings of the study in a larger, less healthy, mixed gender population. “There’s very little public health messages about muscle-strengthening activity,” says Gray. The research is therefore targeting the public and sports facilities with the aim of educating people that resistance training can be performed in different ways. Ismail, A.D., Alkhayl, F.F., Wilson, J., Johnston, L., Gill, J.M., Gray, S.R. The effect of short-duration resistance training on insulin sensitivity and muscle adaptations in over-
weight men. Experimental Physiology 104, 540-545
(2019).
I N T E R ST I D / IS TO C K / G ET T Y I M AGE S P LUS
FEATURE
KAIMRC Experimental Medicine
Three state of the art vivarium facilities are located in Riyadh, Jeddah and Al Hasa. The vivariums are planned and designed according to international standards. They aim to assist biomedical research by providing animals and veterinary expertise. Moreover, they offer training and education in animal use for research. The facilities also work on the development and implementation of institutional policy, animal care and use policy including animal husbandry and veterinary care.
Studying the body of a recently deceased patient, KAIMRC’s Yaseen Arabi and co-workers found that viral particles of MERS-CoV collect in various organs in the body, including the lungs and kidneys.
56
June 2019
A gracious host for Middle East respiratory syndrome
P
atients suffering from infection with Middle East respiratory syndrome coronavirus (MERS-CoV) typically display a wide array of symptoms, ranging from a self-limiting cold-like illness to complete respiratory failure and death. However, little is known about the spread of the disease throughout the body, or which organs are predominantly affected. Now, KAIMRC intensive care consultant Yaseen Arabi and co-workers have conducted an analysis of disease-related changes to key organs and of the dissemination of MERS-CoV viral particles in the body of a recently deceased patient. Their findings indicate that viral particles collect in various organs in the body, including the lungs and kidneys. Organ dysfunction is a common element of severe MERS-CoV infection, particularly acute renal (kidney) failure, which is reported in 75 percent of critically ill patients. Alsaad’s team analysed organ tissue samples from a 33-yearold male patient who died in hospital following MERS-CoV infection in 2015. They collected samples from his heart, liver, kidneys, thigh muscles, brain and lungs within 45 minutes of death and conducted investigations using immunohistochemical staining and electron microscopy. The lung tissues showed severe haemorrhagic pneumonia. The researchers found varying degrees of damage across the lungs, with worst affected areas containing large amounts of blood and fibrous mesh growths that impeded blood flow, together with disrupted air sac pores. The kidney tissue showed significant changes to innovations.kaimrc.med.sa
tubular epithelial cells, which play a key role in kidney function. Some inflammation was found in the liver, but the team found no obvious changes to the heart and brain. Alsaad’s team then traced accumulations of viral particles throughout the samples. They demonstrated that MERS-CoV is expressed in several cell types, including pneumocytes (cells responsible for gas exchange in the air sacs of the lungs), renal cells and the cells that line the interior of blood vessels. Renal cells appear to encourage MERS-CoV replication and generate significantly more infectious viral particles than bronchial cells. The researchers also identified viral particles entering skeletal muscle tissues via host macrophages. Their findings suggest the possibility that the cells and tissues of the kidneys and skeletal muscles support the growth of the MERS-CoV virus, a phenomenon known as tropism. “It is possible that our patient’s reaction to MERS-CoV infection was atypical [he also suffered from lymphoma],” say the team in their paper published in the journal Histopathology. “Further detailed studies are needed to explore the morphological changes associated with MERS-CoV infection, and ultrastructural as well as immunohistochemical localisation studies are required to further enhance our understanding of viral pathogenesis.” Alsaad, K. O., Hajeer, A. H., Al Balwi, M., Al Moaiqel, M., Al Oudah, N. et al. Histopathology of Middle East respiratory syndrome coro-
navirus (MERS-CoV) infection – clinicopathological and unilateral study. Histopathology 72, 516–524 (2018).
Issue No.5
57
N AT I ON A L I N S T I T UT E OF A LLER GY A N D I N F EC T I OUS DI S EAS ES (N I A I D)
Kidney tissues could support the growth of Middle East respiratory syndrome coronavirus.
Western strain of hepatitis C on the rise in Saudi Arabia National efforts to curb transmission are in place to limit the virus’s spread.
58
June 2019
Expatriates have brought different strains of the hepatitis C virus to the kingdom from the one predominant in the Middle East.
T
he most prevalent strain of hepatitis C in Saudi Arabia is becoming less dominant as people from elsewhere carrying different strains of the virus settle in the kingdom. A KAIMRC-led study analysed the medical records of 630 people with the hepatitis C virus (HCV) treated between 2007 and 2011 at King Abdulaziz Medical City. innovations.kaimrc.med.sa
It showed that genotype 4 is still the dominant subtype, affecting 61 percent of HCV-infected individuals at the Riyadh hospital. But genotype 1, a dominant strain throughout much of the rest of the world, is on the rise in Saudi Arabia, especially among young infected males. The virus levels in the bloodstreams of people carrying HCV genotype 1 were three times
higher than those carrying genotype 4. These shifting infection trends are important for efforts to treat patients in Saudi Arabia; not only because genotype 4 is generally the most difficult to treat, but also because the presence of genotype 1 can impact therapeutic decision-making. Based on the HCV genotype, as well as other factors including the presence of liver cirrhosis or other viral infections, doctors may be more or less likely to administer older and cheaper immune-modulating agents, such as interferon, as opposed to newer, and more expensive, direct-acting, anti-viral therapies. “Confirming the HCV genotype is essential for deciding on treatment modalities and predicting patient responses to the specific therapy,” says Amen Bawazir, an epidemiologist at KAIMRC who led the study. Bawazir notes that the slight rise in hepatitis C cases with genotype 1 has coincided with a shift in the demography of Saudi Arabia, where approximately one third of the population was born abroad. He suspects that people arriving from places where the strain is more common, such as North America and Europe, brought different genotypes to the kingdom, which spread through the sharing of needles to inject drugs, and, more rarely, by blood transfusions. Bawazir is hopeful that transmission of all genotypes of HCV will decline. With better screening of blood supplies, the requirement for foreign workers applying for work visas to test negative for the virus, and the local availability of effective therapies, “all the most effective steps to eliminate hepatitis viral infection in KSA are already in place,” he says. Bawazir, A., AlGusheri, F., Jradi, H., AlBalwi, M. & AbdelGader, A. Hepatitis C virus genotypes in Saudi Arabia: a
future prediction and laboratory profile. Virology Journal 14, 208 (2017).
Issue No.5
59
N O P PA RI T / I S TO CK / GE T T Y I M AG ES P LUS
Genotype 4 is still the dominant subtype, affecting 61 percent of Infected individuals at the Riyadh hospital.
Chronic HBV infection is a major risk factor for hepatocellular carcinoma
60
June 2019
Targeting hepatitis B virus vulnerabilities
P
eople with chronic hepatitis B virus (HBV) 47 and 139 metabolites were significantly altered infection are at high risk of developing by HBV, whereas 28 and 149 metabolites were sighepatocellular carcinoma — the most nificantly altered by the HBV X protein. Among common form of liver cancer. Despite the these metabolites, seven were significantly availability of an HBV vaccine, there is currently no altered by both HBV and the HBV X protein. These effective treatment for chronic HBV infection. alterations, if reversed, may help restore the balMichael Bouchard and co-workers at the Drexel ance of the liver and, subsequently, alleviate or University College of Medicine in Philadelphia, treat chronic HBV infection. US, have now identified a host of new drug targets Most of the severely altered metabolites were for chronic HBV infection associated with glucose, using state-of-the-art pho s phol i pid a nd f at They found that 24 and 48 techniques. They identified metabolism. The result severely altered metabolites shows that, by analysing hours after infection, 47 and metabolic pathways in the expression levels of and 139 metabolites were hepatitis B-infected rats, metabolites and the metwhich could help guide the abolic pathways they are significantly altered by HBV. design of new therapies for involved in, there may be alleviating the infection that key compounds that can affects nearly 240 million people worldwide. be targeted in treating diseases. HBV primarily affects the liver, an organ with The researchers noted in their paper that a comvital roles in many metabolic processes, including plete understanding of the cellular consequences amino acid and lipid metabolism. The researchers of an HBV infection is critical, and that their results suspected that HBV may cause distinct changes in represent an important step towards the identificathe expression levels of metabolites, and that the tion of novel therapeutic targets for the treatment tipping of the balance is what causes the malady. of HBV. They are hopeful that with new profiling To hone in on these metabolites, the researchers col- technologies, other groups may further expand the lected samples from liver cells 24 and 48 hours after knowledge base of metabolic alterations. infecting rats with an adenovirus expressing HBV or the HBV X protein (the requisite part of HBV needed to Lamontagne, R. J., Casciano, J. C. and Bouchard, M. J. A broad invescause chronic HBV infection). They then profiled the tigation of the HBV-mediated changes to primary hepatocyte physexpression levels of 369 metabolites in the samples. iology reveals HBV significantly alters metabolic pathways. MetaboThey found that 24 and 48 hours after infection, lism Clinical and Experimental 83, 50–59 (2018).
innovations.kaimrc.med.sa
Issue No.5
61
DR LI N DA S TA N N A R D, UC T /S C I EN C E P H OTO LI B R A RY
Metabolic pathways altered by chronic hepatitis B virus infection may give clues to novel treatment.
A study on the prevalence of MERS-CoV in Gulf Corporation Council countries shows the virus has taken its greatest toll in Saudi Arabia.
An intermittent fasting regimen can reduce the size of white fat tissue cells (grey) and induce antiinflammatory immune cell activity (red).
A
team of scientists from Saudi Arabia has examined 1,550 reported cases of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection across the Gulf Corporation Council (GCC) countries to reveal disease prevalence in the Arabian Peninsula.
62
June 2019
MERS-CoV was first identified in Saudi Arabia in 2012. Since then, the World Health Organisation has reported nearly 2,000 cases of MERS-CoV infection worldwide. Infected patients have been identified in 27 countries and the highest occurrences have been reported in the Middle East and Korea. Due to the high
Aly, M., Elrobh, M., Alzayer, A., Aljuhani, S. & Balkhy, H.
Occurrence of the Middle East Respiratory Syndrome
Coronavirus (MERS-CoV) across the Gulf Corporation Council countries: Four years update. PLoS ONE (2017).
Y. K H A LI L/N AT U R E
Saudi Arabia worst hit by MERS
fatality rate among patients with laboratory-confirmed MERS-CoV, there is an urgent need for measures to contain it. KAIMRC’s Mahmoud Aly and colleagues found that 93 percent of MERSCoV cases reported in GCC countries between June 2012 and July 2016 were in Saudi Arabia, with the capital region Riyadh being the worst hit ( 52.4 percent of national cases). The reason for the high prevalence of MERS-CoV in Saudi Arabia remains unclear. The origin of the virus has been traced to African bats, but in 2014 it was isolated from dromedary camels and there is evidence suggesting that they may have acted as an intermediate host for the virus for several decades. Little is known about the transmission of the virus from camels to humans, but only 8.6 percent of the MERS-CoV infected patients stated that they had been exposed to animals. Speculating about the reason for MERS-CoV prevalence in Saudi Arabia, Aly says, “Saudi people could have a genetic predisposition that may contribute to their susceptibility to the virus infection.” Future studies into the genetics of affected individuals may shed further light on this possibility. Although virus transmission among the general population is not very efficient, the study confirms that once MERS-CoV enters a healthcare or hospital setting, it poses a great risk, especially to the elderly and patients receiving intensive care. These findings highlight the need for strict control measures in these settings. The study’s results will inform public health policies and the development of prevention strategies. “We hope to reduce the risk of new outbreaks by highlighting the importance of infection prevention and control infrastructures that will allow physicians and scientists to identify and immediately respond to the virus,” says Aly.
Translational Research Unit Is the Hub for clinical Trials with additional unique feature, phase 1 clinical Trials.
EMAIL: TRU@NGHA.MED.SA PHONE NUMBER: +966-11-429-4516
The Unit consists of: • • • • • • •
Reception Ward with 16 Beds Phlebotomy Room Volunteers Screening Room Volunteer Recreation Room Centrifuge and Freezer Room Chemistry Lab
FEATURE
Obesity and anaemia rife among Saudi female adolescents
A
new study1 has raised the alarm on the health and nutrition of Saudi adolescent girls, indicating that 77.6 percent of girls aged 16 to 18 suffer from iron deficiency anaemia, 18.2 percent are overweight and 11.5 percent obese. The study also indicates that they are likely to skip breakfast and follow a diet that is high in sugar, consuming a large amount of fast food, and soft drinks. Work by King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) examined the links between dietary trends, family income levels, excessive use of electronic devices, and insufficient exercise. The findings are largely in line with those of earlier studies, such as a previous study2 by the College of Medicine Taibah University demonstrating that 64 percent of female undergraduate students in Saudi Arabia suffer from anaemia. The prevalence of obesity and overweight among young people in the Arab world has been of concern in the past decades, particularly in Gulf countries where levels of affluence have been on the rise and obesity in children and adolescents reached
64
June 2019
18 percent in some countries, according to a 2014 study3 by Sultan AlNohair of Qassim University’s Department of Family and Community Medicine. “It is certainly clear that obesity is on the rise; the rates have multiplied over the past 15-20 years, and women are particularly susceptible to the disease,” argues AlNohair. He notes projections4 by a study conducted at KSAU-HS that predicts the overall obesity rate in Saudi Arabia to increase to 41 percent of men and 78 percent of women by 2022, whereas in 1992 the latter was at a mere 20.7 percent. “Obesity is associated with diabetes, heart disease, joint pain, osteoporosis, and numerous other health issues. Significant awareness efforts are needed to curb and limit obesity levels,” AlNohair says.
A sweet tooth
The 2018 study by KSAU-HS examines the reasons contributing to obesity among young women, the age group where females in Gulf countries are reportedly almost twice as likely to be obese than their male peers. Maha Al Turki, programme director of the Clinical Nutrition Program at KSAU-HS
and the lead researcher on the 2018 study, says that the eating habits observed in the Riyadh female adolescent demographic are likely similar to those elsewhere in the region. “I believe that that the eating patterns observed in the study might be similar to other patterns reported in previous studies,” she explains. For instance, in neighboring Bahrain, adolescents consume a diet high in some animal protein such as chicken, packaged foods such as potato chips, and low in fruits and vegetables, Al Turki adds. The study demonstrates that dietary patterns among female adolescents is not nutritious, pointing to consumption of calorie-high foods that are low in iron and fiber. Regularly drinking canned fruit juice, for example, was strongly linked to a higher percentage of body fat among the stated demographic. The study also notes that high sucrose and low fiber consumption aggravates the risk of metabolic syndrome and liver laceration. The intake of sweets is also noted to be somewhat higher among adolescent females versus their male peers, and research5 dating back to 2013 finds this to also be true of adolescent women in
Y. K H A LI L/N AT UR E
Study shows obesity and iron-deficiency are common among young women in Riyadh.
Poor diets and a sedentary lifestyle
Following a diet high in sugar and canned drinks, skipping breakfast and excessively using electronics, Saudi girls aged 16 to 18 are mostly leading a rather unhealthy lifestyle.
77.6 %
18.2 %
11.5%
54.5%
of girls aged 16 to 18 suffer from iron deficiency anaemia.
are overweight
are obese
of obese adolescent females come from families with a monthly income higher than SAR 10,000
Regular consumption of canned sugary drinks was common among those with higher body fat percentage.
Excessive use of electronic devices was linked to a sedentary lifestyle.
77.6% of anemic girls were found to consume more fast food.
37.5% of girls skipped breakfast. Girls in that age group consume a diet high in sugar. innovations.kaimrc.med.sa
Issue No.5
65
Kuwait. “Several studies have reported that hormonal fluctuations and stress among females may drive their desire to consume sugary foods. Another proposed explanation for this observed sugar cravings is that sugar intake stimulates the release of endorphins, which increases [a fleeting sense of] calm and well-being; since females tend to have lower levels of neurotransmitters, such as serotonin, they may consume more serotonin-boosting foods like sugar,” Al Turki says, urging further research on this aspect. The 77.6 percent of anemic individuals in the demographic were found to consume more fast food, fatty food and less meat than their non-anemic peers. More than a third of the young women in the study (37.5 percent) reported habitually skipping breakfast, a three-fold increase from a 12 percent rate Al Turki found in a study of primary-school children, further signifying the heightened risk of poor eating habits and related disorders, such as obesity, among young women as they hit puberty and enter adulthood. Female adolescents were more likely to be obese or overweight in families with higher income levels; 54.5 percent of obese adolescent females came from families with a monthly income higher than SAR 10,000 ($2,666). The study also 66
June 2019
“The study demonstrates that dietary patterns among female adolescents is not nutritious, pointing to consumption of caloriehigh foods that are low in iron and fiber.“ reports that 71.1 percent of individuals in the demographic habitually participate in some form of exercise, although it does not state the level of exercise intensity or the type of exercise performed. The study argues that frequent use of technological devices is inversely linked to optimal levels of physical activity. Similarly, the study AlNohair conducted attributes technological advancements, declining levels of physical activity, rapid urbanization and increased consumption of fast foods as major causes of rising obesity levels in Gulf countries. “The new lifestyle and the collapse of traditional reliance on naturally grown produce, a diet that was heavier in fibres, is a primary contributor to these issues,”
AlNohair says. He adds that the traditional Bedouin lifestyle of the past was less sedentary than that of modern-day cities in the Arab world. “Attention to healthcare and social care is cornerstone to Saudi Vision 2030,” says Al Turki, referring to increased public sector focus on developing medical services, awareness and treatment. “Several Saudi ministries have developed plans targeting lifestyle improvement and reducing the risk ofdiet-induced disease. In the academic year 2017-18, the Ministry of Education also approved the introduction of physical education classes for girls, encouraging female students to participate in exercise. While the government is taking positive steps to improve the health of the younger generation, there is still a lot more to be done. I would suggest perhaps including nutritional awareness topics in the national school curriculum, which would have a major [positive] impact.” AlNohair similarly lauds the Ministry of Health’s efforts to curb obesity rates, such as the development of pedestrian walking trails in major cities and the Saudi Arabia is Walking initiative, which launched in 2017 via Twitter. “Such initiatives need to be replicated more widely. In schools, teachers need to constantly educate students concerning health and lifestyle-related illnesses, particularly as obesity rates continue to rise among the younger generation. Also, school cafeterias need to offer more nutritious meal options,” he says. 1. Al Turki,M. et al Breakfast consumption habits among
schoolchildren: A cross-sectional study in Riyadh, Saudi Arabia. International Research Journal of Medi-
cine and Medical Sciences 6, 50-55, (2018) 2. Al Hassan, N. The prevalence of iron deficiency ane-
mia in a Saudi University female students. Journal of
Microscopy and Ultrastructure 3, 25-28 (2015). 3. AlNohair, S. Obesity in Gulf Countries. International
Journal of Health Sciences 8, 79-83 (2014).
4. Alqarni, S.S. A review of prevalence of obesity in Saudi Arabia. Obesity & Eating Disorders 2 (2016).
5. Allafi, A. et al. Physical activity, sedentary behaviours ans habits among Kuwaiti adolescents: gender difference. Public Health Nutrition 17, 2045-2052 (2014).
OL E KSA NDR A NAU M E NKO / A L A M Y S TOCK P HOTO
FEATURE
Stay connected with
KAIMRC
@kaimrc_ksa King Abdullah International Medical Research Center www.kaimrc.med.sa
innovations.kaimrc.med.sa
SAUDI GENOME PROJECT
The Saudi Human Genome Project (SHGP) is a national program that aims for the identification of disease-associated variants for rare and common disease in the Saudi population. The ultimate objective of this endeavor is to create a national database for genetic variants at King AbdulAziz City for Science and Technology (KACST) and to make this information available for the national and international scientific community. This program is considered one of the largest life sciences research programs in Saudi Arabia. EMAIL: KAIMRC_BGD@NGHA.MED.SA