December 2016 - Issue No.2
ISSN 7901-2398 innovations.kaimrc.med.sa
MAKING ROOM FOR REGENERATION Boosting nerve repair in multiple sclerosis P. 19
A KINGDOM WITH A KNOWLEDGE PLAN Saudi Arabiaâ&#x20AC;&#x2122;s promising journey to a knowledgebased economy. P. 50
STRIKING AT THE MERS INFECTION
S A U D I A R A B I A' S M U LT I P R O N G E D AT TA C K A G A I N S T T H E V I R U S P. 5 6
Excellence for Genomics KACST is a pioneer in the field of genomic studies. Through its national and international collaborations, KACST has decoded the Arabic camel genome, the genome of the date palm, and the red palm weevil. Through its collaboration with the King Faisal Specialist Hospital and Research Center, KACST has also established and runs the Saudi Human Genome Project to understand diseases and rare genetic disorders found in the Saudi population. www.kacst.edu.sa
P. 7 GENE DEFECTS REDUCE LEUKAEMIA SURVIVAL
P. 8 HONING IN ON THYROID CANCER
Genetic variations can explain poorer survival rates in Pakistani children from a prevalent type of leukaemia.
A closer look at gene expression in papillary thyroid cancer opens new opportunities for its detection.
P. 10 GO MEDITERRANEAN FOR CANCER PROTECTION
P. 12 THE SAUDI APPROACH TO CURING LEUKAEMIA
A Mediterranean diet reduces the risk of colorectal cancer by half in Italy.
The survival rate for paediatric acute myeloid leukaemia in Saudi Arabia has rose to equal developed nations.
P. 14 SHEDDING LIGHT ON TUMOURS
P. 16 POWERFUL TOOL PROBES ENTIRE HUMAN PROTEOME
A contrast agent lights up solid tumours on magnetic resonance imaging scans.
The technology could give the search for new drugs, especially for cancer and terminal diseases, a significant boost. Issue No.2
COVER CREDITS: Â©NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES (NIAID)
TABLE OF CONTENTS
TABLE OF CONTENTS
P. 19 MAKING ROOM FOR REGENERATION
P. 20 ELIMINATING RISK FACTORS OF HEART ATTACK
Scar-preventing drugs could facilitate nerve repair in several disorders.
A personâ&#x20AC;&#x2122;s sex has no effect on increasing the risk of a major heart attack for patients with extensive coronary artery disease.
P. 22 EXPLORING DIABETES IMPACT ON TEENAGERS
P. 23 OBESITY SURGERY CAN ALSO RESOLVE DIABETES
A multidisciplinary approach is needed to support diabetics and their families.
Large-scale study shows bariatric surgery helps keep weight down and can resolve diabetes and hypertension.
P. 24 IMAGING COULD MONITOR DIABETES PROGRESSION
P. 26 PREDICTING THE SEVERITY OF HEART FAILURES
Radioactive peptides effectively image insulin-producing cells, with potential to chart disease progression in diabetes.
Atomic force microscopy helps scientists identify which chronic heart failure patients are likely to suffer complications.
P. 28 TARGETING BURKITTâ&#x20AC;&#x2122;S LYMPHOMA
P. 30 CHINESE HERBAL REMEDIES YIELD ANTI-CANCER DRUG LEADS
P. 32 LIGHT-RESPONSIVE SHAPECHANGING MOLECULES
Antibody-driven death if lymphoma cells may lead to anti-cancer treatments.
A Chinese medical plants repository may help in the search for new cancer drugs.
Ligh-sensitive nanowires could act as artificial tails to steer drugs around the body.
P. 33 REACHING CANCER THROUGH THE SKIN
P. 34 SMART NANOPARTICLES FOR CANCER DRUG DELIVERY
P. 36 AN ATTRACTIVE AND ABUNDANT STEM CELL ALTERNATIVE
Cargo-carrying peptides may deliver medicines through the skin.
Nanoparticles successfully deliver anticancer drug to breast cancer cells.
Stem cells derived from the human placenta may find unique therapeutic applications.
P. 37 BALANCING CT DOSE AND IMAGE QUALITY
P. 38 AN ANTI-CANCER MOLECULE WITH A BACK-UP PLAN
New techniques to improve image quality in CT scans while reducing radiation dose may cause misdiagnosis.
Anti-cancer agent kills cells in two different ways, offering an effective avenue for treatment. Issue No.2
TABLE OF CONTENTS
P. 40 THE GENETICS OF SMOKING BEHAVIOUR
P. 42 REACHING FOR SUCCESS IS EASIER FOR THE TALL
P. 43 A NEW PLAYER IN GENE REGULATION
Genes may determine a person’s risk of tobacco addiction.
Genes controlling height and weight may affect socioeconomic prospects.
A familiar molecule may affect the molecular mechanism controlling gene expression.
P. 44 CAUSE FOUND FOR RARE AMINO ACID DISEASE
P. 46 GENE TIES AUTISM AND KIDNEY ISSUES
P. 47 THE MYSTERIES OF INTELLECTUAL DISORDERS
A young girl’s metabolic disorder may be due to a newly-discovered gene mutation.
Mutations in a single gene cause an autism syndrome and kidney problems in children.
DNA sequencing offers help for patients with unexplained intellectual disorders.
P. 48 SMART PARTNERSHIPS
P. 50 A KINGDOM WITH A KNOWLEDGE PLAN
While some enterprises strive to be the biggest, a new biotechnology park in Riyadh has set smaller perimeters with a sharp focus.
A shift to a knowledge economy in Saudi Arabia is a necessity that holds much promise.
P. 54 POTENTIAL FOR A MERS ANTIBODY THERAPY
P. 56 STRIKING AT THE HEARTLAND OF MERS
P. 58 HOW HEPATITIS C TAKES CONTROL
MERS patients may produce sufficient antibodies to help more recent victims.
Dozens of new cases of MERS have been reported, but Saudi Arabia is fighting back.
The hepatitis virus commandeers key cellular machinery to keep itself safe.
P. 61 PREVENTING FLU IN KIDNEY TRANSPLANT PATIENTS
P. 62 HEPATITIS B: PREDICT, TREAT, AVOID
P. 64 ‘YOUNG BLOOD’ A DEFENCE AGAINST INFECTION
A flu shot used for people over 65 may also benefit younger transplant patients.
A newly-discovered biomarker can help predict hepatitis B virus reactivation.
A potent immune response helps children fight hepatitis C better than adults.
KAIMRC INNOVATIONS IS PUBLISHED FOR THE KING ABDULLAH INTERNATIONAL MEDICAL RESEARCH CENTER (KAIMRC) BY THE PARTNERSHIP AND CUSTOM MEDIA UNIT OF NATURE RESEARCH, PART OF SPRINGER NATURE. KING ABDULLAH INTERNATIONAL MEDICAL RESEARCH CENTER (KAIMRC) AR RIMAYAH, RIYADH 14611, SAUDI ARABIA EMAIL: KAIMRC@NGHA.MED.SA WEB: KAIMRC.MED.SA NATURE RESEARCH THE CAMPUS – 4 CRINAN STREET – LONDON, N1 9XY, UK EMAIL: NATURE@NATURE.COM WEB: WWW.NATURE.COM
KAIMRC INNOVATIONS PHONE: +966 11 429 4516 EMAIL: INNOVATIONS@NGHA.MED.SA WEB: INNOVATIONS.KAIMRC.MED.SA THE RESEARCHER NEWSLETTER PHONE: +966 11 429 4516 EMAIL: THERESEARCHER@NGHA.MED.SA WEB: INNOVATIONS.KAIMRC.MED.SA/EN/NEWSLETTER
S S Shared Enabling E C C U S S Platforms FACTOR 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.
Genetic variations can explain poorer survival rates in Pakistani children from a prevalent type of leukaemia.
akistani children affected by B cell acute lymphoblastic leukaemia (B-ALL), a common type, show poor survival compared to children in other parts of the world. A study conducted by KAIMRC in collaboration with hospitals and universities in Pakistan found that some genetic abnormalities normally associated with more aggressive types of cancer are common in B-ALL patients from the India-Pakistan region. B-ALL is the most prevalent type of cancer in children. It develops in blood-forming cells and is characterised by the overproduction of immature white blood cells. One of its causes is the presence of fusion oncogenes (FOs), which are genes
B cell from a patient with leukaemia
that form when two previously separate genes unite. Scientists analysed 188 blood samples from 2- to 15-year-old Pakistani children with B-ALL who were being treated at oncology centres in Lahore, Faisalabad, Islamabad and Peshawar. They found that 87.2% of the patients had FOs. In particular, the study investigated how four types of FOs were correlated to disease biology and treatment outcome. Similar to previous studies conducted in Pakistan and India, the fusion oncogene BCR-ABL was found to be the most common, detected in almost half of the patients. This mutation seems to be rare (2-5%) in B-ALL paediatric patients in Europe, the US, Saudi Arabia, Korea and Japan, but overrepresented in the India-Pakistan region. It is associated with older children (7 to 15 years old), lower remission (meaning temporary recovery) rates and poor survival. BCR-ABL codes for a mutant protein called tyrosine kinase, which causes unregulated cell division. Similarly, the FO MLL-AF4 was found to be relatively higher in the Pakistani patients (18%) compared to B-ALL patients in other parts of the world (1 to 17% depending on location) and it is correlated with short survival (52 weeks on average).
“Pakistani children with B-ALL have uniquely high frequencies of the FOs BCR-ABL and MLL-AF4. This, together with delays in diagnosis as well as shortage of specialised health professionals and treatment facilities may be some of the most important reasons for the overall poor outcome of paediatric B-ALL patients in Pakistan. We recommend the mandatory use of molecular testing for diagnosis and prognosis, the provision of tyrosine kinase inhibitors for treatment and the construction of more hematopoietic stem cell transplantation facilities at cancer centres,” says KAIMRC geneticist Zafar Iqbal, the leading author of this study. The reason some FOs are more abundant among Pakistanis is not clear. “Further studies with comprehensive genetic analyses are necessary to deepen our understanding of the genetic basis of the patients’ poor prognosis,” he says. Iqbal, Z., Akhtar, T., Awan, T., Aleem, A., Sabir N., et al. High frequency and poor prognosis of late childhood BCR-ABL-positive and MLL-AF4-positive ALL define the need for advanced molecular diagnostics and improved therapeutic strategies in pediatric B-ALL in Pakistan. Mol Diagn Ther. 19, 277-287 (2015).
© STEVE GSCHMEISSNER / SCIENCE PHOTO LIBRARY / GETTY IMAGES
Gene defects reduce leukaemia survival
Papillary thyroid cancer is the most common form of thyroid cancer.
Honing in on thyroid cancer A closer look at gene expression in papillary thyroid cancer opens new opportunities for its detection.
© SCIEPRO/ SCIENCE PHOTO LIBRARY / GETTY IMAGES
n their quest to understand the root causes of thyroid cancer, researchers around the world have increasingly turned their attention to PAX8: a member of a family of proteins involved in transcribing information from DNA, that are closely linked to embryonic development and cancer growth. PAX8 plays a critical role in the development and function of the thyroid gland and its expression is often reduced in patients with thyroid carcinoma. Francesca Rosignolo and co-workers in Italy compared the expression of 11 genes thought to be controlled by PAX8 in papillary thyroid carcinoma (PTC), the most common type of thyroid cancer worldwide, accounting for 70 to 80% of all cases. Rosignolo and her team’s study yields new insights into genes of particular interest as potential thyroid cancer biomarkers. “We identified several PAX8 target genes that were significantly over or underexpressed in PTC tissues, and some were specifically associated with tumour aggressiveness,” she explains. Five of the 11 genes displayed notable differences in transcript levels, a reliable measure of gene activity, in tumour tissues compared to normal thyroid tissues, reinforcing the idea that they have a key involvement in the development of PTC. The research team also singled out two genes that hold potential to improve detection and prognosis of thyroid cancer: the lipocalin 2 (LCN2) gene, which was found to be markedly overexpressed, and
the glypican 3 (GPC3) gene, which was notably underexpressed in tumour tissue compared with normal tissue. Based on advanced protein analysis, the researchers found that the protein coded by the GPC3 gene could be detected in all normal tissue but in none of the tumour tissue samples. This finding implies that staining for the GPC3 protein could offer an effective way to distinguish between normal and papillary thyroid cancer cells. Although developing and validating biomarkers is “a long, arduous task,” Rosignolo is confident that “these preliminary results from our study suggest that the expression of certain PAX8 target genes might in future be assessed to diagnose PTCs or identify tumours that may need particularly close surveillance.” “Our next research projects will focus mainly on the identification and validation of biomarkers that can accurately predict PTC aggressiveness and recurrence in the early stages,” says Rosignolo. She emphasises that international collaboration is “fundamental for stimulating scientific progress and improving our knowledge of cancer. Advances in communication technologies have certainly facilitated this approach, but more efforts are needed to break down barriers.”
"These preliminary results from our study suggest that the expression of certain PAX8 target genes might in future be assessed to diagnose PTCs or identify tumours that may need particularly close surveillance.”
Rosignolo, F., Sponziello, M., Durante, C., Puppin, C., Mio, C. et al. Expression of PAX8 target genes in papillary thyroid carcinoma. PLoS ONE 11, e01566658 (2016).
A Mediterranean diet lowers the risk of colorectal cancer in Italy.
Go Mediterranean for cancer protection A Mediterranean diet reduces the risk of colorectal cancer by half in Italy.
ticking to a Mediterranean diet reduces the risk of colorectal cancer, according to recent research conducted in Italy. The combined analysis of three previous studies showed that diet could lower the risk by as much as 50%, confirming previous findings.
Certain foods and nutrients are known to affect the risk of colorectal cancer, but as foods are not eaten in isolation, the effect of diet as a whole is likely to be more relevant. Previous studies have suggested that a Mediterranean diet lowers the risk of several types of cancer, including colorectal cancer, but the impact in specific coun-
tries is unclear. This led Valentina Rosato from the UniversitĂ degli Studi di Milano and colleagues to assess the effects of a Mediterranean diet on the risk of colorectal cancer in Italy. Rosato and colleagues analyzed data from three previous studies conducted in Italy, which included more than 10,500
© RAWPIXEL/ ISTOCK / GETTY IMAGES PLUS
people. For each participant, a Mediterranean diet score between 0 and 9 was calculated according to their adherence to the diet, defined as frequent consumption of vegetables, legumes, fruit, nuts, cereals, fish and olive oil, modest intake of wine, low-to-moderate consumption of dairy products, and low consumption of meat. An individual’s score was a reflection of whether their intake of nine dietary components in the preceding two years was above or below the average for participants who did not develop colorectal cancer. The researchers found that people who scored highest for overall adherence to the diet were half as likely to develop colorectal cancer compared with people who scored the lowest on adherence, suggesting a clear benefit of the diet. They also found that the effects on risk differed between each of the dietary components. The risk was lowered by a high intake of vegetables, legumes,
fruit, nuts and fish; a high ratio of monounsaturated fats to saturated fats; and a low intake of meat. By contrast, the risk was increased by a high intake of cereals and potatoes, and a low intake of milk and dairy products. Alcohol intake had no effect. The relationship between diet and colorectal cancer was consistent regardless of age, sex, level of education, body mass index, levels of physical activity, total energy intake and history of intestinal cancer. The authors say that differences between countries and experimental design make comparisons between studies difficult, but the new work confirms previous findings in studies conducted in Italy.
A high intake of vegetables, legumes, fruit, nuts and fish; a high ratio of monounsaturated fats to saturated fats; and a low intake of meat.
Rosato, V., Guercio, V., Bosetti, C., Negri, E., Serraino, D. et al. Mediterranean diet and colorectal cancer: a pooled analysis of three Italian case–control studies. British Journal of Cancer. 115, 862-5 (2016).
© OGPHOTO/ ISTOCK / GETTY IMAGES PLUS
AML represents approximately 14% of all registered paediatric leukaemia cases in Saudi Arabia.
The Saudi approach to curing childhood leukaemia The survival rate for paediatric acute myeloid leukaemia in Saudi Arabia is now equal to that of developed nations thanks to a risk– response strategy.
cute myeloid leukaemia (AML) — a type of cancer characterized by the rapid growth of abnormal white blood cells in the bone marrow — accounts for roughly 15–20% of all leukaemia cases in children. With recent advances in treatment and supportive care, the survival rates of AML for children in developed nations, such as Ireland, the United Kingdom and the United States, have greatly improved to 60–70%. However, the status of AML for children in developing nations, particularly those in the Middle East, is unclear. Wasil Jastaniah at the Princess Noorah Oncology Center, part of Saudi Arabia’s Ministry of National Guard—Health Affairs, and co-authors have now performed a retrospective study on the status of AML for children in the kingdom. They found that a risk–response strategy has boosted the 12
survival outcomes in the kingdom to worldclass standards. Relapse — the recurrence of AML in patients — is currently the biggest obstacle to leukaemia treatment and recovery. The researchers followed the status of 175 AML patients aged 14 years or younger treated across nine medical institutions in Saudi Arabia over five years. They noted that of the 175 AML patients, treatment of 21 (12%) failed in the first phase, 67 (38.3%) experienced relapse and 66 (37.7%) died within the study period. The cumulative incidences of relapse and non-relapse mortality were determined to be 43.1% and 9.8% respectively. Most significantly, the overall survival was estimated to be 58.8 ± 4%, which was comparable to that of North America (65.4 ± 4%) and those of United Kingdom, Ireland, Netherlands and New Zealand
(61%). They attributed the unexpectedly high survival rate in Saudi Arabia to two things: hematopoietic stem cell transplantation and tailored treatment. The latter, in particular, utilises a risk- and response-based stratification system that optimises the selection of AML therapies for different patients. Saudi Arabia is a high-income, resource-rich country that has been providing free cancer treatment to its nationals. The number of cancer centres in Saudi Arabia has increased over the past 20 years, resulting in improved access to treatment and supportive care. The findings from this study suggest that tailored treatment for AML patients using a risk–response strategy has significant benefits and that, with the right implementation, developing countries can achieve comparable survival outcomes as those of developed countries. “Future improvements in outcomes of childhood AML in Saudi Arabia would require further refinement of risk stratification and tailoring therapy based on risk and response,” says Jastaniah. Jastaniah, W., Al Ghemlas, I., Al Daama, S., Ballourah, W. Bayoumy, M. et al. Clinical characteristics and outcome of childhood de novo acute myeloid leukemia in Saudi Arabia: A multicenter SAPHOS leukemia group study. Leukemia Research 49, 6672 (2016).
Stay connected with
@kaimrc_ksa King Abdullah International Medical Research Center www.kaimrc.med.sa
Shedding light on tumours A contrast agent, containing nanoparticles that are sensitive to acidity, lights up solid tumours on magnetic resonance imaging scans. 14
A pH figure is used to express a solution’s acidity or alkalinity. Figures above seven signify an alkaline solution, while those below seven signify an acidic solution. Kazunori Kataoka at the University of Tokyo and co-workers have now developed a contrast agent that amplifies magnetic resonance signals when the surrounding pH drops below 6.7. If injected into patients, the contrast agent could illuminate tumours and improve the contrast of their pathological features on MRI scans. The researchers prepared pH-sensitive nanoparticles — the crucial ingredient in this newly developed contrast agent — by encapsulating manganese ions and calcium phosphate fragments in polyethylene glycol shells. The manganese ions are designed to amplify magnetic resonance imaging, while the calcium phosphate fragments are designed to bind manganese ions under normal conditions and subsequently release them when the pH drops below a critical value. Kataoka and his team examined how these nanoparticles behave at different pH ranges, including pH 5–6 (intracellular conditions), pH 6.5–6.8 (tumour microenvironment) and pH 7.4 (blood). They found that after four hours, 95%, 71% and 36% of manganese ions were discharged from the nanoparticles at pH 5.0, 6.5 and 6.7 respectively. In comparison, less than 8% of manganese ions were released at pH 7.4.
The results show that the nanoparticles rapidly and selectively bind solid tumours and brighten them up through contrast enhancement.
agnetic resonance imaging (MRI) enables physicians to see inside bodies in great detail without invasive surgery. Contrast agents can further extend the capacity of MRI to include cancer diagnosis by reacting to changes associated with lesions and tumours, such as an increase in the surrounding acidity.
The researchers then tested the contrast capability of their nanoparticles in tumour-bearing mice. They found that the tumour/ normal tissue (T/N) ratio of the nanoparticles reached 130% within 30 minutes after administration through intravenous injection. The high T/N ratio lasted for hours, providing sufficient time for MRI scans to be taken. Altogether, the results show that the nanoparticles rapidly and selectively bind solid tumours and brighten them up through contrast enhancement. Lastly, Kataoka and his team checked whether their nanoparticles could trace spreading tumours. They applied the nanoparticles to a mouse liver that had been tainted with colon cancer cells. The spreading tumours lit up and revealed their migratory paths within one hour of administration through intravenous injection. The team reports that its nanoparticles were thus useful both for cancer diagnosis and the visualisation of metastases. Mi, P., Kokuryo, D., Cabral, H., Wu, H., Terada, Y. et al. A pH-activatable nanoparticle with signal amplication capabilities for non-invasive imaging of tumour malignancy. Nature Nanotechnology 11, 424-730 (2016).
© CULTURA CREATIVE (RF) / ALAMY STOCK PHOTO
The newly developed contrast agent may enable faster and more accurate detection of solid tumours using MRI scans.
The new technology employs mass spectrometry to test how the entire human proteome reacts to various drugs. 16
Powerful tool invented to probe entire human proteome The technology could give the search for new drugs, especially for cancer and terminal diseases, a significant boost.
© IMAGENAVI/ GETTY IMAGES
he advent of a new screening method that combines mass spectrometric imaging and microarray technology holds promise for protein-based pharmaceuticals. The technology can target large sets of human proteins simultaneously; what scientists call ‘massively parallel’ analysis, using a scattergun approach. Mass spectrometry allows scientists to detect, quantify and distinguish proteins and drugs by composition, down to their smallest atoms. Microarrays can ‘capture’ specific proteins. The scientists used the combined technique to probe new and existing drug-protein interactions, as well as for drug discovery, since the new tool can simultaneously screen multiple drugs against all protein targets. “This will not only dramatically accelerate the discovery of new drug targets, but also allow pharmaceutical companies to see how candidate drugs might bind to ‘off-target’ proteins, so they can choose drugs with minimal side-effects,” says Mark Lim, the vice president and chief scientific officer at US lab AmberGen, a spin-off company from the Boston University Photonics Center. Proteins are vital nutrients and essential components of all cells. They also help maintain cells, dictate their phenotypes and mediate cell signalling. This makes them a key target for drug development. When proteins over-perform or don’t work, they can trigger pathological changes in cells that lead to medical conditions like cancer. When drugs target them inappro-
priately, it can cause adverse side-effects. Previously, researchers have not been able to examine drugs’ interactions with the 100,000-plus proteins in the body – known as the human ‘proteome’ – because the drugs had to be fluorescently labelled in order to be identified. The labelling could alter their interaction with proteins, leading to false results. Testing methods that didn’t require labelling meant that researchers needed a good idea about the activity of the specific protein and drug under scrutiny, making wide-scale screening difficult.
"The potential impact of proteome-wide drug discovery is that one obtains a much more global picture of how drugs might alter the cellular process." Bead-GPS, the test developed by Lim and colleagues, however, uses microscopic beads that attach to both a unique coding agent and specific proteins through ‘linkers’. Photocleavable linkers create links that can be broken by specific types of UV light and are used to attach coding agents to the microscopic beads. The scientists can detect molecules bound to these beads using mass spectrometry. Proteins are attached to the beads by non-cleavable linkers. “In the particular type of mass spectrometry used, the light from the instrument’s laser beam breaks the photocleav-
able linker that attaches the coding agent to the bead so that it may be detected. The drug, which is non-covalently bound to the bead through the protein, is also released by other means,” says Lim. AmberGen’s test therefore doesn’t influence the drugs’ activity in the way fluorescent labelling would have, allowing researchers to observe how any drug interacts with any number of proteins. “The potential impact of proteome-wide drug discovery is that one obtains a much more global picture of how drugs might alter the cellular process, thereby allowing detection of potential side-effects at a much earlier stage in the drug discovery process than animal or human testing,” Lim says. He adds that this new method can also help them ‘repurpose’ existing drugs to treat diseases they haven’t been previously intended for. The entire process takes place on a single chip, roughly the size of a microscope slide. The researchers studied proteins known as kinases, which play a key role in cancer cell proliferation. “We anticipate Bead-GPS will have a major impact in oncology, due to the dominance of kinase inhibitors in targeted cancer therapy,” he says. “However, since it will work for all types of protein classes, it is not limited to specific diseases or classes of disease.” Zhou, Y., Liu, Z., Rothschild, K.J., Lim, M.J. Proteome-wide drug screening using mass spectrometric imaging of bead-arrays. Scientific Reports 6, 26125 (2016).
S S E C C U S S FACTOR Innovative Systems
With branches spread out across the kingdom, KAIMRC offers researchers an exceptional setup to further their translational and clinical research goals. KAIMRC and the National Guard Health Affairs have made history by launching the first Stem Cell Donor Registry in the Arab world. This registry is a KAIMRC national project launched in line with international standards, and is currently in the World Marrow Donor Association (WMDA) accreditation and is already part of the World Wide Bone Marrow Registry. sscdr.org.sa
Making room for regeneration Drugs that prevent the accumulation of scar-forming molecules could facilitate nerve repair in multiple sclerosis and other disorders.
Oligodendrocyte precursor cells help maintain the myelin sheath that surrounds and insulates neuronal axons.
rodent model of MS. “This approach therefore represents a two-pronged attack on the disease,” says Yong.
"CSPGs can inhibit axonal regeneration at injury sites, and so our approach may benefit this field as well." The details on the mechanisms by which specific CSPGs inhibit OPC function remain unclear. Yong and colleagues now intend to delve into these questions and to pursue the development of even
better inhibitors. He notes that the implications of this work could reach well beyond MS to encompass other disorders of the central nervous system. “CSPGs are laid down following most types of neurological insults,” says Yong. “In traumatic spinal cord injury, for example, CSPGs can inhibit axonal regeneration at injury sites, and so our approach may benefit this field as well.” Keough, M.B., Rogers, J.A., Zhang, P., Jensen, S.K., Stephenson, E.L. et al. An inhibitor of chondroitin sulfate proteoglycan synthesis promotes central nervous system remyelination. Nature Communications 7, 11312 (2016).
© 2016 VOON WEE YONG
ultiple sclerosis (MS) causes the immune system to attack the central nervous system leading to a gradual loss of function as neurons lose their ability to communicate. Scar formation at these damaged sites directly interferes with neuronal repair processes, but researchers led by Voon Wee Yong at the University of Calgary in Canada have identified a potential strategy for promoting regeneration. In MS, the immune cells strip away a protein called myelin, which forms a coating around the axons of neurons and helps preserve the strength and speed of neuronal signalling. Yong and colleagues had uncovered evidence that molecules called chondroitin sulfate proteoglycans (CSPGs) might be critically involved in this myelin loss. “The role of CSPGs at sites of central nervous system damage is unclear and may even involve trying to limit the area of injury,” says Yong, “but the consequence is a scar-forming material that impedes attempts at remyelination.” CSPGs interfere with the growth of oligodendrocyte precursor cells (OPCs), which ultimately coordinate the replacement of lost myelin. The researchers initially set out to identify drugs that might counter this effect. However, the inhibitory activity of accumulated CSPGs proved too potent to overcome and OPC growth remained stalled in cell culture experiments regardless of the treatment used. As an alternative, Yong and colleagues screened for compounds that prevent this accumulation. CSPGs are synthesized by cells called astrocytes. After treating cultured astrocytes with various molecules, the researchers identified one that greatly reduced CSPG production. This compound, fluorosamine, proved capable of restoring OPC growth in both cell culture and rodent models and even facilitated the repair of demyelinated nerves. Intriguingly, fluorosamine also appeared to directly suppress damaging immune activity in a
Eliminating risk factors of heart attack If a person has extensive obstructive coronary artery disease, either male or female, they are at increased risk of suffering a major cardiovascular event.
he likelihood of suffering a significant cardiovascular event, such as a heart attack, is significantly increased if a patient suffers from obstructive coronary artery disease (CAD). Now, a study by an international team of researchers, including KAIMRC’s Mouaz Al-Mallah, has verified that a patient’s sex has no influence on their risk of a major cardiovascular event if they are suffering from obstructive CAD. CAD occurs when the arteries that supply blood to the heart become hardened and partially blocked by fat deposits known as plaques. The condition gradually worsens, and eventually the heart muscle no longer receives the blood needed to function effectively. This can lead to severe chest pain, blood clots, heart attacks and sometimes sudden death. “Women tend to have more symptoms suggestive of CAD, including chest pain, chest heaviness or shortness of breath, but they appear to have a lower prevalence of obstructive CAD than men,” says Al-Mallah. “We did not know if sex plays a role in the relation between coronary artery blockages and clinical outcomes, and so when the international CONFIRM [Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter] registry was set up we sought to clarify this issue.” In the first long-term study into sex-specific associations in CAD, the research team followed the progress of 5,632 male and female patients with CAD from the CONFIRM registry over a period of five years. The patients were regularly screened to
determine CAD extent using coronary computed tomography angiography: CT scanning of the main vessels supplying the heart. Those patients displaying 50% or more narrowing of a coronary vessel were classed as having obstructive CAD. “We found that men were more likely to have obstructive CAD than women,” says Al-Mallah. “However, there was no evidence that a person’s sex played a role in increasing the chances of a major cardiovascular event if they suffered from obstructive CAD. For both men and women, the greater the extent of obstructive CAD, the higher the risk of suffering a severe heart episode.”
"Women tend to have more symptoms suggestive of CAD, but they appear to have a lower prevalence of obstructive CAD than men.” The researchers note that current methods for measuring the extent of CAD in the body must be improved. Further investigations are also needed to determine whether there are differences in plaque characteristics between the sexes that impact clinical outcomes. Schulman-Marcus, J., o Hartaigh, B., Gransar, H., Lin, F., Valenti, V. et al. Sex-specific associations between coronary artery plaque extent and risk of major adverse cardiovascular events: The CONFIRM long-term registry. JACC: Cardiovascular Imaging 9, 364-372 (2016).
© SEBASTIAN KAULITZKI / ALAMY STOCK PHOTO
A person’s sex has no effect on increasing the risk of a major heart attack for patients with extensive coronary artery disease.
Exploring diabetes impact on teenagers and their families © BEN EDWARDS/ THE IMAGE BANK / GETTY IMAGES
A multidisciplinary approach to treating teenage diabetics is needed to improve quality of life for patients and their families.
iabetes is a rapidly growing problem, with 382 million people affected worldwide. The disease affects 24% of Saudi Arabia’s predominantly youthful population; meaning many of the country’s diabetics are teenagers. KAIMRC researchers have conducted investigations into the impact of diabetes on adolescents and their families, from physical discomfort to the psychological and social impacts of living with a chronic condition. “In Saudi Arabia we have been focusing a great deal on the medical management and control of type I diabetes among our youth,” says paediatrician Fadia AlBuhairan from King Saud bin Abdulaziz University for Health Sciences. “However, we have failed to address the psychosocial impact on patients and their families.” AlBuhairan and her colleagues investigated the full impact of type I diabetes on teenagers and their caregivers. They gathered data from health-related quality-of-life questionnaires given to 315 patients aged 12 to 18 at three hospitals. The patients’ caregivers completed the same questionnaire, plus a second one related to family impacts of the disease. “We had an excellent response rate,” says AlBuhairan. “This reflects our participants’ sincere interest in addressing the complexities of this lifelong condition.” The team found that all scores were lower for Saudi Arabian families than equivalent studies in other countries. Caregivers tended to give lower scores on the quality-of-life questionnaire than the teenage patients. The lowest scores for both caregivers and teens were in the ‘worry’ category, with parents’ emotional
Teenage diabetics and their families are in need of a multidisciplinary approach to improve their quality of life.
well being affected by concern for their child’s future. Female patients in later teenage years (ages 15 to 18) were also more likely to report a lower health-related quality of life. This may partly be due to the complexities of treating diabetes in young women, as hormonal fluctuations mean their bodies require more insulin than males. Sometimes there are also issues related to unhealthy weight control practices. “Research generates the evidence needed to impact practice,” says AlBuhairan.
“Implementing a multidisciplinary care approach to diabetes and other chronic diseases is essential. We hope to study other adolescent patient populations to find out if key findings in this study, such as low ‘worry’ scores, also cut across other disease categories.” AlBuhairan, F., Nasim, M., Al Otaibi, A., Shaheen, N. A., Al Jaser, S., & Al Alwan, I. Health related quality of life and family impact of type 1 diabetes among adolescents in Saudi Arabia. Diabetes Research and Clinical Practice 114, 173-179 (2016).
Obesity surgery can also resolve diabetes Large-scale study shows bariatric surgery helps keep weight down and can resolve diabetes and hypertension.
any people who are severely obese and have difficulty achieving permanent weight loss through diet and exercise, eventually turn to bariatric surgery. Few large-scale, long-term studies have investigated the longevity of weight loss after surgery, and whether the incidence of obesity-linked diseases such as type II diabetes, hypertension, heart attack, and sleep apnea is reduced. Researchers at the London School of Hygiene and Tropical Medicine set out to answer these questions. They identified 3,882 patients, who underwent one of three types of bariatric surgery, from a large UK database that hosts anonymous
clinical information submitted by primary care physicians. They then compared the data from these patients with that of comparably obese patients who had not had the surgery. They found that people who had bariatric surgery lost weight rapidly, at a rate of almost five kilograms per month during the first four months post-surgery, and then lost weight more slowly over the following four years. Those who did not have surgery did not lose weight during that period. There was greater initial weight loss in patients who underwent gastric bypass and sleeve gastrectomy compared to those who underwent gastric banding,
all procedures designed to reduce the size of the section of the stomach that receives food. Also, patients who had surgery had a lower risk of developing type II diabetes, hypertension, angina, heart attack, and obstructive sleep apnea. In many patients who had type II diabetes and hypertension at the time of surgery, the conditions resolved. “While avoiding obesity in the first place remains a key aim in public health, bariatric surgery is an intervention that works, and is not used as often here in the UK as elsewhere,” says epidemiologist Ian Douglas from London School of Hygiene and Tropical Medicine. Widening the availability of bariatric surgery could lead to substantial health benefits for many people who are morbidly obese, the researchers conclude. Douglas, I., Bhaskaran K., Batterham, R., Smeeth, L. Bariatric Surgery in the United Kingdom: A Cohort Study of Weight Loss and Clinical Outcomes in Routine Clinical Care. PLOS Medicine 12, e1001925 (2015).
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Few large-scale, long-term studies have investigated if the weight loss after bariatric surgery is long lasting.
Beta cells in the pancreas (red) are responsible for insulin production. Their mass decreases over time in patients with diabetes.
Radiolabeled peptides could monitor diabetes progression
collaboration between Pfizer and the Washington University School of Medicine offers a possibility for improved treatment of diabetes. Radiologist Suzanne Lapi and colleagues have succeeded in developing an imaging technique that allows them to ‘see’ the mass of insulin-producing beta cells present in the pancreas. This development could lead to more tailored treatment plans for diabetes patients, based on the progression of the disease. In diabetics, the body doesn’t use insulin effectively, leading to increased insulin production and a gradual decrease in the mass of pancreatic beta cells. Until recently, the only way to quantify beta cell mass was by autopsy. Lapi and her team were able to visualize beta cell mass using a PET scan, an imaging technique that uses the body’s metabolism of radioactive compounds to map organs and tissues. They separately tagged exendin-4, a synthetic peptide that selectively binds to pancreatic beta cells, with the radioactive isotopes copper-64 and gallium-68 to visualize beta cell mass in rats. “We have a long history of radio-labelling peptides, mostly in cancer,” says Lapi. “The idea of using molecular imaging to look at the biology of cancer and drug delivery is a much more mature field that we've
looked at for a long time. With our collaborators we started discussing whether we could use this for other things—such as imaging beta cells.” The team also assessed how well the isotopes bound to exendin-4 by means of two different metal chelators (molecules that bind metal ions). “The subtle variations in the structure of the peptide changes its metabolism, and also the affinity to the receptor. Tiny changes can have a big impact when you’re designing these agents, just like when you're designing a drug,” says Lapi. By detecting the radioactivity of the bound radioisotopes with a PET scanner, researchers and clinicians can chart the state of an animal’s, or patient’s, insulin-producing capability. The study may prove beneficial for drug development by highlighting compounds that bind and enter the beta cells. “It's a two-pronged approach. We can use these tools to see what's going on in the body, but we can also label new compounds to assess their suitability for drug development.”
"Tiny changes can have a big impact when you’re designing these agents, just like when you're designing a drug."
Bandara, N., Zheleznyak, A., Cherukuri, K., Griffith, D. A., Limberakis, C. et al. Evaluation of Cu-64 and Ga-68 Radiolabeled Glucagon-Like Peptide-1 Receptor Agonists as PET Tracers for Pancreatic β cell Imaging. Molecular Imaging and Biology 18, 90-98 (2016).
© SEBASTIAN KAULITZKI / ALAMY STOCK PHOTO
Radioactive peptides effectively image insulin-producing cells, with potential to chart disease progression in diabetes.
Scrutinizing cellular bonds in heart failure patients Atomic force microscopy can help scientists identify which chronic heart failure patients are more likely to suffer complications.
cientists in Portugal have identified a potential biomarker that can gauge the severity of chronic heart failure using an advanced type of scanning probe microscope. Cardiovascular diseases are the leading cause of mortality worldwide, responsible for about one third of all deaths. Ischaemic cardiomyopathy is the most common cause of heart failure. It involves weakening of the heart muscle that can cause blood clots, cutting off the main blood supply to the heart. High levels of fibrinogen, a protein com-
mon in the bloodstream and essential for clot formation, are a potential risk factor for cardiovascular diseases, but the underlying biological mechanisms remain unclear. Increased aggregation of erythrocytes, or red blood cells, has been linked to high levels of fibrinogen. The team of scientists scrutinized the interaction between fibrinogen and erythrocytes. They used atomic force microscopy (AFM), a very high-resolution microscopy to the order of fractions of a nanometre, to examine how red blood cells aggregate in chronic heart failure patients. “We show that the force required to break the binding between fibrinogen and erythrocytes is higher in patients with chronic heart failure than in healthy people,” says biochemist Nuno Santos from Universidade de Lisboa. The bonds were also stronger in patients with ischaemic
chronic heart failure compared to non-ischaemic patients. Chronic heart failure patients with higher fibrinogen-erythrocyte binding forces were hospitalized more frequently in the 12 months that followed the initial assessments. “This technique has also allowed us to study red cell stiffness. Erythrocytes from these patients showed changes in their elasticity and behaviour while in the blood stream,” says Santos. These changes are thought to have an effect on the strength of the bond red cells form with fibrinogen. Santos praises the potential of AFM in disease severity identification, labelling it “an important advancement in the field of nanotechnology for cardiology.” He acknowledges, however, that the study is limited by the relatively small number of cohorts. The study shows how nano-based technologies can be used to identify cardiovascular problems in a field where biomarkers relevant to cardiovascular risk still have limited applicability. Guedes, A.F., Carvalho, F.A., Malho, I, Lousada, N., Sargento, L. Atomic force microscopy as a tool to evaluate the risk of cardiovascular diseases in patients. Nature Nanotechnology 11, 687-693 (2016).
© JANICE HANEY CARR/ CDC
Scientists have found bonds between red blood cells and fibrinogen are stronger in patients with ischaemic heart disease compared to patients with other forms of chronic heart failure.
S S E C C U S S FACTOR
Capacity Building KAIMRC has developed state-of-the-art research buildings. With a total of 50,000 square meters spread across the country, KAIMRC is nurturing cutting edge research led by KAIMRC scientists, the university faculty and the medical services clinicians. KAIMRCâ&#x20AC;&#x2122;s Medical Research Core Facility and Platforms are working to provide NGHA scientists with research reagents, assays, samples and data analysis ton conduct their research. It also provides training in research platforms such as cellular imaging, confocal and confocal and electron microscopy.
Targeting Burkitt’s lymphoma Insight into the antibody-driven death of lymphoma cells may lead to anti-cancer treatments with enhanced efficacy and selectivity.
© BSIP SA / ALAMY STOCK PHOTO
© STEVE GSCHMEISSNER /SPL / GETTY IMAGES
AIMRC researchers have unveiled the transmembrane receptor expressed how the so-called transmembrane in these malignant cells. receptor CD-95 governs the proThe antibody treatment caused the cangrammed death, or apoptosis, of cer cells to undergo apoptosis. Furtherlymphoma cells. This breakthrough more, the expression of the Pim-1 protein, is expected to give rise to novel therapies against aggressive forms of cancer, such as Burkitt’s lymphoma (BL). More prevalent in Africa than in the United States and Western Europe, BL is a rare type of lymphoma that affects adults and children. It starts in immune system cells called B-cells before growing and spreading rapidly in the body. Existing anti-cancer therapies, including chemotherapy and radiation, have proven unsuitable against BL because of its aggressiveness. Specifically, when applied to BL, these conventional approaches are linked to high risk of tumour lysis syndrome, a potentially fatal complication that disrupts electrolyte and metabolite levels in blood resulting from the release of cancer cell content into the bloodstream. Sabine Matou-Nasri and co-workers investigated the molecular mechanisms underlying CD95-mediated apoptosis to eliminate these side-effects and improve the clinical outcomes of anti-BL treatments. “Elucidating these mechanisms was necessary to identify novel therapeutic targets and enhance the efficacy and specificity of immunotherapy,” she adds. The researchers evaluated the response of lymphoma B-cells to anti-CD95 monoclonal antibody, which Burkitt’s lymphoma is a rare form of cancer that is more common in Africa than in the US and Western Europe. specifically binds to and activates
“Elucidating molecular mechanisms was necessary to identify novel therapeutic targets and enhance the efficacy and specificity of immunotherapy.”
which stimulates cell survival and proliferation in addition to inhibiting apoptosis, decreased. This antibody treatment also reduced the cell viability and phosphorylation of protein kinase B, an enzyme involved in cell survival pathways, by 50% in 72 hours. However, the team found that the cell death rate remained below 46%. According to Matou-Nasri, her team has demonstrated that the anti-CD95 monoclonal antibody treatment partly destroyed BL because of the partial inhibition of survival pathways. “Our results have proven that targeting Pim-1 is insufficient to fully eradicate BL, which suggests a need for combinatory treatments against other main survival cytoplasmic proteins,” she adds, noting the current tremendous efforts deployed to develop pharmacological inhibitors that block Pim-1 anti-apoptotic activities. These treatments would associate the anti-CD95 monoclonal antibody with target-specific chemotherapeutic agents. “In future work, we are planning to undertake a gene–immune therapy approach against BL by knocking down the gene expressing Pim-1, then targeting its induced cell surface proteins that are likely to be involved in cell survival,” says Matou-Nasri. Matou-Nasri, S., Rabhan, Z., Al-Baijan, H., Al-Eidi, H., Bin Yahya, W. et al. CD95-mediated apoptosis in Burkitt’s lymphoma B-cells is associated with Pim-1 down-regulation, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease S0925-4439, 30230-7 (2016).
The jiaogulan climbing vine Gynostemma pentaphyllum contains more than 100 anticancer compounds.
Chinese herbal remedies yield anticancer drug leads
edicinal plants used in traditional remedies offer a potential treasure trove of compounds for drug companies looking for the next blockbuster cancer treatment. But, with so many different plants used by healers, it’s been difficult to know which contain the richest supply of possible drug-like molecules. Now, scientists have developed a prediction method for finding only the most potent plants. They’ve zeroed in on just 57 plants that could be laden with different anti-cancer compounds from a list of more than 2,400 included in the traditional Chinese medicine (TCM) Database@Taiwan, the world’s largest open repository of traditional Chinese medicines. The database includes details about the relationship between these plants and more than 21,000 pure compounds. This diverse group of 57 plants and the compounds they contain “are worthy of further studies and provide more chances for the development of new cancer drugs,” says bioinformatics researcher Shao-Xing Dai from the Chinese Academy of Sciences’ Kunming Institute of Zoology. Dai and his colleagues used computational methods to determine which of the thousands of compounds in the TCM Database@Taiwan have anti-cancer potential. CDRUG is a computational method they developed in 2012 that compares the chemical structure of molecules of unknown activity with those in a large library where the anti-cancer properties of the molecules have been established. Using this method, they honed in on 5,278 compounds with molecular similarities to known anti-cancer drugs and drug candidates.
Dai’s team then looked for plants that had an abundance of these compounds. Their analysis found 57 plants, each with at least eight compounds with tumour-targeting potential. The jiaogulan climbing vine, Gynostemma pentaphyllum, had the most with 104. A literature search revealed that other scientists had previously identified many of these plants as having anti-cancer properties. These included ginseng, red sage, Chinese bellflower, and several other herbs and shrubs. However, 24 of the plants enriched with potential anti-cancer compounds had never been studied extensively before. These newly identified plants, says Dai, offer “a broader scope to mine for potential anti-cancer agents.” It’s an approach that has had some success in the past. More than 50 years ago, for example, the chemotherapy drugs vinblastine and vincristine were isolated from the rosy periwinkle plant, a staple of Chinese traditional medicine. Both of these chemotherapeutics are now included on the World Health Organization's List of Essential Medicines, the most important drugs needed in a basic healthcare system. Dai and his colleagues’ analysis suggests other plants for investigation for further leads. Their predictive methods could be extended to catalogues of medicinal plants used in other cultures, including traditional Arabic medicine.
The researchers identified 57 plants that could be laden with different anticancer compounds.
Dai, S. X., Li, W. X., Han, F. F., Guo, Y. C., Zheng, J. J., Liu, J. Q., Wang, Q., Gao, Y. D., Li G. H., Huang J. F. In silico identification of anti-cancer compounds and plants from traditional Chinese medicine database. Scientific Reports 6, 25462 (2016).
© MANFRED RUCKSZIO / ALAMY STOCK PHOTO
A shortlist of Chinese medicinal plants containing the most anticancer compounds could yield new drugs for patients.
Light-responsive shape-changing molecules Nanowires that undergo reversible shape changes in response to light could act as artificial tails to steer drugs around the body.
© JAMES KING-HOLMES/OCMS/SCIENCE PHOTO LIBRARY/ GETTY IMAGES
dvances in nanotechnology are often inspired by designs found in nature. Tiny molecules that can change their shape in response to stimuli and swim through the body, mimicking bacteria, might one day help scientists develop novel, targeted drug delivery systems. Based on this principle, KAIMRC researchers have developed nanowires that bend in response to visible wavelengths of light and revert back in the presence of UV light. “We were inspired by the way bacteria propel themselves through liquid using their flagella, or tails, utilizing chemical energy as fuel,” explains Rabih Al-Kaysi, the KAIMRC materials chemist who led the project in collaboration with scientists at the University of California Riverside in the US. “We aimed to mimic nature by fabricating flagella-like nanowires that could move using light as fuel instead.” Scientists have already developed molecular crystals that respond to light of different wavelengths and undergo conformational changes. These ‘photomechanical’ properties are highly desirable, particularly if the shape-changes are reversible, so that a motion can be repeated or the molecule can be re-used. There are two types of reversibility: T-type (in which a molecule induced to change by light slowly reverts to its original shape after a time) or P-type (where shape-change is controlled in both directions by exposure to light of different wavelengths). “Until now, researchers were unable to create a nanoscale light-activated P-type actuator – a component that converts energy into mechanical motion,” says Al-Kaysi. “By synthesizing the appropriate organic molecule, we have generated the first P-type photomechanical actuators with nanometer thickness.”
Under X-ray diffraction, the scientists found the molecules switched between two shapes, allowing them to move through a liquid.
The researchers synthesized their novel molecule, called 9DVAM, by reacting a derivative of the hydrocarbon anthracene with an organic compound called malononitrile and fabricating molecular crystal nanowires that bent and straightened repeatedly under light stimulation. Further analysis of 9DVAM’s structural changes using X-ray diffraction revealed that the molecule was switching between two isomer shapes (different orientations of the atoms within the molecule) in response to light. “These conformational changes offer the largest possible displacement in the molecule, meaning maximum energy is generated,” explains Al-Kaysi. “This lays
the foundations for building molecular switches, or making artificial robotic flagella that could be attached to drug-loaded carriers, allowing them to be steered towards target tumour sites.” “We’re at the early stages of developing systems that can be used inside the body, where it is dark. By utilising clever synthesis, we could develop molecules activated using near-infrared radiation, which can penetrate the body.” Zhu, L., Tong, F., Zaghloul, N., Baz, O., Bardeen, C.J. et al. Characterization of a P-type photomechanical molecular crystal based on the E – Z photoisomerization of 9-divinylanthracene malonitrile. Journal of Materials Chemistry C 4, 8245-8252 (2016).
More medicines could soon be delivered through the skin by cargo-carrying peptides.
he skin’s protective barrier is impermeable to most compounds, making it a challenging conduit for drug delivery. Finding a solution to this problem is attractive because, unlike the intravenous route, the delivery of therapeutics through the skin is non-invasive and bypasses the digestive system, which can improve patient compliance. “This is the reason delivery of therapeutic molecules through the skin has gained tremendous scientific attention over the years,” says bioinformation scientist Ankur Gautam of the CSIR-Institute of Microbial Technology in India.
Gautam and his colleagues have found that a peptide (a compound of linked amino acids) they had previously revealed to have cell-penetrating properties, can also deliver therapeutic cargo across the membranes of cancer cells. The peptide, called IMT-P8, belongs to a family of cell-penetrating peptides (CPPs) that have an inherent ability to pass through biological membranes without causing significant damage. They are also capable of transporting a variety of cargoes, such as small molecules, peptides, proteins, nucleic acids and nanoparticles, into the cell.
"We believe that, in the future, many other potential CPPs will be evaluated for their topical ability to deliver therapeutics."
outermost dead-cell layer of skin. This finding suggests that, in the future, IMT-P8 could be a potential candidate to deliver various drug formulations for the treatment of local skin infections. Gautam notes that the study is preliminary and the topical delivery of therapeutics using small peptides is still in its infancy. “Our study is a step forward in this direction. We believe that, in the future, many other potential CPPs will be evaluated for their topical ability to deliver therapeutics,” he says. Many more steps need to be taken before the findings can be translated to humans. “We have tested IMT-P8 on mouse skin and we plan to evaluate the potential of IMT-P8 on human skin biopsy samples.” The research team is also planning to design different formulations of IMT-P8 to improve its penetration and delivery capability. Gautam, A., Nanda, S.J., Samuel S. J., Kumari, M. et al.
Their most exciting finding, says Gautam, was discovering that, in mice, IMT-P8 could also cross the stratum corneum, the
Topical delivery of protein and peptide using novel cell penetrating peptide IMT-P8. Scientific Reports 6, 26278 (2016).
© PHOTOTAKE INC. / ALAMY STOCK PHOTO
Reaching cancer through the skin
Researchers are testing new compounds that could have the ability to transport drugs across the skin and into cancer cells.
Smart nanoparticles for cancer drug delivery Magneto-fluorescent nanoparticles successfully deliver anti-cancer drug to breast cancer cells.
Drug-loaded nanoparticles target and kill breast cancer cells.
doxorubicin and evaluated the effects on two types of cancerous breast cells and on healthy cells the results surpassed expectations. Not only were the drug-loaded particles more effective at killing the cancerous cells than the free doxorubicin, but, more importantly, their effect was greater on the cancerous cells than on the non-cancerous cells. Thanks to the particles’ magnetic and fluorescent properties, the authors were able to electronically image the drug-loaded nanoparticles and demonstrate cell uptake, even in tumour tissue derived from patients with breast cancer. Unlike free doxorubicin, which is internalised by passive diffusion through the cell membrane, the drug-loaded nanoparticles trigger endocytosis, a process whereby the cell actively engulfs them.
"Even with a passive-targeted, well-designed delivery system, enhanced toxic responses [in cancerous cells] can be attained” The ability of these particles to selectively deliver the chemotherapy drug to cancerous cells is somewhat surprising given that they have not been designed against a molecular target on these cells. In El-Boubbou’s own words “these results suggest that even with a passive-targeted, well-designed delivery system, enhanced toxic responses [in cancerous cells] can be attained,” offering huge potential as selective anti-cancer drug carriers. El-Boubbou, K., Ali, R., Bahhari, H. M., AlSaad, K.O., Nehdi, A., et al. Magnetic fluorescent nanoformulation for intracellular drug delivery to human breast cancer, primary tumors, and tumor biopsies: Beyond targeting expectations. Bioconjugate Chemistry 27, 1471-1483 (2016).
© J. SZULCZEWSKI, D. INMAN, K. ELICEIRI, P. KEELY \ NCI \ CARBONE CANCER CENTER AT THE UNIV. OF WISCONSIN
hemotherapeutics have markedly increased cancer survival rates. However, they cause serious side-effects due to their inability to differentiate between cancerous and healthy cells. Research aiming to reduce these adverse effects is important to ensure treatment compliance and improve patients’ quality of life. Kheireddine El-Boubbou has been designing nanoparticles that combine diagnostic and therapeutic capabilities, also known as theranostics, for more than ten years. In a recent study published in Bioconjugate Chemistry, El-Boubbou and his team at King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center and Saudi Arabia’s Ministry of National Guard—Health Affairs describe how novel magnetic and fluorescent nanoparticles are able to deliver an anti-cancerous drug to breast cancer cells with high selectivity. Magnetic metal oxide nanoparticles have demonstrated considerable promise for disease diagnosis, as magnetic resonance contrast agents, and as drug delivery agents, but mass production of such particles for clinical applications has been particularly challenging. Researchers led by El-Boubbou have developed a unique approach for producing magnetic metal oxide nanoparticles easily, cheaply and safely. Their ‘Ko-precipitation Hydrolytic Basic (KHB)’ methodology allows the synthesis of particles two to six nanometres in size from affordable, non-toxic and readily available starting materials at far lower temperatures (80 °C) than existing thermal techniques (200–300 °C). With the appropriate coating, the generated particles can be used for widespread biomedical applications, such as disease diagnosis and to aid targeted drug delivery, explains El-Boubbou. When the researchers loaded their nanoparticles with the chemotherapy drug
© JAMES DAVIES / ALAMY STOCK PHOTO
Stem cells extracted from the placenta could have properties that surpass those derived from other parts of the body.
An attractive and abundant stem cell alternative Stem cells derived from the maternal side of the human placenta may find unique therapeutic applications given their special properties.
esenchymal stem cells (MSCs) are ‘multipotent’, having the potential to differentiate into many adult cell types including bone, cartilage and fat cells. The majority of MSCs used in therapeutic applications are derived from bone marrow. However, they are difficult to extract and their potential to differentiate typically decreases as the age of the donor increases. Harvesting them is also notoriously time-consuming and invasive for the donor, prompting scientists to search for alternative MSC sources. Cell biologist Mohamed Abumaree, from King Abdullah International Medical Research Center, with local and international
colleagues, has extracted and characterized MSCs from the ‘decidua basalis’, a part of the human placenta that is highly exposed to inflammation and oxidative stress during early pregnancy. The team found that decidua basalis and bone marrow MSCs can similarly differentiate into bone cells, cartilage cells and fat cells. More importantly, decidua basalis MSCs secrete a cocktail of cytokines, growth factors and immunomodulatory molecules that are normally used to safeguard the foetus. The researchers believe that the decidua basalis may prove to be an equally good source of MSCs, if not better, for use in therapeutic applications, particularly those related to neurodegenerative and autoimmune diseases.
A great variety of MSC types — including those derived from the liver, dental pulp, adipose tissues, endometrium, muscle tissues, amniotic fluid, umbilical cord blood and the placenta — has been studied in the past. However, not much study has been focussed on the genetic makeup and growth properties of decidua basalis MSCs. The researchers isolated decidua basalis MSCs and characterized their genetic and protein expression profiles. They found that these cells express adhesion molecules that help other cells bind together. They also migrate to sites of inflammation or injury upon stimulation. These properties have implications not only for regenerative medicine but also for tissue engineering where stem cells must securely bind to a scaffold called the extracellular matrix. Decidua basalis MSCs are highly abundant and can be easily collected after the delivery of babies. The researchers would like to further investigate how they can be used to treat diseases such as atherosclerosis, Alzheimer’s disease and Parkinson’s disease. Abomaray, F. M., Al Jumah, M. A., Alsaad, K. O., Jawdat, D., Al Khaldi, A. et al. Phenotypic and Functional Characterization of Mesenchymal Stem/Multipotent Stromal Cells from Decidua Basalis of Human Term Placenta. Stem Cells International 2016, 5184601 (2016).
Balancing CT dose and image quality New techniques to improve image quality in CT scans while reducing radiation dose may compromise quality at certain thresholds, potentially resulting in misdiagnosis.
ew sophisticated imaging algorithms have allowed clinicians to reduce patient exposure to radiation while maintaining the quality of the images from CT scans. But researchers warn these algorithms have their limits, compromising image quality and diagnosis. Since 2011, clinicians at Saudi Arabia’s Ministry of National Guard—Health Affairs (MNGHA) have been using an image reconstruction algorithm called adaptive statistical iterative reconstruction (ASIR) to reduce image ‘noise’ in CT scans and improve image quality. Image noise can be thought of as the visual equivalent of the subtle background hiss in old radios. On a CT image, noise appears as random speckles that can significantly reduce image quality, making it more difficult to pick up lesions or abnormalities on a scan. Achieving a sharp image has always been a challenge for radiologists. Tradition-
ally, they used a method called filter back projection (FBP) to reduce image noise. Advances in computer technologies have enabled the use of complex mathematical models, like ASIR, to provide good image quality at reduced radiation doses. This is particularly important for people needing to undergo a series of CT scans. These models learn from the data they receive from the X-ray machine and reconstruct those parts of the CT images affected by noise. The Saudi researchers noticed reduced sharpness on some ASIR images, so they decided to assess the impact of ASIR on image quality to make sure the technique was not compromising the diagnostic information on the CT images. They measured image quality obtained at various radiation doses using both conventional FBP and ASIR. They discovered that while ASIR undoubtedly offered an improved image quality, this was dependent on the level
of radiation exposure applied by the radiologist and the percentage level of ASIR applied in the scan. In other words, ASIR improved the resolution of a scan up to a certain threshold, beyond which it started to degrade the quality of the image. “This threshold changes to higher or lower values depending on the scanning dose used to obtain the image,” write the researchers in their study published in the Journal of Applied Clinical Medical Physics. When the resolution or sharpness of an image starts degrading, some information that may be clinically significant is removed from the image, they add. “Physicians need to be careful when acquiring CT images using ASIR.” As a result, the team now avoids the use of higher levels of ASIR. More research is needed, they say, to identify the exact anatomical information that is lost when the sharpness of the images starts to degrade. “I believe [the findings] will make scientists in the field re-think when and how to use ASIR and similar algorithms,” says Fahad Ahmed Hussain of MNGHA. Hussain, F., Mail, N., Shamy, A., Alghamdi, S. & Saoudi, A. A qualitative and quantitative analysis of radiation dose and image quality of computed tomography images using adaptive statistical iterative reconstruction. Journal of Applied Clinical Medical Physics 17, 419-432 (2016).
© SERGIO AZENHA / ALAMY STOCK PHOTO
Sophisticated algorithms allowing high quality images with reduced radiation levels may have their limits.
An anti-cancer molecule with a back-up plan Anti-cancer agent kills cells in two different ways, offering an effective avenue for treatment. 38
Deguelin is known to cause apoptosis, but the mechanism by which it acts is still under investigation.
Many chemotherapy drugs act by blocking cell division or otherwise damaging cells, causing the cells to activate a process of controlled death known as apoptosis.
esearchers in Saudi Arabia and Pakistan have uncovered the molecular mechanism behind the effectiveness of the anti-tumour agent, deguelin. Many chemotherapy drugs act by blocking cell division or otherwise damaging cells, causing the cells to activate a process of controlled death known as apoptosis.
Apoptosis is an effective way for the body to remove unhealthy cells, but it needs to be carefully regulated. In healthy cells, maintenance proteins constantly destroy or disable apoptotic proteins responsible for activating the process. Although deguelin is known to cause apoptosis, the mechanism by which it acts is still under investigation. To understand
To confirm these findings, the team tested the effect of disabling the ERK proteins in human cancer cell cultures. Following inactivation of ERK, they detected an increased level of the apoptotic protein it normally regulates, similar to the response to treatment with deguelin. Together, these results show that deguelin acts by disabling the systems controlling apoptosis. While earlier work has also shown that deguelin activates apoptosis, this study demonstrates that the drug interferes with two separate pathways controlling the process. While further research is still needed, deguelinâ&#x20AC;&#x2122;s dual activity may offer a more effective, robust alternative to other chemotherapy drugs. Hafeez, S., Urooj, M., Saleem, S., Gillani, Z., Shaheen, S., et al. BAD, a proapoptotic protein, escapes ERK/ RSK phosphorylation in deguelin and siRNA-treated HeLa cells. PLOS ONE 11, e0145780 (2016).
ÂŠ ALAN HOLDEN / ALAMY STOCK PHOTO
how deguelin works, the researchers used physical simulations to predict how the drug binds to maintenance proteins. They found that deguelin blocks the docking site for the apoptotic proteins. This prevents them from becoming inactivated by the maintenance proteins and leads to apoptosis. The simulations showed that deguelin also binds to another group of proteins involved in controlling apoptosis, the ERK proteins. The ERKs are part of a signalling circuit that controls certain apoptotic proteins. By binding to ERK, deguelin interferes with the signalling process. As a result, the ERK-controlled apoptotic proteins arenâ&#x20AC;&#x2122;t marked for destruction, leaving them free to initiate apoptosis.
Genetic signals have been found to be implicated in tobacco addiction and the risk of developing chronic obstructive lung disease.
The genetics of smoking behaviour and lung disease
any smokers suffer severe airflow obstruction, or chronic obstructive pulmonary disease (COPD), while others who smoke may not become as ill. Some people seem to get hooked after a few cigarettes, while others do not. Researchers have long sought to understand these differences, and a new study of the genetics of smoking behaviour, lung function and COPD is offering clues. Biomolecular scientist Ian Hall, from the University of Nottingham, and a team of international researchers analysed genetic data from 50,008 samples stored at the UK Biobank. The chosen samples were from smokers and those who have never smoked, each group including similar numbers of people with low, average and high respiratory function. Lung function is measured with an instrument, called a spirometer, that measures the amount of air exhaled with force after inhaling as deeply as possible. The team found common genetic causes for low lung function in never-smokers and heavy smokers and in people with and without asthma. They found six new genetic variations associated with extremes of lung function that were also associated with COPD, including in individuals with no history of smoking. These variations determine how the lungs develop and how they are damaged and therefore who gets more severe lung disease how early in life, Hall explains.
“The team also identified five new genetic signals for smoking behaviour,” he says. Certain genetic variations relate to nicotine receptors in the brain and how they affect the reward pathway and addiction. They identified one genetic region that appears to regulate the expression of a number of other genes and may act like a master switch, Hall says. “This genetic information can potentially help us target at-risk individuals with treatment to help people stop smoking,” he says.
“This genetic information can potentially help us target at-risk individuals with treatment to help people stop smoking.” “While this information may in the future be used to build a risk profile based on genetic variations, the public health message is not that it is OK to continue smoking even if you are in a lower risk group; as there are many other health risks related to smoking,” Hall says. Wain, L.V., Shrine, N., Miller, S., Jackson, V.E., Ntalla I., Hall, I. et al. Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank. The Lancet Respiratory Medicine 3, 769-781 (2015).
© CULTURA CREATIVE (RF) / ALAMY STOCK PHOTO
Samples reveal specific genetic signals that determine a person’s risk for tobacco addiction and lung damage from smoking.
© BRIAN JACKSON / ALAMY STOCK PHOTO
Reaching for success is easier for the tall A broad survey of British men and women suggests hereditary differences in height and weight affect prospects for socioeconomic positioning.
everal studies have found that higher levels of education and financial security tend to be linked to increased height and lower body mass index (BMI)—presumably due to a more nutritious diet and a healthier overall lifestyle. However, recent findings from molecular geneticist Timothy Frayling, from the Royal Devon and Exeter Hospital in the UK, and colleagues suggest that an individual’s socioeconomic status can be affected by innate differences in weight and stature. Although higher standards of nutrition in childhood have a bearing on height and BMI, both traits also have well-established hereditary components. Indeed, researchers have identified numerous genetic markers that seem to directly affect these physical characteristics. Frayling and colleagues took advantage of the UK Biobank, a massive repository of biological specimens and biomedical data from more than half a million individuals. Based on a sample of roughly 120,000 UK Biobank contributors, they hoped to determine the extent to which differences in career, educational and economic achievement might be an effect rather than a cause of physical differences. In keeping with past results, individuals who were taller and exhibited a lower BMI tended to fare better from a socioeconomic standpoint. These individuals
Physical differences can predict degree of academic and career success.
generally received more education, earned more money, and were more likely to hold down skilled jobs. This pattern generally held true for men and women. However, interesting causal patterns began to emerge when genetic data were taken into account. Among men, a genetic predisposition to shorter stature appears to be a predictor of reduced educational and career success. For example, a genetically associated height difference of 6.3 centimetres above the average height was associated with a considerably higher likelihood of working in a skilled profession, and this height difference also correlated with a £1,580 increase in household income. This height-related pattern was not observed among women, but female subjects with higher BMI appear to suffer equivalent setbacks in the working world. Women who were relatively heavier as a
consequence of genetic factors generally took a hit in their earnings — an increase of 4.6kg/m2 in BMI was associated with a £2,940 drop in household income. These women were also more likely to experience other indicators of socioeconomic deprivation, such as unemployment, lack of a car or overcrowding in their home. For both men and women, these differences are likely to represent the consequences of social discrimination. Given that many societies consider taller men to be stronger and better leaders and thinner women to be more attractive, genetic determinants of these traits could have profound impacts on an individual’s success and long-term well-being. Tyrrell, J., Jones, S.E., Beaumont, R., Astley, C.M., Lovell, R. et al. Height, body mass index, and socioeconomic status: mendelian randomisation study in UK Biobank. BMJ 352, i582 (2016).
A new player in gene regulation
ctin, a protein generally considered a structural component of cells, is also involved in controlling the translation of DNA into RNA, a new study has found. The additional complexity revealed in regulating this transcription process, which is the first step in gene expression, may eventually shed light on diseases and disorders that are not understood. “Usually when people talk about actin, they’re thinking about its role in support, transport, or movement rather than in transcription,” says KAIMRC’s Bader Almuzzaini, the study’s lead author. Following earlier work that suggested actin might be involved in reprogramming gene expression, Almuzzaini used a technique to isolate fragments of DNA attached to actin and then sequence them, enabling them to identify regions of the mouse genome where actin was bound. They found that actin binds throughout the genome and is enriched in specific regions, such as between genes and around promoters that control gene
expression, supporting its hypothesized role in regulating transcription. Next, the team used cells in which actin had been disabled to directly investigate its function, focusing on the regulation of the transcription of the ribosomal RNA (rRNA) gene, which plays a central role in protein synthesis. They found a significant decrease in rRNA synthesis in the absence of actin. Further investigation revealed that several molecules involved in controlling transcription were not attached to the rRNA gene when actin was missing. When the researchers reintroduced actin into the cells, the molecules bound properly to the rRNA gene, and its transcription level went back to normal. “That was an exciting moment,” says Almuzzaini. “Our results all came together and we knew we had a clear story to tell.” These results led the researchers to suggest that actin tethers various factors involved in transcription, bringing them alongside regulatory regions of the genome. Once in place, these factors add
and remove tags, known as epigenetic markers, which influence DNA transcription, partly by altering how tightly it is wound. While this particular model might be specific to rRNA and similar genes, the team has shown that actin is involved in regulating other types of genes as well. For Almuzzaini, this study is just the first step towards understanding diseases and disorders. “To me, actin itself isn’t the essential story. The essential story is the overall mechanism, which includes actin and various other factors and epigenetic modifications that control transcription,” he says. Almuzzaini hopes that understanding these varied factors will shed light on why certain leukaemia patients suffer relapses and don’t respond to chemotherapy, despite being classified as low-risk. Almuzzaini, B., Sarshad, A. A., Rahmanto, A. S., Hansson, M. L., Euler, A. V. et al. In β-actin knockouts, epigenetic reprogramming and rDNA transcription inactivation lead to growth and proliferation defects. The FASEB Journal 30, 2860-73 (2016).
Research suggests that actin tethers together various factors involved in DNA transcription, bringing them alongside regulatory regions of the genome. Issue No.2
© LAGUNA DESIGN /SCIENCE PHOTO LIBRARY / GETTY IMAGES
The molecular mechanism controlling gene expression is found to involve a familiar molecule.
Cause found for rare amino acid disease A young Saudi girlâ&#x20AC;&#x2122;s metabolic disorder can be explained by a newly discovered gene mutation.
© ©MAJID ALFADHEL / HUMAN GENETICS
he rare genetic disorder known as glycine encephalopathy is usually caused by defects in the enzyme system that breaks down the amino acid glycine, resulting in an accumulation of the protein building block in the body’s tissues and fluids. Now, a team, led by geneticists from KAIMRC and King
Saud bin Abdulaziz University for Health Sciences, has discovered that mutations in a protein that controls the shuttling of glycine within the brain can also trigger the disease. In a case report, Majid Alfadhel and his colleagues describe an infant girl, born to Saudi first cousins, who had all the clinical symptoms of glycine encephalopathy; which is also known as non-ketotic hyperglycinemia and affects an estimated one in 60,000 newborns worldwide. Her symptoms included breathing problems, seizures, low muscle tone and elevated glycine levels in various bodily fluids. Yet, the patient harboured no disease-causing mutations in any of the three glycine degradation genes previously implicated in the disorder. In search of a genetic culprit, Alfadhel’s team sequenced all the protein-coding portions of the infant’s genome. They honed in on a defect in the SLC6A9 gene that encodes the glycine transporter 1 (GlyT1) protein. The patient had two copies of this defective mutation, while her parents and older sister all had just one copy, indicating that the aberrant DNA acts in a recessive fashion. Structural analysis showed that the mutation alters the shape and chemical properties of the GlyT1 protein to disrupt its normal function. Previous research revealed that the mutation causes a disease in rodents that’s similar to the one in human patients. When Alfadhel told the parents of the
affected child that he had discovered the molecular offender responsible for their daughter’s disorder, “they were very happy,” he says, “because they had struggled for a long time, going from clinic to clinic without a diagnosis.” Now, that family — and others around the world — can undergo pre-implantation genetic testing to avoid passing on the disease to future offspring.
"[The family] had struggled for a long time, going from clinic to clinic without a diagnosis.” Although the clinical consequences of this newly discovered mutation are the same as other known genetic defects responsible for glycine encephalopathy, the mechanism is quite different. GlyT1 mutations only lead to glycine build-up in the brain, whereas defects in glycine degradation cause a backlog of the amino acid throughout the body. The importance of this distinction is unclear, however, and further cases are needed to “confirm the full spectrum of SLC6A9-related phenotypes and genotypes,” says Alfadhel. Alfadhel, M., Nashabat, M., Qahtani, H. A., Alfares, A., Mutairi, F. A. et al. Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans. Human Genetics 135, 1263-1268 (2016).
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An MRI image of the brain of the Saudi girl, showing hyper-intensity in the white matter, caused by the accumulation of glycine.
© LAURENT FASANO 2016
Gene ties autism and kidney issues Mutations in the “teashirt” gene cause both an autism syndrome and kidney problems in children.
gene previously implicated in swollen kidneys also contributes to an autism syndrome, a finding that could help with diagnosis of both conditions. The gene is known as teashirt zinc-finger homeobox family member 3, or TSHZ3. Its discoverer, Laurent Fasano, first described the fruit fly version of this gene 25 years ago. Fasano and his colleagues at France’s Developmental Biology Institute of Marseille have since shown in mice and humans that TSHZ3 plays pivotal roles in the differentiation of the smooth muscles that help transport urine from the kidney to the bladder and in the development of neurons in the hindbrain that regulate breathing. A curious clinical observation led the researchers to investigate yet another function of TSHZ3. Joris Andrieux, a medical geneticist at France’s Jeanne de Flandre Hospital in Lille, had a patient who was missing part of the TSHZ3 gene. This child exhibited developmental delays, intellectual disabilities and other autistic features, in addition to kidney tract problems. Because of the genetic similarity, Fasano and his colleague Xavier Caubit decided to take a closer look at their mice for signs of neurocognitive deficits. Sure enough, the animals with mutations in the mouse version of TSHZ3 displayed behavioural abnormalities consistent with an autism spectrum disorder (ASD). Andrieux then helped Fasano reach out to physicians around the world to see if anyone knew of other patients who had 46
TSHZ3-expressing neurons (red) are located in deep layers (L5 and L6) of the embryonic mouse cerebral cortex.
both autism and kidney problems owing to a TSHZ3 mutation. He found such cases in France, Sweden, the United Kingdom and the United States. “This study was only possible because scientists and clinicians with different and complementary expertise have decided to share their data and the result is just amazing,” Fasano says.
"This study was only possible because scientists and clinicians with different and complementary expertise have decided to share their data and the result is just amazing."
TSHZ3 trigger an autism syndrome. They looked at genes expressed in a developing fetal human brain, and found 34 that contribute to ASD that were also highly expressed alongside TSHZ3. Furthermore, they showed that the TSHZ3 gene itself was most active in deep layers of the brain’s neocortex known to contribute to the development of autism. The researchers confirmed these findings in Fasano’s mouse models. These mice with Tshz3 mutations can now be used to look for new treatments for ASD. Moreover, Fasano notes, children who have kidney issues or signs of an autism syndrome can now have their TSHZ3 gene status tested to see whether they need to be screened for other health problems. Caubit, X., Gubellini, P., Andrieux, J., Roubertoux, P.L.,
Back in the laboratory, Fasano and his research team dug deeper into the molecular mechanisms by which mutations in
Metwaly, M. et al. TSHZ3 deletion causes an autism syndrome and defects in cortical projection neurons. Nature Genetics 48, 1359-1369 (2016).
Unravelling the mysteries of intellectual disorders © MAJID ALFADHEL 2016
DNA sequencing offers diagnoses and treatments for patients with unexplained intellectual disorders.
KAIMRC’s Majid Alfadhel specializes in finding genetic causes of unexplained paediatric disorders.
equencing the entire protein-coding portion of the genome in people with unexplained intellectual development disorders can offer diagnoses and new treatment options for a large number of people. A Canadian-led team, which included KAIMRC paediatric geneticist Majid Alfadhel, conducted extensive clinical evaluations and DNA sequencing on 37 children and four adults with unexplained intellectual development disorder, a condition that affects an estimated 3% of the population worldwide. This approach yielded a genetic diagnosis for 28 of the patients, including a four-year-old Saudi girl with recurrent breathing problems, skin pigmentation abnormalities and fat deposits in her liver. Sequencing the 1% of this child’s genome that codes for proteins revealed that mutations in a gene called H6PD, which encodes an enzyme involved in cellular stress responses, were responsible for her condition. No therapeutic intervention could be
found for the young girl, but the clinicians were able to change treatment protocols for 18 of the affected individuals in the study. In one patient with a newly-described condition that affects mitochondria (the power factories of the cell), the researchers found that treatment with a drug called carglumic acid could correct a dangerous imbalance of metabolites. In another, with sleep problems and seizures, amino acid and vitamin supplements brought the seizures under control and improved other symptoms caused by mutations in a gene called GOT2 that encodes a different mitochondrial enzyme. Sixty-eight percent of the people genetically analysed in this study received diagnoses—a diagnostic rate much higher than the 16% documented in previous reports using the same sequencing approach to explain unexplained intellectual disorders. Alfadhel credits the comprehensive patient evaluations for much of the high diagnostic yield. This allowed the team to isolate the sequencing of DNA only for
individuals who were likely to benefit from the approach. However, Alfadhel also points to the close collaboration between the clinical physicians and the computational scientists performing the data analyses. “Data sharing and open communication between scientists and researchers across the globe are the keys to maximizing the diagnostic potential of next-generation sequencing and its clinical benefit for patients and their families,” says Alfadhel, who trained at the British Columbia Children's Hospital in Vancouver, Canada, where most of the patients in the study were treated. This international experience, he adds, will enable “more collaboration and communication between international experts and my team, which will definitely benefit our patients in Saudi Arabia.” Tarailo-Graovac, M., Shyr, C., Ross, C.J., Horvath, G.A., Salvarinova, R. et al. Exome sequencing and the management of neurometabolic disorders. N Engl J Med 374, 2246-2255 (2016).
Smart partnerships © KAIMRC
While some Saudi enterprises strive to be the biggest, a new biotechnology park in Riyadh has set smaller perimeters with a sharp focus.
Saudi Arabia's biotech parks bridge the divide between science and application.
hat could a cancer patient in Al Hafayer, in Saudi Arabia’s eastern province, and a stem cell researcher at Harvard University Medical School on the east coast of the United States have in common? The latter would perhaps be poring over data about the former, the two strangers offering each other anonymous assistance through a link in Riyadh. A new biotechnology park has been set up in the capital city to forge links between biomedical research in the kingdom and commercial opportunities. “We have huge infrastructure for biomedical research. We have put in a lot of investment. The only thing that was missing was turning research into commercial diagnostic and therapeutic tools,” says Abdelali Haoudi, head of strategy and 48
business development at King Abdullah International Medical Research Center (KAIMRC). By establishing its biotech park, KAIMRC is looking to plug the gap. KAIMRC’s efforts are part of a wider trend, across the kingdom and the region, of concerted attempts at tapping into the commercial potential of scientific research. More than three dozen technology parks have sprung up in rapid succession over the past decade — from Jeddah and Doha to Muscat and Casablanca — according to a tally by a UN agency. Riyadh’s new biotech park, with access to research results and patient data from far-flung corners of the kingdom, is charting its own path. It aims to set itself apart by zeroing in on a relatively small set of diseases, championing sustainable and mutually beneficial partnerships, and
by taking advantage of the patient data uniquely available to it from the large medical ecosystem of hospitals and clinics that KAIMRC belongs to.
A small number of big-time ailments Technology parks may be prone to overreaching when they direct limited resources in disparate directions. Aware of this risk, the architects of KAIMRC’s park have established a “less is more” vision when it comes to the diseases that will receive the bulk of energy and resources. The park will focus only on a handful of diseases from each of the five most locally ubiquitous health conditions: cancer, diabetes, infectious diseases, cardiovascular diseases and neurological diseases. In the cancer category, for example, only leukaemia, lymphoma, and colorectal and breast
Playing to strength KAIMRC, established in 2006, is part of the larger medical research and care system that is King Abdulaziz Medical City. With headquarters in Riyadh, the medical city has offshoots in Al Ahsa, the kingdom’s eastern province, and Jeddah, in the western province. Each of the three campuses undertakes three functions: medical care through hospitals, teaching through medical colleges, and biomedical research through KAIMRC facilities in each location. The number of hospitals or colleges varies from campus to campus, with Riyadh’s being the largest. The medical city system was founded and is run by the health affairs department at the Ministry of National Guard. Through this ecosystem, KAIMRC, as well as its new biotech park, has access to growing and fresh troves of patient data from across the kingdom. This will help in routinely monitoring the prevalence and nature of the park’s designated focus disease areas. Such a wealth of patient data, says Haoudi, makes the new park more attractive to
To foreign researchers, the park's patient data is one of its more attractive facets.
MERS-CoV, a viral disease discovered in the kingdom in 2012, is among the park's research focal points.
academic and pharmaceutical partners than many other science and technology parks in the region. Extensive patient data, along with research-enabling facilities and expertise will also make for mutually beneficial partnerships. KAIMRC’s park would seem a natural ally for a pharmaceutical company or an academic researcher interested in the particular profile of a type of diabetes or cancer in Saudi Arabia or the Gulf.
Every intractable medical puzzle is an occasion to bring together the best minds inside and outside Saudi Arabia. For the park, whose operations are planned to start in earnest next fall, such partnerships can channel the ingenuity of researchers from prestigious institutions to develop products and services that address local and regional health issues. This mode of partnership — where parties are brought together by shared interest in the same medical puzzle, with each
contributing something unique — is more sustainable, says Haoudi. KAIMRC is already finalizing partnership agreements with Harvard Medical School and Harvard Stem Cell Institute in the US and Oxford University in the UK. Discussions are also ongoing with a biotech firm interested in the Middle East respiratory syndrome coronavirus (MERSCoV), a viral disease that was discovered in Saudi Arabia in 2012, where it has also caused the highest number of fatalities. The spirit at KAIMRC’s new park is properly entrepreneurial: not only in the sense of breathing new life into the “development” part of “research and development,” but in recasting the kingdom’s health challenges as opportunities. From such a vantage point, every intractable medical puzzle is an occasion to bring together and forge collaborations with the best minds inside and outside Saudi Arabia, benefiting the kingdom, and enhancing its place as part of the global science enterprise. “Science, by its nature, knows no borders,” says Haoudi. “And the more we embrace science’s openness, the better off we are as society and the better science’s outcomes get.” A sentiment perhaps shared by those strangers in Al Hafayer and Harvard. Issue No.2
cancers will be targeted. There were two factors for selection: a high rate of incidence in Saudi Arabia; and the extent of research expertise available to KAIMRC and its network of partners and affiliates. “We cannot afford to do more than that,” explains Haoudi, a geneticist by training who moved into the area of science policy, with career stints in France, the United States and most recently Qatar.
A kingdom with a knowledge plan
audi Arabia’s first five-year development plan, issued in 1970, made a prediction and a vow: “Economic growth over the coming decades will chiefly rely on oil production and revenues. But that is what the development plan aims to change, gradually, by diversifying the kingdom’s economy, exports, and the government’s sources of income.” The prediction materialized, facilitated by the unforeseen jump in oil prices in the wake of the 1973 war. The vow — to diversify the economy in order to decrease the reliance on capricious oil markets — proved more challenging. But it was not due to a lack of trying. The kingdom, over successive plans, continued to hold out the diversification goal as official policy, perhaps no more articulately than in the tenth iteration, covering the years 2015-2019. The current plan offers a more solid understanding as to how the hoped-for diversification should occur. “The first five years of the 10th Development Plan mark the start of the 15-year transformation of the Saudi economy into a knowledge economy,” a high-ranking Saudi offi-
cial told Oxford Business Group, a research firm, in “The Report: Saudi Arabia 2015”. ‘Knowledge economy’ is a broad label denoting products and services whose value derives chiefly from their knowledge content. In Saudi Arabia, a shift to a knowledge-based economy means the creation of economic sectors that draw on innovation in science labs and technology incubators, not the sale of hydrocarbon derivatives. The areas that the kingdom has started investing in include alternative energy and biomedical research. A shift to a knowledge economy in the kingdom is both a necessity and an opportunity. While oil has made possible modern infrastructure across the country and underpinned expansive social welfare programs over the past five decades, the endurance of viscous crude as the kingdom’s main source of income has caused financial instability — as in the fiscal crises of the early 1980s and late 1990s when oil prices tumbled. Meanwhile, over the past two decades, mounting scientific evidence connecting the burning of fossil fuel to long-trend atmos-
© PHOTOBYLOVE / ISTOCK / GETTY IMAGES PLUS
A shift to a knowledge economy in Saudi Arabia is a necessity that holds much promise.
The boom in oil prices allowed Saudi Arabia to invest heavily in research and development, which is starting to pay off.
pheric change has prompted dramatic responses in policymaking circles. In mid-October this year, an international deal was inked in Kigali, Rwanda, to limit the use of hydrofluorocarbons, a big contributor to climate change. John Kerry, the US secretary of state, described it as a “monumental step forward” in efforts to slow down disconcerting climate trends. Along with India, the Gulf states have negotiated a nine-year exemption from implementing the Kigali accord, starting in 2028 instead of 2019. The Kigali agreement came shortly after the Paris Agreement late last year, in which 195 countries have legally bound themselves to limit greenhouse emissions. The two largest greenhouse emitters, China and the US, have ratified the agreement. In industry circles, two developments have occurred over the past decade, one in response to climate concerns, and both disruptive to oil supply and demand. On the one hand, we have witnessed the rise of novel ways to extract the coveted crude oil from under the ground. Consider, for instance, the advances in extracting oil from shale rocks through so-called ‘hydraulic fracture’ (or as it is commonly known, ‘frack-
ing’), a process that led to a glut in oil supply in 2015, further depressing its price. On the other hand, climate change fears have led to higher investment and innovation in alternative, greener energy and devices — from solar panels to advanced lithium-ion batteries and electric vehicles. Combined, these factors have shifted the conversation in several oil-rich countries. The question is no longer how long oil reserves can sustain governments and societies into the future; it is how fast available oil riches can be deployed to develop alternative, sustainable sources of economic value. In placing its bets on knowledge economy as the new engine of economic vigour, Saudi Arabia is opting for a model of proven validity. Abdelali Haoudi, KAIMRC’s head of strategy and business development, says countries large and small that have allotted significant resources to research and development (R&D), such as the US and Singapore, have reaped handsome payoffs in terms of commercially successful innovations and high-paying jobs. Saudi Arabia has already taken several steps in the pursuit of such an ambition. Over the past decade, the government has
“In placing its bets on knowledge economy as the new engine of economic vigour, Saudi Arabia is opting for a model of proven validity.”
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accelerated its efforts to modernize and re-energize its higher education and science institutions. In 2002, the government announced its National Plan for Science, Technology and Innovation, which went into effect in 2008, with a budget (through 2010) of SR8.1 bn (~US$2.16 bn). The past decade has also witnessed a notable increase in the number of public and private universities, from 20 in 2005 to 34 in 2012, including three modern women-only universities. Promising Saudi students have now three all-expenses-paid programs to pursue college and graduate studies abroad: the King Abdullah Scholarship Program since 2005, Saudi Aramco’s, and since 2008 from King Abdullah University of Science and Technology (KAUST). These efforts were reflected in improved metrics for the kingdom’s performance on various indicators on science and innovation. For example, the number of scientific publications from the kingdom surged from 1,686 in 2008 to 7,000 in 2012, according to a 2014 report marking progress on knowledge economy indicators in Saudi Arabia. In 2013, the World Bank ranked Saudi Arabia 4th in the Arab world on a compound indicator for ‘knowledge economy’ (including education, innovation, economic incentives for science and innovation, and information and communications technology). Also in 2013, Saudi Arabia ranked first among Arab states (and 29th globally) in the number of US patents it received, about a quarter of which came from Saudi Aramco. 52
Still, these successes come with their fair share of challenges. The infrastructure and regulatory environment have room for improvement, says Haoudi. While his area of interest and expertise — biomedical research — does have some powerful players operating in Saudi Arabia, they confine their activities to marketing and distribution, and conduct their R&D elsewhere. That is another challenge: to convince individuals and groups in the science community that Saudi Arabia is one of the better venues for doing science-producing innovation. At the same time, Saudi Arabia occupies an advantageous position because of its oil revenues. Scientific research and innovation are increasingly a costly enterprise. The start-up costs for scientific research infrastructure pose an entry barrier that not all aspirants to knowledge economy can surmount, says Stephen Weber of the University of California, Berkeley. Weber, a professor of political science, served as adviser to several Gulf governments, including Saudi Arabia’s and Qatar’s, on innovation and development projects. An example of this advantage is on display in the creation and renowned performance of KAUST, which is fast becoming a regional science powerhouse. The trick, however, is to channel, in one direction, the energy from this flurry of effort and initiative. One solid indicator that such efforts are bearing fruit is if we see decreasing reliance on oil revenues over the coming years; for this has always been the original plan.
NATURE INDEX (2016)
The Nature Index monitors a list of the highest impact journals in different disciplines of natural sciences. The actual count (AC) is a measure of how many papers have been published with at least one scientist with an affiliation to a Saudi research institute or university. The weighted fractional count (WFC) measures the level of contribution of Saudi institutes to the papers being published.
S S E C C U S S FACTOR Technology commercialization & industrial collaboration
KAIMRC and its academic medical center stakeholders are promoting the countryâ&#x20AC;&#x2122;s overall move to a knowledge-based economy by supporting biotechnology and commercialization activities. Joining forces with the National Guard Health Affairs and KAIMRC, UFC Biotechnology established the joint venture UFC Biotech to manufacture needed cell and microbial culture media and supplements, and to satisfy the needs of the market in the Arab world. www.ufcbiotech.com
Electron microscopy image of the MERScausing virus.
Patients with Middle East respiratory syndrome may produce sufficient antibodies to help fight the viral infection in more recent victims.
he blood plasma of people recovering from Middle East respiratory syndrome (MERS) could be a source of antibodies to treat patients in the grip of the disease. Researchers at KAIMRC reached this conclusion from a feasibility study conducted at Saudi Arabia’s Ministry of National Guard—Health Affairs (MNGHA) with co-workers elsewhere in Saudi Arabia and in the US, Canada and Europe. Their research did not involve trials of the proposed antibody therapy, but it did establish that collecting sufficient antibodies from patients may be a realistic proposition. MERS is caused by a virus that was first identified in 2012 in a patient in Saudi Arabia. More than 36% of identified cases have proved fatal; and although the disease has been detected in many countries, 80% of cases have been in Saudi Arabia. “No therapy options have been proven to be effective, so developing a treatment using donated plasma would be of great value,” says MNGHA’s Yaseen Arabi, who led the feasibility study. Administering donated blood plasma containing anti-viral antibodies is known to be an effective treatment for other serious viral diseases. The researchers explored three possible sources of therapeutically useful plasma. These were 196 patients with acute respiratory illness and confirmed or suspected MERS virus infection, 230 healthcare workers who had been in contact with MERS patients, and 17 household contacts of patients. Blood samples from these three groups of potential donors were screened for the presence of antibodies able to bind to the MERS virus. Significant amounts of antibody were
detected in only a small number of the sample participants, with recently recovered MERS patients seeming to be the most suitable source. Although potentially useful amounts of antibody were detected in fewer than 3% of the study participants, Arabi remains positive, saying, “Our results do indicate it could be possible to obtain plasma, although with the small pool of potential donors, collecting large quantities to use in therapeutic studies may be challenging.” Moving on to clinical trials of donated plasma is the obvious next step, but there are several challenges ahead before reaching that stage.
"No therapy options have been proven to be effective, so developing a treatment using donated plasma would be of great value.” “We do need to explore other ways to obtain sufficient plasma with therapeutically useful amounts of antibody,” says Arabi. Possible options may be to use samples from patients who have just recovered from more severe disease. Also, strict criteria must be met to include potential plasma donors in clinical trials. With the feasibility of the approach demonstrated in principle, such issues can now be addressed. Arabi, Y. M., Hajeer, A. H., Luke, T., Raviprakash, K., Balkhy, H. et al. Feasibility of using convalescent plasma immunotherapy for MERS-CoV infection, Saudi Arabia. Emerging Infectious Diseases 22, 1554-1561 (2016).
© NIAID / CC. BY 2.0
Potential for a MERS antibody therapy
Striking at the heartland of the MERS infection At least a dozen additional cases of Middle East respiratory syndrome (MERS) were reported in Saudi Arabia in September 2016, bringing the number of cases in the kingdom to more than 1,450, of which 610 have been fatal.
Identifying the source MERS is a respiratory illness caused by the MERS-Coronavirus (MERS-CoV), which was initially thought to spread from bats to humans via consumption of food contaminated with bat droppings. In 2014, however, researchers from King Faisal University, working with collaborators in Egypt and Hong Kong, reported that they had isolated the MERS Coronavirus 56
© NIAID IN COLLABORATION WITH COLORADO STATE UNIVERSITY/ CC BY 2.0
ERS emerged in Saudi Arabia in September 2012, but laboratory-confirmed cases of infection have since been reported in 27 countries. Though more than 1,800 MERS cases have been reported worldwide, Saudi Arabia has been the site of the lion’s share. Every year, several million people take the Hajj pilgrimage to Mecca, increasing fears of a rapid global spread of MERS and other infectious diseases. As the epicentre of the syndrome, Saudi Arabia has become intrinsic to international efforts to combat its spread. Research carried out in the kingdom has contributed to understanding the virus’s biology and to the development of vaccines. “Saudi researchers have made significant contributions to identifying the clinical presentation of the disease, so that physicians are better able to identify infections,” says KAIMRC’s Hanan Balkhy, also executive director of the Infection Prevention and Control Department at the Ministry of National Guard–Health Affairs. “They have also made important progress in identifying risk factors for the disease, and in evaluating the effectiveness of treatments.”
MERS-CoV particles on camel epithelial cells.
from a herd of dromedary camels1 on a farm in the oasis region of Al-Hasa, in eastern Saudi Arabia. This confirmed that camels harbour MERS-CoV as intermediate hosts for the virus, which replicates in large quantities in their cells. Camels are likely responsible for spreading the infection to people who come into close contact with them. Later that year, researchers at the King Fahd Center for Medical Research provided evidence of direct transmission of MERS-CoV from camels to humans2. More recently, Saudi researchers published the first MERS case control study — a method used to compare patients
with a particular disease to those without it and establish how frequently they have been exposed to risk factors. This helps determine the relationship between risk factors and the disease. Researchers from the King Faisal Specialist Hospital and Research Centre in Jeddah, together with collaborators from the U.S. Centers for Disease Control and Prevention, identified all 535 known cases of MERS infection reported in Saudi Arabia between March and November 2014, and compared them to 116 uninfected individuals by assessing their underlying medical conditions and direct environmental exposure to known risk factors.
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This showed once again that those people who came into direct or indirect contact with dromedary camels were far more likely to be infected with MERS. The study findings3 reiterated that activities such as milking, feeding and slaughtering camels increased risk of infection, whereas drinking unpasteurised camel milk did not. Shortly after these findings were published, the Saudi Arabian Ministry of Agriculture issued a statement advising people who come into regular contact with camels to “exercise caution and follow preventative measures” to minimise the spread of infection by wearing face masks and gloves, and washing their hands before and after any contact. Health officials have also warned people to avoid contact with camels altogether, unless necessary.
Developing prevention strategies Since then, the Saudi government has been working closely with the World Health Organization to put effective measures in place for the Hajj pilgrimage. Efforts include raising awareness about MERS infection and heightened surveillance to prevent outbreaks. Visitors to Mecca are also advised to cover their mouths and noses when coughing or sneezing and to wash their hands regularly to minimise spread. Healthcare workers are at a particularly high risk of infection, and there have been a number of MERS outbreaks in Saudi hospitals in the past three years. Immediately after each of these events, the Saudi Arabian Ministry of Health dispatched rapid response teams to the hospitals to identify others who may have been infected and enforce measures of infection control. Balkhy says that the research has led to major changes in healthcare policies surrounding infection risk. “Identifying the method of transmission of the virus and the risk to healthcare providers has created a major transformation in the quality and standards in hospitals,” she says. “The research also led to the creation of a specific unit in the Ministry of Health that audits infection control practices, in order to ensure that hospitals are properly prepared.”
Researchers have identified dromedary camels as a possible reservoir for the coronavirus causing MERS.
Even so, much remains unknown. The exact mechanism of animal-to-human transmission is still unclear, for example, and researchers in Saudi Arabia and elsewhere are scrambling to develop an effective vaccine.
“Identifying the method of transmission of the virus and the risk to healthcare providers has created a major transformation in the quality and standards in hospitals.”
accelerate the fight against MERS. According to the workshop report, all interested parties recognize the need to cooperate, and have resolved to formalize collaborations to maximize investment in MERS research, produce reliable data, and influence public health policy. Balkhy says that she and her colleagues at KAIMRC are already collaborating on many other projects, most notably with researchers at the University of Oxford, to realise these goals. 1. Hemida, M. G., Chu, D. K. W., Poon, L. L. M., Perera, R. A. P. M., Alhammadi, M. A., et al. MERS coronavirus in dromedary camel herd, Saudi Arabia. Emerging Infectious Diseases 20, 1231-1234 (2014).
Last year, the King Abdulaziz City for Science and Technology (KACST) launched a comprehensive MERS-CoV research program in co-operation with the Ministries of Health and Agriculture. Working with the International Vaccine Institute, the Saudi Ministry of Health also co-organized a workshop in Riyadh for researchers, funding agencies and non-governmental organizations, to discuss how to
2. Azhar, E. I., El-Kafrawy, S. A., Farraj, S. A., Hassan, A. M., Al-Saeed, M. S. et al. Evidence for camel-to-human transmission of MERS coronavirus. The New England Journal of Medicine N. Engl. J. Med. 370, 2499-2505 (2014). 3. Alraddadi, B. M., Watson, J. T., Almarashi, A., Abedi, G. R., Turkistani, A. et al. Risk factors for primary Middle East respiratory syndrome coronavirus illness in humans, Saudi Arabia, 2014. Emerging Infectious Diseases 22, 49-55 (2014).
How hepatitis C takes control The hepatitis C virus commandeers key cellular machinery to keep itself safe.
esearchers have revealed how the hepatitis C virus uses a special structure to organize its reproduction in host cells and evade their immune response. The virus, which affects roughly 170 million people worldwide, rearranges the host cellâ&#x20AC;&#x2122;s internal membranes into a structure called the membranous web. Researchers had already shown that some viral proteins include markers for transport into the nucleus, called nuclear localization signals. Michael Joyce, a researcher at the University of Alberta, suspected that hepatitis Câ&#x20AC;&#x2122;s membranous web was co-opting a structure in the nucleus that controls traffic to and from it, called the nuclear pore complex (NPC). To test this idea, Joyce teamed up with his colleague Richard Wozniak, whose lab at the university focuses on the NPC. In previous studies published in 2013 and 2014, the team showed that hepatitis C hijacks the NPC and that several of the virusâ&#x20AC;&#x2122;s proteins have functioning localization signals1,2.
“This third paper brings the idea back almost full circle and ties it to the innate immune response,” says Joyce. The team demonstrated that the membranous web employs components of the NPC to control access to its internal compartments. They also found that key viral proteins were isolated within the membranous web while host proteins that activate the immune response were kept outside. The membranous web thus serves as a gated community for vulnerable viral components, creating space for them to interact undetected by the cell’s immune machinery3. Next, the team tested whether the addition of a nuclear localization signal could get the immune-response proteins past the gatekeeper. Proteins with the signal were carried into the membranous web, where they could detect and recognize various viral components and activate the cell’s immune machinery. The team showed that the same mechanism is at work in the group of viruses hepatitis belongs to, which includes the dengue and Zika viruses, though the details differ. “This is a new way of looking at how viruses work,” says Joyce. “I hope there will be many more studies elucidating these mechanisms in the life cycles of different viruses.” 1. Neufeldt C.J., Joyce M.A., Levin A., Steenbergen R.H., Pang D., et al. Hepatitis C virus-induced cytoplasmic organelles use the nuclear transport machinery to establish an environment conducive to virus replication. PLoS Pathogens 9, e1003744 (2013). 2. Levin A., Neufeldt C.J., Pang D., Wilson K., Loewen-Dobler D., et al. Functional characterization of nuclear localization and export signals in hepatitis C virus proteins and their role in the membranous web. PLoS One 9, e114629 (2014). 3. Neufeldt, C.J., Joyce, M.A., Van Buuren, N., Levin, A., Kirkegaard, K. et al. The Hepatitis C Virus-Induced Membranous Web and Associated Nuclear Transport Machinery Limit Access of Pattern Recognition Receptors to Viral Replication Sites. PLoS Pathogens 12, e1005428 (2016).
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The hepatitis virus uses the membranous web to hide vulnerable parts of the virus from the cell.
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Discovery and Innovation
KAIMRC recognizes the value and the importance of creativity. We encourage and support innovation through high-quality R&D programs and shared enabling platforms. The Saudi Biobank is designed as a longitudinal investigation of demographic and environmental factors influencing illnesses in Saudi Arabia. It aims to implement the highest standards of biological banking as it is vital for building genomic and proteomics databases.
Preventing flu in kidney transplant patients A flu shot may also benefit transplant patients under age 65.
The influenza vaccine Fluad is typically given to people over 65 but was found to be effective in younger kidney transplant patients.
is licensed for use in people over 65, this study shows that it could be a better option in organ transplant recipients who are 65 or younger,” explains Mona Al-Dabbagh from Saudi Arabia’s King Abdulaziz Medical City.
"The study found that there was not a significant increase in antibodies against the transplanted organ after vaccination.”
“Although some doctors suggest transplant patients should not be vaccinated because of the risk of rejection, this study found that there was not a significant increase in antibodies against the transplanted organ after vaccination,” explains Al-Dabbagh. “The next challenge is to understand if it is safe to administer Fluad early after the transplant, and to develop an effective vaccine for transplant recipients over 65,” says Al-Dabbagh. Kumar, D., Campbell, P., Hoschler, K., Hidalgo, L., Al-Dabbagh, M., et al. Randomized controlled trial
The team also checked if patients produced antibodies against the transplanted organ, which could lead to rejection.
of adjuvanted versus nonadjuvanted influenzavaccine in kidney transplant recipients Transplantation 100, 662-669 (2016).
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he first trial of the influenza vaccine, Fluad, in kidney transplant recipients shows that this vaccine is safe and at least as immunogenic as the standard flu shot, Agriflu. Fluad contains an adjuvant that boosts the immune response and is normally approved only for people over 65. Agriflu is non-adjuvanted and authorized for anyone over six months. In the clinical trial, Fluad was found to be more effective in kidney transplant patients under the age of 65. While most people recover quickly from influenza, a common flu can cause serious complications in organ transplant receivers, including death. Vaccination is recommended for these patients, but their response to vaccines is suboptimal and there have been cases of transplant rejection after vaccinating against the 2009 swine flu. A research team comprised of members from Canada, the UK and Saudi Arabia administered either Fluad or Agriflu to 60 kidney transplant recipients and compared their responses. Following the patients over six months after injection, the researchers found that both vaccines were well tolerated, with only minor side-effects. Then, they analyzed seroconversion: the development of enough antibodies against influenza. Among the 31 people who received Fluad, 71% demonstrated seroconversion to at least one of the three influenza antigens contained in the vaccines. Agriflu, on the other hand, was effective in 55.2% of the other group. Although this difference was not statistically significant, when the research team looked at the age difference, they found that the seroconversion rate of patients between 18 and 64 was significantly greater with Fluad (84.6%) than Agriflu (58.3%). “Although the vaccine
Hepatitis B: Predict, treat, avoid A biomarker has been found that can help predict the reactivation of the hepatitis B virus in immunosuppressed patients.
cientists from Hong Kong have identified a blood-borne protein that signals the likelihood of hepatitis B virus (HBV) reactivation in patients undergoing high-risk immunosuppressive therapy, such as cancer patients or those with autoimmune disorders. The presence of this biomarker, called hepatitis B core-related antigen (HBcrAg), could lead to more informed decisions about when to start potentially life-saving preventive medication. This is of particular importance in the developing world, where limited resources mean judicious dispensing of medicines. Patients undergoing acute hepatitis B infection can be diagnosed via the presence of viral surface proteins (HBsAg) in the blood. However some patients with chronic infection show no symptoms while remaining at-risk of viral reactivation. Man-Fung Yuen of the University of Hong Kong stresses that doctors need guidance on when to administer prophylaxis to these patients. Yuen’s team studied a cohort of 124 suitable patients undergoing one of two immunosuppressive therapies: rituximab-containing chemotherapy or allogeneic (received from a genetically similar donor) hematopoietic stem cell transplantation. The patients in the study were all HBsAg-negative, but tested positive for antiHBc (hepatitis B core) antibodies, signifying previous exposure to the hepatitis B virus. The therapies were chosen for their potent immunosuppressive effects and therefore their heightened risk of inducing HBV reactivation. Testing for anti-HBc only indicates an individual has previously been exposed to HBV, but does not differentiate between those with a past infection from asymptomatic, chronically infected patients at-risk of hepatitis B virus reactivation.
Increasing the early detection of HBV reactivation can allow for better control of the virus before it is too late in the disease course. The study group were monitored for HBV reactivation whilst levels of the biomarker HBcrAg were monitored. The team found that HBcrAg-positive patients had a much higher rate of viral reactivation, with 72% experiencing virus reactivation within two years. “HBV reactivation is becoming a common problem because of advances in using more potent immunosuppressives,” says Yuen. In some parts of the world such as East Asia, incidence of anti-HBc-positive individuals can reach 68%, while treatments involving immunosuppressive therapy are on the rise. Where cost-effectiveness of treatment is key, Yuen hopes his team’s research will benefit patients “[by increasing] the early detection of HBV reactivation, allowing for better control of the virus before it is too late in the disease course,” ultimately improving survival rates and clinical outcomes for at-risk patients with dormant hepatitis B virus infection. Seto, W., Wong, D., Chan, T., Hwang, Y., Fung, J. et al. Association of hepatitis B core-related antigen with hepatitis B virus reactivation in occult viral carriers undergoing high-risk immunosuppressive therapy. The American Journal of Gastroenterology 7, 825-830 (2015).
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Hepatitis B can lie dormant in some patients for years—a serious consideration for those undergoing immunosuppressive therapy.
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‘Young blood’ a defence against infection Signatures of a more potent and durable immune response may explain why children fend off chronic hepatitis C infection better than adults.
lthough children can acquire chronic infection with hepatitis C virus (HCV), their risk is lower than adult patients. A study by Hugo Rosen and colleagues at the University of Colorado Denver in the US has now revealed features of the juvenile immune response that might contribute to more effective antiviral defence. The vast majority of HCV infections occur in adults, with transmission occurring via shared needles or transfusion with contaminated blood. Children born to HCV-positive mothers can potentially contract the virus, and one recent study estimated that there are between 23,000 and 46,000 HCV-positive children in the US at present. However, children are also more likely than adults to eliminate the virus on their own, with 25-40% of paediatric patients achieving spontaneous viral clearance compared with around 20% of adult patients. Little is known about the paediatric response to HCV infection, so Rosen’s team set out to profile the immune function of 16 HCV-positive children and adolescents relative to an equal number of healthy controls. Meanwhile, they examined 20 adults with HCV in order to distinguish age-related differences in the anti-HCV response. All three groups of patients had simi64
Children are able to clear the hepatitis C virus much more effectively than adults.
lar numbers of T cells, the immune subpopulation that helps clear HCV infection. However, there were intriguing signs of differences in immune function between the various cohorts. Immune cells from HCV-positive children displayed clear evidence of an ongoing battle against the virus, whereas those from healthy children were more likely to be ‘naïve’ — meaning they had not yet been trained to respond to a specific infectious threat. The differences relative to adults were more striking. One of the hallmarks of chronic infection is a phenomenon known as exhaustion, in which activated T cells gradually lose their ability to respond effectively to the virus. The researchers found that a key subset of T cells from HCV-positive children were more likely to produce proteins associated with ongoing immune
activity, whereas those from adults tended to exhibit typical signatures of exhaustion. These results offer evidence that the immune systems of younger patients may take longer to enter this exhausted state, giving them a better chance of successfully fighting off HCV infection. The authors caution that this is a relatively small study group, and that this more robust immune response could also be the result of a shorter infection duration relative to adults. Nevertheless, the results offer an intriguing potential explanation for the differences observed in the outcome of paediatric HCV infection. Sheiko, M. A., Golden-Mason, L., Giugliano, S., Waasdorp Hurtado, C., Mack, C. L. et al. CD4+ and CD8+ T cell activation in children with hepatitis C. The Journal of Pediatrics 170, 142-148 (2016).
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
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Marketing, Communication & Outreach Effective marketing and communication position KAIMRC as an international player within its priority research areas, increasing the visibility of KAIMRC research programs around the world. This year’s 7th Annual Forum for Medical Research is held under the theme “Aligning with the Saudi National Vision 2030: Innovative Medical Research Impact on Economy”. It will bring together national and international leading scientists, R&D experts and senior representatives from academia, the private sector and the government to discuss the challenges, opportunities and way forward to make medical research a cornerstone of the knowledge-based economy in the Kingdom of Saudi Arabia to achieve the goals of the Saudi National Vision 2030.