KAIMRC Innovations Issue 3 by Nature Research Custom Media

JULY 2017 - Issue No.3

ISSN 7901-2398 innovations.kaimrc.med.sa

MINIMISING COLL ATER A L DA M AGE Test could identify colorectal cancer patients with most to gain from chemotherapy. P. 8

A DIE T TO LIV E BY Sensory neurons and dietary restrictions linked to longevity. P. 42

NE W E V IDE NC E TRACES C ONGE NI TA L HE A R T DE F E C T S T O HE A LT H Y PA R E N T S . P. 40

TRACING ROOTS

Center of

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

Transforming health through science and innovation:

A strategic approach for MNG–HA/KAIMRC he Saudi national vision 2030 calls for a reduction of Saudi Arabia’s dependence on oil, the diversification of its economy, and the development of important service sectors such as health, education, infrastructure, recreation and tourism. It will truly be a social and economic transformation. The Ministry of National Guard–Health Affairs (MNG– HA) has chosen to develop excellent clinical care supported by innovative research and development. It is investing in patient care and biomedical and clinical research at King Abdullah International Medical Research Center (KAIMRC), which aims to become a world-leading institution in these fields. MNG-HA is constantly striving to improve the quality of care through its hospitals that are part of large medical complexes around the country. We are confident that we will be able to advance biomedical research, in particular precision medicine, through the innovative research taking place in KAIMRC labs, bringing direct benefits to patients. Recently, there have been concerted efforts to exploit innovative findings from our labs, or from our collaborations with national and international partners, to establish biotechnology companies at our medical biotechnology park. This is a phenomenal development in our strategy, allowing us to effectively contribute to Saudi Arabia’s Vision 2030. Through our medical biotechnology park, we aim to develop new diagnostic and therapeutic solutions and to provide cutting-edge research and development services. The planned knowledge-based economy is no longer an alternative; it’s a destiny. The medical biotechnology park will host both innovative R&D projects as start-up or joint venture companies as

well as R&D services to support the research and clinical communities. Among the services planned for the biotech park, we are planning to offer: 1) direct business development assistance, 2) professional network and relationship support, 3) start-up and technology development funding, 4) educational programs and 5) facility-based services. The strategies developed at KAIMRC and MNG–HA demonstrate a thorough understanding of the conditions required for progress: unlimited support and prioritizing of research and development focus areas, and a sustainable advancement of biomedical research, knowledge, capacity building and infrastructure. As such, MNG–HA, through its KAIMRC centres around the country, has fulfilled its present mission, and kept an eye on its goals. We intend to inform scientists, clinicians, faculty, students, government representatives and R&D executives about innovative findings in biomedical and clinical research and to create opportunities for national and international partnerships. Innovations magazine, in its Arabic and English versions, published online and in print, as well as our annual medical research forum, were launched to share this information and to help spread new medical R&D progress from our labs, and from around the globe, among the scientific community and the general population.

Dr. Abdelali Haoudi

Director, Medical Biotechnology Park Head, Strategy and Business Development King Abdullah International Medical Research Center Ministry of National Guard Health Affairs Issue No.3

P. 7 RECONSTRUCTING PATHWAYS OF TUMOR GROWTH

P. 8 GENE MUTATIONS AND COLORECTAL CANCER

Reconstructing the genetic programs that lead to brain tumour formation reveals that stem cells drive tumour growth.

Test could identify colorectal cancer patients with most to gain from chemotherapy.

P. 10 BATTLING A TRANSPLANTED RISK

P. 12 WIDENING THE NET

Current strategies are not reducing the incidence of infectionrelated malignancies after organ transplantations.

A novel strategy seeks therapeutic targets in cancers by examining the genes retained in their genomes.

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 2

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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

COVER CREDIT: ©SEBASTIAN KAULITZKI/SCIENCE PHOTO LIBRARY/GETTY IMAGES

TABLE OF CONTENTS

P. 13 KEEPING A CLOSE EYE ON DIABETES COMPLICATIONS

P. 14 BETA CELL BOOST COULD REPLACE INSULIN INJECTIONS

P. 16 THE DRUGS THAT TEACH ABOUT A DISEASE

Survey highlights link between molecular markers and potential complications of type II diabetes.

A strategy for deriving beta cells from patients with type I diabetes could transform disease treatment.

Novel antibacterial properties in existing multiple sclerosis treatments hint at a possible cause of the disease.

P. 18 NEW MUTATION LINKED TO LEIGH SYNDROME

P. 20 CLAMPING DOWN ON POST-STROKE INFECTIONS

P. 21 DISTURBED SLEEP PATTERNS NEGATE FASTING BENEFITS

A new mutation causing Leigh syndrome has been detected in two newborns in Saudi Arabia.

Specialized cells that impair the immune system after a stroke could be targeted to protect patients from infection.

Disturbed sleep offsets the health benefits from fasting in the holy month.

P. 22 THE RIGHT TO KNOW

P. 23 WEIGHING TREATMENT OPTIONS IN HEART DISEASE

A survey in Saudi Arabia finds broad support for returning significant results to biobank donors.

Stents and bypass surgery are better than drugs, but only for patients with more severe forms of heart disease. Issue No.3

TABLE OF CONTENTS

P. 24 CONCERNS RAISED ABOUT DIGOXIN SAFETY

P. 26 SAUDIS AND THE TRANSFUSION ADVANTAGE

A drug commonly used to treat heart failure could be associated with an increased risk of death in certain patient groups.

Transfusions are more likely to succeed in Saudi blood cancer patients thanks to a lack of genetic diversity.

P. 27 PREDICTING STEM CELL THERAPY OUTCOMES

P. 28 RUNNING SENSORS ON PATIENT POWER

DNA ringlets carried by immune cells could provide routine insight into the progress of stem-cell-based immunotherapy.

Sensors that generate electricity from the digestive tract may enable long-term monitoring of patient health.

P. 30 GOING WITH THE FLOW IN BRAIN MAPPING

P. 32 NANOCARRIERS TO LIGHT UP AND TREAT DISEASE

P. 34 HOW TO TELL BONE MARROW CELLS APART

Recording changes in cerebral blood flow makes mapping active brain areas possible during visual stimulation.

Diseases could be diagnosed, treated and monitored by multi-tasking biodegradable nanoparticles.

Stem cells may express different molecular markers depending on whether they form bone or other tissue types.

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P. 36 RAISING THE BAR FOR GENE THERAPY TESTS

P. 38 DETERMINING THE ROOTS OF DERAILED DEVELOPMENT

P. 40 UNDERSTANDING THE GENETICS OF CONGENITAL HEART DEFECTS

Researchers develop a strategy to improve contamination detection in gene-doping tests.

Mutational profiling homes in on a protein domain with a role in human neurological development.

New evidence traces congenital heart defects to healthy parents.

P. 41 STRATEGY URGED TO TACKLE GENETIC DISEASE

P. 42 DEMYSTIFYING A DIET TO LIVE BY

P. 44 TWENTY NEW MUTATIONS LINKED TO RARE GENETIC DISEASE

A high rate of inherited metabolic disorders in Saudi Arabia is prompting calls for action.

A new connection is found between sensory neurons, diet and longevity.

Study finds mutations in a rare inherited disease called pyroglutamic aciduria.

P. 45 CUTTING DOWN THE COSTS OF DIAGNOSIS

P. 46 BIOINFORMATICS: FAST AND DELETERIOUS

P. 48 TREATING CANCER PATIENTS WITH RARE GENETIC CONDITIONS

A test that screens for genetic mutations in skin cancer can help identify patients with a particular type of thyroid cancer.

A new computational method can identify noncoding sites in the human genome where mutations may have harmful effects.

A case study of a boy with Bloom syndrome highlights the need to screen patients for rare disorders before treatment for cancer. Issue No.3

TABLE OF CONTENTS

P. 50 FORUM OILS THE WHEELS OF RESEARCH PROGRESS

P. 56 THE LEAP FROM LAB TO MARKET

Biomedical research investment could help diversify an economy heavily reliant on oil.

Saudi Arabia is at the beginning of a culture of entrepreneurship in the biomedical sector.

P. 58 ANTIBIOTIC MISUSE A LOOMING CRISIS FOR SAUDI ARABIA

P. 59 HEPATITIS C: TRANSFORMING TREATMENT FOR TRICKY GENOTYPES

P. 60 MERS VIRUS EVADES IMMUNE RESPONSES

A hepatitis C genotype prevalent in the Middle East can be treated by combining existing drugs with a new antiviral.

A single surface protein helps the MERS coronavirus survive by inhibiting the immune system.

P. 62 GRAPES COULD OFFER MERS TREATMENT

P. 63 HOPE FOR RESTORING IMMUNE DEFENSES IN HEPATITIS

P. 64 MIXED MESSAGES ON WIDER EFFECTS OF VACCINES

Initial investigations show a certain antiviral drug could also be effective against MERS.

Antioxidants might reverse changes that allow hepatitis B virus to persist.

Some vaccines may affect other aspects of health.

Warning over high levels of illegitimate antibiotic dispensing and public misconceptions about their use.

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S CI E NCE HI S TORY I M AG E S / A L A M Y S TOCK P HOTO

Oligodendrogliomas can exist for years before they are diagnosed.

Reconstructing the pathways of tumour growth

Reconstructing the genetic programs that lead to brain tumour formation reveals that stem cells drive tumour growth. Cancers develop when cells multiply uncontrollably. A tumour can contain a variety of cell types that contribute to the development of the cancer. Researchers in the US, led by Mario Suvà at Massachusetts General Hospital and Aviv Regev at the Broad Institute

of Harvard and MIT, investigated the hierarchy of cells in oligodendroglioma brain tumours. “We found the tumour is fuelled by a subpopulation of cells with stem cell characteristics,” says Suvà. The role of stem cells in solid cancers has been unclear. This new insight offers

some clarity and will help develop more effective treatments. Oligodendrogliomas account for almost ten per cent of primary brain cancers in adults, and a smaller proportion in children. They are thought to arise from cells called oligodendrocytes, or their precursors. These cells create the protective myelin sheaths surrounding nerves. The researchers investigated more than 4,000 individual cells from six human oligodendrogliomas using RNA sequencing. By characterizing the RNA molecules that carry the instructions for making proteins in individual cells, they deduced the developmental path and differentiation programs followed by the cancer cells. In addition to cells with oligodendrocyte-like characteristics, the tumours also contained cells with the characteristics of astrocytes, which normally support and regulate nerve transmission. They also contained undifferentiated cells with neural stem cell characteristics. Suvà explains that this is the first study to show that this specific type of brain tumour can be driven by stem cells in humans. This suggests two approaches to therapy that might be beneficial. One possibility would be to use drugs to force the tumour’s stem cells to differentiate into other types of cells and thus halt its growth. “We know how to do this in vitro [in the lab], but not in patients, so that is work still to be done,” says Suvà, indicating an obvious next step for the research program. He points out that some blood cancers have already been treated with such ‘differentiation therapies’. Another approach may be to target specific cells with immunotherapy, having now identified the type of cell to be targeted. Suvà says the research groups also want to apply the single-cell RNA sequencing procedure to other types of brain tumours. He describes it as a “very impressive” technique with considerable potential to better understand cancer. Tirosh, I., Venteicher, A.S., Hebert, C., Escalante, L.E.,

Patel, A.P. et al. Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma. Nature 539, 309–313 (2016).

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Gene mutations linked to spread of colorectal cancer Test could identify colorectal cancer patients with most to gain from chemotherapy.

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KAIMRC

A team of researchers from Uppsala University in Sweden have identified a genetic mutation that is associated with metastases in colorectal cancer. The finding could lead to tests that identify patients at risk of the cancer spreading who would benefit from chemotherapy. Although much is known about the role of gene mutations in causing cancer, little is known about their role in its spread.

“This could help explain why cancer cells with these mutations can more easily spread to other organs, as they are no longer restricted by correct cell positioning.”

Colorectal tumour with mutant (red) and normal (green) ephrin receptor molecules.

formation, and the development of the nervous system in embryos. “In adults, these genes are responsible for regulating how cells are positioned in the intestine to ensure correct formation of the structures that help to digest and absorb nutrients,” explains Mathot. The researchers discovered that intestinal cells in patients with mutated genes were no longer able to correctly align, and their growth became disorganised. “This could help explain why cancer cells with these

mutations can more easily spread to other organs, as they are no longer restricted by correct cell positioning,” says Mathot. The team’s next phase of research will involve a larger scale evaluation of mutations found in the ephrin receptor family of genes using data produced by other sequencing efforts. Mahot, L., Kundu, S., Ljungstrom, V. Somatic ephrin receptor mutations are

associated with metastasis in primary colorectal cancer. Cancer Research 77, 1730-1740 (2017).

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“Unnecessary therapy, with severe side effects, could potentially be avoided for patients with a lower risk of metastases, whereas patients with a higher risk can receive adjuvant therapies that can improve their chances of survival,” says Lucy Mathot from Uppsala University’s department of immunology, genetics and pathology. The research team analysed tumour samples from colorectal cancer patients with and without metastases. They discovered that a group of genes were predominantly mutated in patients with metastatic cancer. This family of genes, known as ephrin receptor genes, control a number of processes including tissue

Battling a transplanted risk Current strategies are not reducing the incidence of infection-related malignancies after organ transplantations.

Patients who receive solid organ transplants have a substantially increased risk of developing cancer due to exposure to tumour-producing viral infections while their immune system is suppressed. But, studies have both supported and refuted the effectiveness of antiviral prophylaxis in transplant recipients. Mona Aldabbagh, at King Abdulaziz Medical City in Jeddah, and colleagues in Canada carried out an extensive review of the published literature to determine whether systematic antiviral administration reduces the incidence of Epstein Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD). They found no significant reduction in the incidence of EBV-associated PTLD among transplant recipients that received prophylaxis compared with those who didnâ&#x20AC;&#x2122;t, regardless of age, type of antiviral used, length of treatment and type of organ transplanted. Aldabbagh was not surprised by the findings. â&#x20AC;&#x153;Data in the literature were very controversial. Conducting a systematic review was needed to resolve the confusion,â&#x20AC;? she says. 10

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“Conducting a systematic review was needed to resolve the confusion.” The authors say PTLD could be prevented more effectively by monitoring EBV viral load in transplant recipients. This will help determine the need to initiate anticancer therapy and reduce immunosuppression if viral activation is detected. They also point out that reducing the systematic use of prophylactic antivirals will contribute to reducing drug-related toxicities (as well as healthcare costs). An EBV vaccine is eagerly awaited as Cancer Research UK estimates it could prevent 200,000 new cancers worldwide annually. Several EBV vaccines have entered clinical trials in transplant recipients, but none has been sufficiently studied to establish safety and efficacy. Aldabbagh, M. A., Gitman, M. R., Kumar, D., Humar, A.,

Rotstein, C. et al. The role of antiviral prophylaxis for the prevention of Epstein-Barr virus-associated posttransplant lymphoproliferative disease in solid organ

transplant recipients: A systematic review. Am J Trans-

plant. 17, 770-781 (2017).

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EBV is a very common virus, affecting about nine in every ten adults. Although it causes no long-term problems for the vast majority of people with a healthy immune system, it is associated with 1.2% of PTLD cases in adults and up to 8.4% in children. This is mainly due to the transmission of EBV from the organ of a previously exposed donor to a recipient that has never been infected with the virus. In these cases, the patients are considered to be at high-risk for EBV infection and developing PTLD, and should be closely monitored post-transplantation. EBV-associated PTLD can progress to non-Hodgkin’s lymphoma and may be fatal. The findings, published in the American Journal of Transplantation, suggest that the routine use of antiviral prophylaxis is ineffective, highlighting the need for further research into better preventive and treatment strategies.

“Our approach to identify targets for deleted tumour suppressors will pave [additional] ways for cancer therapeutic development.”

Identifying synthetic essential genes is key to developing treatments for cancers with specific tumoursuppressor deficiencies.

Widening the net

A novel strategy seeks therapeutic targets in cancers by examining the genes retained in their genomes.

rostate cancer is a major global cause of death for men worldwide. It is also a cancer type marked by a specific tumour-suppressor deficiency: up to 70% of prostate cancers show loss of the gene encoding PTEN, a tumour suppressor protein required for inhibiting cell division and promoting cell death. Alan Wang and Ronald DePinho at the University of Texas MD Anderson Cancer Center and co-workers studied the pattern of gene deletions in prostate cancer

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using various genome databases. They uncovered a new therapeutic target by screening for synthetic essential genes: genes that are deleted in some prostate cancers, but are consistently retained in those lacking PTEN. The notion of finding therapeutic targets by studying gene deletions is not new. Previous studies have demonstrated the effectiveness of this approach in breast cancer types marked by BRCA1 deficiency. By screening for mutated genes that are harmless in most breast cancers but

The researchers also identified the gene encoding the chromatin remodelling factor CHD1 as an additional potential therapeutic target. To validate this, they genetically edited PTEN-deficient prostate and breast cancer cell lines so that their CHD1 expression was reduced. They found that CHD1 depletion profoundly and specifically suppressed cell proliferation, cell survival and tumorigenic potential of the cancer cells. This suggests that CHD1 inhibitors might be effective against PTEN-deficient prostate cancer. The study demonstrates the feasibility of finding therapeutic targets in cancers marked with specific tumour-suppressor deficiencies using the synthetic essentiality approach. “Our approach to identify targets for deleted tumour suppressors will pave [additional] ways for cancer therapeutic development,” says Wang. Zhao, D., Lu, X., Wang, G., Lan, Z., Liao, W. et al. Syn-

thetic essentiality of chromatin remodelling factor CHD1 in PTEN-deficient cancer. Nature 542, 484– 488 (2017).

L E I G H P R AT HE R / A L A M Y S TOCK P HOTO

deadly in those lacking BRCA1, researchers identified the gene encoding PARP1 enzymes as a therapeutic target in BRCA1-deficient cancers. The finding ultimately led to the development of new treatment regimens for breast and ovarian cancers based on PARP1 inhibitors. In the new approach, Wang and his team searched for deleted and retained genes. After several screens of the Cancer Genome Atlas database and other prostate cancer databases, they identified synthetic essential genes that could serve as therapeutic targets in PTEN-deficient cancers. Among them were genes encoding PARP1 and PLK enzymes, whose inhibitors are already in use for the treatment of prostate, colorectal and endometrial cancers.

G A R O/ P HA NI E / A L A M Y S TOCK P HOTO

and cardiovascular complications. A team of researchers across the kingdom wanted to know if there was a relationship between the type of treatment used in 153 type II diabetes patients at two hospitals in Saudi Arabia, how well their glucose levels were controlled, their risk factors for heart disease, and their serum CRP and GGT levels.

Diabetes was responsible for more than 20,000 deaths in 2015 alone.

Keeping a close eye on diabetes complications Survey highlights link between molecular markers and potential complications of type II diabetes. Monitoring additional molecular markers may help avoid complications in people with diabetes, according to research from Saudi Arabia. The kingdom has one of the world’s highest rates of diabetes, with nearly 3.5 million people living with the disease and more than 20,000 deaths caused by it in 2015 alone. Current guidelines in Saudi Arabia recommend treating inadequately controlled diabetes with insulin, alone or together with oral glucose-lowering drugs. Research shows an increasing dependence by physicians on insulin therapy to

decrease vascular complications in these patients. Despite its benefits, insulin therapy is associated with weight gain and more frequent episodes of low blood glucose levels. Weight gain due to insulin therapy can directly and indirectly lead to cardiovascular complications. An increased risk of cardiovascular disease is also associated with increased blood levels of C-reactive protein (CRP), considered a non-specific marker of disease. Also, increased levels of γ glutamyl transferase (GGT) are associated with an increased risk of diabetes, hypertension

They found generally higher glucose levels in patients receiving insulin therapy alone compared to those also taking oral glucose-reducing drugs. The researchers caution, however, that this finding could be caused by lack of patient compliance with their insulin treatment program. They also found that the type of treatment received did not affect CRP and GGT levels. High GGT levels were associated, however, with poor control of blood glucose levels, irregular levels of blood lipids, hypertension and obesity in the abdominal region. High CRP levels were also associated with an increased waist circumference. The researchers recommend routinely measuring CRP and GGT in diabetes patients to assess factors that might increase the risk of complications such as cardiovascular disease. Others, however, say the recommendation is premature. “The data show associations in a very small population of patients, and there’s no evidence of a causal connection. The findings would need to be replicated in multiple other cohorts before these signals could be recommended for routine monitoring,” says Rhonda Cooper-DeHoff, a professor of pharmacotherapy and cardiovascular medicine at the University of Florida, who was not involved in the study. Bahijri, S. M., Ahmed, M., Al-Shali, K., Bokhari, S., Alhozali, A. et al. The relationship of management modality in Saudi patients with type 2 diabetes to components of metabolic syndrome, γ glutamyl transferase

and highly sensitive C-reactive protein. Therapeutic

Advances in Chronic Disease 7, 246-254 (2016). Issue No.3

Beta cell boost could replace insulin injections A strategy for deriving beta cells from patients with type I diabetes could transform disease treatment.

isease-specific stem cells show great promise because they can be used for cell replacement therapies, drug screening and investigating disease progression. Now, scientists from the US have developed viable beta cells (β cells), which are responsible for generating insulin in the body, using stem cells derived from patients with type I diabetes (T1D). Their results may mean that diabetic patients could receive personalized β cell boosts instead of having to inject insulin. β cells, located in the pancreas, make, store and release insulin in response to peaks

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in blood sugar levels. T1D is caused by the autoimmune-fuelled destruction of these cells. Since β cells are the main targets in T1D progression, stem cell therapy aimed at replenishing them could prove invaluable. “In 2014, we developed a strategy for generating functional β cells from human pluripotent stem cells,” says Jeffrey Millman at Washington University School of Medicine, who led the project. “Now, we have extended this approach to generate β cells from stem cells derived from T1D patients. We have never had access to β cells from T1D before because they are so

Beta cells from a Type I diabetic (blue) transplanted into a mouse, where the cells successfully secreted insulin (green) in response to glucose injections.

β cells were fully functional and secreted insulin when they sensed glucose levels rising. There was no discernable difference between them and β cells from healthy individuals. There are two key benefits of this technology. Firstly, these cells could be transplanted into patients, meaning they wouldn’t need insulin injections and their blood glucose control would improve considerably. Since these cells can be derived from the patient, there would be no immune rejection of the transplanted cells when combined with a therapy to suppress autoimmunity, Millman adds. Secondly, this presents an opportunity to study T1D β cells for the first time. “New insights into diabetes initiation could be uncovered that may one day lead to a preventative therapy,” says Millman. Millman, J.R., Xie, C., Van Dervort, A., Gürtler, M., Pagliuca, F.W. & Melton, D.A. Generation of stem cell-derived β-cells from

patients with type 1 diabetes. Nature

Communications 7, 11463 (2016).

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quickly damaged or destroyed during disease progression.” The researchers began by deriving immature pluripotent stem cells from skin samples taken from T1D patient volunteers. Pluripotent stem cells are reprogrammed adult cells that have the ability to turn into other kinds of cells. Millman’s team then used chemicals and proteins to manipulate the necessary signalling pathways and mimic the signals necessary to trigger differentiation into β cells. “The technology required for this to work has only become available in the last two years. Before then, performing this project was literally science fiction,” says Millman. “We had no idea whether the T1D-derived β cells would even be viable.” The team tested their T1D β cells in cultures and in diabetic mice to see how the cells would respond to glucose injections. They found that the

The drugs that teach about a disease Novel antibacterial properties in existing multiple sclerosis treatments hint at a possible cause of the disease.

ultiple sclerosis (MS) is a debilitating condition affecting the central nervous system, causing weakness, stiffness, and sensory and cognitive problems. Traditionally, MS is considered an autoimmune disease, where the body’s own immune system attacks the fatty myelin sheaths that protect nerves. However, recent research suggests microbial pathogens may also be involved. Medical microbiologist K. Rashid Rumah of Rockefeller University and colleagues from elsewhere in the US investigated the mechanism of MS drugs, in the hope of shedding light on what causes the condition. They focused on three ‘disease-modifying drugs’ (DMDs): fingolimod, teriflunomide and dimethyl fumarate. These slow MS progression by suppressing the immune system. They are taken orally, meaning they could also influence the digestive system. The research was sparked by the observation that some bacteria produce potent neurotoxins. In particular, Clostridium perfringens, commonly found in livestock,

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Rumah, K. R., Vartanian, T. K. & Fischetti, V. A. Oral multiple sclerosis drugs inhibit the in vitro growth of epsilon toxin producing gut bacterium Clostridium perfrin-

gens. Frontiers in Cellular and Infection Microbiology 7: 11 (2017).

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produces an ‘epsilon toxin,’ which localizes to sites — the blood-brain barrier and central nervous system myelin — implicated in MS. “Clostridium perfringens’ epsilon toxin is known to damage the blood-brain barrier of dairy animals. Coincidentally, the blood-brain barrier is compromised in MS … I am yet to see another toxin that so specifically targets the exact tissues damaged in MS,” says Rumah. Remarkably, the DMDs all disrupted the growth of C. perfringens and showed significant antibacterial activity at concentrations similar to those found in the human gut under normal recommended dosages. The researchers then searched for compounds related to these DMDs that might match or even exceed their antibacterial activity whilst minimizing side-effects. They found that gambogic acid, a natural compound used in Chinese medicine that is related to dimethyl fumarate, was particularly effective against C. perfringens. Similarly, compounds related to fingolimod were antibacterial, yet likely to cause fewer side-effects since they lack fingolimod’s immunosuppressive properties. The research provides intriguing insights, not only into the potential underlying causes of MS, but also into possible new treatments based on neurotoxin-producing microbes. However, at present, the results can only be considered as circumstantial. “What we have shown is very provocative,” says Rumah, “but it is a small piece of the puzzle.” He and his team are now investigating whether the epsilon toxin is present in MS patients. “If the epsilon toxin is identified as the cause,” Rumah continues, “current anti-inflammatory treatments may become a thing of the past. We would know exactly which molecule and organism to target … We could both prevent people from developing MS and halt progression in those already diagnosed.”

New mutation linked to Leigh syndrome A new mutation causing Leigh syndrome has been detected in two newborns in Saudi Arabia.

July 2017

“A disruption in just one step of a common pathway of metabolism can lead to big changes in our bodies.”

Advances in genetic screening are critical for diagnosing extremely rare cases of Leigh syndrome

eigh syndrome is a severe genetic disorder that leads to potentially fatal respiratory failure, brain abnormalities and loss of muscle strength. In most cases, enzyme defects are thought to cause the disease by interfering with the body’s ability

P rev i o u s s t u d i e s h a d revealed different Leigh syndrome-causing mutations in the ECHS1 gene, carried by either the father or the mother. However, for the first time, researchers at KAIMRC, in collaboration with King Faisal Specialist Hospital and Research Centre in Riyadh, identified a novel homozygous variant (carried by both parents) that causes a lethal phenotype of this condition. “Given the consanguineous nature of the parents and apparent recurrence of the same condition, we assumed it is caused by a shared homozygous ancestral mutation,” says Fuad Al Mutairi, a clinical geneticist at KAIMRC. At first, despite extensive analyses using “all commercially available next-generation sequencing genetic

tests”, Al Mutairi says that the mutation remained undetected. By repeatedly ‘zooming in’ on the shared genomic region between the two children using exome sequencing, a technique that targets protein-coding portions of the genome, the researchers were able to pinpoint a single homozygous variant of the ECHS1 gene. A disruption in “just one step of a common pathway of metabolism can lead to big changes in our bodies,” says Al Mutairi. “In this rare case, there was severe damage to protein synthesis, which affected the whole gene function and stopped enzyme activity.” The study highlights the limitations of conventional genetic screening techniques, and the need for advances in bioinformatics and wider availability of population-based genomic data. To this end, the Saudi Human Genome Project, a growing resource for population-based genomic data, will play a central role in enhancing the discovery of gene–disease associations. “Knowing the cause and understanding the pathophysiology of the disease gives hope in other cases where therapeutic options may be available,” says Al Mutairi. “Identifying the genetic defect as a first step can be enormously helpful for families in order to prevent recurrence of the disease.” Al Mutairi, F., Shamseldin, H.E., Alfadhel,

M., Rodenburg, R.J. & Alkuraya, F.S. A lethal neonatal phenotype of mitochondrial short-chain enoyl-CoA hydratase-1

deficiency. Clinical Genetics 91, 629– 633 (2016).

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to produce energy in the mitochondria. Around one in 36,000 people are born with the condition. Now, a case study of two siblings, both who died within two days of birth, has led to the first report of a rare mutation that shuts down a key enzyme called short-chain enoyl-CoA hydratase (SCEH). Encoded by the ECHS1 gene, SCEH plays an essential role in converting fat into energy for healthy development, and has only recently been investigated in the context of Leigh syndrome.

Clamping down on post-stroke infections A stroke, caused by constricted blood flow to the brain, severely affects the immune system, which can make patients highly susceptible to potentially fatal infections. The cellular and molecular mechanisms that impair the immune system after a stroke are not yet fully understood. Connie Wong, Paul Kubes and colleagues at Monash University in Melbourne, Australia and the University of Calgary in Canada have revealed crucial details about how a stroke triggers a large shift in the activity of specialized immune cells called invariant natural killer T-cells (iNKT cells)1. “It has been proposed that the brain suppresses the immune system after a stroke to protect itself from overwhelming inflammation,” says Wong. “But a side-effect of activating anti-inflammatory pathways is an increased susceptibility to infection.” In previous work on animals2, the team showed that iNKT cells played a key role in regulating the host response to infection after stroke. To investigate whether the function of iNKT cells was also affected in humans after strokes, the researchers collected blood from 36 patients on several occasions after they were admitted to hospital, and screened for infections such as pneumonia, cellulitis and urinary tract infection. The blood results showed that iNKT cells were three times more active in stroke patients than in healthy ones. This was associated with an increased production of an anti-inflammatory cytokine called interleukin-10, suppressing the immune response and rendering the host more 20

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ZEP H Y R / S P L / G ET T Y I M AG E S

Specialized cells that impair the immune system after a stroke could be targeted to protect patients from infection.

Following a stroke, the immune system is often compromised, but researchers are not sure why.

vulnerable to bacterial infections. This shift in immunity was seen in iNKTs in the blood and in the liver, and often persisted three months after the initial stroke. The findings fit the general emerging theory that brain damage after a stroke is not only linked to cerebral processes, but mediated by the wider immune system. Moreover, therapies that target iNKT cells could present promising alternatives to antibiotics for tackling post-stroke infections, especially given the growing problem of antibiotic resistance in pathogens. “In the future, we will assess the capacity of novel agents that specifically target and modulate iNKT cells, with the aim of reversing immune deficits in stroke

patients,” says Wong. Immunomodulation therapies that augment the immune system to combat infections are an attractive avenue, the researchers conclude in their study published in the journal Frontiers in Neurology. However, they warn caution is needed to ensure further cerebral injury is avoided. 1. Wong, C. H. Y., Jenne, C. N., Tam, P. P., Léger, C., Venegas, A. et al. Prolonged activation of invariant natural

killer T cells and TH2-skewed immunity in stroke patients. Frontiers in Neurology 8 (2017) .

2. Wong, C.H.Y., Jenne, C.N., Lee, W.Y., Léger, C., Kubes,

P. Functional innervation of hepatic iNKT cells is immunosuppressive following stroke. Science 334, 101-

105 (2011).

T I M E WHI T E / A L A M Y S TOCK P HOTO

Disturbed sleep patterns negate Ramadan fasting benefits Disturbed sleep offsets the health benefits from fasting in the holy month. Modern Ramadan practices in Saudi Arabia, where fasting is combined with a radical shift in sleeping schedules, are probably detrimental to health, according to a recent study. Saudis fasting during Ramadan stay up at night and sleep through much of the day, mimicking the patterns of shift workers. “I had read so much about the benefits of intermittent fasting, but I’d also read about the adverse effects of disturbed sleep patterns from shift work. I wanted to study the two together, which nobody has done,” explains Suhad Bahijri of the Saudi Diabetes Research Group at King Abdulaziz University in Jeddah. Bahijri and colleagues studied 23 Saudis before the start of Ramadan and again two weeks into the holy month. They measured the levels of several cardiovascular risk factors and the expression of three genes related to our biological clock. While some risk factors improved

during Ramadan, others worsened. “Even though we found some benefits from fasting, they are masked by the disturbance in sleep patterns which introduce adverse effects,” says Bahijri. “Also, very few people restrict caloric intake in Ramadan. In fact they eat more, increasing their health risk.” According to Bahijri, sleep patterns during Ramadan changed in the 1980s, as malls and restaurants became more common in the country and young, fasting Saudis began looking for all-night entertainment. “Our changing lifestyle is increasing the risk of chronic diseases because our genes are not evolving fast enough to cope with it,” she says, linking the rise in chronic diseases such as type II diabetes and metabolic syndrome to eating and sleeping habits during Ramadan, as well as more general lifestyle changes. Bahijri recommends a return to a more traditional way of practicing Ramadan.

“During Ramadan, have a light breakfast, a snack before going to bed at around midnight, and wake up before dawn to have a light meal, pray, and get some more sleep,” she advises. Bahijri planned a follow-up study to disentangle the consequences of sleep disturbance and Ramadan fasting, which is different from intermittent fasting, but found it difficult to find participants who fast “the right way.” Instead, her next project will focus on the metabolic effects of shift work in Saudi nurses. “Hopefully, we’ll come up with recommendations to help plan shift work so it doesn’t affect their metabolism adversely.” Ajabnoor, G. M. A., Bahijri, S., Shaik, N. A., Borai, A., Alamoudi, A. A., et al. Ramadan fasting in Saudi Ara-

bia is associated with altered expression of CLOCK, DUSP and IL-1alpha genes, as well as changes in car-

diometabolic risk factors. PLoS ONE 12:e0174342 (2017).

Issue No.3

Having clear laws and data-handling guidelines would benefit both biobanks and donors in Saudi Arabia.

The right to know Biobanks are research facilities that collect biological specimens and health data from human donors. A scientist may find results that are clinically relevant to one or several donors â&#x20AC;&#x201D; such as biomarkers that could predict oneâ&#x20AC;&#x2122;s likelihood of inheriting certain genetic diseases. There has been much debate around the world as to whether biobanks should pass these results to donors, and whether donors should have the right to refuse knowledge of these results. Ghiath Alahmad at King Abdullah International Medical Research Center (KAIMRC) in Riyadh, Saudi Arabia and Kris Dierickx at KU Leuven in 22

July 2017

Belgium conducted a survey laypeople working, receiving in Saudi Arabia to gauge the treatment or visiting inpatients opinions of various stakeholdat King Fahd Hospital in Riyadh. ers on the return of results to Around 45% of them agreed donors. They that donors 80% of people found that had the right most people to be informed surveyed felt agreed that biof important biobanks should oresults. banks should However, pass important only 9% agreed pass important results to results to donors, t h a t d o n o r s donors, and had this right but only 30% that donors if results were should have the felt unimportant insignificant. right to refuse Also, around results should be 80% knowledge of of those passed on. these results. surveyed agreed The researchthat biobanks ers surveyed 180 people, should pass significant results including KAIMRC researchto donors. However, if the ers, as well as physicians and results were unimportant,

only 30% thought the results should be passed on. Lastly, around 47% of those surveyed agreed that donors should have the right to refuse knowledge of important results. The numbers closely match those reported in Western countries. The results show that despite cultural differences, people living in Saudi Arabia might opt for transparency and access to research results that are of clinical significance. Alahmad, G. & Dierickx, K. Return of research results in the Saudi biobank:

An exploratory survey. Genetic Testing

and Molecular Biomarkers 21, 166â&#x20AC;&#x201C; 170 (2017).

SC IE N C E / GE N O M E R E UT E R S / P HI L N OB LE

A survey in Saudi Arabia finds broad support for returning significant results to biobank donors.

“The benefit of coronary revascularization on survival in stable patients with obstructive coronary artery disease is still controversial.”

The benefit of revascularization procedures depends on the type of heart disease.

Weighing treatment options in heart disease

Stents and bypass surgery are better than drugs, but only for patients with more severe forms of heart disease. Medical procedures to improve blood flow to the heart can help reduce the risk of death for people with severely clogged arteries. But, a large study has found that those with milder signs of heart disease can probably get by with medication, improved diet and regular exercise. An international study called CONFIRM followed more than 5,500 patients after they received a heart CT scan to diagnose suspected coronary artery disease. Patients then had medical procedures to restore blood circulation. They were either treated with a stent implant or bypass surgery, collectively referred to as coronary revascularization, or they received blood-thinning drugs,

cholesterol-lowering pills and other medications. The investigators, including KAIMRC cardiologist Mouaz Al-Mallah who leads the advanced imaging division at the King Abdulaziz Cardiac Center in Riyadh, then tracked their health outcomes for at least five years. “The benefit of coronary revascularization on survival in stable patients with obstructive coronary artery disease is still controversial,” Al-Mallah explains. Many studies had previously shown that stents and bypass grafts often improve symptoms of chest pain or discomfort, but the data were mixed on whether these interventions were better than drug therapies at preventing heart attacks and boosting

In the study, Al-Mallah and his colleagues found that the benefit of revascularization depended on the degree of heart disease. For those with high-risk heart disease—defined as having significant narrowing of critical blood vessels supplying the heart — revascularization helped lower the mortality risk compared to drug treatment both one and five years after the procedure. In contrast, revascularization offered no such benefit among those with low-severity disease over the same period. Intermediate-risk patients who received a stent or bypass had a reduced mortality rate at one year, but the benefit dissipated by the five-year mark. In light of the results, Al-Mallah advises: “If a patient has high-risk anatomy, then it is better to treat them with revascularization. Intermediate-risk anatomy is still an area of research, and low-risk anatomy can be treated medically.” Al-Mallah does offer one caveat, though. The CONFIRM study was entirely observational in nature, so “we need to confirm these findings in randomized controlled studies prior to wide adoption.” Schulman-Marcus, J., Lin, F. Y., Gransar, H., Berman,

D., Callister, T. et al. Coronary revascularization vs. medical therapy following coronary-computed tomographic angiography in patients with low-, interme-

diate- and high-risk coronary artery disease: results from the CONFIRM long-term registry. European

Heart Journal Cardiovascular Imaging 18, 841-848 (2017).

Issue No.3

CHA NAWI T S I T T HI S OM BAT / A L A M Y S TOCK P HOTO

patient survival rates. Since the revascularization procedures can be riskier and more expensive than drug treatments, many cardiologists were left uncertain. The CONFIRM study should help inform that decision-making.

July 2017

Concerns raised about digoxin safety

Researchers at KAIMRC have shown that the commonly used drug digoxin, used to treat heart failure and irregular heartbeat, is linked with increased risk of mortality in certain patient groups.

A I M RC re s e a rch e r s have shown that a drug, commonly used to treat various types of heart failure, appears to increase mortality risk in certain groups of patients when it is used in place of current guideline-recommended treatments. Digoxin is used extensively in combination with other medications in the treatment of heart failure, and is often prescribed to patients with atrial fibrillation — a kind of irregular heartbeat — to help slow and stabilize their heart rate. However, concerns have recently been raised about potentially harmful effects of digoxin, with research pointing to an association between digoxin and increased chances of death under certain circumstances. “Many patients are still regularly using this medication for heart failure or irregular heartbeat,” says KAIMRC’s Mouaz Al-Mallah, who led the study with colleagues from the King Abdulaziz Cardiac Center. “However, digoxin has a narrow therapeutic window and as a result it can easily reach toxic levels in the

body. We were keen to establish the long-term effects of taking digoxin, and to determine which patient groups might be at risk of any potential ill-effects.”

77%

Researchers found that digoxin use was associated with a 77% higher risk of mortality Al-Mallah’s team conducted a retrospective study of 2,298 patients seen at the heart failure clinic at the Ministry of National Guard–Health Affairs in Riyadh between 2000 and 2015. All the patients received appropriate treatment as outlined by current guidelines. The team matched 325 digoxin users with 750 non-digoxin users, making sure that considerations such as clinical variables and demographics were matched as closely as possible between individuals in each group. This helped to

limit other factors influencing the patients’ health, and allowed the team to achieve a meaningful analysis of the effects of digoxin. The researchers followed up patients two to six years after they commenced digoxin treatment. They found that digoxin use was associated with a 77% higher risk of mortality, mostly in digoxin users who did not suffer from atrial fibrillation. “We’ll investigate whether digoxin can still be helpful in certain subgroups of patients, but we believe digoxin users should be closely monitored for side-effects and switched to other safer drugs as soon as clinically possible,” says Al-Mallah. “We also hope to verify if the digoxin-associated increase in mortality can be prevented if the levels are closely monitored and are kept within a therapeutic range.” Al-Khateeb. Qureshi, M. W., Odeh, R.,

Ahmed, A. M., Sakr, S. et al. The impact of digoxin on mortality in patients with

chronic systolic heart failure: A propensity-matched cohort study. The Inter-

national Journal of Cardiology 228, 214-218 (2017).

Issue No.3

S EB AS T I A N K AULI T ZK I / A L A M Y S TOC K P H OTO

A drug commonly used to treat heart failure could be associated with an increased risk of death in certain patient groups.

JOS E OTO/ BS I P SA / A L A M Y S TOCK P HOTO

Saudis and the transfusion advantage Transfusions are more likely to succeed in Saudi blood cancer patients thanks to a lack of genetic diversity.

Transfusions to prevent bleeding after chemotherapy — in patients with blood malignancies, like leukaemia, and those undergoing haematopoietic stem cell transplantation — are more often successful in Saudi Arabia than elsewhere, according to a recent study. Chemotherapy decreases the platelets in a patient’s blood, reducing its ability to clot and thus increasing the risk of serious complications due to bleeding. Patients with low platelet counts are given transfusions to mitigate this risk, but these sometimes fail to increase the number of platelets, a condition known as platelet transfusion refractoriness (PTR). While PTR rates have been measured in several populations, they haven’t been studied in Middle Eastern populations. A team of researchers tracked 29 patients at Saudi Arabia’s Ministry of National Guard Health Affairs (MNG-HA) hospital, monitoring their platelet count before and after platelet transfusions. Four of the patients had low platelet counts after two consecutive transfusions and were diagnosed with PTR; a 14% incidence rate. Patients with acute myeloid leukaemia or non-Hodgkin’s lymphoma were more likely to develop PTR. The rate was slightly higher (17%) when measured as a fraction of the number of transfusions (102), rather than patients, but was still notably lower than the 25-35% reported 26

July 2017

New research suggests that platelet transfusions could be more successful in Saudi blood cancer patients than others elsewhere.

in studies of other populations. Despite the low incidence in Saudi patients, PTR should still be considered a serious problem, says King Abdullah Medical City (KAMC) oncologist Khadega Abuelgasim, who led the study. “That particular patient will be at risk of fatal bleeding complications. PTR also drains blood products from the blood bank, straining the system,” she explains. The researchers suggest that the low rate may be due to low genetic diversity in the Saudi population, where marriages between cousins are very common. “Because of this, there’s a very high chance of having a matched donor in the Saudi population by chance,” says Abuelgasim, which improves the chances of transfusion success. Another factor contributing to the lower incidence rate may be the way the

platelets are prepared. All of KAMC’s blood products are filtered to remove white blood cells, reducing the chance of a platelet transfusion being rejected. Blood products given to chemotherapy patients are also irradiated. The researchers recommend these measures become standard practice throughout the kingdom, though some facilities don’t have the capacity to irradiate blood products. They also highlight the need for larger, multicentre follow-up studies to measure how PTR correlates with clinical and demographic factors. Abuelgasim, K., AlHumaid, S., AlOtaibi, A., AlKhashan, M., and Ali, Y. Platelet transfusion refractoriness among patients with hematological malignancies in a

tertiary center in Saudi Arabia. Journal of Oncology

Translational Research 2, 112-115 (2016).

M OP I C / A L A M Y S TOCK P HOTO

DNA circles help predict stem cell therapy outcomes DNA ringlets carried by immune cells could provide routine insight into the progress of stem-cellbased immunotherapy.

Tiny DNA remnants from the birth of immune T cells carry valuable information about the progress of immune system reconstitution following haematopoietic stem cell transplantation (HSCT), a research review involving KAIMRC scientists has found. These blood-borne biomarkers could be used to track the progress of HSCT therapy and help improve clinical outcomes for a wide range of blood and autoimmune diseases. The transplantation of blood-forming ‘haematopoietic’ stem cells is one of medicine’s fastest expanding therapies for diseases like leukaemia and various haematological and immunological disorders. The therapy works by replacing the dysfunctional immune system of the patient with a ‘reconstituted’ immune system derived from the transplanted healthy HSCs. Yet there are many ways in which this reconstitution can go wrong. In the first months, HSCT patients have profound immunodeficiency and are at high risk of infection. As reconstitution progresses, they then become increasingly susceptible to potentially lethal immunological responses, such as graft-versus-host disease (GVHD), in which the newly

DNA excision circles could be used as biomarkers to track the progress of haematopoietic stem cell transplantation therapy.

reconstituted immune system starts attacking the patient’s own cells. Complications like these are very difficult to treat, as the immunosuppressive drugs used to treat GVHD impair the immune system’s ability to combat infections. Tracking the progress of reconstitution and pre-empting the need for intervention thus remains a major obstacle to improving HSCT therapy. Based on a rapidly improving understanding of these interactions, the director of KAIMRC’s stem cells and regenerative medicine department, Muhamed Abumaree, and collaborating researchers from Karolinska Institutet in Sweden have been reviewing research into possible biomarkers that could be used to monitor the progress of immune system reconstitution. Their review focused on ‘T cell receptor excision circles’ (TRECs): tiny ringlets of DNA left over from the creation of immune T cells, which can be found in sufficient concentrations in blood to be detected using conventional DNA analysis methods.

From an extensive data and literature review, the team identified a certain type of DNA excision circle, called single-joint T cell receptor excision circles (sjTRECs), that could be used to distinguish between the activity of the early-developing innate immune system and the more powerful but slower-developing adaptive antigen-specific immune system. Abumaree and his co-workers suggest that such a biomarker could be used to identify problems or delays in immune system development and provide useful information regarding the status of the reconstitution of functional T cell immunity, with significant potential as a standard clinical approach to predict the risk of severe infection and hence improve HSCT survival rates. Gaballa, A., Sundin, M., Stikvoort, A., Abumaree, M.,

Uzunel, M., Sairafi, D., Uhlin, M. T cell receptor excision

circle (TREC) monitoring after allogeneic stem cell transplantation; a predictive marker for complications and clinical outcome. International Journal of Molec-

ular Sciences 17, 1705 (2017).

Issue No.3

Running sensors on patient power Sensors that generate electricity from the digestive tract may enable long-term monitoring of patient health.

July 2017

This ingestible temperature sensor is driven by electrodes that can generate a week’s worth of power from the chemical environment of the digestive tract.

a consumable biogalvanic cell-powered sensor that monitors body temperature. The device proved highly durable, and although it was prone to some power fluctuations, it drew enough electricity to reliably transmit temperature data to an external receiver for about six days. “There was a lot of power available that we could harvest for up to one week,” says Nadeau, “and it worked through the normal routines of the animal, like feeding and moving around.”

“One potential application is an ingestible vital signs monitor.” Their prototype sensor is small, but could be made smaller and more energy-efficient. Such improvements will be sought in future iterations of the device — along with extensive investigation of biosafety as a prelude to testing in humans. Nadeau believes that such devices could be coupled with controlled drug-release systems or designed to remain longer in the digestive tract for long-term, non-invasive health tracking. “One potential application is an ingestible vital signs monitor,” says Nadeau, “which could measure and transmit heart rate and breathing information to a nearby external device, like a smartphone.” Nadeau, P., El-Damak, D., Glettig, D., Kong, Y.L., Mo, S. et al. Prolonged energy harvesting for ingestible devices. Nat.

Biomed. Eng. Nature Biomedical Engineering 1, 0022 (2017).

Issue No.3

K M R C2 0 1 70 1 4 CHA NDR A K ASA N F I G U R E

ha n k s to s te a dy advances in miniat u r i z at ion a nd wireless technology, scientists now envision a future in which doctors can collect valuable medical data from tiny sensors swallowed by patients. Continual access to power is a limitation for such devices, but researchers at the Massachusetts Institute of Technology (MIT) and colleagues have now demonstrated a promising strategy that essentially turns the gastrointestinal tract into a battery. Swallowing a battery could be harmful to health, so the researchers, led by Robert Langer, Anantha Chand ra k a s a n a n d G i ov a n n i Traverso, designed a sensor powered by a ‘biogalvanic cell’. Rather than relying on the toxic and corrosive chemicals found in batteries, their device generates power by immersing a pair of metal electrodes into the surrounding acidic digestive fluid, fuelling an electricity-generating reaction. “These cells offer a potentially safer and lower cost alternative to traditional batteries,” says MIT electrical engineer Phillip Nadeau. Such approaches had been demonstrated as proof of concept in the past, but only for shortterm studies. Nadeau and colleagues now sought to develop a biogalvanic cell that is viable for extended use. One key improvement was selecting a more durable material for the device’s anode that would not degrade over the course of the power-generating chemical reaction. As a test, they performed a series of studies in pigs, with

Blood flow resulting from increased brain activity can be automatically converted to a map of brain regions.

July 2017

Going with the flow in brain mapping

Recording changes in cerebral blood flow makes mapping active brain areas possible during visual stimulation.

M ED IC A L R F. C O M/ GE T T Y I M AG E S

new method for imaging the areas of the brain that pro c e s s v i s ua l information builds a detailed map which allows for more accurate experimenting. “Mine is one of many labs interested in how cortical circuits process information,” says Edward Callaway of the Salk Institute for Biological Studies, California. Callaway and his team recently published a step-by-step guide that describes their method for imaging the areas of the brain that process visual information. Callaway’s team attached a head frame to mice, allowing them to hold their heads in place in relation to their camera apparatus and visual stimuli. They also exposed a clean region of the skull over the visual cortex for imaging purposes. The researchers moved a bright checkerboard bar across the mouse’s visual field while recording the exposed skull, measuring changes in specific wavelengths of light that signal the presence of oxygen-carrying blood. “The

visual stimulus results in metabolically demanding neuronal activity, which increases blood flow and changes the amount of long-wave red light that’s absorbed,” explains Callaway. Capturing images of changes in cerebral blood flow is not new. The technique, known as intrinsic signal optical imaging (ISI), was first described in the 1980s and has since been common in neuroscience. Callaway and his team, however, have shown how ISI can be applied to map the visual-processing areas of the mouse brain in a far more precise way than by using physical landmarks — as the precise location and size of these areas differ between individuals of any species. The technique can be adapted to other species depending on the needs of an experiment. The team’s particular system is quicker than traditional ISI and allows for many repetitions, which minimizes the effect of breathing and heart rate on recordings. From the absorption data acquired, the researchers

The experiment offers a useful and flexible tool to neuroscience researchers working with small animals, in which these brain areas may be less than a quarter of a millimetre wide.

produced visual maps of the sections of the visual cortex that were activated as the stimulus moved horizontally and vertically. The maps were then converted to a distinct chart of known brain areas, using open-source computer code produced by Calloway’s lab. The completed map shows the precise boundaries of specific brain areas, allowing for more accurate experimentation on the brain. The team’s experiment offers a useful and flexible tool to neuroscience researchers working with small animals, in which these brain areas may be less than a quarter of a millimetre wide. “We do this practically every day because we’re now studying in detail the circuitry between these areas . . . We make these maps regularly to guide our subsequent experiments,” says Callaway. Juavinett, A.L., Nauhaus, I., Garrett, M.E.,

Zhuang, J., Callaway, E.M. Automated identification of mouse visual areas with intrinsic signal imaging. Nature

Protocols 12, 32–43 (2017).

Issue No.3

Nanocarriers to light up and treat disease Cancer and other diseases could be diagnosed, treated and monitored by multi-tasking biodegradable nanoparticles.

July 2017

affecting more women in Saudi Arabia every year2. “We will investigate the potential on animals with breast cancer and leukaemia, then hopefully move onto tests with cancer patients,” he says. “The multi-functional ability is the key advantage of our system.”

“We hope our work will eventually help to treat cancer with minimal side effects on healthy cells.” The ability to follow the distribution of the micelles by MRI and fluorescence imaging techniques will be used to find the most efficient method to get the micelles to selectively target diseased tissues. Such targeting could also prove useful to indicate if a cancer, for example, is shrinking after treatment and to reveal the extent to which a disease has spread to other regions of the body. Once any targeting procedure has been validated it could be used in the early stages of clinical investigation to diagnose where a specific cancer is located and how far it has advanced. “We hope our work will eventually help to treat cancer with minimal side effects on healthy cells,” says Abu-Salah. 1 Asem, H., Zhao, Y., Ye, F., Barrefelt, Å., Manuchehr, A-V. et al. Biodistribution of

biodegradable polymeric nano-carriers loaded with busulphan and designed for multimodal imaging. Journal of Nanobi-

otechnology 14, 82 (2016).

2 Saggu, S., Rehman, H., Abbas, Z. K. &

Ansari, A. A. Recent incidence and descriptive epidemiological survey of breast cancer in Saudi Arabia. Saudi Med-

ical Journal 36, 1176-80 (2015).

Issue No.3

L E VE NT KONU K / I S TOCK / G E T T Y I M AG E S P LU S

Most serious diseases present three key challenges: diagnosis, targeted treatment, and monitoring of disease progression and response to therapy. KAIMRC researchers, led by nanoscientist Khalid Abu-Salah, with colleagues in Sweden and the US have developed nanoparticles that might perform these roles simultaneously1. Their system is based on therapeutic and diagnostic nanocarriers built of tiny spherical structures called micelles, composed of poly-ethyleneglycol (PEG) and poly-caprolactone (PCL) polymers. The micelles have been used as vehicles to carry the anti-cancer drug busulphan along with iron oxide particles that make them visible in MRI scans. They can also be labelled with fluorescent dyes to become readily detectable under suitable illumination. They are compatible with biological tissues, promoting no adverse reactions such as inflammation, and have biodegradable properties that assist their excretion after they have fulfilled their mission. The researchers hope to be able to target specific sites of disease by coating the micelles with molecules, such as antibodies, that selectively bind to receptors on the surface of diseased cells. The combined drug delivery and imaging system has been tested in mice. These animal trials were complemented by tests with cultured cells that demonstrated efficient release of the drug over timescales that could prove clinically useful. Abu-Salah is keen to target breast cancer, which is

Stem cells found in the bone marrow are not all the same. These cells comprise different subpopulations, each with their own distinct morphological and functional characteristics. A Saudi-led investigation has discovered a molecular marker that can differentiate between bone-forming and other types of precursor stem cells in the marrow. In the future, the findings could be put to clinical use to enhance bone regeneration following injury, for example. This application would be relatively straightforward, according to Amer Mahmood, a stem cell biologist from King Saud University (KSU) in Riyadh. “A clinician could sort the bone marrow cells and only inject those involved in making bone to get better results and faster healing in patients,” he says. The team of researchers isolated two groups of bone marrow cells on the basis of their morphology under the microscope. One subpopulation of cells, which he and his colleagues call CL1, had a cuboid-like geometry, whereas the other, dubbed CL2, was composed of spindle-shaped cells. Both cell populations expressed some of the same surface markers that denote bone marrow stem cells (BMSCs). 34

July 2017

A protein called ALP delineates a population of bone-marrow stem cells, known as CL1, which can form bone tissue.

However, a complete gene expression analysis revealed some major differences. CL1 cells, the researchers found, were enriched for more than 80 different genes related to bone mineralization and skeletal muscle development. In contrast, CL2 cells exhibited higher expression levels of

some 75 genes involved in regulating the immune system. The researchers tested the differentiation potential of each cell type. CL1 cells could more readily be coaxed into forming bone or fat precursors. However, blocking the expression of a gene called alkaline phosphatase (ALP) impaired this potential and reduced the expression of 62 genes involved in bone formation. This revealed the central role of ALP in guiding CL1 cells toward bone formation. What’s more, the team showed that simply testing for the expression of ALP alone could discriminate between CL1 and CL2 cells in a mixture of BMSCs. “ALP is a unique marker of osteoblast differentiating cells,” Mahmood says. Heterogeneous concoctions of BMSCs are currently used to treat everything from orthopaedic disorders, such as osteoarthritis, to autoimmune diseases, like lupus. The findings suggest that pre-sorting the stem cells and using only the subpopulation involved in the disease process being treated could improve health outcomes. Elsafadi, M., Manikandan, M., Atteya, M., Hashmi, J. A., Iqbal, Z. et al. Characterization of cellular and molec-

ular heterogeneity of bone marrow stromal cells. Stem

Cells International 2016, 9378081 (2016).

A M E R M A H M OOD @ 20 1 6

Stem cells in the bone marrow express different molecular markers depending on whether they form bone or other tissue types.

JUA N G A E R T NE R / S P L / G E T T Y I M AG E S

How to tell bone marrow cells apart

S S E C C U S S FACTOR

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.

kaimrc-biobank@ngha.med.sa

Raising the bar for gene therapy tests

team of researchers in Australia has developed a new strategy to design synthetic reference materials for tests that detect gene doping or the illegal use of gene therapy by athletes. Unscrupulous athletes could potentially use gene therapy to enhance performance by tweaking their genes or introducing additional copies of genes, such as EPO, which regulates red blood cell production. While gene doping remains a hypothetical problem, the World Anti-Doping Agency has been funding research on detection techniques since 2004. Gene doping tests routinely include a ‘positive’ sample that contains the genetic material being tested for in order to verify that the detection procedure is working properly. However, DNA from the positive control may contaminate the test sample, resulting in a false result. Even mild contamination can prove problematic since most of the tests involve the amplification of minute quantities of DNA. Anna Baoutina of Australia’s National Measurement Institute and her colleagues developed a reference design strategy that overcomes the problem of cross-contamination. To detect the foreign genetic material used for gene doping, known as a transgene, scientists employ a commonly used amplification reaction that produces millions of copies of target segments

July 2017

between specific anchors in the transgene. To avoid contamination with a positive control, Baoutina’s team designed a reference material with enough similarity to the transgene to be amplified in the same reaction, but with a key difference that makes them distinct. The anchors in the reference material are the same as in the transgene, but are positioned differently in the sequence, resulting in amplified target segments of different sizes. This difference enables the reference sequence to be distinguished from the transgene, so it can serve as a positive control without the risk of cross-contamination with the test sample. Baoutina set out to test her team’s new method while they were designing a reference for the EPO gene. On analysis of one of their samples, they were able to detect one instance of cross-contamination that would have previously gone unnoticed. One of the blank samples used, containing all the reagents but no DNA, returned a positive signal. The team showed that it had become contaminated by DNA from the control EPO sample with which their reference was compared. In addition to demonstrating the strategy’s effectiveness, this highlights the difficulty of avoiding contamination, even in a national reference lab following the best practices.

“This study does a very good job of highlighting the issue of cross-contamination and the need for methods to detect it,” says Perikles Simon, a gene doping researcher and professor at the Johannes Gutenberg University of Mainz who was not involved in the study. However, Simon points out that it won’t detect contamination from other sources, such as genetic material

WL A D I M I R B U LG A R/ S P L / G ET T Y I M AG E S

Researchers develop a strategy to improve contamination detection in gene-doping tests.

Cross-contamination during gene doping tests can often result in false results.

“Research related to gene doping has led to developments that could be helpful in other areas, such as detecting minimal residual disease.”

in the lab, and that techniques using this approach may not be sensitive enough to detect gene doping. “Gene doping itself isn’t a big issue because there isn’t a gene transfer technology at hand that could give a significant performance improvement,” he says. “Nevertheless, research related to gene doping has led to developments that could be helpful in other areas, such

as detecting minimal residual disease,” any few cancer cells that may remain in a patient following treatment and are difficult to detect. Baoutina, A., Bhat, S., Zheng., M., Partis, L., Dobeson, M., et al. Synthetic certified DNA reference material

for analysis of human erythropoietin transgene and transcript in gene doping and gene therapy. Gene Ther-

apy 23, 708-717 (2016)

Issue No.3

Determining the roots of derailed development Mutational profiling allows researchers to home in on a protein domain with a critical role in human neurological development.

July 2017

Children born with mutations in one particular segment of the gene coding the DYRK1A protein experience severe problems during brain development that can result in debilitating neurological and intellectual disabilities.

Issue No.3

OLEKS I Y M A KS Y M EN KO P H OTOG R A P HY / A L A M Y S TOCK P HOTO

ith an organ as complex production of the protein altogether. But as the brain, there are the other five were more subtle mutations numerous ways in which and the researchers were subsequently even a minor mutation able to map these to the various functional can cause profound developmental probdomains of DYRK1A. lems. A genetic analysis of children born DYRK1A is an enzyme that transfers a with neurological problems now reveals phosphate chemical group from a molehow various genetic disruptions effectively cule called ATP onto other target proteins. disable a protein with a prominent role in All five mutations in some way affected brain formation. the ‘kinase domain’ A protein called of the enzyme The DDD study profiled DYRK1A helps regthat facilitates this thousands of children ulate the exprest ra n s fer . S ome sion of key genes with neurodevelopmental mutations had obviinvolved in nervous ous effects, such disorders and their system developas disrupting ATP unaffected parents in ment. The loss of binding, and these even one of the two were a s s o ciate d order to home in on copies of the gene with more severe potential mutations encoding it can have disability. In consevere neurologicausing them. trast, other mutacal consequences, tions that exerted including seizures, autism and intellecless direct effects on DYRK1A function by tual disability. To better understand the slightly destabilizing the protein’s strucimportance of this protein, researchers ture were also associated with milder led by Caroline Wright of the Wellcome impairments. Trust Sanger Institute in the UK combed The researchers subsequently examthrough genetic data collected by the ined a large number of other previously Deciphering Developmental Disorders reported variants in the DYRK1A gene. (DDD) study. Notably, gene variants with no ill effects The DDD study, coordinated by Wright, were far less likely to occur within the profiled thousands of children with neukinase domain than those associated with rodevelopmental disorders and their developmental problems. The details of unaffected parents in order to home in DYRK1A function are still poorly underon potential mutations causing them. stood, but these results reveal a critical The researchers found that 0.5% of these role for this enzyme’s kinase activity in children carried mutations in the gene brain development, and the authors proencoding DYRK1A. All of these children pose that similar mutations in related had intellectual disabilities, and the vast kinases might contribute to other diseases majority also had notable physical develas well. opmental problems including microcephaly — an abnormal shrinkage of the skull. Evers, J.M., Laskowski, R.A., Bertolli, M., Clayton-Smith, Wright’s team then profiled the varJ., Deshpande, C. et al. Structural analysis of pathogenic ious DYRK1A mutations these children mutations in the DYRK1A gene in patients with develcarried. Fourteen out of the 19 were so opmental disorders. Hum. Mol. Genet. 26: 519-526 disruptive as to effectively terminate (2017).

One in every 100 babies are born with congenital heart disease.

Congenital heart defects are one of the leading causes of infant death worldwide.

Understanding the genetics of congenital heart defects New evidence traces congenital heart defects to healthy parents. One of the largest international genetic studies of congenital heart disease (CHD) highlights the significance, in particular forms of the disease, of spontaneous gene mutations not inherited from parents. Congenital heart defects develop in the womb and are the most common cause of birth defect-related infant death worldwide, affecting approximately one in every 100 newborns. Several CHD-associated genes have been identified, but other factors, such as maternal diabetes or taking anticoagulant or antiepileptic 40

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medications during pregnancy, have been shown to slightly increase the risk of CHD. To shed more light on the genetic basis of CHD inheritance, Matthew Hurles at the Wellcome Trust Sanger Institute in Cambridge, UK and colleagues sequenced the protein-coding part of the genome of 1,891 children with CHD and their parents. Patients were recruited from medical centres in the UK, US, Canada, Germany, Belgium and Saudi Arabia. Their findings, published in Nature Genetics, provide the first clear evidence

But, children with isolated defects of the heart, known as non-syndromic CHD, did not have such spontaneous mutations and often inherited damaging gene variants from their healthy parents. The authors also describe three new rare syndromic CHD disorders caused by new mutations in genes not previously associated with CHD. Establishing the function of these genes will shed further light on important biological mechanisms involved in normal embryonic development. These findings could be useful in the design of future genetic studies. To determine the most dominant CHD-associated genes, studies of non-syndromic CHD patients, which make up 90 percent of CHD patients worldwide, will benefit from sequencing the genomes of parents and unaffected siblings. Understanding the potential causes of CHD not only accelerates research into disease mechanisms and possible therapies, it also helps physicians give more accurate advice to parents about their chances of having a second child with the disease. “These findings have an immediate and direct impact on how patients are counselled, on family planning and on prenatal diagnosis,” explains molecular pathologist Saeed Al Turki of King Abdulaziz Medical City in Riyadh. Sifrim, A., Hitz, M-P., Wilsdon, A., Breckpot, J., Al Turki, S.H., et al. Distinct genetic architectures for syndromic

and nonsyndromic congenital heart defects identified

by exome sequencing. Nature Genetics 48, 1060– 1065 (2016).

I LYA NAY M U S HI N/ R E U T E R S / A L A M Y S TOCK P HOTO

of genetic differences between two forms of the disease. In syndromic CHD, where the disease is one among several developmental problems, such as abnormalities in other organs or an intellectual disability, the defects were found to be more likely due to new mutations that aren’t inherited from the parents.

Strategy urged to tackle genetic disease

audi Arabia has one of the highest rates of inherited metabolic disorders in the world, according to a 13-year review of children diagnosed at one of the largest hospitals in the country. This grave finding, the study authors say, points to the need for urgent and coordinated action to reduce the number of people suffering from so-called inborn errors of metabolism (IEMs). “The incredibly high rate of IEMs in Saudi Arabia compels the healthcare administration in the country to develop a long-term strategic plan for the prevention of such disorders,” says KAIMRC paediatric geneticist, Majid Alfadhel, who led the research. IEMs are rare genetic disorders caused by mutations that impair the ability of different enzymes to break down parts of food into energy. Collectively, the incidence of all IEMs is generally less than 1 in 2,500 throughout much of the Western world. But in countries where marriages between cousins are common, such as Saudi Arabia, the incidence is often much higher. One 25-year study from a hospital in Dahran, in the Eastern Province of the

A recent study shows the incidence of inborn errors of metabolism in Saudi Arabia to be 1 in 635 children, well above international rates.

Kingdom, documented an incidence of about 1 in 667 . Apart from that study, however, publications in the Saudi literature have been limited to case reports and case series. This piecemeal reporting led Alfadhel to wonder whether the numbers from Dahran were representative of the country as a whole.

“The incredibly high rate of IEMs in Saudi Arabia compels the healthcare administration in the country to develop a long-term strategic plan for the prevention of such disorders.” He and colleagues from King Abdulaziz Medical City in Riyadh looked at their records. Between 2001 and 2014, a total of 110,601 children were born at the hospital complex, 187 of whom were diagnosed with an IEM. That translated to an incidence rate of 1 in 591; on par with

what researchers had found previously in Dahran. Combining the results of the two studies yielded an incidence rate of 1 in 635, one of the highest ever documented in the world. Alfadhel’s team classified the 187 patients by their type of disorder. This should help doctors know what to look for, so they can intervene with medicines when appropriate. The authors also chronicled 43 mutations never seen before by scientists, observations that could aid in future diagnoses. Based on his findings, Alfadhel has a number of recommendations for healthcare administrators in Saudi Arabia. These include a national registry to determine the most common disorders and mutations, public health educational campaigns, and genetic screening among high school students so that, when they marry and have children, they can make informed decisions about family planning. Alfadhel, M., Benmeakel, M., Hossain, M. A., Al Mutairi,

F., Al Othaim, A. et al. Thirteen year retrospective review of the spectrum of inborn errors of metabolism present-

ing in a tertiary center in Saudi Arabia. Orphanet Journal

of Rare Diseases 11, 126 (2016).

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A high rate of inherited metabolic disorders in Saudi Arabia is prompting calls for action.

Demystifying a diet to live by A new connection is found between sensory neurons, diet and longevity.

July 2017

The roundworm Caenorhabditis elegans can offer a hint about the science of aging.

transcription factor DAF16, the master regulator of a large number of genes related to oxidative stress and dauer (hibernation-like state). Moreover, since DAF-7 levels decrease with age, old roundworms do not respond to the longevity effect of dietary restriction, perhaps explaining why previous studies showed that older animals undergoing dietary restriction do not show life extension.

Eating around 30 to 40% less than free-feeding levels leads to a longer life and thwarts agerelated diseases. T h e re s e a rch e r s c o n clude that, since their study suggests that roundworm response to food restriction could be modulated through specific neuroendocrine pathways, it is possible that drugs targeting similar pathways in mammals may be able to promote longevity when used together with dietary modifications. Fletcher, M. & Kim, D. H. Age-depend-

ent neuroendocrine signaling from

sensory neurons modulates the effect of dietary restriction on longevity of

Caenorhabditis elegans. PLOS Genetics 13(1): e1006544 (2017).

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H EI T I PAVES / A L A M Y Â S TOCK P HOTO

he longevity-promoting effect of mo derate d ie tary restriction in roundworms could be due to the secretion of a protein that ultimately affects metabolism-regulating genes. This highlights the importance of neuroendocrine regulation in the ageing process and in treatments aimed at increasing longevity. From single-celled organisms to mammals, eating around 30 to 40 percent less than free-feeding levels leads to a longer life and thwarts age-related diseases. However, the reason for these benefits is unclear. Scientists are using the transparent, millimetre-long roundworm nematode Caenorhadbitis elegans as a model for deepening our knowledge about the biology of ageing . A recent study by researchers at the Massachusetts Institute of Technology in the US found a new mechanism by which C. elegansâ&#x20AC;&#x2122; sensory perception of available food modulates the effect of dietary restriction on longevity. The research team focused on a small protein in C. elegans called DAF-7. They found that when the roundworm senses that food is limited, like during dietary restriction, a pair of sensory neurons secrete DAF-7. This activates the

Study finds mutations in a rare inherited disease called pyroglutamic aciduria.

Only seven patients with a very rare form of a hereditary disease called 5-oxoprolinuria have been reported in scientific literature. Its genetic and clinical features are still poorly understood. An international study, involving Saudi Arabia’s Ministry of National Guard Health Affairs, shed light on this disease by analyzing the DNA of 14 affected families from various ethnic groups. The condition thwarts the production of glutathione, a molecule needed by the body to neutralize other harmful molecules generated during energy production. It is also needed to build cellular components like DNA and proteins, and to metabolize foreign chemicals such as drugs and environmental pollutants. The specific symptoms of the disease vary in severity from mild, affecting only red blood cells, to severe, affecting many cell types in the body. An indicator of 5-oxoprolinuria is a large concentration of the compound 5-oxoproline in the urine. This disease can be caused by several factors, including the mutation of the glutathione synthetase (GSS) gene or the 5-Oxo-L-Prolinase ( OPLAH ) gene. While the former has been reported in several dozen patients, 44

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S HU NY U FA N/ I S TOCK / G E T T Y I M AG E S P LU S

Twenty new mutations implicated in rare genetic disease Glutathione is is an important antioxidant that can help protect against damage caused by certain molecules produced within the body.

this study focuses on the latter, which is also known as 5-oxoprolinase deficiency, and is rarer.

“More research is needed to draw the line between asymptomatic and symptomatic disease.” By analyzing the DNA of children affected by 5-oxoprolinase deficiency and their family members, the researchers discovered 20 new and unique mutations in the OPLAH gene. They found that the disease manifests when patients inherit two copies of the abnormal gene, one from each parent. Parents can carry a single copy of the faulty gene without showing the symptoms, and have a 25% risk of having an affected child with each pregnancy. Consanguinity is common in Saudi Arabia, increasing the chance of the altered gene being passed on. Unexpectedly, none of the patients

were affected by premature breakdown of red blood cells, known as haemolytic anaemia, which is a key clinical feature of patients with GSS mutations. But other symptoms varied widely: some patients had none at all, while others had psychomotor symptoms, developmental disabilities, and inappropriate weight loss. The researchers were unable to clarify the causal relationship between the symptoms and the OPLAH mutations. “More research is needed to draw the line between asymptomatic and symptomatic disease. Also, we cannot rule out that new symptoms could appear later in the life of these children, or that current symptoms might be caused by other genetic defects,” says King Saud bin Abdulaziz University for Health Sciences professor Majed Alfadhel. Sass, J. O., Gemperle-Britschgi, C., Tarailo-Graovac, M., Patel, N., Walter, M., et al. Unravelling 5-oxoprolinuria

(pyroglutamic aciduria) due to bi-allelic OPLAH muta-

tions: 20 new mutations in 14 families. Molecular

Genetics and Metabolism, 119, 44-49 (2016).

“The immunohistochemistry test demonstrated here only costs a few dollars, and could therefore prove invaluable in resource-poor places.”

Medullary thyroid cancer originates in neuroendocrine cells in the thyroid.

Cutting down the costs of diagnosis

A test that screens for genetic mutations in skin cancer can help identify patients with a particular type of thyroid cancer. The search for suitable, inexpensive alternatives to molecular genetic testing for rare but life-threatening diseases could transform their diagnosis and treatment, particularly in resource-poor parts of the world. Scientists in Australia have shown how a simple immunohistochemistry test developed for diagnosing skin cancer can also help identify patients with a severe form of thyroid cancer. Medullary thyroid cancer (MTC) is a rare type of thyroid cancer, responsible for a disproportionately high number of deaths. Genetics plays a significant role in MTC: around 25 per cent of patients have a hereditary cancer syndrome called MEN2 that causes tumours in glands controlling hormone production. MEN2 is caused

by mutations on the RET gene, and in resource-rich countries genetic testing is offered to all MTC patients and their families to check for RET mutations. However, between 10 and 45 per cent of patients with MTC harbour mutations on another gene: RAS. The specific mutation is known as HRASQ61R, and now Anthony Gill and Jessica Reagh at the University of Sydney, Australia and co-workers have demonstrated that a simple test developed for skin cancer can also identify patients with the HRASQ61R mutation. “My team and I have a keen interest in validating mutation-specific immunohistochemistry or simple morphology for use in routine surgical laboratories,”

Gill’s team took samples from the patients and trialled the immunohistochemistry test that uses the rabbit antibody SP174. The SP174 test picked out seven potential tumours harbouring the HRASQ61R mutation. Further sequencing on these seven tumour samples confirmed the existence of HRASQ61R, thus identifying MTC. “Because the two mutations in MTC are mutually exclusive — you either have one or the other — a simple test for RAS mutation automatically excludes patients with RET mutations, or MEN2,” says Gill. “The immunohistochemistry test demonstrated here only costs a few dollars, and could therefore prove invaluable in resource-poor places. It could be used to identify those patients needing further genetic testing for MEN2, and also to double-check DNA tests, ensuring higher quality testing.” Gill’s team plans to continue searching for other scenarios where simple mutation-specific tests can replace more expensive, time-consuming genetic testing that requires highly skilled personnel. Reagh, J., Bullock, M., Andrici, J., Turchini, J., Sioson,

L. et al. NRASQ61R mutation-specific immunohistochemistry also identifies HRASQ61R mutation in

medullary thyroid cancer and may have a role in triaging genetic testing for MEN2. American Journal of

Surgical Pathology 41(1):75-81 (2017)

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says Gill. “We realised that the amino acid sequences for RAS mutations in skin cancer and RAS mutations in MTC were identical, meaning that an existing simple test could theoretically pick up on the HRASQ61R mutation. We decided to trial this theory on 68 MTC patients.”

Bioinformatics: Fast and deleterious

A new computational method can quickly identify noncoding sites in the human genome where mutations are likely to have harmful effects. 46

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LINSIGHT outperforms state-of-the-art methods in identifying diseaseassociated noncoding sites.

D E C O / A L A M Y STO C K P HO TO

hen people think of genetic mutations, they often think of cancer, birth defects and inherited diseases. But genetic mutations are also a crucial part of evolution. They are responsible for the differences in traits between species, like humans and chimpanzees, as well as

within species, like between one person and another. These traits, in turn, reflect the fitness of an organism: its ability to survive and reproduce in the environment. Adam Siepel and co-workers at Cold Spring Harbour Laboratory in New York previously developed a computational method, called

fitCons, for identifying sites in the human genome that do not code for proteins, called noncoding sites, that are under selective pressure and, therefore, are likely to be biologically important. The researchers have now introduced an improved version called LINSIGHT that could efficiently and accurately predict whether genetic mutations at these sites have fitness consequences. LINSIGHT and fitCons both assess the impact of natural selection on noncoding sites by comparing patterns of genetic mutations between and within species. They then assign a score to each noncoding site based on the probability of mutations leading to fitness consequences. A major limitation of fitCons is that it requires partitioning the genome into clusters prior to analysis. The number of clusters that need to be considered increases exponentially with the amount of data. LINSIGHT has vastly improved speed, scalability and prediction power because it bypasses the clustering step of fitCons and pools information across sites using a model that scales linearly, rather than exponentially, with the size of functional genomic data. Tests showed LINSIGHT outperforms currently available state-of-the-art methods for identifying disease-associated noncoding sites. More importantly, LINSIGHT has relatively high resolution and could pinpoint single nucleotides

instead of regions that are hundreds of nucleotides long. The results are encouraging and suggest that LINSIGHT can be exploited to mine ‘bigger data’ that are set to emerge in this bioinformatics era. In testing LINSIGHT, the researchers were able to identify factors that influence fitness consequences.

“We have been thinking for years about how best to combine functional genomic and evolutionary data to shed light on regulatory function. LINSIGHT is our best effort at solving this problem yet, and it performs very well in our evaluation tests.” “We have been thinking for years about how best to combine functional genomic and evolutionary data to shed light on regulatory function,” says Siepel. “LINSIGHT is our best effort at solving this problem yet, and it performs very well in our evaluation tests.” Huang, Y. F., Gulko, B. & Siepel, A. Fast, scalable prediction of deleterious noncoding variants from functional and population genomic data. Nature Genetics 49, 618-624 (2017).

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“When a child presenting with cancer also has physical characteristics associated with conditions like Bloom syndrome it is absolutely crucial to rule out genetic factors that might impede cancer treatment.”

Genetic disorders may influence the choice of the best cancer treatment for a patient.

Treating cancer patients with rare genetic conditions

A case study of a boy with Bloom syndrome highlights the need to screen patients for rare disorders before treatment for cancer. Some genetic disorders leave patients more susceptible to developing cancer, and less responsive to standard chemotherapy. A recent case study by an MNG–HA researcher has illustrated the importance of ruling out rare genetic disorders prior to cancer therapy. Bloom syndrome is a rare genetic disorder caused by a mutation that disrupts DNA repair. This results in chromosomal instability, which manifests with a variety of symptoms including growth retardation, immunodeficiency and cancer susceptibility. “I work as a consultant in paediatric oncology, and recently an 11-year-old boy arrived in a critical condition with 48

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mature B cell lymphoma,” says Wasil Jastaniah of Princess Noorah Oncology Center. “We started him urgently on standard chemotherapy, but he suffered severe side-effects and we had to find an alternative treatment.” Jastaniah treated the boy with rituximab, an existing therapy designed for children sensitive to conventional chemotherapy. Rituximab had previously been shown to be safe and effective against mature B cell lymphoma. “At this point, we had not diagnosed the patient with Bloom syndrome,” says Jastaniah. “He responded well to rituximab-based chemotherapy and went on to make a full recovery from the lymphoma.

The patient was later diagnosed with Bloom syndrome, and Jastaniah realised that successful cancer treatment with rituximab might be a viable option for such patients in the future. To date, there have been no previous studies into the treatment of cancer in patients with Bloom syndrome, and the case reveals promise for future therapies for those with the condition. Jastaniah is keen to highlight the importance of early diagnosis of inherited cancer-predisposing syndromes to optimize surveillance and treatment. “When a child presenting with cancer also has physical characteristics associated with conditions like Bloom syndrome, such as growth retardation, it is absolutely crucial to rule out genetic factors that might impede cancer treatment,” says Jastaniah. “This case study should also trigger further investigations into cancer treatments in patients with Bloom syndrome and similar disorders because data are so limited at present.” The rarity of these genetic conditions means that individual countries are unlikely to come across many cases. Jastaniah hopes to see the development of an international registry that would help researchers access data regarding cancer management in patients with chromosomal instability. Jastaniah, W. Successful treatment of mature B-cell lymphoma with rituximab-based chemotherapy in a

patient with Bloom syndrome. Pediatric Blood and Can-

cer 7: e26385 (2016).

T HE KOP M Y L I FE / I S TOCK / G E T T Y I M AG E S

The fact that standard chemotherapy was so toxic for him, however, suggested an underlying inherited cancer predisposition syndrome.”

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.

kaimrc-core@ngha.med.sa

A LY H A Z Z A A

FORUM OILS THE WHEELS OF RESEARCH PROGRESS

Biomedical research investment could help diversify an economy heavily reliant on oil, said scientists gathering last December in Riyadh.

odern-day Saudi Arabia is no stranger to change. Before it was founded in 1932, the people of the land were largely nomadic and a main source of the country’s revenue came from the annual Muslim pilgrimage to the holy city of Mecca. But in 1938, an American-owned company

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struck oil on Saudi Arabia’s east coast and struck it big, signalling a new era for the demographics, infrastructure and lifestyle in Saudi Arabia. Today, Saudi Arabia is one of the world’s top oil producers and exporters, churning out 10.2 million barrels per day in 2015. Oil revenues account for about 87% of the country’s budget. But if

GLOBAL COMPETITIVENESS INDEX 2016/2017

Saudi Arabia ranked 29 out of 138 states on the Global Competitiveness Index for 2016/2017, only surpassed by two other Arab states. The report, produced by the World Economic Forum, recognized the kingdom’s efforts to diversify its economy through Saudi Vision 2030. 5.26

UNITED ARAB EMIRATES QATAR

SAUDI ARABIA

4.53

KUWAIT

4.84

5.23

4.47

BAHRAIN 4.29

JORDAN

4.28

OMAN

4.20

MOROCCO 3.98

ALGERIA TUNISIA

3.92

LEBANON

3.84

EGYPT

3.67

YEMEN

2.74 0

Saudi Arabia continues to pump oil at this rate, it will drain its 266.455 billion barrels of proven crude reserves in about 70 years. Diversification attempts by successive governments have traditionally been focused on power generation, telecommunications, natural gas exploration and the petrochemical sector. In April 2016, the Saudi Arabian government, under the leadership of King Salman bin Abdulaziz Al Saud, released Saudi Vision 2030, a diversification blueprint to boost non-oil-based revenues; tapping into other natural resources such as gold, copper, uranium and aluminium; enhancing the role and contributions of small- and medium-sized enterprises; and increasing dependence on and investment in renewable energy sources, among others. The kingdom seems well on its way to an economic transformation, now ranking 29 on the Global Competitiveness Index 2016/2017, which looks at the drivers of different economies’ productivity and prosperity. The index assesses the competitiveness landscape of 138 economies based on 114 indicators grouped under broad categories that include infrastructure, health and higher education, training, goods and labour market efficiency, financial market development, technological readiness, business sophistication, and innovation.

Moving toward a knowledge economy In the areas of health and higher education, training, technological readiness, and innovation King Abdullah International Medical Research Center (KAIMRC), the research institute of the Ministry of National Guard-Health Affairs (MNG-HA), steps in. KAIMRC is one arm of a huge academic, medical and research complex that spans Saudi Arabia, with its main headquarters in Riyadh, the capital. This and other institutions across the kingdom are integral to plans to move the country to a knowledge-based economy. “The main aim [of Saudi Vision 2030] is encapsulated by KAIMRC’s strategy and activities,” explained Ahmed Alaskar, KAIMRC’s executive director, during the opening ceremony of the institution’s 7th Annual Forum for Medical Research held last December. MNG-HA’s strategy focuses on investing in education and training to support the ambitions and potential of Saudis. “It is also to sustainably invest in people’s minds by conducting medical and innovative research guided by a strategy to have a positive impact on people’s health and on the national economy,” said Alaskar. KAIMRC’s executives point to it as a source of knowledge and a centre of

collaboration with science researchers around the world. “KAIMRC is keen on adopting new, creative and innovative research that will achieve a paradigm shift in healthcare services,” said Bandar AlKnawy, chief executive officer of MNG-HA and president of King Saud University of Health Sciences. “In this way, we are developing the healthcare sector and the knowledge economy.” The influence of medical research But, AlKnawy told around 4,000 participants from the Middle East, the US, UK, France, Germany and Belgium at the meeting in Riyadh, innovation presents challenges. These include transforming investment in research and development (R&D) into competitive new products, and stimulating growth and employment by encouraging collaborations between small and large companies, universities, and national laboratories. KAIMRC plans to establish a biotechnology park to “incubate, produce, commercialize and collaborate on research products,” said Alaskar. Biotechnology parks can be significant sources of revenue. Shanghai Zhangjiang Hi-Tech Park, for example, accounts for a quarter of the city’s gross domestic product, half of its foreign trade, and a third of Issue No.3

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ADVERTISEMENT FEATURE its foreign investment, said Alaskar. In the US, Research Triangle Park includes more than 200 companies and 50,000 employees. The park is located between three of North Carolina’s tier-one research universities, in which industries invest more than US$296 million in R&D each year; double the average R&D investment for innovation clusters elsewhere in the country, he added. KAIMRC anticipates its latest endeavour will bring similar benefits to Saudi Arabia. The park represents “a key component of KAIMRC’s strategy to support the kingdom’s knowledge-based economy and to align with the Saudi Vision 2030,” said Alaskar. It will provide R&D services and support; act as incubator of start-up technology companies; and will be designed to foster the transfer of technology to the marketplace. “Technology is seen as a clean industry with growth potential that aligns well with the economic development platform,” said Alaskar during his talk. Public-private partnerships are a way to incentivize innovation in the management of diseases which have significant impact, said Philip Larsen, chairman of Europe’s largest public-private partnership, the Strategic Governance Group for Innovative Medicines Initiative (IMI) Metabolic Disorders. KAIMRC also houses the Saudi Biobank, a repository of information on the general and unique genetic and physiologic characteristics of the Saudi population. It plans to store tissue samples from 200,000 people in this facility.

A long history of consanguineous marriage in Saudi Arabia makes the population ideal for genetic research.

Saudi Arabia’s long tribal history and consanguineous relationships mean that its population has a unique genetic makeup with many rare diseases. Exploring this phenomenon will not only advance science, said Klaus Lindpaintner, vice president and global head of worldwide research and development at Pfizer Inc, but will also generate significant new revenue flows. “Investing in the establishment of a large, well-characterized, world-class biobank would fit very well into the Saudi Vision 2030, which aspires to a more diversified economy,” he said. “Given mounting international competition in

this field, however, actions would need to be taken swiftly and decisively.” Strategic focus areas of disease Rather than spread its efforts too thin, KAIMRC identified a handful of strategic areas of biomedical research to create real impact on the health of the Saudi population, Bandar Alknawy told forum participants during the 7th Annual Forum for Medical Research. These include infectious diseases, diabetes, cardiovascular diseases and cancer, and were the focus of the forum as KAIMRC brought in international experts to discuss the latest research.

DURING THE FORUM’S OPENING CEREMONY, SAUDI ARABIA’S MINISTER OF THE NATIONAL GUARD, PRINCE MUTAIB BIN ABDULLAH BIN ABDULAZIZ, LAUNCHED THE KING ABDULLAH MEDICAL RESEARCH AWARD. THE AWARD AIMS TO RECOGNIZE MEDICAL RESEARCH EXCELLENCE IN SAUDI ARABIA, TO EMPHASIZE THE GOVERNMENT’S COMMITMENT TO CREATE AN ENVIRONMENT CONDUCIVE TO HIGH QUALITY RESEARCH AT A NATIONAL COMPETITIVE LEVEL, AND TO ENHANCE THE DELIVERY OF RESEARCH WITH DIRECT IMPACT ON HUMAN HEALTH AND ON THE COUNTRY’S ECONOMY. THE WINNING RESEARCHER WILL RECEIVE SR 1 MILLION (ABOUT US$267,000). 52

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Klaus Lindpaintner, vice president and global head of worldwide research and development at Pfizer Inc.

Diabetes Statistics show that one in every 11 adults worldwide had diabetes in 2015. This figure is expected to rise to one in every ten adults by 2040. In Gulf Cooperation Council countries, said KAIMRC endocrinologist Ali Alqarni, somewhere between 10 and 18% of the populations suffer from diabetes, with Saudi Arabia showing the highest prevalence. In 2015, Saudi Arabia ranked fifth in the world for the number of new cases of type 1 diabetes per 100,000 children per year. Obesity, also common in Saudi Arabia, is an established risk factor for type 2 diabetes. A study that surveyed participants from 20 countries from 2002 to 2004 found that 40% of those sampled in Saudi Arabia reported low levels of physical activity, while 33.8% and 26.2% reported moderate and high levels respectively. In comparison, 15.9% of those surveyed in the US reported low levels of physical activity, while 22.1% and 62% reported moderate and high levels respectively. “The economic boom in GCC countries has been associated with the emergence of diabetes as a major problem,” said Alqarni. This is why researchers at KAIMRC stress

that research for improving prevention, diagnosis and treatment of the disease is especially pertinent. Philippe Froguel, chair in genomic medicine at Imperial College London, told the conference that since 40 to 90% of type 2 diabetes has a genetic origin, establishing a competitive genomic medicine research centre could play an important role in diabetes research, KAIMRC plans to launch a central headquarters for basic, translational and clinical genetics-related research. Genome-wide association studies have already identified more than 50 loci associated with an increased genetic risk of type 1 diabetes. Understanding how interactions between genes and the environment lead to diabetes could result in patient-tailored preventive, diagnostic and therapeutic approaches. The French multinational pharmaceutical company, Sanofi, is working on a drug based on years of research into the effects of bariatric surgery on diabetes patients. Philip Larsen, Sanofi’s global head of diabetes R&D, explained that bariatric surgery reduces the risks of several conditions, including diabetes. Laparoscopic gastric bypass was found in one study, for

Cardiovascular diseases Cardiovascular diseases cause 46% of deaths in Saudi Arabia. In the past few years, research groups, including his, have discovered human heart stem cells that can turn into cardiac muscle cells, giving the heart the force it needs to contract. Lee and his team have also demonstrated that blood stem cells can be used to stimulate the heart’s stem cells to repair damaged tissue. In addition to discussing regenerative approaches to cardiac problems, speakers Issue No.3

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example, to lead to resolution of type 2 diabetes in 83% of cases. “Several important gut hormones potentially mediate the metabolic benefits of bariatric surgery,” said Larsen. Among these, the hormone oxyntomodulin, which is found in the colon, suppresses the appetite. “Clinical experimentation with oxyntomodulin demonstrates impressive weight loss efficacy,” said Larsen. One of the drawbacks of the natural hormone, however, is its short half-life of around 12 minutes in humans, and its rapid degradation in the body and rapid clearance by the kidneys. Sanofi is currently working on an oxyntomodulin analogue, called SAR425899, which works by mimicking the actions of the glucagon-like peptide-1 (GLP-1) and glucagon receptors, stimulating the release of insulin, and inducing weight loss by suppressing the appetite and increasing energy expenditure. Clinical trials have so far shown the drug to be safe and generally well tolerated. It improves glycaemia and significantly decreases body weight in obese people with type 2 diabetes. Stem cells are also being studied as a potential replacement for destroyed pancreatic beta cells for type 1 diabetes. Richard Lee, professor of stem cell and regenerative biology at the Harvard Stem Cell Institute, said the most recent research involves the generation of insulin-producing beta cells from induced pluripotent stem cells derived from a type 1 diabetes patient’s own peripheral blood cells. This research could potentially lead to patient-specific cell replacement therapy.

at the conference also surveyed congenital heart diseases (CHD) that may have genetic roots. Saudi Arabia has a particularly high prevalence of CHD. Whereas cardiovascular malformations are found in eight of every 1,000 live births globally, the incidence in Saudi Arabia is 10.7 per 1,000 live births, said paediatric cardiologist Riyadh Abu Sulaiman of King Saud bin Abdulaziz University for Health Sciences. Abu Sulaiman recently worked with local and international peers to investigate the differences in gene mutations implicated in isolated congenital heart disease (non-syndromic CHD) and syndromic CHD. They found that children with syndromic CHD tend to have new genetic mutations, while mutations in non-syndromic CHD children were inherited from their parents. Identifying the genetic basis of congenital heart disease will improve insight into the patho-biological basis of the disease, said Abu Sulaiman.

“WE ARE COMING OUT OF A DECADE OF GREAT ENTHUSIASM FOR STEM CELLS TO REPLACE DESTROYED HEART CELLS,” — RICHARD LEE. KAIMRC researchers have recently developed a molecular test, in collaboration with US-based colleagues, which recognizes a gene variant associated with breast cancer and may be used as a diagnostic tool in the early stages of the disease. They have also begun testing a compound, called G-11, which targets cells that develop a mutation commonly found in acute myeloid leukaemia. The compound could play a role in preventing relapse of the disease.

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Cancer Cancer incidence in Saudi Arabia is relatively low (87.6 new diagnoses/100,000 people annually) compared to many European (300.4/100,000 in France), North American (300.2/100,000 in the US) and some Asian countries (181/100,000

in China and 200.5/100,000 in the Russian Federation). According to the 2013 Saudi National Cancer Registry report, the most common cancers in the kingdom are breast, colorectal, thyroid, non-Hodgkin lymphoma, leukaemia and liver cancers.

KAIMRC researchers are identifying gene mutations related to different diseases. 54

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Another KAIMRC research team is also trying to better understand colorectal cancer by analysing the genomic and transcriptomic changes associated with the disease. At the conference, David Kerr, professor of cancer medicine at the University of Oxford, described how a spinout company from the University of Oxford. The company, Oxford Cancer Biomarkers, is developing a range of cancer biomarkers that can improve patient response to therapy. One such marker is used to determine whether patients who have undergone colorectal cancer surgery are at low, standard or high risk of relapse, he explained. This can help clinicians decide which patients will most benefit from chemotherapy and which ones have a high likelihood of being cured with surgery alone. A second biomarker is being used to determine which patients might be at high risk for severe toxicity from a chemotherapeutic drug commonly used to treat colorectal cancer; allowing clinicians to select safer doses. A third biomarker can identify healthy people who might be more at-risk for colorectal cancer so clinicians can help them minimize their risk of getting the disease. Farzin Farzaneh, professor of molecular medicine at King’s College London,

Research outputs A large number of Saudi patients seek medical treatment abroad every year, Ibrahim Al Jufali, executive vice president for drug affairs at the Saudi Food and Drug Authority, told attendees. Many of these patients enrol in clinical trials to benefit from the latest advances in science. “Increasing the number of clinical trials in Saudi Arabia would allow some of these patients to be treated at home,” he said. Conducting clinical trials in Saudi Arabia will also contribute to making new treatments safer and more effective for the local population, he added. Enrolling Saudi patients in clinical trials addresses significant unmet medical needs

in the country, especially since Saudi Arabia has a high prevalence of rare diseases, such as haemophilia, sickle cell anaemia and beta-thalassemia. Al Jufali explained that domestic clinical trials could also help attract and retain talent, encourage pharmaceutical companies to operate in the country, and create a new strand for economic diversification. There are barriers, however, to increasing clinical trials in the kingdom. Researchers and clinicians in the country have limited experience with international multicentre trials, and adequate clinical trial support staff are needed. Traditionally lower salaries for research positions may also make the country less attractive for conducting these trials. Nevertheless, Saudi Arabia’s more than 25 medical colleges, large number of hospitals, world-class lab facilities, and stateof-the-art IT infrastructure mean the kingdom has great potential for conducting clinical trials in the future, said Yassin Arabi, chairman of the intensive care department at King Saud bin Abdulaziz University for Health Sciences. Saudi Arabia is already making strong headway in publishing; its research is appearing in high-quality peer-reviewed journals. It had the fastest growth for the

Western Asia region in the Nature Index, a database of author affiliation information collated from research articles published in 68 high-quality science journals. The kingdom currently ranks second-highest in the region, surpassing traditional powerhouses such as Turkey and Iran,the index shows. The bulk of Saudi Arabian research published in journals monitored by the Nature Index is in the fields of chemistry and the physical sciences, and indicators point to strong collaborations between Saudi-affiliated researchers and their international colleagues. “While Saudi biomedical research is still in an early growth phase, this represents a great opportunity to make targeted and well-considered investment decisions for its future,” said Klaus Lindpaintner, vice president and global head of worldwide research and development at pharmaceutical giant Pfizer. “The forum was highly instrumental and effective in alerting participants from abroad about this potential, and I for my part am looking forward to learning more, to engage in additional discussions, and, if possible, to contribute to turning the extant opportunity into concrete value propositions,” he said. Issue No.3

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described recent international research efforts into cancer immunotherapy, which focus on developing agents that can activate the immune system so it can recognize and kill cancer cells. For example, one target involves blocking a pathway, called the programmed death 1 pathway, which is upregulated in many cancer types. This pathway represses the immune response to tumours from helper T cells. “Immune therapy-based approaches are enabling deeper and longer-lasting remissions,” said Farzaneh.

The leap from lab to market

Biomedical research and entrepreneurship could help diversify Saudi Arabia’s economy.

Saudi Arabia has the beginnings of a culture of entrepreneurship in the biomedical sector. But many challenges remain. “I still remember the Saudi patent office calling to say my patent had been registered. This has given me more courage and pushed me to work harder,” enthuses Alotaibi Muhayl, internal medicine resident at Saudi Arabia’s Ministry of National Guard–Health Affairs (MNG-HA). He patented a cartilage prosthetic implant that relieves joint pain caused by arthritis or injury, sparing patients some of the complications of existing surgical techniques. A self-taught entrepreneur, Alotaibi knows that bringing an idea from the lab to the market can be one of the most rewarding experiences. Given the right training and incentives, it could become a reality for more Saudi researchers. Recently, Saudi Arabia embarked on a programme to diversify its sources of income, aiming to transition toward a knowledge-based economy, to offer more job opportunities to youth, and train the next generation of entrepreneurs. In such an entrepreneurial environment,

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the biomedical sector has the potential to become one of the cornerstones for development. A budding infrastructure Universities and research institutes are historically a birthplace of early-stage innovations, which have the potential to generate new licenses, investments and jobs. However, the kingdom has limited experience in getting commercial ideas out of the lab. One of the most recent initiatives to bridge the technology adoption gap is the Saudi Arabia Advanced Research Alliance (SAARA). It was created in 2015 to help commercialize technologies and benefit the economy. With the help of collaborations between industry, academia and the Saudi government, SAARA has helped launch two companies that aim to engender entrepreneurship among scientists and engineers. The government has enacted several

laws and regulations that protect intellectual property rights to ease the transition to a knowledge-based economy. Technology transfer offices and commercialization firms have also been established at several major academic and research institutions in the kingdom. KAIMRC’s innovation and technology transfer management office (ITTMO) was launched in 2012 to offer support to its researchers and those working at King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) and the Ministry of National Guard–Health Affairs. It also aims to enable partnerships between industries and academia. King Abdulaziz City for Science and Technology (KACST) established similar technology transfer consultancy services and an inventors’ and intellectual property support unit, which together have assisted more than 1577 projects and provided financial support to 55 inventors. KACST now owns more than 220 patents

and has 590 more pending. It also initiated the Technology Innovation Center for Personalized Medicine and the first Saudi bio-business incubator. The latter opened in 2010 through a broader KACST initiative called Badir, or initiate, which supports budding entrepreneurs in several scientific fields. Badir has incubated 106 projects, generating 699 jobs and a market value of SR232 million for 28 of the projects. Riyadh Valley Company, based at King Saud University (KSU), is one of several venture capital firms in Saudi Arabia investing in innovation-based start-ups. It has funded several technology companies, including Saudi Health Information Systems and Advanced Dental Technology. Awards for researchers with exceptional records of publications, innovation, funding and mentorship, like the MNG-HA awards, represent an additional incentive for academics with an innovative bent. “Innovation is important to me. I want to make a difference as an academic and a social entrepreneur. I believe it is possible to do well financially by doing good in society,” explains Mowafa Househ, associate professor at the College of Public Health and Health Informatics at KSAU-HS. Househ has won several innovation awards, including top researcher in the 2015 MNG-HA awards, the entrepreneurship and start-up award in the 2014 Middle East Broadcasting Corporation ‘Doing Good’ competition, and he was one of ten finalists in the Innovative Finalist Projects for the 2013 Massachusetts Institute of Technology (MIT) Enterprise Forum Pan Arab. KAIMRC also recently launched a new monetary prize, the King Abdullah Medical Research Award, for biomedical scientists from any Saudi institution. The award recognizes excellent biomedical research projects that have resulted in a new prototype, device or process and made an impact on health and the economy. Many challenges Despite progress, the technology transfer field is still a relatively new one in the kingdom and has not yet been fully integrated into academia. “A basic understanding of technology

transfer is lost, or wrongly understood, among senior management at some Saudi academic institutions,” says Anas AlHunaihin, ITTMO’s commercialization manager. “The current structure of research promotion works against technology transfer. Researchers are more interested in getting their research findings published. By doing so, they disclose their innovative ideas publicly, which might jeopardize their ownership,” adds Ahmed Aldraihem, manager of KAIMRC’s technology transfer office.

“I believe it is possible to do well financially by doing good in society.” “Technology commercialization potential should be considered as an important criterion in the early stages of the research proposal selection process. When you work at the university, you have to teach and do research. Innovation is just an afterthought. I love innovation and I see the fruits of it, but other researchers might think: why should we engage? More incentives and training opportunities are necessary,” Househ says. Scientists also need commercial

awareness training. ITTMO director Ali Almuntashri stresses the importance of writing a business plan to avoid draining funds for proof of concept models of products with limited market value. He also warns against ‘technology transfer brokers’, who claim to provide commercialization assessments but offer nothing. Finally, another obstacle to building an innovation ecosystem is the lack of entrepreneurship infrastructure and prototyping facilities. “Our generated innovations need to be licensed outside Saudi Arabia due to absence of platforms that can be utilized to produce our new technologies,” explains Ahmed Aldraihem. Alotaibi Muhayl explains that preparing his first patent was an important learning experience. “I spent a lot of time formulating the patent idea. I learned step-by-step how to search in patent databases and find the best marketplace for manufacturing and selling the patent,” he says. He registered his patent at the Saudi patent office first and received assistance from the ITTMO to submit it to the World Intellectual Property Organization and the United States Patent and Trademark Office. With one patent under his belt, working on new patents has been much easier for him. He has already submitted a new patent and hopes for further success.

Well-equipped facilities for research and prototyping could attract biomedical companies and entrepreneurs. Issue No.3

FS TOP I M AG E S G M BH / A L A M Y S TOCK P HOTO

Researchers warn of major public health concerns, should policies and attitudes towards antibiotic use remain unchanged.

Antibiotic misuse a looming crisis for Saudi Arabia

Warning over high levels of illegitimate antibiotic dispensing and public misconceptions about their use. A recently published study from Saudi Arabia describes widespread illegal prescription of antibiotics by pharmacists under pressure from an ill-informed public of the potentially dire consequences of their overuse, and even the circumstances in which antibiotics are effective. Respondents to surveys admitted to hazardous attitudes and behaviours toward antibiotic use. The researchers suggest this is a wake-up call for policymakers to tighten restrictions on antibiotic dispensing and educate the public on the dangers. The increasing problem of antimicrobial resistance has frequently been reported as one of the greatest impending public health disasters in human history. Bacteria undergo random mutations, making them tolerant to previously effective treatments. Bacteria share their genetic traits via a 58

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process called horizontal gene transfer. By doing so, a harmless bacterium could transfer antimicrobial resistance to a pathogenic one. Antibiotic overuse increases the likelihood of this process occurring as more bacteria carry the genome for resistance to a given treatment. In their study, published in the Journal of Infection and Public Health, a team of researchers from King Fahd Medical City and King Saud bin Abdulaziz University for Health Sciences in Riyadh, Saudi Arabia surveyed 475 individuals, with the questions revolving around two key themes: public perception towards antibiotics and their use, and the accessibility of antibiotics to the population. The results were disconcerting: almost half of the participants used antibiotics without a physicianâ&#x20AC;&#x2122;s consultation or prescription. Compounding this, over a

third of those surveyed reported a belief that antibiotics could be used to treat viral diseasesâ&#x20AC;&#x201D;conditions in which they have no efficacy whatsoever. Other findings included a high propensity towards sharing antibiotics and stopping a treatment course before its completion. The study authors urge stricter control of antibiotics, such as registering them as controlled medications and requiring their provision logged and monitored via a national registry. Additionally, a large-scale education campaign is recommended, targeted at prescribers and the public, to warn against self-diagnosis and medication. Bin Nafisah, S., Bin Nafisa, S., Alamery, A.H., Alhumaid M.A., et al. Over-the-counter antibiotics in Saudi Arabia, an urgent call for policy makers. J Infect Public

Health (2017).

Hepatitis C: Transforming treatment for tricky genotypes

A hepatitis C genotype prevalent in the Middle East can be treated by combining existing drugs with a new antiviral. S TOC K T R EK I M AG ES , I N C . / A L A M Y S TOCK P HOTO

n international team of scientists, including KAIMRC’s Faisal Sanai, have had encouraging results using a new combination of antivirals on patients with a hepatitis C virus genotype common in the Middle East. Their results suggest that the combination therapy is highly effective, especially if the infection is caught in the early stages. The development of new antiviral drugs to treat the hepatitis C virus (HCV) has transformed our ability to tackle the disease, but there is scope for improvement. One challenge is to create fast-acting treatments, reducing discomfort for patients and limiting costs. HCV is a leading cause of liver disease and, if left untreated, can lead to liver cancer and cirrhosis. The virus is categorised into seven genotypes, each responding to treatment with varying degrees of success. Genotype 4 is most prevalent in the Middle East, where it accounts for 80 per cent of cases. However, it is notoriously difficult to treat, requiring a 48-week treatment regimen using peg-interferon α and ribavirin (known together as PR), with only a moderate success rate. The development of drugs called ‘direct-acting antivirals’, or DAAs, used in combination with PR, has enabled scientists to target the virus more efficiently than ever before. However, the cost of DAAs limits availability to patients, particularly in resource-poor places. The research team trialled a combination treatment of a DAA, called simeprevir, and PR on 67 patients with HCV genotype 41 who had never received treatment. All patients had mild to moderate fibrosis: thickening and scarring of liver tissues. Those who responded well to the treatment within the first two weeks, and

An international study involving KAIMRC has trialled a combination therapy that shows promise in curing early-stage hepatitis C virus (genotype 4).

who showed undetectable levels of HCV RNA by week eight, were eligible for cessation of treatment at week 12. All others continued treatment until week 24.

“[Such] regimens may broaden the range of patients able to access effective treatment.” Of the 67 patients treated, 34 received the 12-week treatment, and all of these patients had undetectable HCV RNA at the end of the course. Further, 97 per cent of the group continued to be clear of the virus three months later. “[Such] regimens may broaden the

range of patients able to access effective treatment … [and] decreasing treatment duration is very appealing to patients and physicians,” state the authors in their paper published in PLOS One, which reports only on the results of the 12-week regimen. “The cost-effectiveness of early treatment is well-established, particularly [considering] the risks of transmission and [disease] complications.” Asselah, T., Moreno, C., Sarrazin, C., Gschwantler, M.,

Foster, G.R. et al. Efficacy of a 12-week simeprevir plus

peginterferon/ribavirin (PR) regimen in treatment-naïve patients with hepatitis C virus (HCV) genotype 4 (GT4)

infection and mild-to -moderate fibrosis displaying early on-treatment virologic response. PLOS One 12(1): e0168713 (2017).

Issue No.3

MERS virus evades immune responses

A single surface protein helps the Middle East respiratory syndrome coronavirus (MERS-CoV) survive by inhibiting the immune system.

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Middle East respiratory syndrome proliferates in humans by stifling the immune system’s response against it.

Issue No.3

S TOC K T R EK I M AG ES / G ET T Y I M AG ES

team of scientists from Saudi substances. The spike protein/DPP4 interArabia and Greece investiaction prevents this from happening. gated how MERS-CoV infects In their study, the team produced a a host organism and found a mock virus that presented just the spike mechanism with which the deadly virus protein on its surface, to exclude the possuppresses white blood cell responses. sibility that other interactions contribMERS-CoV was first identified in uted to the resistance of the MERS-CoV. humans as recently as 2012 and has They then evaluated the effects of the infected more than 1,900 people, killing MERS-CoV spike protein’s interaction over a third of them, as of March 2017. with the DPP4 of isolated immune cells. The disease caused by the virus instigates As well as its role in the survival of MERSsevere respiratory tract infection, shock CoV, the DPP4 receptor is also a target for and multiple organ therapeutics research, failure. “Our findings provide a s a y s A l - Q a h t a n i . The group, spear“DPP4 is well known potential mechanism headed by King Faisal for its function in Specialist Hospital to explain why MERS- immune cells and DPP4 and Research Center inhibitors are used as infected individuals immunologist Ahmed anti-diabetic drugs.” Al-Qahtani, found fail to eliminate the Al-Qahtani’s team that the viral-surface hopes their discovery virus as they may do ‘spike’ protein induces will, one day, provide with other respiratory a significant benefit the suppression of the infected host’s to patients infected viruses” immune system. It with MERS-CoV. “Our does this by binding to a specific recepfindings provide a potential mechanism to tor, named DPP4, on the surface of macexplain why MERS-infected individuals rophages — a type of white blood cell that fail to eliminate the virus as they may do eliminates pathogens by engulfing and with other respiratory viruses, and sugdigesting them. The DPP4 receptor is also gest a potential treatment to boost immune present on the cells lining the respiratory responses and anti-viral responses in tract. The binding of the virus’s spike proinfected patients,” Al-Qahtani says. tein to these receptors enables the virus to adhere to and invade cells, greatly helping Al-Qahtani, A.A., Lyroni, K., Aznaourova, M., Tseliou, infection of the host. M., Al-Anazi, M. et al. Middle East respiratory synMacrophages would usually respond to drome corona virus spike glycoprotein suppresses the foreign particles by releasing pro-inmacrophage responses via DPP4-mediated inducflammatory signaling molecules that tion of IRAK-M and PPARγ. Oncotarget 8: 9053-9066 kick-start the body’s reaction to infectious (2017).

2 0 1 7 S HI H-CHAO L I N & TON Y WA N G

Grapes could offer MERS treatment Initial investigations show an antiviral drug, derived from grape and cranberry plants, could also be effective against the virus that causes MERS.

There is an urgent need to find therapies to curb the rising threat of infection from Middle East respiratory syndrome coronavirus (MERS-CoV). Researchers in the US and Asia have shown that an existing antiviral drug, resveratrol, may be a potent anti-MERS agent. “It is crucial that we soon find a vaccine or antiviral drug effective against MERSCoV infection, especially considering the mortality rate is as high as 35%,” says Tony Wang of the American nonprofit research institute SRI International, who worked on the project with scientists in China and Taiwan. MERS-CoV is believed to have originated from camels and was first identified in Saudi Arabia in 2012. As of December 2016, the pathogen had killed 652 people out of 1842 confirmed cases. The infection manifests as an acute respiratory illness, with symptoms including fever, cough and severe breathlessness, and the virus has recently been shown to predominately attack the lungs and lower respiratory tract. “Resveratrol is a natural derivative found in plants, including grape and 62

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MERS-CoV infected cell cultures; cell nuclei (blue) surrounded by MERS-CoV N protein (red).

cranberry,” says Wang. “It is effective against many conditions, including reducing tumour growth in cancers and limiting inflammation across the body. It has also shown considerable promise in tackling viral infections including respiratory conditions, which is why we selected to trial resveratrol against MERS-CoV.” The team infected cultured cells with MERS-CoV before treating them with different concentrations of the drug. After 48 hours, they imaged and analysed each cell culture to determine resveratrol’s ability to reduce cell death from MERS-CoV and limit viral cell expression and proliferation. The drug proved to be highly effective against MERS in infected cells, and showed limited toxicity to healthy cells

even in high concentrations. In any case, notes Wang, the toxicity of resveratrol is negligible in the face of MERS-CoV’s toxicity. The exact mechanisms inherent in resveratrol’s activity against MERS are not yet clear, but it appears to promote cell survival and limit cellular damage in the face of infection. “Our next step is to conduct trials [inside a living organism]…, possibly using humanised mouse models,” says Wang. “We are encouraged by these initial findings and hope they lead to a novel therapy for tackling MERS-CoV.” Lin, S-C., Ho, C-T., Chuo, W-H., Li, S., Wang, T.T., & Lin, C. Effective inhibition of MERS-CoV infection by

resveratrol. BMC Infectious Diseases 17:144 (2017).

Hope for restoring immune defenses in hepatitis The World Health Organization estimates that chronic hepatitis B (CHB) affects around 240 million people, putting them at high risk of cirrhosis and cancer of the liver. New treatment options for the infection may emerge from research into components of the immune system that become impaired and unable to target persistently infected cells. Carlo Ferrari and colleagues at the University of Parma, with co-workers elsewhere in Italy, focused on the problem of specific immune system cells called CD8 T cells that become ‘exhausted’ in the chronic form of the disease. “We are looking for strategies to correct this problem,” says Ferrari. He said existing therapeutic approaches are limited and cause side effects. The researchers began with a widespread analysis of the activity of all the genes in virus-specific T cells isolated from patients with CHB. They looked for changes that might explain why the patients’ immunity against the virus had become impaired. This helped them

Computer-generated image of the hepatitis B virus outer shell structure.

identify an extensive decreased expression of genes in mitochondria—cellular organelles that supply cells with energy.

This crucial insight in studies using isolated cells leads to the hope that antioxidant therapy may prove useful as a treatment. “Having identified these mitochondrial alterations, we looked for specific strategies to correct them,” says Ferrari. A promising option came in the form of antioxidant molecules that counteract ‘reactive oxygen species’, which can cause chemical damage that impairs the activity of genes and other cellular components. Treating the T cells with two promising antioxidants brought about a marked recovery in the cells’ antiviral activity. This crucial insight in studies using isolated cells leads to the hope that

antioxidant therapy may prove useful as a treatment. There are a variety of possible antioxidants to consider, focusing on those that best target mitochondria. There is also a long road of exploration and testing to travel before a possibility identified in isolated cells can lead to a safe and effective therapy in patients. The first steps generally involve moving on to animal trials, which the researchers are considering to undertake using a virus similar to hepatitis B that infects woodchucks. These animals are not an ideal model for human hepatitis B virus, so Ferrari suggests that the team may perhaps also move directly to human trials. “This may be the most logical next step, since antioxidants targeting mitochondria have already been clinically tested in other diseases,” says Ferrari. Fisicaro, P., Barili, V., Montanini, B., Acerbi, G., Ferracin, M. et al. Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific

CD8 T cells in chronic hepatitis B. Nature Medicine 23, 327–336 (2017).

Issue No.3

L AG UN A DES I G N / S P L/ G ET T Y I M AG ES

Antioxidants might reverse changes in immune cells that allow hepatitis B virus to persist.

Mixed messages on wider effects of vaccines

large-scale review of the use This finding has led some academics and of vaccines against five serimedics to question the wisdom of current ous diseases has explored DTP vaccination procedures. evidence related to their Co-author Arthur Reingold of the potential effects beyond protective benefits. “Making changes to the The results support the possibility of some additional effects other current infant and childhood than those intended. The authors immunization schedule with do not recommend any immediate changes in vaccination policy, but the DTP vaccine is unwise they do urge further studies to clarat this time.” ify whether such alterations might be advisable. Following a recommendation from the World Health Organization, the international team of researchers, led by Julian Higgins of Bristol University in the UK, reviewed published data on the use of the BCG vaccine against tuberculosis; the DTP vaccine against diphtheria, tetanus and pertussis; and the measles vaccine. The data came from 68 research papers reporting observations of 34 cohorts of children in 15 countries in Africa, Asia, North America and the Caribbean. The studies compared children given one of the three vaccines against children who were not. A key conclusion was that the BCG and measles vaccines might reduce overall mortality in young children by more than would be expected from their protective immunization effects alone. The DTP vaccine, however, may be associated with an increase in morA postage stamp with the image of vaccine pioneer Edward tality once the protective effect on Jenner recognizes the contribution to health made by vaccination programs. the targeted diseases is discounted.

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University of California, Berkeley, emphasizes that the studies included in the review were observational rather than more rigorous, randomized, double-blind, placebo-controlled trials. He suggests that such studies are difficult to interpret because there was no prior control over which children received the vaccine and which did not. He suggests that differences in factors such as nutritional status and living conditions could generate spurious findings. “It is plausible that much or all of the observed effects of DTP vaccination are attributable to such factors,” says Reingold. He adds that the current immunization schedule prevents large numbers of illnesses and deaths from the targeted diseases. Overall, Reingold concludes that “making changes to the current infant and childhood immunization schedule with the DTP vaccine is unwise at this time.” Professor Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center and Harvard Medical School, says the paper is a review of multiple prior studies of varying quality, different populations, and conflicting results. “The findings associated with DTP vaccination in this study are not convincing,” he says. Higgins, J., Soares-Weiser, K., López-López, J.,

Kakourou, A., Chaplin, K. et al. Association of

BCG, DTP, and measles containing vaccines with childhood mortality: systematic review.

British Medical Journal 355, i5170 (2016).

POSTAGE STAMP COLLECTION / AL AMY STOCK PHOTO

Vaccines against tuberculosis, diphtheria, tetanus, pertussis and measles may have effects on other aspects of health.

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