KAIMRC Innovations Issue 1 by Nature Research Custom Media

July 2016 - Issue No.1

ISSN 7901-2398

A protective coat for nanoparticles Tricking the bodyâ&#x20AC;&#x2122;s immune system for better drug delivery P. 36

NEW CHEMOTHERAPY PROMISING FOR BREAST CANCER

New chemotherapy treatment has shown promising results for locally advanced breast cancer. P. 15

SAFEGUARDING DIABETES PATIENTS IN RAMADAN

Muslims with diabetes are at risk if they fast during Ramadan without guidance. P. 31

REVERSING IMMUNE DECLINE

Targeting a certain gene could help promote healthy aging. P. 56

GENE TWEAK INDUCES STRONGER IMMUNITY

A small genetic tweak can make some vaccines more potent. P. 64

KAIMRC Centers The Custodian of the Holy Mosques King Salman bin Abdulaziz AlSaud has inaugurated the new research facilities of KAIMRC. The research buildings now extend across the country in Riyadh, Jeddah and Alahsa, bringing the research facilities to a total area of 50,000 square meters. The new state-of-the-art facilities are furnished with the most advanced equipment, enabling research into molecular imaging, stem cells, medical genomics, nanomedicine and gene therapy. They are also home to modern animal research facilities.

innovations.kaimrc.med.sa

These platforms make it possible to position KAIMRC and MNGHA as an innovative and competitive research and development institution in the Kingdom of Saudi of Arabia, capable of conducting the most advanced and novel basic, translational and clinical research.

A vision for the future ing Abdullah International Medical Research Center (KAIMRC) is witnessing the dawn of a new era with a strategy that focuses on selected diseases as priority areas for research and development (R&D). Our new roadmap will help focus KAIMRC’s resources and ensure the best possible management of this young yet thriving R&D center, which is represented by multiple branches across the Kingdom of Saudi Arabia. There is no doubt that KAIMRC has succeeded in only a few years to competitively position itself at the level of other major national biomedical research institutions. KAIMRC aims to establish a strong foothold on the path toward success with the goal of reaching the global biomedical R&D stage within a few years. The Saudi National Vision 2030, which was recently announced internationally, puts a strong emphasis on supporting and strengthening R&D and commercialization of research across the kingdom, in order to contribute to producing a national knowledgebased economy. At KAIMRC, our long-term strategy is closely aligned to that vision, and we are set to be an integral part of the country’s visionary strategy. We are regularly and continuously working to translate that strategy into a workable plan that spans the next five years. This five year strategic plan is a first step towards identifying clear goals and objectives for KAIMRC, so we can achieve tangible outcomes and optimize our resources and investments. Our aim is to develop a robust and well-defined five year strategic plan that will help transition KAIMRC into

a truly leading international biomedical and clinical research center. We are also developing a number of new international academic and industrial partnerships to ensure that we can progress further at a faster pace, and to share knowledge and expertise with other elite international R&D institutes. A cornerstone of KAIMRC’s strategy is the setup and development of a thriving medical biotechnology program as a practical approach to effectively contribute to the Saudi National Vision 2030. As part of our ambition, we want to communicate science and research widely and effectively. In an attempt to reach all our stakeholders and partners locally, regionally and internationally, we are launching this new magazine, called Innovations, which is dedicated to covering R&D activities within KAIMRC in addition to highlighting global biomedical R&D of relevance to KAIMRC’s strategic areas of focus. We hope that Innovations will represent an attractive window for potential partners as well as those interested in joining KAIMRC to learn more about our activities and to share our enthusiasm for building a vibrant biomedical and clinical research center in the Kingdom of Saudi Arabia.

Dr Ahmed Alaskar KAIMRC Executive Director

Issue No.1

TABLE OF CONTENTS

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A BIOMARKER FOR COLORECTAL CANCER

NEW ANTICANCER MOLECULE PROMISES IMPROVED THERAPY

A mutated tumour suppressor gene could provide a useful marker for the diagnosis and prognosis of bowel cancer.

HOW LONG DO WE TREAT THE CRITICALLY ILL?

Chemotherapy without side effects, or the risk of relapse, could soon be possible.

11 12

A SAFER ROUTE TO A CURE

Researchers are developing objective measures to determine whether critically ill cancer patients can benefit from intensive care.

Less toxic therapy may lead to a full recovery for many adolescent Hodgkin lymphoma patients.

MOLECULAR TOOL DETECTS EARLY-STAGE BREAST CANCER

NEW CHEMOTHERAPY PROMISING FOR BREAST CANCER

A cheap, simple test shows potential for reducing uncertainty in the diagnosis of early-stage breast cancer.

A trial for a new chemotherapy treatment has shown promising results for locally advanced breast cancer.

GENETIC VARIANTS ALTER BREAST CANCER RISK

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Genetic variants of the DNA repair protein RAD51 are associated with differential risks of breast cancer in Saudi women. 2

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ORAL CANCER IN THE ARAB WORLD

Qat and tobacco chewing have been linked to a higher incidence of oral cancer in Yemen, Sudan and Saudi Arabia.

AUTISTIC CHILDREN COULD RECEIVE TAILORED TREATMENT

DONATING BLOOD MIGHT IMPROVE DIABETES

A new method of identifying autism means the hope of earlier treatment for children.

Recent research suggests giving blood may temporarily improve insulin production and glucose tolerance.

EARLY FITNESS IMPROVES HEART ATTACK SURVIVAL Keeping fit early on can increase chances of survival from a heart attack later in life.

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THE TRUTH ABOUT FATTY ACIDS

NEW PROBE SHINES LIGHT INSIDE ARTERIES

A Dutch cohort study shows that saturated fatty acids might not be as bad as people think.

A new design of catheter probe reveals complete, detailed pictures of fat deposits inside arteries for the first time.

THE HUNT FOR DEMENTIA’S MOLECULAR TRIGGERS

SAFEGUARDING DIABETES PATIENTS IN RAMADAN

Gender differences provide molecular clues for scientists seeking better ways to treat dementia.

Millions of Muslims with diabetes are at risk if they fast during Ramadan without guidance.

UNMAKING A MUSCLE

The ‘missing links’ in a process that drives muscle wasting in heart failure patients may offer promising drug targets.

MORE MAY NOT BE BETTER FOR THE CRITICALLY ILL A diet containing lower calories may offer better chances to critically ill adults. Issue No.1

TABLE OF CONTENTS

A PROTECTIVE COAT FOR NANOPARTICLES Nanoparticles coated in a ‘don’t-eat-me’ protein can evade the body’s immune system, improving chances of successful drug delivery.

SILKWORMS’ SWEET SUCCESS Researchers are using silkworms to safely test a new preventative therapy for type II diabetes.

RECIPES FOR BETTER DRUG DELIVERY Fine-tuned nanocarriers loaded with natural products may improve targeted drug delivery and enhance anti-cancer activity. 4

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MANIPULATING METALS FOR MEDICINE A simple and robust synthetic method could help magnetic metal oxide nanoparticles reach their potential as a powerful clinical tool.

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NANO DRUG CARRIERS NOT REACHING TARGETS The targeted delivery of drug-carrying nanoparticles to solid tumours needs improvement before it can be effective in humans.

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DRUG STUDY SHINES NEW LIGHT ON RECEPTORS Identifying the binding site of an antagonist is expected to transform the treatment of diabetes and other metabolic diseases.

FANCONI ANAEMIA MAY BE UNDER-DIAGNOSED

Genetic analysis of Saudi patients with Fanconi anaemia reveals new mutations and distinct patterns of mutation that may affect diagnosis.

LATEST TECHNIQUE DELIVERS CRISPR GENE SCREENS The latest gene editing technique helps perform better large-scale screening of gene functions than conventional methods.

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UNDERSTANDING RISKS OF CONSANGUINEOUS REPRODUCTION

THE METABOLOMICS REVOLUTION

TRACKING THE EFFECTS OF THERAPEUTIC GENES

Saudi Arabia needs a strong education program on genetic risks to children born in inter-family marriages.

Understanding the bodyâ&#x20AC;&#x2122;s metabolic profile is transforming drug discovery and personalized medicine.

Targeted nanoparticles offer hope of better methods for tracking the effects of gene therapy.

STRICTLY CONFIDENTIAL Protecting confidentiality is a major priority in medical settings, crucial to the effectiveness of Saudi Arabia's newly established biobank.

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REVERSING IMMUNE DECLINE

Targeting a certain gene could help promote healthy aging. Issue No.1

TABLE OF CONTENTS

HEPATITIS B POSES LIFETIME CANCER RISK

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A PROMISING PROTEIN TARGET FOR MERS

Clearance of active hepatitis B virus from the blood does not reduce the risk of liver cancer.

A structural analysis of proteins in the Middle East Respiratory Syndrome virus reveals a promising new target for treatments.

PEPTIDE PROMISE FOR DIAGNOSTICS

FIRST MERS AUTOPSY YIELDS ‘CRITICAL INSIGHTS’

Rapid diagnosis of HIV may soon be possible thanks to a novel peptide-based diagnostic tool.

The world’s first autopsy of a patient with Middle East respiratory syndrome shows that the lungs are the infection’s main target.

GENE TWEAK INDUCES STRONGER IMMUNITY Changing the switch that turns on vaccine protein production elicits a stronger immune response against malaria and influenza in mice. 6

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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

Supporting Scientific Excellence KAIMRCâ&#x20AC;&#x2122;S Publication Office helps scientists to translate their research into high impact publication through a wide array of services: Editing support: Offers full editing services for all different types of publications conducted at academic medical centers around the country. Institutional affiliation: Makes sure that all manuscripts submitted for publication include an affiliation to NGHA. Patent Review: Helps researchers coordinate with the Office of Technology Transfer (ITTMO) to consider patent opportunities for their work. Communication: Brings the science conducted at NGHA to the wider national and international science communities.

innovations.kaimrc.med.sa

A biomarker for colorectal cancer A mutated tumour suppressor gene could provide a useful marker for the diagnosis and prognosis of bowel cancer.

n individual’s genetic make-up, including their ethnicity, determines how likely they are to develop certain diseases. A team of researchers from Saudi Arabia and India has pinpointed a mutation in a gene that may prove useful as a biomarker, indicating the presence and severity of bowel cancer. The healthy gene, called tumour suppressor gene, is responsible for protecting cells from one of the steps on the path to cancer. Genes can take a variety of different forms known as alleles. Humans have a copy of each gene (two alleles) — one from each parent — at each locus on the chromosome. The gene pairs can be identical, with two copies of the same allele, or they can be different. Such genetic diversity produces differences in inherited characteristics and can give rise to genetic propensity toward disease. Sometimes, one of the two alleles at a particular locus can be missing entirely, a phenomenon called ‘loss of heterozygosity’ (LOH). “Since LOH is a gross chromosomal mutation, it leads to a higher degree of genetic instability. For example, LOH at genes on chromosome 10 have been implicated in multiple cancers,” explains biochemist Aga Syed Sameer of King Saud bin Abdulaziz University for Health Sciences in Saudi Arabia. “We had previously analyzed the role of tumour suppressor genes in colorectal cancer, including one called PTEN found on chromosome 10. We decided to examine whether LOH at PTEN impacted on cancer progression.” 8

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Sameer’s team focused on bowel cancer in North Indian patients. They collected 223 tissue samples from patients visiting a New Delhi hospital between 2008 and 2012. They extracted DNA from each sample and searched for LOH at PTEN. They compared the results with a control group of healthy tissue samples. They found LOH at PTEN in 102 out of 223 cases. More significantly, they found PTEN LOH was significantly associated with cancer-related clinical factors such as the level of lymph node invasion and tumour growth. LOH is associated with a decrease in PTEN expression and consequently increases the chances of tumours developing. “We conducted further analysis on early and advanced stage colorectal cancer tissues and found that patients with advanced metastases were more likely to display PTEN LOH. The mutation could therefore be an invaluable biomarker for disease diagnosis and prognosis,” says Sameer. The team hopes that this research will help improve the diagnosis of bowel cancer, and Sameer himself may investigate similar cancer-related mutations within the Saudi Arabian population in the future. Ali, A., Mehdi, S.J., Hajela, K., Saluja, S.S., Mishra, P.K., et al. Allelic loss at PTEN locus leads to progression of colorectal carcinoma among North Indian patients. Biomarkers http://dx.doi.org/10.3109/13 54750X.2016.1172115 (2016)

ÂŠBRAIN LIGHT/ALAMY

Missing alleles in the tumour suppressor gene PTEN may indicate a propensity towards colorectal cancer in North Indian patients.

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Ayman Saleh is developing a new compound that has the potential to specifically target cancer cells while sparing healthy ones.

New anti-cancer molecule promises improved therapy Chemotherapy without side effects, or the risk of relapse, could soon be possible.

cientists have developed an anti-cancer agent that, in lower doses, can kill cancer cells and spare healthy ones — presenting a favourable therapeutic scenario in which relapse is unlikely. Cancer accelerates cell division and disrupts their ability to become more specialized; a process called differentiation. An ideal chemotherapeutic drug will stop proliferation of cancer cells and promote cell differentiation. Chemotherapy is a widely used option, but drug resistance is common and the treatment can be toxic to normal tissues. Pharmaceutical chemists are trying to find potent, resistance-free and safe drugs to treat cancer. This is what G-11, a new compound proposed by Ayman Saleh, lead author of two new papers on the subject is promising. The G11 molecule targets cells that develop a mutation in the FLT3 receptor, which is important for cell propagation and

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proliferation. The mutant is most common in acute myeloid leukaemia1, which represents approximately 90% of all acute leukaemias in adults. Chemotherapy is initially effective, but relapse is common and long-term survival rates are below 20%. “If the cancer is smart, once [a chemotherapeutic] drug targets a pathway, the cancer will find a new way to propagate. A few resistant cells will be left behind, they will flourish and become more vicious,” says molecular biologist Saleh from King Saud bin Abdulaziz University for Health Sciences. “Our drug, however, can target both existing and potential pathways, preventing relapse.” “What we’re doing here is developing a superior weapon; an air fighter that would minimize collateral damage by diving inside an enemy cell and killing its organelles,” he says. Organelles are the complex cell structures enclosed within lipid membranes inside a cell. These membranes carry the

1. Saleh, A. M., Taha, O. M., Aziz, M. A., Al-Qudah, M. A., AbuTayeh, R. F. et al. Novel anticancer compound [trifluoromethyl-substituted pyrazole N-nucleoside] inhibits FLT3 activity to induce differentiation in acute myeloid leukemia cells. Cancer Letters. http:// dx.doi. org/10.1016/j.canlet.2016.02.028 (2016) 2. Saleh, A. M., Aziz, M. A., Abdou, I. M., Taha, O. M., AlQudah, M. A. et al. Cytotoxic activity of the novel heterocyclic compound G-11 is primarily mediated through intrinsic apoptotic pathway. Apoptosis http://dx.doi. org/10.1007/s10495-016-1248-z (2016)

genetic material and nucleolus. Their fuel comes from the mitochondria, another organelle that functions as the cell’s powerhouse, providing energy for all cellular activities, including growth and division. G-11 precisely targets the mutated receptor FLT3 in a cancer cell, shutting down its power supply. By disrupting mitochondrial functions, Saleh’s anti-cancer molecule destroys a cell from the inside while keeping the outer shell of the cell intact. How the cell dies makes all the difference. In necrosis, a form of premature cell death, the cell bursts, contaminating healthy cells with its contents and triggering an aggressive immune response, ultimately leading to organ damage. Many available cancer drugs can cause cell necrosis. By keeping the outer membrane of the cell unscathed in death, G-11 causes apoptosis2, which is “the dignified way to die” from a cellular perspective, says Saleh. Apoptosis doesn’t have side effects. G-11 not only inhibits FLT3 expression, but also promotes cell differentiation of blood cancer cells into mature cells1 – cells that are no longer able to divide. The compound was checked against a broad spectrum of cancers and proved effective1. It was more toxic to cancer cells than normal cells. Killing normal cells would require triple the G-11 dose that kills cancer cells. Saleh tested the compound on acute myeloid leukaemia blood samples. The promising results are “encouraging us to start the next step, which is investigating the compound in a leukaemia animal model to potentially qualify the compound to be tested on humans,” he says.

Doctors often admit critically ill patients to intensive care for a limited time to test how well they might respond to treatment.

How long do we treat the critically ill? Researchers are developing objective measures to determine whether critically ill cancer patients can benefit from intensive care.

hysicians often struggle when deciding about the appropriateness of exposing critically ill patients to intensive care; particularly in the case of cancer patients given poor prognoses who they feel might not gain substantive benefits by doing so. Doctors sometimes admit patients to the intensive care unit (ICU) for a limited time period to test whether they will benefit from the treatment. Until now, however, the optimal amount of time for an ICU trial has not been objectively determined. Researchers at Harvard University in Boston, Massachusetts and King Abdullah International Medical Research Center in Riyadh set out to determine whether time-limited trials of aggressive

ICU treatment for cancer patients could provide comparable patient survival to unlimited care, and if so, what the optimal length would be. The team constructed a computer-based model using data from 920 critically ill patients admitted to a hospital in Boston, Massachusetts. The model simulates the clinical problem, gives scores to patients based on how well their organs are functioning, and calculates the probability of dying, improving, deteriorating or of discharge from ICU. The results were compared by using the model on data from three other sets of patients, 624 in total, in Boston and Riyadh. The team found that critically ill cancer patients whose acute condition was less

severe benefited most from longer trials of intensive care. Trials as short as one to four days were sufficient for patients with poor-prognosis solid tumors such as mesothelioma, glioblastoma, pancreatic cancer, and small-cell lung cancer. “In cancer patients with poor prognoses, ICU physicians have to balance aggressive treatment with comfort measures,” says the study’s primary investigator, Mark Shrime, from Harvard Medical School in Boston. “Based mostly on expert opinion, physicians have often chosen to treat for 48 to 72 hours to help determine a patient’s responsiveness to ICU care, but there has been little research to determine whether that is enough time,” he says. “Studies at the end of life to provide evidence-based recommendations can be performed, as we have demonstrated, instead of relying on expert opinion alone,” says Shrime. shrime, m., ferket, b., scott, d., joon, l., & lai, p., et al. Time-limited trials of intensive care for critically ill patients with cancer: How long is long enough? jama oncol. http://dx. doi:10.1001/jamaoncol.2015.3336 (2016).

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A safer route to a cure Clinical data suggests many adolescent Hodgkin lymphoma patients can achieve full recovery with a less toxic course of therapy.

he odds are good that patients with low-risk Hodgkin lymphoma will conquer their cancer, but some treatment regimens may cause excessive toxicity. After closely examining clinical data on treatment outcomes, Ali Algiraigri at King Abdulaziz University Hospital and Mohammed Essa at King Abdullah Specialist Children Hospital in Saudi Arabia have concluded that it may be possible to minimize the risk of such harms while still maintaining a high cure rate. Hodgkin lymphoma is a cancer affecting white blood cells that is especially common in young adults. Data from Cancer Research UK indicates 66,000 new cases are diagnosed with the disease annually in the world. Many patients with early-stage disease receive a combination of chemotherapy and radiotherapy. The necessity of the latter remains the subject of considerable debate among clinicians because of the high risk of subsequent complications years down the line. This is particularly concerning because many patients are adolescents, with their whole lives ahead of them. Algiraigri and Essa sought to clarify whether doctors could pursue less aggressive treatments in these patients without compromising patients’ odds for a full recovery. They analyzed published clinical trials in which adolescent patients received multiple rounds of various chemotherapy combinations, either with or without radi-

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ation therapy. “There are lots of regimens around the world to treat these patients,” says Essa. “In the end, the outcome is almost the same but with a different safety profile for each regimen and different complications.” Their analysis showed that certain chemotherapy combinations with relatively mild side effects were sufficient to fully eradicate Hodgkin lymphoma on their own. Outcomes could be further improved by using results from positron-emission tomography (PET) to determine whether there is residual cancer that may require further treatment with radiation. In one key trial, this approach meant that three-quarters of patients could forego radiation therapy. Essa notes that many experts in the field already avoid prescribing radiotherapy for their adolescent patients whenever possible, and that there are several on-going trials that aim to provide even more decisive support for this approach. “Avoiding radiotherapy will probably decrease certain

long-term side effects such as secondary malignancy and early cardiac disease,” says Essa. Importantly, there are also several highly effective treatment options for use in case of recurrence, some of which might potentially be applied to further bolster chemo-

therapy efficacy. “The oncology field moves so fast,” says Essa. “Targeted therapies, like the drug brentuximab which is an important agent for post-relapse treatment, are now being tested as first-line therapies.” With more options at hand, it may not be long until radiation is only a last resort for early- and intermediate-stage Hodgkin lymphoma patients. algiraigri, a.h. & essa, m.f. Management of adolescent low-risk classical hodgkin lymphoma: Which chemotherapy backbone gives the best chance of omitting radiotherapy safely. j adolesc young adult oncol. dx.doi. org/10.1089/jayao.2015.0038 (2016).

Radiation therapy for Hodgkin lymphoma in adolescents may sometimes cause unnecessary and toxic side effects.

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Molecular tool detects early-stage breast cancer A cheap, simple test shows potential for reducing uncertainty in the diagnosis of earlystage breast cancer.

new molecular test that distinguishes between gene fragments may serve as a reliable marker of early-stage breast cancer. Developed by a team of researchers from Saudi Arabia and the US, the test focuses on the Lamin A/C gene, which is associated with several kinds of cancer, as well as other diseases. When the gene is expressed, it is processed into one of five variants, similar to how a LEGO® set can be assembled into either a car or a plane. “The methods available now can’t distinguish between the variants, so they can’t reveal each variant’s biological effect or expression in different types of tissues,” explains biochemist Ahmad Aljada from KAIMRC. The new method is based on a standard molecular biology technique, called polymerase chain reaction (PCR), which makes multiple copies of DNA fragments. Aljada’s team carefully designed four pairs of “primers” – short DNA fragments that are complementary to the DNA being copied – together with helper molecules that increase their specificity. These tools helped detect and distinguish the four variants found in breast tissue. 14

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Scientists at KAIMRC may have found a new method to diagnose early-stage breast cancer.

Aljada’s team used the new technique to uncover differences in the concentration of the four variants in 47 different normal tissues and organs, though the biological significance of these differences remains a mystery. “We see that these variants have different functions and effects, but it’s going to take some time to really understand their impact on different cells and different pathways,” says Aljada. The team also measured the four variants’ concentration in 128 samples from breast cancer patients. They found that breast tumours had higher levels of one variant, Lamin C, and lower levels of another, Lamin A. The change in ratio between the two variants serves as a reliable breast cancer marker, even in early-stage tumours that are difficult to diagnose with certainty using traditional approaches. “It’s a simple,

affordable test that can be conducted in any molecular diagnostics lab,” says Aljada. “Hopefully we’ll finish larger scale studies to evaluate it clinically within two years.” The change in ratio might also be useful for diagnosing other cancers, though too few samples were tested to be certain. The team is currently screening for drugs that reverse the change in ratio, as well as exploring some of the questions raised by their findings. “Is there a correlation with prognosis? Can we use it to measure the response to chemotherapy? We don’t know at this stage,” says Aljada. Aljada, A., Doria, J., Saleh, A.M., Al-Matar, S.H., AlGabbani, S., et al. Altered Lamin A/C splice variant expression as a possible diagnostic marker in breast cancer. Cellular Oncology http://dx.doi.org/10.1007/ s13402-015-0265-1 (2016)

Coloured sagittal magnetic resonance imaging (MRI) scans of a breast of a 39- year-old woman with breast cancer.

New chemotherapy promising for breast cancer A trial for a new chemotherapy treatment has shown promising results for locally advanced breast cancer.

reast cancer is the most common type in women worldwide. When confined within the breast and the lymph nodes of the armpit it is referred to as “locally advanced breast cancer” (LABC). These patients receive a combination of anti-cancer drugs before surgery to reduce the volume of the tumour and to improve chances of survival. When successful, breast conservation, rather than mastectomy, is possible. Researchers in Saudi Arabia, Kuwait, Egypt and the United Arab Emirates conducted a clinical trial of a new pre-surgery chemotherapy treatment on 80 LABC patients to test its effectiveness and safety. The trial showed promising results, even in aggressive types of LABC. In chemotherapy, a cocktail of drugs is used to attack cancer cells. However, it is hard to know which combination leads to the best results, with the lowest toxicity. In this trial, LABC patients received a 24-week treatment of the chemotherapeutic agents FEC100, cisplatin and docetaxel. Patients

whose cancer cells had a high number of human epidermal growth factor 2 (HER2) receptor proteins were also given trastuzumab, which targets these receptors. HER2-positive breast cancers tend to grow faster and are more likely to spread and recur compared to HER2-negative ones. A quarter of the patients could not complete the course because of unacceptable toxicity. But, the invasive tumour cells were completely eliminated from the breast alone of 4% of the remaining women, the armpit alone in 32%, and from both breast and armpit in another 32%. “It is an encouraging result, considering that almost half the patients in our hospital have LABC and begin chemotherapy when the tumour is relatively large,” says oncologist Omalkhair Abulkhair from Saudi Arabia’s Ministry of National Guard – Health Affairs. Around 15% of breast cancers are classified as “triple negative” because they do not have oestrogen or progesterone receptors on their cell membranes and do not overexpress HER2. Triple negative

tumours are difficult to treat since most chemotherapies target these receptors specifically. Moreover, triple negative cancers tend to occur more often in younger women and grow more quickly than other types of breast cancer. The trial achieved good results with these more aggressive types of cancers: 36% of the triple-negative breast cancers were eradicated, as well as 62% of the HER2-positive, hormone receptor–negative group. However, “further studies are needed to improve the response of HER2-negative, hormone receptor-positive patients and to evaluate the efficacy of a shorter therapy,” says Abulkhair. AL-Tweigeri, T., AlSayed, A., Alawadi, S., Ibrahim, M., Ashour, W. A multicenter prospective phase II trial of neoadjuvant epirubicin, cyclophosphamide, and 5-fluorouracil (FEC100) followed by cisplatin-docetaxel with or without trastuzumab in locally advanced breast cancer. Cancer Chemotherapy and Pharmacology http://dx.doi.org/10.1007/s00280015-2906-5 (2016).

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Genetic variants alter breast cancer risk Genetic variants of the DNA repair protein RAD51 are associated with differential risks of breast cancer in Saudi women.

ariations in a crucial DNA repair gene can alter the risk of breast cancer in Saudi women, according to new research. The findings add weight to studies of other populations and could help identify patients at high risk of the disease. Cumulative DNA damage can disrupt cell growth and division, leading to cancer. DNA repair mechanisms usually suppress cancer, but can be faulty. RAD51 is an essential component of a protein com-

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plex that repairs DNA. Its levels are low in some women with breast cancer. The same repair complex also includes other proteins associated with breast cancer, so RAD51 has been proposed as a significant protein in protecting against the disease. Genes can vary between individuals owing to changes in single letters of the DNA code, known as single nucleotide polymorphisms (SNPs). These SNPs in the gene that encodes RAD51 might be expected to alter the risk of developing breast cancer, given its proposed role in suppressing the disease. Several studies have assessed the effects of genetic alterations in RAD51 on this risk, but different results have been found in different populations. Biochemist Arjumand Warsy from King Saud University in Saudi Arabia and colleagues from other institutions in the kingdom investigated the effect of RAD51 variants on the risk of breast cancer in Saudi women, a population in which this association has not been previously studied. The researchers sequenced the gene that encodes RAD51 in healthy women and in women with breast cancer. They compared the variation in genotype at

three specific sites. At each of these sites, women had either a ‘normal’ genotype or one of two variants. Genetic variation at one of the specific sites made no difference to the risk of breast cancer; a result in line with findings in US and Polish populations but contradicts analyses that showed SNPs at this site increase the overall risk of cancer. At the other two sites, the ‘normal’ sequence was associated with a higher risk of breast cancer and the variants protected against the disease. The results indicate a relationship between genetic variation in RAD51 and the risk of breast cancer in Saudi women. The variants associated with a lower risk of breast cancer are thought to facilitate the production of RAD51, thus promoting DNA repair. This mechanism could explain the protective effect of the variants, but needs to be confirmed in future studies.

"The findings suggest a relationship between genetic variation in RAD51 and the risk of breast cancer in Saudi women. The variants associated with a lower risk of breast cancer are thought to facilitate the production of RAD51, thus promoting DNA repair, which could explain their protective effect."

Tulbah, S., Alabdulkarim, H., Alanazi, M., Parine, N. R., Shaik, J. et al. Polymorphisms in RAD51 and their relation with breast cancer in Saudi females. Oncotargets and Therapy http://dx.doi.org/10.2147/OTT. S93343 (2016).

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Faulty DNA repair mechanisms can lead to accumulation of DNA damage that causes cancer.

Yemenis commonly chew qat leaves, a practice that is thought to be leading to higher incidences of oral cancer in the country.

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Oral cancer in the Arab World Qat and tobacco chewing have been linked to a higher incidence of oral cancer in Yemen, Sudan and southern Saudi Arabia than in other Arab countries.

©OSCAR ELIAS / ALAMY

n analytical review of 19 research studies has revealed high rates of oral cancer in some Arab countries, possibly due to widespread tobacco chewing. But, a lack of national cancer registries and population-based studies means the true prevalence of this disease in the region is unknown. The review, conducted by epidemiologist Ashraf El-Metwally and colleagues from King Saud bin Abdulaziz University for Health Sciences in Riyadh, found the incidences of oral cancer in Yemen and southern Saudi Arabia were possibly among the highest in the Arab world. Oral cancer is diagnosed in people younger than 40 in these two regions and could be related to widespread chewing of qat leaves and tobacco. The exact prevalence of oral cancer in the Arab world appears to range from 0.5 per

100,000 people in Syria to 10 per 100,000 in southern Saudi Arabia and Yemen, according to studies. Very high rates of oral cancer are also seen in Sudan, where a snuff known as Toombac dipping is widely used and a habit for 34% of oral cancer patients. In Jordan, narghile, or water-pipe smoking, is popular. Both practices are significantly associated with oral cancer diagnoses in individuals averaging 45 years. Elsewhere in the world, oral cancer is usually diagnosed in people over 50.

"One of the most significant issues is that oral cancers are not caught early enough when they are more treatable." Oral cancer is the eighth most commonly diagnosed cancer worldwide, with an incidence of more than 300,000 new cases annually. In Sudan, however, it is the fifth most common type of cancer. “While men account for a higher percentage of oral cancer cases in the Arab world, we are seeing an increase in this

disease in women in the southwest areas of Saudi Arabia,” says El-Metwally. The research review found that squamous cell carcinoma was the most frequently detected kind of oral cancer in the Arab world and that it is frequently diagnosed in its late stages. “One of the most significant issues is that oral cancers are not caught early enough when they are more treatable. This occurs in areas in which patients do not have regular access to dental care,” says El-Metwally. In Saudi Arabia, oral cancer recurs in 56% of patients during the five-year period following initial diagnosis and treatment. El-Metwally says there is a pressing need to educate people about risk factors for oral cancer, such as smoking, qat and tobacco chewing, spicy food, and alcohol. It is also important that people have regular dental check-ups, which can help in the early detection of the disease, potentially increasing the five-year-survival rate to 60% for patients with early-stage tumours, compared to 20% in advanced disease. al-jaber, a., al-nasser, l., el-metwally, a. Epidemiology of oral cancer in Arab countries. saudi medical journal. doi: 10.15537/smj.2016.3.11388 (2016).

Issue No.1

A simple screening tool can help doctors tailor the treatment of autistic children according to their individual needs.

Autistic children could receive tailored treatment A new method of identifying autism means the hope of earlier treatment for children.

simple tool used by doctors to screen parents could lead to earlier identification and intervention for children with autism. Researchers from King Abdullah International Medical Research Center have found that the autism treatment evaluation checklist (ATEC) not only identifies which children have the condition, but also helps health professionals glean how they are most affected. Their research could help give parents and carers the resources they need to help tailor treatment to the child’s needs, says KAIMRC clinical psychologist Sarah Al Shirian. 20

July 2016

Autism is a complex neurodevelopmental disorder in which a child’s ability to communicate and interact with others is impaired. Children with autism often display restrictive or repetitive behaviours and interests. The condition ranges hugely in severity from mild to acute. The ATEC is a simple, one-page test covering four key areas – known as “domains”: speech and language; sociability; sensory awareness and cognitive ability; and health and physical behaviour. Each domain has a number of questions that help build a qualitative picture of the child’s experience. For example, can the child say three meaningful words in a sen-

Al Shirian S, Al Dera, H. Descriptive characteristics of children with autism at Autism Treatment Center, KSA. Physiology & Behavior http://dx.doi.org/10.1016/j. physbeh.2015.09.001 (2015).

tence, or can they hold a meaningful conversation with peers or family? In contrast, commonly used diagnostic tools, such as the Diagnostic and Statistical Manual of Mental Disorders, do not include a focus on physical or systemic issues and are more limited in the areas that are assessed. The team used ATEC to assess 60 children between two and eight years of age who had been diagnosed with autism by specialists at the Prince Nasser Bin Abdulaziz Autism Center in Saudi Arabia. The screening tool clearly identified a range of symptoms among the children, with more than half demonstrating hyperactivity and more than 90% unable to have a meaningful conversation. It also found a range of other symptoms, with more than 60% getting “hooked” on words, or displaying what are known as “stemming” behaviours, such as head banging. Almost 60% were wetting the bed. “The key finding in our study was that health, physical and communication dysfunctions were very common among the children that were studied,” Al Shirian says. “This will have a huge impact on the quality of life of each autistic child, because both clinicians and other carers will know where to start with their medical management, education and improving social skills,” she says. “We also believe that using the ATEC will help autism centers categorize students into groups, allowing them to focus on the domains that are affected in each group.” For example, some children might need extra help understanding social cues, while others may need help with movement and speech. “When we know which domain is most affected in an autistic child, we can use this to assess the management, care and prognosis of each child individually,” says Shirian. Al Shirian says this is particularly important in Saudi Arabia, where autism is becoming more common, but is not always treated optimally.

Donating blood might improve diabetes Recent research suggests giving blood may temporarily improve insulin production and glucose tolerance.

eart attack, stroke and type II diabetes have all been shown to be less common in individuals that regularly donate blood. But, according to a new study led by researchers at King Abdullah International Medical Research Center (KAIMRC), just a single blood donation can temporarily improve a person’s insulin production and glucose tolerance. KAIMRC pathologist Anwar Borai led an international team that tested the levels of several key diabetes-related biomarkers in the blood of 42 healthy male donors. Biomarkers, including those related to glycaemic status (the level of glucose in the donor’s blood), insulin production and iron levels, were tested before donation and then one day, one week, three weeks and three months after giving blood. The results show that regular, repeated blood donation is not required to see a beneficial effect on the donor’s glucose tolerance. “The glycaemic status of the donor can be improved even after a single blood donation,” Borai says. The improvement was particularly evident three weeks after donation. By three months, most of the tested biomarkers returned to their pre-donation levels. Borai says improvements could continue if donors

Donating blood lowers the body’s iron stores, with potential health benefits.

made healthy lifestyle changes after donation. The team suspects that the improvement in glucose tolerance is linked to the levels of iron and other metals in the bloodstream. “It is well known that low iron stores may contribute to enhanced insulin sensitivity,” Borai says. Iron-containing compounds in the blood can produce damaging molecules, known as reactive oxygen species, which have been shown to interfere with insulin signalling, lowering a person’s tolerance of glucose. As Borai’s results confirm, giving blood removes some iron from the body, perhaps helping restore insulin signalling. The team next plans to repeat the study with people who have impaired glucose tolerance and full-blown type II diabetes. “Blood donation could be an alternative

way to improve glycaemic status, particularly in people with impaired glucose tolerance who are on a diet and have not started their treatment yet,” says Borai. The technique may also be used to assess how blood donation affects other areas of health, including levels of white blood cells called lymphocytes, which form part of the immune system. “I am preparing the second part of the study which is about changes in lymphocyte subsets and general immunity after whole blood donation,” Borai says. Borai, A., Livingstone, C., Farzal, A., Baljoon, D., Al Sofyani, A., et al. Changes in metabolic indices in response to whole blood donation in male subjects with normal glucose tolerance. Clinical Biochemistry dx.doi.org/10.1016/j.clinbiochem.2015.08.023 (2015)

Issue No.1

Early fitness

The researchers searched for links between exercise capacity and heart attacks later in life. 22

July 2016

Keeping fit early on can increase chances of survival from a heart attack later in life.

“The outcome for people who have a heart attack is better if they had a high level of fitness years beforehand”

large multi-ethnic study demonstrates that a history of strong exercise capacity can be beneficial even for those who eventually suffer heart health problems. It has long been known that keeping fit can reduce the risk of heart disease, but the effect of a history of fitness on what happens if you have a heart attack years later has not been well-studied. The Henry Ford Exercise Testing Project (FIT) addressed this knowledge gap by recording the fitness regime of a large sample of people, then monitoring them as they aged. Mouaz Al-Mallah, the project’s principal investigator, undertook this research with colleagues at several medical institutions in the US, where the study was based. “The outcome for people who have a heart attack is better if they had a high level of fitness years beforehand,” says cardiologist Al-Mallah of King Abdullah International Medical Research Center. Nearly 70,000 people were recruited

into the project between 1991 and 2009. They were monitored while exercising on a treadmill to determine their “exercise capacity” (EC). This measures the maximum amount of physical exercise a person can sustain. More than 2,000 participants, who at the time of the treadmill test had no history of heart problems, eventually suffered myocardial infarction: a sudden deficiency in blood supply to the heart muscle causing a heart attack. The researchers then looked back at the FIT project data in search of links between the EC levels measured earlier and the fate of patients after their heart attacks. The data clearly revealed that patients who had very high EC levels before their heart attack were 52% less likely to die in the first year after a heart attack than those who had lower EC levels. The protective effect was identified up to one year after the heart attack. “Everyone, but especially patients who are at risk for myocardial infarction, should maintain high fitness levels since it improves survival,” says Al-Mallah. He and his co-workers are now planning further studies in other similar populations. This work will also investigate if exercise training in people with existing low fitness levels can improve their chances of survival after subsequent heart attacks. shaya, g. e., al-mallah, m. h., hung, r. k., nasir, k., blumenthal, r. s. et al. High exercise capacity attenuates the risk of early mortality after a first myocardial infarction: The Henry Ford Exercise Testing (Fit) Project Mayo Clinic Proceedings http://dx.doi.org/10.1016/j. mayocp.2015.11.012 (2016).

Issue No.1

improves heart attack survival

The truth about fatty acids A Dutch cohort study shows that saturated fatty acids might not be as bad as people think.

ÂŠ PHOTOCUISINE RM / ALAMY

aturated fatty acids are widely considered a villain in heart-related diseases because they have long been blamed for raising bad cholesterol levels. Early studies have even suggested a link between saturated fatty acid intake and ischaemic heart disease, which causes reduced blood supply to the heart and kills more than seven million people worldwide each year. Yvonne van der Schouw at the Julius Center for Health Sciences and Primary Care in the Netherlands and co-workers have now put this long-held belief under scrutiny. They assessed the lifestyle, diet and physical status of 35,597 Dutch people from the European Prospective Investigation into Cancer and Nutrition study; one of the largest cohort studies ever conducted on the relationships between diet, cancer and other chronic diseases. The information for the study was obtained through general questionnaires, food-frequency questionnaires and physical examination. The team then tracked the fate of these people, with special attention paid to the number of ischaemic heart disease cases, over the course of 12 years.

July 2016

In total, Schouw and her team discovered 1,807 cases of ischaemic heart disease over the study period, of which 158 (8.7%) were fatal. After adjustment for age, gender, body mass index, education level, physical activity, smoking/alcohol consumption patterns and a host of other potentially important factors, they found that a higher intake of saturated fatty acids resulted in a 17% reduction of ischaemic heart disease risk. In contrast, the substitution of saturated fatty acids with total carbohydrates or animal proteins led to higher ischaemic heart disease risks. In particular, high-glycaemic-index carbo-

hydrates (those that raise blood glucose levels higher than others) appeared to have the largest impact. The researchers also examined how saturated fatty acids of different chain lengths and from different food sources might affect ischaemic heart disease risk. They observed slightly lower ischaemic heart disease risks in people who consumed more short-to-medium-chain saturated fatty acids and whose sources of saturated fatty acid intake were from butter, cheese, milk and dairy products. Schouw and her team are uncertain why the results from their study are so different

to those from other studies. One possibility is that their study only considered a limited range of saturated fatty acids. Perhaps, in populations that consume a wider range of saturated fatty acids, the relationships found are opposite. The researchers believe there remains much to be learned from the data. Their findings on the associations between ischaemic heart disease risk and saturated fatty acids of different carbon chain lengths will open avenues for further research.

Praagman, J., Beulens, J. W. J., Alssema, M., Zock, P. L., Wanders, A. J. et al. The association between dietary saturated fatty acids and ischaemic heart disease depends on the type and source of fatty acid in the European Prospective Investigation into Cancer and Nutritionâ&#x20AC;&#x201C;Netherlands cohort. American Journal of Clinical Nutrition http://dx.doi.org/10.3945/ajcn.115.122671 (2016).

The saturated fatty acids from milk, butter, cheese and other dairy products may lower the risk of developing ischaemic heart disease.

Issue No.1

A new probe based on photoacoustic imaging provides detailed pictures of the arterial fat deposits in cardiovascular disease. The probe could also prove useful in other biomedical imaging applications.

July 2016

New probe shines light inside arteries A new design of catheter probe reveals complete, detailed pictures of fat deposits inside arteries for the first time.

Issue No.1

ÂŠ BRAIN LIGHT / ALAMY

he accumulation of fat in arteries is a major factor in cardiovascular disease, but monitoring the composition and growth of such deposits inside the body is very difficult. Now, researchers in the US and China have created an intravascular catheter probe that produces accurate, detailed images of fat deposits inside arteries for the first time. The excessive build-up of lipids (fat molecules) and fibrous material inside artery walls is known as atherosclerosis. These deposits, called plaques, commonly have a lipid core with a fibrous outer layer, and can grow to either block the artery or rupture suddenly resulting in acute heart failure and death. The precise imaging of different stages of arterial plaques is crucial to identify those most likely to rupture. Intravascular photoacoustic (IVPA) imaging techniques show promise for this purpose. IVPA works by sending out light from a fast-pulsing laser. Tissue molecules respond to the light stimulation by emitting ultrasound signals that vary depending on their composition. These signals are then analysed to create three-di

Optical beam

Mirror

Optical fiber

Ultrasonic wave Transducer

Merged IVPA/US image of a human coronary artery

Outer boundry

Lumen

Lipid

Periadventitial fat

Precise imaging of different stages of arterial plaques is crucial to identify those most likely to rupture.

mensional images showing the location and composition of tissues inside the body. Now, Ji-Xin Cheng and co-workers at Purdue University in the US, in collaboration with scientists in China, have designed a new IVPA probe capable of imaging artery walls at an appropriate depth and speed to achieve high-resolution pictures of plaques for the first time. “We designed our probe to allow the light and sound waves to follow the same path throughout the imaging process,” says Cheng. “This ‘collinear’ design means we can see through the entire blood vessel wall, because the penetration depth is enhanced by the overlapping optical and sound waves.” In previous designs, the emitted light and resulting sound waves crossed paths, distorting the final image and misrepresenting

depth, exact plaque location and tissue composition. The accuracy and detail provided by the new probe greatly improves on previous versions, and works at fifty times the speed of existing IVPA probes. “We trialled our probe using ‘dummy’ fat deposits – namely butter and pig fat – and the clarity and detail of the picture allowed us to differentiate between them,” says Cheng. “Further imaging of pig and human arteries ex vivo [outside the body] provided detailed images of the lipid core and fibrous outer layers of plaques.”

"Further imaging of pig and human arteries ex vivo provided detailed images of the lipid core and fibrous outer layers of plaques."

July 2016

Cao, Y., Hui, J., Kole, A., Wang, P., Yu, Q. et al. High-sensitivity intravascular photoacoustic imaging of lipid-laden plaque with a collinear catheter design. Nature Scientific Reports http://dx.doi.org/10.1038/srep25236 (2016).

Collinear IVPA probe design

KAIMRC ITTMO The Custodian of the Holy Mosques King Salman bin Abdulaziz AlSaud has inaugurated the new research facilities of KAIMRC. The research buildings now extend across the country in Riyadh, Jeddah and Alahsa, bringing the research facilities to a total area of 50,000 square meters. The new state-of-the-art facilities are furnished with the most advanced equipment, enabling research into molecular imaging, stem cells, medical genomics, nanomedicine and gene therapy. They are also home to modern animal research facilities.

Women are more likely than men to develop dementia, and cases among female patients are, on average, more severe.

The hunt for dementia’s molecular triggers Gender differences provide molecular clues for scientists seeking better ways to treat dementia.

omen may be at greater risk of dementia because they are more prone to the degeneration of proteins with integral roles in communication and energy provision for the brain. Scientists, who have identified molecular clues to the basis of gender differences in the prevalence of dementia, hope the discovery will hasten the hunt for new treatments. Dementia is a general term used to describe several different diseases of the brain that cause varying symptoms, including problems with memory, language and information processing. It frequently occurs with cerebrovascular disease (CVD) such as stroke. 30

July 2016

Women are more likely than men to develop dementia, and cases among female patients are, on average, more severe. Singapore-based researchers used this gender difference to learn about the link between damage to the white matter that forms connections between brain cells and the degeneration of small blood vessels in the brains of those with dementia associated with CVD. When they assessed brain samples from deceased patients, they initially found no differences between genders in the loss of myelin, the protective sheath that surrounds nerve cell connections. In contrast to the more traditional analysis of one or two proteins at a time, the

Gallart-Palau, X., Lee, B., Adav, S., Qian, J., Sze, S. et al. Gender differences in white matter pathology and mitochondrial dysfunction in Alzheimer’s disease with cerebrovascular disease. Molecular Brain

http://dx.doi.org/10.1186/s13041-016-

0205-7 (2016).

group, led by biological scientist Siu Kwan Sze from Nanyang Technological University, used an advanced proteomic approach to measure levels of several thousand proteins at a time. Loss of cognitive functions in dementia patients has been found to be associated with accumulations of certain damaged proteins that have undergone spontaneous chemical reactions, called degenerative protein modifications (DPMs), which alter their structures and functions. Using mass spectrometry, Sze found samples from dementia sufferers exhibited greater accumulations of degenerated myelin basic protein (MBP), which is important for maintaining nerve cell connections, and of other proteins associated with brain signalling. Specifically, he found increased degenerative protein modifications called citrullination and deamidation in MBP in samples from female patients. Sze believes that in healthy people, degenerated MBP is usually degraded by a specific set of enzymes, and that reduced production of these enzymes ultimately impairs brain signalling, and causes brain cell death and dementia. When the researchers looked at proteins in the mitochondria, they found lower levels of a set of enzymes that synthesise adenosine triphosphate (ATP), the molecule that stores and transports energy, in the female samples. This is consistent with previous reports of women with cognitive disorders having impaired metabolism in the brain and suggestions of mitochondrial dysfunction. “We are the first to find these gender-specific modifications at the molecular level,” says Sze. “A better understanding of the molecular mechanisms that explain why women are more likely to get dementia could lead to the development of new diagnostic and clinical interventions.”

ÂŠ INCAMERASTOCK / ALAMY

Diabetics are advised to monitor their blood glucose levels if they insist on fasting.

Safeguarding diabetes patients in Ramadan Millions of Muslims with diabetes are at risk if they fast during Ramadan without guidance.

new review of recent research has issued crucial caveats on fasting during Ramadan for Muslims with type II diabetes. Based on the global prevalence of diabetes, an estimated 50 million Muslims around the world have the disease. During the fasting month of Ramadan, Muslims refrain from drinking, eating, using medications or smoking from dawn to dusk. The exact duration of the fast depends on geographical location and the seasons, as the Islamic calendar is a lunar one. In the summers in some countries, fasting can last up to 20 hours a day. The ill are usually exempt from the fast, according to Islamic rulings. Still, many Muslims choose to fast against the advice of doctors and religious authorities.

Researchers from King Fahad Medical City and King Saud bin Abdulaziz University for Health Science in Saudi Arabia reviewed recent studies on type II diabetes in adults. According to an Epidemiology of Diabetes and Ramadan (EPIDIAR) study done in 2004 and published in Diabetes Care, 78.7% of type II diabetes patients who fast for at least 15 days during Ramadan are 7.5 times more likely to experience low blood glucose, or hypoglycaemia, leading to hospitalization. They are also five times as likely to experience excess in blood glucose, or hyperglycaemia, after eating. The population-based EPIDIAR study examined a total of 12,243 patients across 13 countries. It found that fasting increases

the risk of both hypoglycaemia and postprandial hyperglycaemia; the latter is a rapid and high increase in blood glucose following the consumption of a large and heavy meal, typical during the breaking of the fast ritual in Ramadan. Research reveals that fasting can also lead to dehydration and blood clotting in the circulatory system. Exasperating the situation is the decision by some patients to stop taking medication altogether, skipping doses, reducing them, or taking them at closer intervals without medical advice. There is also a lack of consensus on the most effective anti-diabetic drug during Ramadan. Some studies mention dipeptidyl peptidase (DPP)-4 inhibitors, enzyme inhibitors affecting metabolic hormones that play a role in insulin secretion and blood glucose regulation. Others cite repaglinide, another agent that works by lowering blood sugar. As a result of their research review, the Saudi researchers suggest many medical professionals lack awareness of the patterns of diabetic patients during Ramadan and how to pre-emptively deal with them. They recommend some medical and lifestyle interventions to ensure patient safety during the holy month. The interventions include daily blood glucose readings and adequate nutrition. Patients should, for instance, be made aware that puncturing the skin with glucose monitoring devices will not affect their ability to fast and is allowed during the fasting hours. â&#x20AC;&#x153;All patients with diabetes who wish to fast for Ramadan should receive a proper medical assessment, educational counselling, and appropriate blood testing one to two months before Ramadan to engage in the fast as safely as possible,â&#x20AC;? write the researchers. They also endorse rigorous meal planning and individualized treatment regimens. Those who are not fit to fast should be made aware of the potential risks, they say. Almalki, M.H. et al. Options for controlling type 2 diabetes during Ramadan. Frontiers in Endocrinology. http://dx.doi.org/ 10.3389/fendo.2016.00032 (2016)

Issue No.1

Unmaking a muscle

trophy is a common consequence of both congestive heart failure and cancer, as skeletal muscle throughout the body undergoes a process of steady degeneration. Researchers have now identified a cellular mechanism associated with this deterioration, which could offer a useful drug target for preventing muscle wasting. Angiotensin II has been identified by scientists, led by Jens Fielitz at Charité Universitätsmedizin Berlin in Germany, as a specific trigger for atrophy in congestive heart failure patients. In the aftermath of cardiac damage, large quantities of this hormone are released into the bloodstream. As it circulates, it sets molecular 32

July 2016

events in motion that result in selective destruction of muscle proteins. A protein called muscle RING-finger-1 (MuRF1) is a critical link in this chain, serving as the enzyme that directly marks doomed proteins for elimination. In an effort to identify the intermediate steps in this process, Fielitz and colleagues conducted a search for proteins that can switch on the gene encoding MuRF1. This led them to a protein known as transcription factor EB (TFEB), which is produced in high levels in both skeletal and heart muscle, and binds to DNA sequences in the genome that are responsible for regulat-

The ‘missing links’ in a process that drives muscle wasting in heart failure patients may offer promising drug targets.

ing MuRF1 production. Intriguingly, TFEB has also been connected with the control of other well-known protein degradation pathways in previous research, although this study represents the first direct link between this molecule and muscle atrophy. Subsequent experiments further strengthened this association. Under normal conditions, muscle cells have inhibitory processes in place that prevent TFEB from stimulating the production of MuRF1. However, when angiotensin II is present in the bloodstream, it triggers specific cellular events that alleviate this inhibition. As a result, MuRF1 levels rise and the process of atrophy begins. Accordingly, the researchers showed that they could thwart angiotensin II-mediated atrophy in cultured muscle cells by directly reducing TFEB levels or selectively eliminating the molecules that relieve the inhibition of TFEB.

“TFEB played a key role in regulating angiotensin II-induced skeletal muscle atrophy.” The authors note that muscular atrophy is the product of many complex physiological processes, including prolonged physical inactivity in congestive heart failure patients. Nevertheless, the central role of angiotensin II is well established, and the authors see strong evidence from their experiments that “TFEB played a key role in regulating angiotensin II-induced skeletal muscle atrophy.” If these findings can be further validated in animal models, the regulatory processes that control TFEB activity might ultimately offer a worthy target for drugs aimed at slowing or reversing the muscle-wasting process. cheng, w., pullin, d. i., & samtaney, r. Angiotensin ii induces skeletal muscle atrophy by activating

The hormone angiotensin II has been identified as a specific trigger for atrophy in congestive heart failure patients.

TFEB-mediated MuRF1 expression. circ. res. http:// dx.doi.org/10.1161/CIRCRESAHA.114.305393 (2015).

Issue No.1

More may not be better for the critically ill Critically ill adults may do as well or better on fewer calories.

large international study has found that critically ill patients may benefit from receiving fewer than their standard caloric requirements. The study involved 894 patients in seven hospitals in Saudi Arabia and Canada. Critically ill, often unconscious patients hospitalized in intensive care units are commonly fed via a nasogastric tube. Nutrition is a crucial part of their care, but doctors do not universally agree about how much they need. Some studies show that patients do better on standard caloric and protein requirements, while other research indicates that critically ill patients may benefit from a reduced regimen of calories. 34

July 2016

Researchers randomly allocated patients to a doctor-prescribed-underfed group (called permissive underfeeding) or a standard-feeding group, which determined whether they received 40 to 60% or 70 to 100% of their estimated standard caloric requirements. The underfed group received additional protein so that both groups had similar protein intake. After 90 days, the team found that the mortality rates for the groups were similar: 27.2% in the underfed group and 28.9% in the standard-feeding group. “One important difference was that patients in the permissive-underfeeding group had lower glucose levels and re-

quired less insulin, which is consistent with other studies,” says Yaseen Arabi, chairman of the intensive care department at King Saud bin Abdulaziz University for Health Sciences in Riyadh, Saudi Arabia. Another finding was that dialysis, needed often in critically ill patients, was needed less frequently in the permissive-underfeeding group, he says. This supports the idea that higher caloric intake and higher blood sugar levels found in critically ill patients may be connected to kidney injury, Arabi and colleagues noted. “Our study opens the door to examine ways to optimize nutritional support during critical illness and provides evidence that, for these patients, more is not better when it comes to calories,” Arabi says. For his next study, Arabi will study the optimal caloric needs for patients in the first few days of critical care. Arabi, Y., Aldawood A., Haddad S., Al-Dorzi H., Tamim H., et al. Permissive underfeeding or standard enteral feeding in critically ill adults. The New England Journal of Medicine. dx.doi.org/10.1056/ nejmoa1502826 (2016).

Doctors do not universally agree on the optimal caloric needs of critically ill patients in intensive care.

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innovations.kaimrc.med.sa

A protective coat for nanoparticles Nanoparticles coated in a ‘don’t-eat-me’ protein can evade the body’s immune system, improving chances of successful drug delivery.

hen nanoparticles are used to deliver drugs to specific parts of the body, they must avoid being mistaken for foreign pathogens by the immune system, which will attack and destroy them. This is a significant hurdle to overcome. Researchers in the US are working to better understand the body’s cellular defences and design nanoparticles that can evade them. The immune system relies on groups of white blood cells called macrophages, which seek out and consume any foreign invaders and diseased tissues that 36

July 2016

“We observed enhanced nanoparticle uptake by activated macrophages [compared to their inactivated counterparts].”

do not have the correct healthy proteins displayed on their surfaces. Macrophages form different sub-populations, or phenotypes, and each phenotype plays a distinctive role in protecting the body. Betty Kim and co-workers at the Mayo Clinic in the US recently published results of a study trialling nanoparticles that carry a special cancer-cell-derived ‘don’t-eatme’ protein on their surface to help them evade macrophage phenotypes. The researchers divided the macrophage phenotypes into two broad categories; M1 macrophages — pro-inflammatory cells

The researchers replicated previous findings in which coated nanoparticles, particularly smaller ones, were partly protected from macrophage activity. They then decided to trial a method of modifying the nanoparticles’ surface by adding a ‘don’t-eat-me’ protein, called CD47, used by cancer cells to evade macrophages. CD47 works by binding to another protein on the macrophage surface, blocking its destructive activity. “We observed a large inhibition of uptake by M1 macrophages, suggesting that CD47 signalling appears to play a greater role in regulating M1 compared to M2,” write the researchers. The CD47 coating protected the larger nanoparticles significantly better than the long-chain polymers did. The team hope their insights will help scientists improve nanoparticle treatments for many different diseases. Qie, Y., Yuan, H., von Roemeling, C.A., Chen, Y., Liu, X., et al. Surface modification of nanoparticles enables selective evasion of phagocytic clearance by distinct macrophage phenotypes. Scientific Reports http:// dx.doi.org/10.1038/srep26269 (2016)

Issue No.1

Researchers in the US have created surface-modified nanoparticles that can evade macrophages, potentially allowing more effective drug delivery.

thought to target foreign invaders — and M2 macrophages, which work to modulate the overall immune system. Kim’s team incubated nanoparticles of three different sizes in culture trays together with groups of inactivated macrophages, M1, and M2 macrophages. Some of the nanoparticles were coated in long-chain polymers, while others weren’t. “We observed enhanced nanoparticle uptake by activated macrophages [compared to their inactivated counterparts],” write the researchers. More importantly, the team discovered that M1 macrophages particularly targeted the larger particles and consumed significantly more nanoparticles of all sizes compared to M2.

Manipulating metals for medicine A simple and robust synthetic method could help magnetic metal oxide nanoparticles reach their potential as a powerful clinical tool. 38

July 2016

agnetic metal oxide nanoparticles have demonstrated considerable promise for a wide variety of biomedical applications, but researchers have struggled to identify an optimal strategy for producing them. Researchers, led by nanobiochemist Kheireddine El-Boubbou of King Abdullah International Medical Research Center, have now developed an approach for producing these particles easily, cheaply and safely. â&#x20AC;&#x153;Tailored nanoprobes of controlled sizes and compositions based on iron oxides can be used for applications such as detection, imaging and drug delivery, both in vitro [in the body] and in vivo [in the lab],â&#x20AC;? says

ÂŠ KAIMRC

El-Boubbou and his team are developing iron oxide nanoprobes that can be used in imaging and drug delivery.

homogeneous populations of iron-oxide nanoparticles. El-Boubbou and colleagues subsequently demonstrated that by modulating the ratio of fatty acid to iron salt solution, they could accurately control the size of the resulting clusters, consistently generating spherical nanoparticles with diameters ranging from two to ten nanometres.

"We will utilize these functional nanoparticles for cancer imaging and as carriers to deliver drugs." This approach proved to extend to metals other than iron—including copper, nickel and zinc—widening the potential range of applications. The researchers were also able to modulate the chemical properties of the final product. The first batch of nanoparticles produced was not

soluble in water, but by modifying their protocol slightly, they were able to generate iron oxide nanoparticles that are. These could prove more useful for applications that require the particles to function within the interior of living cells. El-Boubbou has spent much of the past decade developing magnetic nanoprobes for biomedical applications. He has already begun to test the performance of these KHB-derived nanoparticles as a clinical research tool. “We will utilize these functional nanoparticles for cancer imaging and as carriers to deliver drugs to tumours in an attempt to develop chemotherapeutic approaches,” he says. El-Boubbou, K., Al-Kaysi, R.O., Al-Muhanna, M.K., Bahhari, H.M., Al-Romaeh, A.I. et al. Ultra-small fatty acid-stabilized magnetite nanocolloids synthesized by in situ hydrolytic precipitation. Journal of Nanomaterials http://dx.doi.org/ 10.1155/2015/620672 (2015).

El-Boubbou. Unfortunately, most existing methods yield aggregation-prone nanoparticles that vary in size and shape, or require the use of costly and toxic chemicals. “The lack of simple, fast, large-scale and cost-effective preparation remains a major hurdle toward real-world biomedical applications,” he says. El-Boubbou and his colleagues devised a strategy they call Ko-precipitation hydrolytic basic (KHB). It involves combining metal-based salts dissolved in water with different fatty acids in the presence of chemicals known as alkylamines. This forms highly stable acid-coated metal oxide nanocrystals. All of the materials involved are inexpensive and readily available, and the process can be performed at much lower temperatures (80 °C) than existing techniques, which require temperatures in the range of 200 to 300 °C. Electron microscopy confirmed that the KHB method can readily produce highly

Issue No.1

Silkworms’ sweet success Silkworms could point toward a new preventative therapy for type II diabetes.

July 2016

Silkworms are being used to test the potential of anti-diabetic treatments for humans.

The team tested a group of bacteria, known as lactic acid bacteria, for their ability to inhibit the hyperglycaemic response in silkworms. One strain of bacteria in particular, Lactococcus lactis #Ll-1, had a strong inhibitory effect on the α-glycosidase enzyme, and therefore on hyperglycaemia, in the haemolymph. Matsumoto suggests that in humans, these bacteria could permanently

ifestyle diseases, such as type II diabetes, are becoming a worldwide public health crisis. Diabetes can be triggered by excessive intake of sucrose, which causes a sudden peak in blood glucose. Now, Japanese researchers are using silkworms – which process sucrose remarkably similarly to mammals – to test potential diabetes treatments. The digestive enzyme α-glycosidase breaks down sucrose into smaller molecules of glucose and fructose, which are absorbed from the gut into the bloodstream. A high sucrose diet results in high blood glucose, or hyperglycaemia, which, if left untreated, can be toxic to cells, causing diseases such as obesity and type II diabetes. Chemical inhibitors of α-glycosidase are already used as anti-diabetic agents, and certain bacteria are supposed to have similar effects. However, both types of treatment will require costly and unpopular animal testing before human clinical trials can begin. A team led by microbiologist Yasuhiko Matsumoto at the University of Tokyo in Japan has identified a potential solution. Silkworms are small enough that a large number can be reared cheaply, yet large enough to be injected easily. Like all insects, silkworms have ‘haemolymph’ instead of blood. According to Matsumoto, haemolymph “has many similar functions to blood, such as the transport of hormones and nutrients.” Silkworms show similar responses to humans when treated with antibiotics or exposed to toxins. Matsumoto bred a diabetic silkworm that can be used to test diabetes treatments. He believes this “original and unique” approach has promise and describes his team as “pioneers in the use of silkworms as an experimental animal.”

colonize the gut, producing a â&#x20AC;&#x153;lasting suppressive effect on hyperglycaemia.â&#x20AC;? Many type II diabetes patients find it hard to maintain a healthy lifestyle. The results reported by the Japanese team suggest lactic acid bacteria could be used as a supportive treatment for type II diabetes, or a preventative approach in those predisposed to the

disease. Matsumotoâ&#x20AC;&#x2122;s silkworm model provides a low-cost way of screening bacteria for this purpose. Matsumoto, Y., Ishii, M., & Sekimizu, K. An in vivo invertebrate evaluation system for identifying substances that suppress sucrose-induced postprandial hyperglycemia. Scientific Reports dx.doi.org/doi:10.1038/srep26354 (2016).

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Drug-carrying nanoparticles not reaching targets The targeted delivery of drug-carrying nanoparticles to solid tumours needs improvement before it can be effective in humans.

uch research has gone into developing carefully engineered nanoparticles to carry drugs directly to specific sites in the body, such as cancerous tumours. Now, an international team has shown that, despite many nanoparticle designs and animal trials conducted over the past decade, the delivery efficiency of nanoparticles to solid tumour targets is still too low for effective treatment in humans. Medical nanoparticles carry drugs on their surface or have a drug-filled core. They release medication in response to triggers such as light or chemical reactions. Certain artificial nanostructures show particular promise in seeking out cancer

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cells in cell cultures and mouse models. “We wanted to know why, despite exciting research over the last decade, very few nanoparticles have been used in patients,” says Warren Chan at the Donnelly Center for Cellular and Biomolecular Research at the University of Toronto. “We decided to look at the field more closely.” There are myriad obstacles to overcome as nanoparticles travel through the body, such as passing through major organs without being destroyed or avoiding the premature release of their drug cargo. As a result, the percentage of administered nanoparticles that reach their destination is far lower than the original dose. Low ‘delivery efficiency’ results in a need to

Researchers have found that the efficiency of drug delivery by nanoparticles targeting cancerous tumours is not yet high enough to be effective in humans.

increase dosage, increasing costs and the potential for toxicity. To investigate current nanoparticle delivery efficiency for cancer tumours, Chan and his team collated and analyzed data from 117 relevant research projects from the last ten years. “We were really surprised by what we uncovered,” says Chan. “We thought the average delivery efficiency would probably be low, say 5-10%, but we were astonished

to find that it was actually less than 1%.” The researchers found that the midpoint – or median – of all the collated data suggested only 0.7% of the administered dose reached solid tumours during animal trials. In response to this discovery, Chan and his team are recommending a new 30-year research strategy for perfecting medical nanoparticles. “Ultimately, we all want to see nanotechnology used in patient care,” says Chan.

“We have built an open-access database into which researchers can input and share new data. The database automatically calculates delivery efficiency and conducts other key statistical analyses. This will help us determine progress more easily.” Wilhelm, S., Tavares, A.J., Dai, Q., Ohta, S., Audet, J. et al. Analysis of nanoparticle delivery to tumours. Nature Reviews Materials http://dx.doi.org/10.1038/ natrevmats.2016.14 (2016)

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Recipes for better drug delivery Fine-tuned nanocarriers loaded with natural products may improve targeted drug delivery and enhance anti-cancer activity.

evelopment of anti-cancer treatments is often thwarted by drug resistance and drug side effects. Researchers are increasingly turning to naturally occurring products to help overcome these challenges. Beta-glucans, sugars found in the cell walls of fungi, yeasts, bacteria and cereals, are of particular interest to cancer researchers, as they are known to activate innate immune responses. A joint study between researchers in Saudi Arabia and Canada has shown that beta-glucans encapsulated into tailor-made “liposomes” — tiny spheres composed of lipids and cholesterol — can be used as an adjunct approach to fight cancer. “Natural products have been gaining attention due to their ability to act as modulators and enhancers for several anti-cancer drugs,” says KAIMRC biomolecular scientist Majed Halwani. “Our liposomal beta-glucan formulations were designed to help reduce

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the adverse effects of doxorubicin — a key drug effective against many types of cancer — and enhance its activity.” By preparing a series of liposomal “recipes” with different lipid-to-cholesterol ratios, the team achieved higher encapsulation efficiency of mushroom-derived beta-glucan as well as higher stability under varying biological conditions. The researchers observed that their formulations with a relatively high amount of cholesterol remained stable in plasma at both four and 37 degrees Celsius.

Beta glucans can be found in the cell walls of the field mushroom.

Three of the liposomal formulations containing the highest amount of beta-glucans were shown to be particularly effective in suppressing human lung cancer epithelial cells. “Combining different phospholipids to form the liposomal vesicles that are able to carry beta-glucan and/or doxorubicin individually or together at the same time is not straightforward,” says Halwani. “We're now collecting new data about this.” “As a first stage, we were interested in presenting formulations that have lower nanometre particle sizes to ensure that they are

suitable for pharmaceutical applications and transportable within the bloodstream.” The next step for the research team will be to examine the effects of the formulations on animal models and conduct other laboratory studies, with the long-term goal of performing human clinical trials. Halwani, M., Hossain, Z., Khiyami, M. A., & Omri, A. Liposomal β-glucan: Preparation, characterization and anticancer activities. Journal of Nanomedicine & Nanotechnology http://dx.doi.org/10.4172/2157-7439.1000319 (2015).

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Drug study shines new light on receptors Identifying the binding site of an antagonist is expected to transform the treatment of diabetes and other metabolic diseases.

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The antagonist MK0893- (shown as colourful balls) binds onto the ribbon-shaped proteins of the glucagon receptor’s outer surface.

The researchers discovered that MK0893 bound to a different site from the natural glucagon position on the receptor. According to Marshall, the structure suggests that the antagonist blocks the glucagon-mediated receptor activation by

"Solving the X-ray structure of a protein allows you to see its exact 3-D shape and this can be used to conceive drugs that fit perfectly into the pocket on the receptor." preventing the changes in receptor shape that usually occur when glucagon binds to it. “This is a new mechanism for this family of receptors,” she adds. Furthermore, contrary to the team’s assumptions, the antagonist attached to

the outside of the receptor instead of its inner core. This implies that the molecule reaches its binding site by passing through the lipid membrane that surrounds the cell and houses the receptor proteins. “This is in contrast to most drugs, which enter the receptor cavity directly from outside the cell,” Marshall says. Marshall’s team is currently working on a rare disease called congenital hyperinsulinaemia that results in uncontrolled high levels of insulin, leading to extremely low blood glucose levels. She says that, using structural information, the researchers are working on drugs that target this disease by thwarting the signalling of the related receptor. Jazayeri, A., Doré, A. S., Lamb, D., Krishnamurthy, H., Stacey M. Southall, S. M. et al. Extra-helical binding site of a glucagon receptor antagonist. Nature http:// dx.doi.org/10.1038/nature17414 (2016).

esearchers in the United Kingdom have unveiled the structure of the binding site for an anti-diabetic molecule called MK-0893, a potential target for diabetes therapies. MK-0893 antagonizes the hormone glucagon, which is secreted by pancreatic cells and promotes glucose production when it binds to receptors on cells of several of the body’s organs. The glucagon receptor belongs to a family of receptors that play a central role in metabolic and bone diseases as well as migraine and hormonal disorders. Several of these receptors work together to control glucose and insulin levels in the blood, but developing oral drugs that successfully regulate their function has proven difficult. In particular, small molecules, such as MK-0893, have been shown to reduce glucose levels in type II diabetes patients. However, in the absence of clear structural information, their modus operandi remains poorly understood; a major hurdle in structure-based drug design. To tackle this problem, Fiona Marshall and colleagues from Heptares Therapeutics studied the structure of the receptor by crystallizing it in the presence of MK-0893. “Solving the X-ray structure of a protein allows you to see its exact three-dimensional shape and this can be used to conceive drugs that fit perfectly into the pocket on the receptor,” she says.

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Fanconi anaemia may be

Fanconi anaemia is the most common form of inherited bone marrow failure that requires bone marrow transplantation therapy in Saudi Arabia. 48

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under-diagnosed in Saudi Arabia

anconi anaemia is an inherited genetic condition of bone marrow that causes a predisposition to cancer. Researchers at King Abdullah International Medical Research Center (KAIMRC) have gained insights into the genetic basis of this condition in Saudi patients. Their work reveals distinct genetic characteristics and may improve diagnosis and treatment in the future. Fanconi anaemia is a rare disease involving mutations in at least 18 genes. These genes encode proteins that perform essential running repairs to DNA that keep most humans healthy, despite the inevitable damage to DNA through wear and tear. With the DNA repair pathways unable to function normally, most of these patients

develop cancer. They also display physical abnormalities, including short stature, and have a life expectancy of around 40 years. Although rare, Fanconi anaemia is the most common form of inherited bone marrow failure that requires bone marrow transplantation therapy in Saudi Arabia. Paediatrician Abdulrahman Alsultan and colleagues at the King Abdullah Specialist Children’s Hospital in Riyadh, together with co-workers at other centers in Saudi Arabia, studied the genetic causes of ten unrelated cases of Fanconi anaemia. The patients were infants and children who were diagnosed with the condition between 2011 and 2015. The researchers used state-of-the-art gene sequencing technology to identify the mutations associated with the disease in these patients. They also looked for links between specific mutations and the varying clinical consequences of Fanconi anaemia among the cohort. The results indicated that the pattern of mutations in these Saudi patients differed significantly from that found in comparable patients in Europe and North America. The researchers suggest that one consequence of these differences could be that a standard test used to diagnose some forms of Fanconi anaemia may fail to diagnose some Saudi patients. The genetic analysis also identified some new mutations to add to the list of those that can cause the disease. One aspect of particular interest is that two patients with one specific mutation belonged to the same tribe. This may indicate what the researchers call a “founder effect or hotspot” that might be used to trace the origin of this mutation. Other mutations are presumed to be “ancient”, due to being found in members of different tribes and ethnic groups. This was a small-scale preliminary study, based on patients at a single institution. Given the potential significance of these early results for diagnosing and understanding Fanconi anaemia, the researchers now plan a much larger multi-institutional follow-up study, again focused on Saudi Arabia. Ghazwani, Y., AlBalwi, M., Al-Abdulkareem, I., Al-Dress, M., Alharbi, T. et al. Clinical characteristics and genetic subtypes of Fanconi anemia in Saudi patients. Cancer Genetics http://dx.doi.org/10.1016/j.cancergen.2016.02.003 (2016).

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Genetic analysis of Saudi patients with Fanconi anaemia reveals new mutations and distinct patterns of mutation that may affect diagnosis.

Latest technique delivers CRISPR gene screens A comparison of gene editing techniques reveals benefits of latest technology over conventional approach.

he latest gene editing technique outperforms the conventional method to perform large-scale screening of gene functions, according to research conducted at The Netherlands Cancer Institute. The insight shows how the CRISPRâ&#x20AC;&#x201C; Cas9 system could help to identify genes involved in diseases such as cancer. Determining the genetics of a cellular process or disease usually involves functional genetic

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screening, in which genes are suppressed one by one to demonstrate their contribution. These large-scale experiments can be used for a variety of research purposes and provide large amounts of useful information. â&#x20AC;&#x153;An ideal genetic screen provides a list of genes that are involved in a certain pro-

CRISPR–Cas9 cuts DNA to edit genomes and is more reliable in genetic screening than conventional techniques.

foreign genetic material and can be exploited to target specific genes in human cells. “CRISPR technology allows very rapid and cheap editing of genomes in ways that easily result in complete functional knockouts of genes,” explains Evers. “In addition, CRISPR technologies seem to suffer less than RNAi from off-target activity.” Evers and colleagues compared the performance of RNAi, CRISPR–Cas9, and a variant technique called CRISPR interference (CRISPRi), in which DNA is not cut but a gene is suppressed. They assessed the ability of all three techniques to identify 46 genes that are known to be essential

"CRISPR technology allows very rapid and cheap editing of genomes in ways that easily result in complete functional knockouts of genes."

for cellular life. They found that the CRISPR–Cas9 system was more reliable than both RNAi and CRISPRi at identifying the genes, largely because of fewer off-target effects and greater consistency between reagents targeting the same gene. “Our findings have implications for synthetic lethal screens in which the goal is to identify genes that are essential for cells in the context of a second perturbation, be it genetic or pharmacological,” explains Evers. Improving this screening with CRISPR technology could, therefore, help in the development of novel therapeutic approaches for cancer and other diseases. Evers, B., Jastrzebski, K., Heijmans, J. P., Grernrum, W., Beijersbergen, R. L. et al. CRISPR knockout screening outperforms shRNA and CRISPRi in identifying essential genes. Nature Biotechnology http://dx.doi. org/10.1038/nbt.3536 (2016).

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cess,” explains Bastiaan Evers, lead author of the new study. “For example, one could study whether disruptions of any gene confers resistance to cancer therapies. That information could be used to better understand, predict and intervene in treatment failure.” Conventional functional genetic screening is performed with a technique called RNA interference (RNAi), which disrupts the process of translating genes into proteins. However, this technique often disrupts genes other than the intended target, or incompletely suppresses the target gene so its function is masked. Evers and colleagues wanted to determine whether a newer technique, called CRISPR–Cas9 gene editing, is more reliable. CRISPR–Cas9 is an immune system in bacteria and archaea (single-celled micro-organisms lacking nuclei) that cuts

“Males are more likely to reject medical information if it is in conflict with the traditional culture” Saudis with a higher educational background were more likely to be aware of the genetic risks of consanguineous marriages.

Understanding risks of consanguineous reproduction Saudi Arabia needs a widespread education program highlighting the genetic risks to children born as a result of marriage within families.

hildren born to genetically related people from the same family — socalled consanguineous marriages — face serious health risks. A recent study conducted in Saudi Arabia, where the practice is still common, shows that women there have a higher awareness of these risks compared to men. Consanguineous marriage can result in children with cognitive difficulties, heart defects, and impaired hearing, as well as other genetically inherited diseases. It can also lead to increased chances of a child inheriting two copies of a defective

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gene from a shared common ancestor, perpetuating otherwise recessive genetic disorders. Anwar Ahmed from King Abdullah International Medical Research Center and a team of researchers from across Saudi Arabia conducted a cross-sectional study of 386 Saudis over the age of 18 to determine their level of knowledge regarding these health risks. Each participant completed two questionnaires. The first aimed to gather social details, including the level of education in their families, and included questions on

“This may be explained by the fact that females in our society tend to accept medical information in an objective manner in contrast to males, who are more likely to reject medical information if it is in conflict with the traditional culture,” the team suggest in their paper. Further, the study revealed that those from a higher educational background, together with those who had received medical information from friends, were more likely to understand the genetic risks and therefore be against consanguineous relationships. Those from backgrounds where families had less education had limited knowledge and were more likely to come from a long-held tradition of consanguineous marriages. The team urge caution in their results, because a larger, more comprehensive study of adult awareness is required. However, they believe that “Saudi Arabia must conduct widespread health awareness on the risks associated with consanguineous marriages.” Ahmed, A.E., Alharbi, O.A., Al-Hamam, A.A., AlShaia, W.A., Al-Marzoug, H.M., et al. Awareness of health consequences of consanguineous marriages among Saudi adults. The Journal of Public Health in Developing Countries. 2016; 2(1): 121-129.

marriage and known inherited diseases. The second questionnaire focused more closely on knowledge of the genetic consequences of consanguineous marriage. Overall, knowledge of the genetic instability caused by consanguineous marriage was lower among Saudi adults than in other countries. Around 6% of respondents lacked any knowledge, and a third of those questioned had never received any information related to genetic diseases. Interestingly, there was a strong disparity between the sexes, with women demonstrating significantly greater understanding of medical consequences than men.

The heel prick test is based on metabolomics and is used to detect nine rare but serious diseases.

The metabolomics revolution Understanding the body’s metabolic profile is transforming drug discovery and personalized medicine.

tudying an organism’s genetic makeup allows us to determine disease risk. But it’s an organism’s metabolic profile, the levels and kinds of metabolites at a given time, which offers unique insights into disease mechanisms and treatment responses. The study of metabolites and metabolism — known as metabolomics — is allowing scientists to explore interaction between genetics and the environment. The science has the potential to detect metabolites associated with disease even before symptoms become apparent. “By being able to detect a specific disease before it manifests, metabolomics will allow patients and physicians to take aggressive preventative action, develop personalised therapies and monitor results,” says biochemist David Wishart of

the University of Alberta in Canada. The field is set for rapid growth as new techniques, such as metabolite imaging, and improved analytical technologies become more accessible. Wishart conducted a review of the latest research in this field, describing recent developments and emerging applications. Metabolomics could offer a more productive and cost-effective route to drug discovery. As Wishart explains, relatively few diseases have a strong genetic basis and genes linked to diseases may not be amenable to drug targeting. Crucially, though, “more and more metabolic biomarkers are being discovered and they are allowing the prediction, or very early diagnosis, of diseases such as diabetes, kidney disease, preeclampsia, heart disease, colon cancer and Alzheimer’s disease”.

Metabolites are providing insights into the underlying causes of disease and revealing unexpected therapeutic targets. In some cases, there could even be a simple therapeutic solution, as levels of a particular metabolite may be corrected with dietary supplements. Metabolomics can also be used to detect optimal responders to a drug in clinical trials as well as to monitor adverse responses. This can help optimize clinical trials and reduce the time needed for new drugs to reach the market. Newborn screening tests are based on metabolomics and are one of the most successful examples of personalized medicine. Testing a blood spot taken from a baby (often referred to as the 'heel prick') for particular metabolites allows the detection of nine rare but serious diseases, such as congenital hypothyroidism and cystic fibrosis.

"By being able to detect a specific disease before it manifests, metabolomics will allow patients and physicians to take aggressive preventative action, develop personalised therapies and monitor results." Many cancers exhibit a distinct metabolic profile. Using metabolomics to characterise tumours holds great promise for the design of customised cancer therapies. As more sensitive technologies emerge, the identification of metabolites will continue to improve. Wishart believes the next major breakthrough will be the development of databases and software that will permit the identification of more than 10,000 metabolites in a single mass spectrometry run. Wishart, D. S. Emerging applications of metabolomics in drug discovery and precision medicine. Nature Reviews Drug Discovery http://dx.doi.org/ 10.1038/nrd.2016.32 (2016).

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Tracking the effects of therapeutic genes Targeted nanoparticles offer hope of better methods for tracking the effects of gene therapy.

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In animal studies, G-CSF has been shown to provide protection in response to brain damage by increasing blood vessel growth, protecting neurons, reversing memory loss and reducing excess in beta amyloid deposits – which have been linked to Alzheimer’s disease and stroke. The survival rate among the brain-damaged mice given the gene therapy eye drops was between 33 and 100%, depending on how soon after oxygen deprivation they were treated, compared to around 25% in a placebo group. “Growth factors have been shown to help reverse brain damage, but we were still surprised at how effective it was,” says Liu. The researchers then attached magnetic

resonance contrast agent nanoparticles to DNA capable of targeting the messenger RNA that expresses hG-CSF, and used MRI scans to successfully track expression from nerve cells in the damaged brains of living mice. The technique has the potential to provide a new targeted way to monitor the expression of introduced genes for scientists working on therapies for conditions including heart attack, stroke, Alzheimer’s and Parkinson’s disease. Ren, Y., Chen, Y. I., Liu, C. H., Chen, P-C., Liu, P. K. et al. Noninvasive tracking of gene transcript and neuroprotection after gene therapy. Gene Therapy http://dx.doi.org/10.1038/gt.2015.81 (2016).

new, non-invasive method has been developed to monitor the effects of experimental gene therapies for cardiovascular disease and neurodegenerative disorders. There is renewed optimism about research into new treatments based on replacing defective genes or inserting new ones. However, in some cases, progress is hampered by an inability to track the expression of introduced genes in experiments. Traditional histological approaches would be counterproductive because these would require removing samples of the very tissues the therapies are designed to protect. Philip K. Liu, of Massachusetts General Hospital, Boston, and colleagues at Florida Atlantic University set out to develop a non-invasive method to monitor the expression of genes introduced to a brain after it has been damaged. They began by observing how blocking the blood supply to the brains of mice for 60 minutes induced edema, or brain swelling, and general, severe weight loss. Also, 75% of the mice died within a week. Brain-damaged mice were then given eye drops containing a virus modified to carry genes that encode human granulocyte colony-stimulating factor (hG-CSF). This is a protein that triggers the release of certain white blood cells and stem cells into the bloodstream.

Strictly confidential Protecting confidentiality is a major priority in medical settings, crucial to the effectiveness of Saudi Arabia's newly established biobank.

he storage of information in biobanks — collections of human samples for medical research — is viewed as essential to improve understanding of human health and disease. Launched in 2014, the Saudi Biobank is emerging as a valuable resource for the region. Its growth will depend on wider discussion of issues such as confidentiality and informed consent. “Biobanks offer a golden opportunity to study multifactorial diseases and relationships between genetics, environments and lifestyles,” says Ghiath Alahmad, a bioethicist at King Abdullah International Medical Research Center (KAIMRC). “Research based on large numbers of samples are needed to investigate diseases that are increasing rapidly among Saudis, such as hypertension and diabetes.” Due to the relative lack of surveys in the Middle East about confidentiality issues, Alahmad says it was “necessary and timely” to conduct a series of questionnaires among five different groups: researchers, physicians, medical students, donors and the general public. The responses from a total of 200 people at King Abdulaziz Medical City, the largest medical complex in Saudi Arabia, revealed

Confidentiality is a fundamental tenet of medical ethics.

that all five groups rate confidentiality as one of the most important aspects of medical care. The groups showed notable differences in the level of willingness to share genetic information with third parties. For example, researchers and physicians were the most reluctant to share information with family members, while donors and laypersons were more prepared to do so.

"Confidentiality is essential in gaining donors' trust and encouraging them to participate in any biobank. It's important to explore all of the ethical repercussions." When asked to suggest examples where confidentiality might justifiably be breached, the two main scenarios raised by respondents were those involving infectious diseases or genetic diseases. The study found that donors and laypersons were more supportive of providing confidential information in those two cases. “Confidentiality is essential in gaining donors’ trust and encouraging them to participate in any biobank,” says Alah-

mad. “As Saudi society is characterised by extended families, strong interfamily relationships and a high percentage of consanguineous marriages, any breach of confidentiality may lead to serious problems such as stigma and discrimination. That's why it's important to explore all of the ethical repercussions.” The Saudi Biobank is a member of the Public Population Project in Genomics and Society (P3G), an international consortium facilitating dialogue between biobank resources internationally. Alahmad notes that, overall, his team's findings are consistent with comparable surveys conducted in other countries. The team aims to conduct further surveys with a larger sampling size. Alahmad adds, “I have also started to explore the issue of [sample] ownership, a highly complex issue in the medical field. Based on fruitful discussions with ethics experts at the Center for Bioethics at Harvard University, we hope to publish our results in the coming months.” Alahmad, G., Hifnawy, T., Abbasi, B., & Dierickx, K. Attitudes toward medical and genetic confidentiality in the Saudi research biobank: An exploratory survey. International Journal of Medical Informatics dx.doi.org/10.1016/j.ijmedinf.2015.12.015 (2016).

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Reversing immune decline Targeting a certain gene could help promote healthy aging.

he human body becomes more susceptible to infection with age because blood-forming stem cells lose the ability to build the immune cells needed to mount a proper defence. Researchers in Germany have now found the cause of this stem cell breakdown: a gene that is otherwise involved in controlling daily circadian rhythms. Wiping out this geneâ&#x20AC;&#x2122;s function allowed mice to live longer, with better clearance of bacteria in response to tissue infection. If the process can be replicated in people, it could offer a new way to treat diseases of human aging.

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Wang, J., Morita, Y., Han, B., Niemann, S., Löffler, B., & Rudolph, K. L. Per2 induction limits lymphoid-biased haematopoietic stem cells and lymphopoiesis in the

Hematopoietic stem cells differentiate into the cells that protect our body against pathogens.

context of DNA damage and ageing. Nature Cell Biology http://dx.doi.org/10.1038/ncb3342

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In both mice and people, the capacity of hematopoietic stem cells (HSCs) to form pathogen-fighting white blood cells declines with age as the cells’ DNA accumulates damage. A team led by K. Lenhard Rudolph, scientific director of the Leibniz Institute on Aging – Fritz Lipmann Institute, set out to find the genes that would halt this process. The researchers bred mice that were engineered to suffer from the kind of DNA damage that harms stem cell function, and then extracted HSCs for study in the lab. Using a pool of specialized RNA molecules that silence the activity of target genes, they then tested the role of 459 candidate genes. From this list, they discovered that a gene known as Per2 (short for period circadian clock 2) helped the capacity of HSCs to survive DNA damage caused by aging. Eliminating Per2 function in mice helped boost the number of HSCs; in particular those stem cells that make immune cells known as lymphocytes. As a result, these mice were more resistant to infections and they lived on average 15% longer than mice with functional Per2 activity, with no elevated signs of cancer or other diseases. “To my knowledge, our study provides the first evidence for a single gene deletion that leads to improved generation of lymphocytes and immune function in aging mice,” Rudolph says. The researchers are now investigating whether Per2 acts the same way in human HSCs. If it does, Rudolph says, “we will start a program to develop chemical Per2 inhibitors to correct the defect and to improve immune functions in aging.” But, they will have to consider the risk of side effects. Per2 normally acts in the brain to control circadian patterns, and mutations in the gene have been linked to sleep disturbances. Rudolph hopes to avoid problems by only targeting Per2 in the blood, while leaving the brain alone.

Hepatitis B poses lifetime cancer risk Clearance of active hepatitis B virus from the blood does not reduce the risk of liver cancer.

ÂŠ BSIP SA / ALAMY

he heightened risk of liver cancer associated with chronic hepatitis B infection is not reduced even if the virus is cleared from the bloodstream, according to recent research. The study, which improved on previous attempts to assess the risk, demonstrates that continued monitoring for liver cancer is warranted in everyone with chronic hepatitis B infection. Chronic infection with the hepatitis B virus (HBV) affects 248 million people worldwide, and increases the risk of liver cancer. Chronic infection can never be cleared completely, as the DNA of HBV integrates into the human genome. However, in some patients, the active virus is cleared

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from the blood, detected as a negative test for hepatitis B surface antigen (HBsAg). It has long been unclear if the subsequent risk of liver cancer is lower if the virus clears from the blood, and guidance on monitoring these patients is lacking. Prabhu Gounder, from the Centers for Disease Control and Prevention in the US, and his colleagues aimed to provide some clarity. Gounder and co-workers analyzed data from a population of native Alaskans first followed in the 1980s as part of a statewide HBV vaccination campaign. Those with chronic HBV infection, regardless of the presence or absence of HBV in their blood, were subsequently monitored for liver cancer over a period of 30 years. Gounder and

The risk of liver cancer is not reduced even if the hepatitis B virus is cleared from the bloodstream.

his team designed a study to give them an advantage over earlier work. “Previous studies included the time during which individuals were HBsAg positive when evaluating the risk of liver cancer,” explains Gounder. “We hypothesized that this might have diluted [a potential] protective effect of losing HBsAg. In our study, we isolated the time period after losing HBsAg and compared that with the equivalent time period among individuals who did not lose HBsAg.”

“Individuals with chronic HBV infection have an increased lifetime risk of developing liver cancer, even after resolving chronic infection.” The analysis revealed that clearance of active HBV from the blood did not reduce the subsequent risk of developing liver cancer. The result, says Gounder, is in line with the understanding that early factors in HBV infection, such as the amount of virus in the blood and the extent of liver inflammation, influence the risk. “The key point is that individuals with chronic HBV infection have an increased lifetime risk of developing liver cancer, even after resolving chronic infection,” states Gounder. He warns that the conclusions need to be confirmed in larger populations, but in the meantime suggests clearer guidance on the basis of the new evidence: “Anyone with current or past chronic infection should be monitored closely for liver cancer.” Gounder, P. P., Bulkow, L. R., Snowball, M., Negus, S., Spradling, P. R. et al. Nested case–control study: Hepatocellular carcinoma risk after hepatitis B surface antigen seroclearance. Alimentary Pharmacology and Therapeutics http://dx.doi.org/10.1111/ apt.13621 (2016).

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A promising protein target for MERS A structural analysis of proteins in the Middle East Respiratory Syndrome virus reveals a promising new target for treatments.

fter the notorious outbreak of severe acute respiratory syndrome (SARS) in 2003, another, potentially more deadly disease emerged. Middle East Respiratory Syndrome (MERS), also known as camel flu, has caused over 400 deaths since the first confirmed case in Saudi Arabia in 2012, and researchers are still searching for effective treatments. Now, a team at National Taiwan University in Taipei have revealed, for the first time, the exact structure of a crucial protein domain in the MERS virus that could be targeted by drugs. MERS is caused by a coronavirus that closely resembles the SARS virus, but it has a much higher mortality rate; 40% of MERS patients die compared to 10% for SARS. To find the reasons for this disparity, Chun-Hua Hsu and his team examined the non-structural proteins (NSPs) used by the coronavirus to rapidly replicate inside a host. Specifically, the team focused on the macro domain, a structure in NSPs that binds to the ester ADP-ribose to regulate cellular processes such as DNA repair, gene regulation and controlled cell death. “Macro domain-containing proteins have diverse biological functions,” says Hsu. “However, there has been no conclusive answer about how viral macro domains function during infection. We found a macro domain on the MERS NSP3, and were curious about how its structure and function compares to macro domains from other coronaviruses.” The researchers studied the macro domain structure using cutting-edge spectroscopy, fluorimetry, calorimetry and x-ray

diffraction techniques. First, however, they had to crystallize their samples, which proved challenging. “The MERS macro domain was quite unstable, and we found it difficult to grow crystals,” explains Hsu. “However, after we provided ADP-ribose, it resulted in crystals with good qualities that were suitable for diffraction data collection.” The structural data showed the ADP-ribose molecule tightly bound in a crevice of the macro domain, where it is most likely stabilized by hydrogen bonds. “We were surprised, because our data suggest that the MERS macro domain is more efficient at ADP-ribose binding than macro domains from other coronaviruses such as SARS,” says Hsu. “We speculate that this higher affinity for ADP-ribose allows the MERS macro domain to modulate host immunity during infection.” Based on their findings, the researchers suggest that antiviral treatments designed to target the MERS macro domain could block viral replication or even clear the virus completely. They now plan to search databases of traditional Chinese herbal medicine in order to identify molecules that could inhibit the MERS macro domain.

“We found a macro domain on the MERS NSP3, and were curious about how its structure and function compares to macro domains from other coronaviruses.”

July 2016

Cho, C.-C., Lin, M.-H., Chuang, C.-Y. & Hsu, C.-H. Macro Domain from Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is an Efficient ADPribose Binding Module: Crystal Structure and Biochemical Studies. Journal of Biological Chemistry http://www.jbc.org/cgi/doi/10.1074/jbc.M115.700542 (2016)

A sculpture of an important protein structure called the macro domain (white surface) from the MERS coronavirus. The MERS macro domain binds very efficiently to ADP-ribose (red and blue spheres). Issue No.1

A new peptide-based tool for diagnosing HIV-1 and HIV-2 works by seeking out and binding to the N-terminal on the HIV p24 protein.

Peptide promise for diagnostics Rapid diagnosis of HIV may soon be possible thanks to a novel peptide-based diagnostic tool.

he human immunodeficiency virus (HIV), and its associated acquired immune deficiency syndrome (AIDS), continues to have a devastating effect on populations worldwide. Now, researchers in South Africa and Saudi Arabia have made a breakthrough in HIV diagnostics, developing a prototype tool, based on antimicrobial peptides, that offers hope of providing rapid, accurate point-of-care diagnosis. The most common diagnostic tool for the two predominant HIV viruses, HIV-1 and HIV-2, is the p24 antigen assay. It detects HIV by searching for the presence of a protein called p24, which it recognises via the p24’s C-terminal. However, false negatives are common using this tool, due to obstruction of the C-terminal by p24 antibodies, which are generated during the body’s immune response to HIV infection. It also takes several days to receive results from the p24 assay, and so a more effective diagnostic tool is urgently needed. “South Africa has the world’s largest HIV

July 2016

infected population and the government is spending millions on HIV kits from overseas. Yet, as far as we know, no company in the country has produced an HIV diagnostics kit,” says Ashley Pretorius from the University of the Western Cape, who worked on the project with colleagues in South Africa, Musa Gabere from King Abdullah International Medical Research Center, and an industrial partner, Medical Diagnostech. “Producing an inexpensive kit locally will allow us to tackle HIV and AIDS more effectively while benefitting the country’s economy.” The team needed to develop a tool that did not rely on the p24 C-terminal. They decided to explore the potential of a naturally occurring subset of immune system proteins called antimicrobial peptides (AMPs), some of which have been shown to bind to the N-terminal of HIV p24. Pretorius’ team modelled combinations of AMPs and modified AMPs to find the best ‘fit’ for p24, to ensure accurate and efficient

HIV detection in samples from patients. “The point of contact between two molecules is important because it determines how tightly the molecules bind to each other,” says Pretorius. “When we have identified a molecule – in this case an AMP – that we know fits well with a target protein, we can substitute amino acids in the right places to make the binding between the two molecules even stronger.” Their resulting AMP-based prototype diagnostic tool, which is now patented, performed very well in initial tests. The tool achieves accurate diagnosis of both HIV-1 and HIV-2 in only 15 minutes; meaning that, for the first time, effective point-of-care HIV diagnosis could be feasible. Williams, M.E., Tincho, M., Gabere, M., Uys, A., Meyer, M., & Pretorius, A. Molecular validation of putative antimicrobial peptides for improved human immunodeficiency virus diagnostics via HIV protein p24. Journal of AIDS and Clinical Research http://dx.doi. org/10.4172/2155-6113.1000571 (2016).

First MERS autopsy yields ‘critical insights’ The world’s first autopsy of a patient with Middle East respiratory syndrome shows that the lungs are the infection’s main target.

he first autopsy performed on a victim of Middle East respiratory syndrome (MERS) has shown the extent of the infection’s impact on the lungs and lower respiratory tract. The post-mortem examination — on a 45-year-old man who died of MERS at a hospital in the United Arab Emirates — yields new insights into how the coronavirus responsible for the disease attacks the body, and offers clues for how to treat the illness. “This investigation can be used for a host of applications ranging from diagnosis and prevention, to treatment and determination of pathogenesis,” says Sherif Zaki, chief of the Infectious Diseases Pathology Branch at the US Centers for Disease Control and Prevention. MERS was first identified in Saudi Arabia in 2012 and has since spread throughout the Arabian Peninsula and into 27 countries worldwide. Of the 1,700-plus confirmed cases, more than a third have

Cells that line the air sacs of the lungs stained for MERS-coronavirus (red).

died. Yet, it wasn’t until earlier this year that pathologists described the first autopsy on a MERS victim, outlining the microscopic details of diseased tissues that help explain how the infection kills.

“One must be cautious when analyzing and making recommendations from the findings of a single autopsy report.” Zaki led the team that performed the autopsy in April 2014, ten days after the patient died. They documented widespread damage to the air sacs of the lungs and lower airways. Staining assays showed that the MERS coronavirus targeted cells in these damaged regions, but not other tissues outside the respiratory tract. The infected cells expressed a protein on their surface called dipeptidyl peptidase 4, or DPP4, supporting earlier evidence from lab experiments that the MERS coronavirus hijacks this protein to enter and infect cells. “This implies,” says Zaki, “that DPP4 inhibitors could have therapeutic value,”

although more research is needed to confirm the potential of this drug target. Some doctors had previously suggested the MERS coronavirus might infect the kidneys. But, no virus was detected in the kidneys in the post-mortem exam. Zaki suspects that any kidney damage associated with MERS is not due to direct viral attack in these organs, but a consequence of general immune dysfunction following lung infection. “One must be cautious when analyzing and making recommendations from the findings of a single autopsy report,” Zaki says. “Much more data is needed from studies of other infected MERS patients [and mortalities] to better understand the pathogenesis and optimal treatment for these patients.” But, he adds, this first autopsy does provide “critical insights” into this new and emerging infectious disease. Ng, D. L., Al Hosani, F., Keating, M. K., Gerber, S. I., Jones, T. L. et al. Clinicopathologic, immunohistochemical, and ultrastructural findings of a fatal case of Middle East respiratory syndrome coronavirus infection in the United Arab Emirates, April 2014. American Journal of Pathology http://dx.doi.org/10.1016/j.ajpath.2015.10.024. (2016).

Issue No.1

Gene tweak induces stronger immunity Changing the switch that turns on vaccine protein production elicits a stronger immune response against malaria and influenza in mice.

July 2016

xperimental vaccines for protection against malaria, influenza and other infectious diseases could be made more potent if their developers made a small genetic tweak. By using a different ‘promoter’ — a DNA sequence that drives the multiplication and expression of genetic material — researchers, led by Naif Alharbi from King Abdullah International Medical Research Center, have found they can induce stronger immunity in mouse models. Modified vaccinia virus Ankara (MVA) is a weakened type of poxvirus known to be safe in humans. Scientists have engineered it to carry the genetic material of various infectious agents — including HIV, tuberculosis, and most recently Ebola — into host cells in an effort to prime the immune response against these pathogens. MVA works well enough as a vaccine carrier, but Alharbi and his colleagues at the University of Oxford’s Jenner Institute wanted to make it even better. They incorporated different naturally found promoters into MVA to see if they prompted a more robust immune response. In mice, the researchers found that two promoters, known as F11 and B8, improved the expression of foreign genetic material in host cells compared to conventional promoters used in existing vaccines.

Changing the gene promoter could help make more robust flu vaccines.

This elicited a strong immune response. F11 and B8 were more active in the early stages of the MVA lifecycle, leading to higher production yields overall. The researchers tested the F11 promoter as an enhancing element to drive stronger expression of vaccine proteins from two microbes: malaria and influenza. Two weeks after vaccinating mice with the F11-containing viruses, they observed elevated levels of infection-fighting T cells directed against these pathogens compared to mice immunized with standard vectors already tested in human clinical trials. “The results show that the F11 promoter induced significantly higher immune responses in mice,” says Alharbi. “[Soon], those improved malaria and influenza vaccine candidates [with the F11 promoter] will be tested in humans by the Jenner Institute scientists [in the UK].”

Alharbi and his collaborator at the Jenner Institute, Sarah Gilbert, have also recently developed a series of vaccines — one of which is based on MVA and includes the F11 promoter — against the coronavirus responsible for Middle East respiratory syndrome, a sometimes-fatal viral illness spread by camels that first appeared in Saudi Arabia in 2012. “Those vaccines have been tested in mice,” Alhabri says, “and will be tested on camels and humans.” Alharbi, N. K., Spencer, A. J., Salman, A. M., Tully, C. M., Chinnakannan, S. K., Lambe, T., Yamaguchi, Y., Morris, S. J., Orubu, T., Draper, S. J., Hill, A. V. & Gilbert, S. C. Enhancing cellular immunogenicity of MVA-vectored vaccines by utilizing the F11L endogenous promoter. Vaccine 34, 49–55 (2016). dx.doi. org/10.1016/j.vaccine.2015.11.028

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