KAIMRC Innovations Issue 9 by Nature Research Custom Media

JUNE 2021 - Issue No.9

ISSN 7901-2398 innovations.kaimrc.med.sa

VACCINES VS VARIANTS: AN ONGOING RACE W H AT T HE R A P ID SP R E A D OF S A R S- C O V-2 VA R I A N T S ME A N S F OR T HE F IGH T A G A IN S T C O V ID -19 P. 28 f

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TABLE OF CONTENTS

FEATURE

P.8 FIGHTING THE PANDEMIC ON ALL FRONTS

P.10 OPTIMISING INFLUENZA VACCINES TO HARNESS PRE-EXISTING IMMUNITY

KAIMRC is at the forefront of the nation’s fight against COVID-19 by ramping up coronavirus research

Understanding how immune cells respond to natural infection vs. vaccination demonstrates how shots could aid immunity

P.12 MERS REMAINS PREVALENT IN CAMELS IN SAUDI ARABIA

P.14 ANTIBIOTIC RESISTANCE IN CIRCULATING BACTERIAL STRAINS

P.16 DNA SEQUENCING ACCELERATES INFECTION DIAGNOSIS

A survey of slaughterhouses in Riyadh reveals continued risk of zoonotic transmission

Sequencing Klebsiella pneumoniae strains from a Riyadh hospital highlights genes that confer resistance to multiple antibiotics

Detection of pathogenic genetic material in body fluids could speed up treatment of serious infections

COVID-19

P.20 A TRIUMPH FOR SCIENCE: HASTENING THE RACE TOWARD A COVID-19 VACCINE

P.24 GLOBAL ACCESSIBILITY: THE PATH FROM VACCINE TRIALS TO PATIENTS

An unprecedented global response by researchers, funders and regulators made it possible to develop COVID-19 vaccines

The unprecedented efforts and challenges to produce and allocate COVID-19 vaccines all over the world

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Issue No.9

TABLE OF CONTENTS

COVID-19

FEATURE

P.27 COVID-19 INFECTION RATE WAS LOW AMONG HEALTHCARE WORKERS EARLY IN THE PANDEMIC

P.28 VACCINES VS VARIANTS: AN ONGOING RACE

Masks, lockdown and vigilance attributed for curbing infection rates among healthcare workers across Saudi Arabia

What does the rapid spread of SARS-CoV-2 variants that affect vaccine potency mean for the fight against COVID-19?

FEATURE

P.32 CHADOX1: MORE THAN A CORONAVIRUS VACCINE

P.35 BETTER ANIMAL MODELS FOR COVID-19 NEEDED

P.36 COVID-19 IMPACT DOES NOT END WITH HOSPITAL DISCHARGE

At the core of a COVID-19 vaccine is a highly adaptable technology with the potential to protect against a range of viruses

The lack of severe illness in animal models of COVID-19 suggests a wide gap between the disease in humans and animal models

Hospital discharge could still mean a long way to full recovery for severe COVID-19 patients

KNOWLEDGE ECONOMY

FEATURE

P.38 TURNING SCIENTIFIC DISCOVERIES INTO COMMERCIAL SOLUTIONS KAIMRC’s Abdelali Haoudi discusses the barriers and solutions to commercialising academic research in Saudi Arabia 4

June 2021

TABLE OF CONTENTS

FEATURE

AGEING AND THE BRAIN

FEATURE

P.40 REDUCING INFLAMMATION REJUVENATES BRAIN CELLS IN MICE

P.42 DEPRESSION LINKED TO PREMATURE BRAIN AGEING

P.44 THE GENETIC ROOTS OF RARE DEVELOPMENTAL DISORDERS

A signalling pathway could be used to reverse age-associated metabolic and immune dysfunction in mice

Evidence is accumulating that depression and premature brain ageing are closely linked

Genomics experts profile patients and families to diagnose childhood diseases derailing healthy neurological development

P.46 HOW MELANOMA MANIPULATES ITS WAY TO METASTASIS

P.48 AI-SUPPORTED DECISION-MAKING IMPROVES SKIN CANCER DIAGNOSIS

A growth factor secreted by melanoma cells makes the immune system ignore metastasis

Researchers showcase a framework for image-based AI systems to assist doctors deliver more accurate diagnoses

P.50 FAMILY SUPPORT HASTENS RECOVERY

P.51 INVESTIGATING THE FACTORS AFFECTING BURN PATIENT SURVIVAL

Family ties are key for successful recovery from injuries that can lead to temporary or permanent disability

Data from patients on mechanical ventilation offers insight into factors affecting survival

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Issue No.9

TABLE OF CONTENTS

P.52 A FATTY DIET DISTURBS CIRCADIAN BRAIN METABOLISM

P.53 A PROPERLY PACKAGED MIX OVERCOMES ANTIBIOTIC-RESISTANT BACTERIA

A high-fat diet changes metabolic oscillations in brain regions that control circadian rhythms

Liposomes carrying the right drug combination could help in the fight against drug-resistant microbes

P.54 ANIMATING THE INANIMATE

P.55 SEATBELT USE IN SAUDI ARABIA REMAINS LOW

P.56 NANOTECHNOLOGY PREVENTS PRETERM BIRTH IN MICE

Swimming crystalline microwires could be the progenitors of futuristic microrobotics systems

A survey reveals that young adults, women and people suffering from depression and anxiety are less likely to buckle up

Formulation helps overcome mucus barriers for targeted drug delivery

P.57 AN ARTIFICIALLY INTELLIGENT ROUTE TO BETTER PREDICTION OF DIABETES RISK A neural network model developed at KAIMRC can identify patients at risk of diabetes with unprecedented accuracy 6

June 2021

TABLE OF CONTENTS

P.58 A KEY ROLE FOR MICROGLIA IN CHILDHOOD GLAUCOMA

P.60 SEQUENCING IMMUNE SYSTEM P.62 A MOLECULAR LINK BETWEEN GENES FOR STEM-CELL TRANSPLANTS DIABETES, OBESITY, AND CELL AGEING

A mutation in Saudi children with primary congenital glaucoma disrupts optic nerve development through microglia

Sequence data from immune system genes of nearly 29,000 Saudi stem cell donors will help match them to patients

Obese people and type-2 diabetes patients have high levels of LMNA, a protein associated with cellular ageing

P.64 PINNING DOWN A GENETIC CAUSE OF PROSTATE CANCER RISK

P.65 DIVERSE DISORDERS FROM A SINGLE SOURCE

P.66 HOW A SINGLE MUTATION CAUSES DIABETES

Propensity hinges on the regulatory role of a rare genetic variant

A complex developmental disorder offers deeper insight into a multi-functional protein linked to cellular processes.

A single mutation shifts the expression of several genes and induces hereditary diabetes in young children

KAIMRC Innovations is published for the King Abdullah International Medical Research Center (KAIMRC) by Nature Research Custom Media. King Abdullah International Medical Research Center (KAIMRC) P.O. Box 3660 Riyadh 11481 Mail Code 1515, Saudi Arabia Email: kaimrc@ngha.med.sa Web: kaimrc.med.sa

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The Researcher Newsletter Phone: +966 11 429 4516 Email: theresearcher@ngha.med.sa Web: innovations.kaimrc.med.sa/en/newsletter

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Issue No.9

Fighting the pandemic on all fronts

KAIMRC is at the forefront of the nation’s fight against COVID-19 by ramping up coronavirus research, says Naif Alharbi, one of Saudi Arabia’s leading virologists

irologist and infectious disease researcher Naif Alharbi has been a central figure in KAIMRC’s coronavirus vaccine efforts. As the director of the vaccine development unit, Alharbi is leading KAIMRC’s phase I MERS vaccine clinical trial while also overseeing SARS-CoV-2-related research. He has spearheaded serostudies on COVID-19 to gauge immune response and to measure past and current disease risk in the Saudi population. The Saudi Ministry of Health is overseeing vaccine acquisition and distribution. While there has been a lull in scheduling vaccinations due to Pfizer/BioNTech supply shortages, the situation is expected to improve as the ministry tops up its stocks.

June 2021

The COVID-19 vaccine developed by AstraZeneca has also been approved for use in the kingdom, which should help relieve supply problems. In addition, new vaccination centres have been opened throughout Saudi Arabia to help meet the ministry’s goal and complete the vaccination of the remaining 26 million citizens by the end of 2021. KAIMRC continues to focus on conducting and supporting vaccine research and testing more vaccines, in collaboration with the ministry, to expand the roster of shots. At the end of 2020, Alharbi and a consortium of researchers published a survey of SARS-CoV-2 seroprevalence in healthcare and medical workers in Saudi Arabia.

He and his colleagues are currently preparing to submit a national COVID-19 seroprevalence study after collecting upwards of 11,000 serum samples from across Saudi Arabia to survey national seroprevalence between June and November 2020. KAIMRC Innovations spoke to Alharbi about this research, the Kingdom’s preparedness for defence against the pandemic and KAIMRC’s unprecedented push towards expanding virus research. Innovations: Many experts believe that KSA had a head start in responding to COVID-19 thanks to its previous experience with MERS. For instance, KAIMRC already had infrastructure such as vaccine development technology and diagnostics

first phase I trial in KSA. That helped us to be more prepared for COVID-19. The ChAdOx1 work we did with the University of Oxford helped with the launch and testing of their ChAdOx1 nCoV-19 vaccine for COVID-19, which was further developed by AstraZeneca. We have also launched a number of clinical trials on COVID-19, including a trial to investigate the efficacy of Favibravir in treating COVID-19 (FACCT trial). Innovations: KAIMRC is now collaborating with the Saudi Ministry of Health and the Saudi Food and Drug Administration (SFDA) to test nine vaccines, all currently in their third stage of clinical trials. Which vaccines are being considered at the moment, and what is their progress?

labs that were partly repurposed for SARS-CoV-2 research. Looking back at 2020, what crucial research did KAIMRC focus on in response to COVID-19? Alharbi: KAIMRC has a research programme on MERS-CoV that’s been going since 2015. This programme has focused specifically on epidemiology, vaccine development, diagnostics, and therapeutic clinical trials. Recently, we published data from our RCT (The MIRACLE Trial) showing the benefit of a combo therapy of anti-viral agents and interferon beta 1B in treating moderate to severe MERS patients and reducing mortality. We also conducted a phase I clinical trial of the ChAdOx1 MERS vaccine, which was the innovations.kaimrc.med.sa

Alharbi: Our Vaccine Unit and Clinical Trial Unit, along with our strategy department and our leadership, have been in extensive negotiations with multiple international partners to accelerate the trials of several candidate COVID-19 vaccines. We have submitted at least three protocols to SFDA, one of which was for a phase III trial evaluating the efficacy of the COVID-19 vaccine CoronaVac, by Chinese biopharmaceutical company SinoVac. After three cycles of extensive reviews, it was rejected by the SFDA. Early in March 2020, we started preparing a phase I/II trial submission for the ChAdOx1 nCoV-19 vaccine together with Oxford, but at the time the rate of infection here wasn’t sufficient to carry out the trials; countries such as Brazil had many more cases, so ChAdOx1 nCoV-19 could be evaluated more quickly there. Innovations: How has KAIMRC handled such a tremendous research effort? Are new labs being set up at KAIMRC and its affiliate institutions and hospitals? Alharbi: KAIMRC has established a Vaccine Unit and a Clinical Trial Unit, and they have been set up as the National Command Center for Clinical Trials (NCCCT). All that has helped in better preparedness. KAIMRC also has various labs focusing on genomics,

microbial genetics, immunology, and cell biology. There’s also clinical research being conducted at the Nat iona l G ua rd Hospitals, KAIMRC’s affiliated medical city. All of these research efforts have been moving together, in parallel. Innovations: Before SARS-CoV-2 emerged, KAIMRC was in pursuit of a vaccine for MERS-CoV, cooperating with the University of Oxford and other top institutions. How has this quest been affected by the COVID-19 pandemic? Were efforts to find a MERS-CoV vaccine shelved or de-prioritised as a result? Alharbi: We managed to complete the phase I trial, conducted entirely from December 2019 to November 2020, during the challenging times of the pandemic. Work on a MERS-CoV vaccine was not de-prioritised, but naturally it has been overshadowed by the global and local focus on COVID-19 research, including at KAIMRC. Innovations: What are some of the questions at the epicentre of research by coronavirus virologists and epidemiologists at KAIMRC? Alharbi: As the world enters the postCOVID-19 research era, KAIMRC is moving into research on the impact of COVID-19 and the long-term effectiveness of, and response to, the vaccines. We conducted collaborative work on neutralising antibodies, as well as a serosurvey of SARS-CoV-2 among hospital workers early in the pandemic. The results, which were published in late 2020, showed that the public health measures, including vigilance in PPE and lockdown, worked to keep the rate of asymptomatic COVID19 in healthcare workers at low levels. We are currently working to submit another national seroprevalence paper with more recent data. This interview has been edited for length and clarity.

Issue No.9

S C I EN C E P H OTO LI B R A RY / A L A M Y S TOC K P H OTO

KAIMRC is now researching the impact of COVID-19 and the long-term effectiveness of, and response to, the vaccines.

Scientists in the US have shown how optimising vaccinations could help plug the gaps and boost the immune system’s ability to neutralise viruses as they evolve.

June 2021

Optimising influenza vaccines to harness preexisting immunity

esearchers in the US have demonstrated why our immune response can struggle to fully neutralise mutated forms of the influenza virus. The study provides insight into how vaccines could be further honed to target specific viral components that our natural immunity might miss. The question of how well our immune system can fight off repeated infections from viruses is critical, particularly as the world struggles to cope with a viral pandemic. When the immune system encounters a virus for the first time, it generates memory B cells that recognise protein segments that are part of the virus. Antibodies released by the memory B cells then bind to these epitopes and work to neutralise the virus. If the immune system encounters the virus again, the existing memory B cells are activated to release the same antibodies and quell infection. “Unfortunately, our memory B cells don’t always recognise epitopes that have mutated or drifted over time, leaving us susceptible to infection by different versions of the same virus,” says Jenna Guthmiller at the University of Chicago, who was part of the research team, along with Haley Dugan and Patrick Wilson. “This is why influenza vaccines must change every year: to ensure they provide protection as viral epitopes evolve.” One outstanding question is whether different routes of initial exposure—natural infection versus vaccination—prompt a different level of recall by memory B cells and affect how protective the resulting immunity is. The researchers investigated this by

innovations.kaimrc.med.sa

comparing antibodies produced by memory B cells taken from people who had naturally been exposed to two influenza subtypes and from healthy people who had received an influenza vaccine. “We found that the specificities of recalled memory B cells are drastically different depending on their original exposure route,” says Dugan. Most antibodies derived from the infection-route B cells recognised conserved epitopes from past strains but would not neutralise current influenza viruses. Newer epitopes that had drifted were often missed by these antibodies. In contrast, antibodies derived from vaccinated individuals targeted both conserved epitopes from previous strains and epitopes which had changed through drift or mutation. “While vaccination-induced antibodies were largely cross-reactive to past strains, they were still capable of neutralising the virus,” notes Dugan. “This suggests the vaccinated response is better at recalling protective antibodies against both drifted and conserved epitopes.” “By developing vaccines focused on specific viral proteins that our immune systems might miss, we can optimize protective antibody responses,” says Wilson. Dugan, H.L., Guthmiller, J.J., Arevalo, P., Huang, M., Chen, Y-Q., Neu,

K.E., Henry, C., Zheng, N-Y., Lan, L., Y-L., Tepora, M.E., Stovicek, O., Bitar, D., Palm, A-K.E., Stamper, C.T., Changrob, S., Utset, H.A., Coughlan, L.,

Krammer, F., Cobey, S., Wilson, P.C. Preexisting immunity shapes distinct antibody landscapes after influenza virus infection and vaccina-

tion in humans. Science Translational Medicine 12 eabd3601 (2020).

Issue No.9

DR _ M I C R OB E/I S TOC K / G ET T Y I M AG ES P LUS

Understanding how immune cells respond to natural infection compared with vaccination demonstrates how vaccines could broader immunity

MERS remains prevalent in camels in Saudi Arabia A survey of slaughterhouses in Riyadh reveals continued risk of zoonotic transmission

June 2021

“MERS-CoV is a virus that circulates in camels and is getting accustomed to camels as a host without a biological or immunological pressure that would push the virus to change its genetic makeup.”

Alharbi, N.K. et al, High Rate of Circulating MERS-CoV in Dromedary Camels at Slaughterhouses in Riyadh, 2019.

Viruses, 12, 1-10 (2020).

R EU T ER S / A L A M Y S TOC K P H OTO

he virus responsible for Middle East respiratory syndrome (MERS) is prevalent in camels slaughtered for meat in Saudi Arabia, according to a new study. Dromedaries, the intermediate host, are the only known source of human MERS infections. The virus was first detected in Saudi Arabia in 2012, and has infected approximately 2,900 people in 27 countries and caused 858 deaths. With a mortality rate of 34.4%, MERS-CoV is considered to be among the deadliest of the three recently emerged human coronaviruses. To assess the risk of future zoonotic transmission, the team surveyed the three main slaughterhouses in Riyadh in the winter of 2019, collecting nasal swabs and blood from 171 young and healthy camels. The nasal swabs were examined using RT-PCR to detect the infection and serum samples were tested using ELISA to detect the neutralising antibodies. Genetic diversity of positive isolates was determined through the amplification and sequencing of the spike gene. The team reported a high prevalence (38.6%) and seropositivity (70.8%) of MERS-CoV. This indicates ongoing circulation of MERS-CoV infection in camels in these slaughterhouses. Efforts should be made to protect people in close contact with camels including veterinarians, and slaughterhouse and camel workers. “The greatest concern is a spillover event that would end up in an outbreak in humans,” says Naif Alharbi, the director of the Vaccine Development Unit at KAIMRC and co-author of the study.

“That could happen at any point.” The researchers also analysed the spike gene of the virus in their samples, and revealed high genetic stability. According to Alharbi, this indicates that “the virus is circulating in camels and getting accustomed to camels as a host without a biological or immunological pressure that would push the virus to change its genetic makeup.” Although public health measures such as strict hygiene and moving camel markets to the periphery of cities were introduced in the Kingdom, Saudi Arabia still experiences the highest caseload of MERS. This highlights the urgent need for further action to prevent zoonotic transmissions and outbreaks. The authors conclude more research is needed to assess the impact of the virus on public health and potential infection control measures. They also highlight the value of developing a vaccine targeting the spike protein to help combat the virus in camels.

Dromedaries, the intermediate host, are the only known source of human MERS infections.

MEDICAL RESEARCH CORE FACILITIES & PLATFORMS They serve the MNG-HA scientific community’s needs for reagents, assays, samples and data analysis for the conduct of research projects as drug discovery and research areas as cancer, cardiovascular & rare diseases.

SERVICES • Cell Culture Facility • Biochemistry, Microbiology and Molecular Biology Lab • Lentivirus and Baculovirus Lab • Bio-Imaging Suite • Immunology and Flow-Cytometry Platform • Mass Spectrometry • Drug Discovery, Medicinal & Analytical Chemistry

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The bacterium K. pneumoniae has rapidly evolved to evade the majority of antibiotics. KAIMRC researchers have sequenced the K. pneumoniae strains circulating in a Riyadh hospital to identify the individual resistanceconferring genes present in strains in the region.

June 2021

Charting antibiotic resistance in circulating bacterial strains

acterial pathogens such as Escherichia coli and Klebcarbapenems. The researchers found that 49 out of the 50 isolates siella pneumoniae are becoming increasingly resistant harboured the CTX-M gene, a common antibiotic-resistant gene to antibiotics, with significant global health implicafound in K. pneumoniae strains across the globe. tions. Multiple antibiotics are available to treat K. pneuThe team also found variants of the OXA gene, which is known moniae infections, but the pathogen has evolved to evade almost to confer carbapenem resistance, in 43 of the isolates, and 16 samall of them, even the carbapenem family of antibiotics that was ples harboured another carbapenem-resistance gene, NDM-1 considered a last line of defence. They also identified two newer OXA phenotypes that were phyMajed Alghoribi, chairman of KAIMRC’s Infectious Disease logenetically distinct from one another, meaning the variants had Research Department, led a team that examined Klebsiella pneuevolved in isolation from each other. moniae strains currently circulating in the National Guard Hospital Polyclonal populations of K. pneumoniae were present within the in Riyadh to determine which specific resistance-conferring genes samples, and the researchers identified four main genotypes. They are present in the region. They hope to expand their study to also verified the genotypes investigate a larger range of of the predominant strains to samples in the near future. This The researchers found that 49 out of the facilitate control programmes. will contribute to the creation 50 isolates harboured the CTX-M gene, a Their findings will inform of a strong database of circulatcommon antibiotic-resistant gene found in infection control intervention ing strains in Saudi Arabia. strategies and help promote As the research team state K. pneumoniae strains across the globe. stringent but effective antibiin their paper, published in otic use. Cureus, “these results may not Bacteria evolve rapidly via various mechanisms, such as mutagive the true picture of antibiotic resistance in the whole countions that alter aspects of their structure so that antibiotics can no try. A multi-centric study involving a larger number of isolates is longer attach to them and destroy them. Bacteria can also share needed [… and] investigations on the plasmids carrying the resistDNA information with one another via fragments called plasance genes would also shed light on horizontal transfer.” mids, which can carry genetic codes that promote resistance. Alghoribi and his team examined 50 K. pneumoniae isolates Khdary, H.N. et al. Investigation on the genetic signatures of antibiotic resistance in mulfrom different clinical sources taken from hospital patients. ti-drug-resistant Klebsiella pneumoniae isolates from National Guard Hospital, Riyadh. All were resistant to more than three antibiotics, including Cureus 12 (11) e11288 (2020). innovations.kaimrc.med.sa

Issue No.9

I M AG E S OUR C E / A L A M Y S TOC K P H OTO

Sequencing Klebsiella pneumoniae strains from a Riyadh hospital highlights genes that confer resistance to multiple antibiotics

DNA sequencing accelerates infection diagnosis

Detection of pathogenic genetic material in body fluids could speed up treatment of serious infections

new diagnostic technique provides fast and accurate identification of a causal pathogen in patients with serious infectious diseases, offering the possibility of accelerated diagnosis and treatment. For patients with serious infectious diseases, rapid identification of the causative pathogen is crucial to enable early administration of the correct treatment. However, the techniques currently used for pathogen identification have significant drawbacks. Growing pathogen cultures takes days or even weeks, and though polymerase chain reaction (PCR) tests can quickly identify pathogens, a different test is needed for each, meaning a specific pathogen must be suspected or multiple tests are needed. A team led by Charles Chiu of the

June 2021

University of California San Francisco, USA, set out to address these problems by developing a more efficient test based on metagenomic next-generation sequencing (mNGS). Their approach involves analysis of all genetic material in a patient’s body fluid sample to identify pathogens present. “The pathogens causing infectious syndromes are often indistinguishable on the basis of the clinical presentation, and the current diagnostic paradigm is slow, laborious and costly,” Chiu explains. “Metagenomic sequencing allows detection of the full spectrum of viruses, bacteria, fungi and parasites that cause infections in a single test.” In the study, 182 samples of various fluids were collected from 160 individuals with serious infectious diseases. Most

were hospitalised, and 39% required intensive care. The samples were analysed with mNGS to detect and identify any pathogens present. The pathogen responsible for the infection was known in 170 of the 182 samples, enabling the accuracy of the new test to be determined. The other 12 samples were from patients with probable infections for which standard tests had not identified the causative pathogen. The mNGS test identified the correct pathogen in more than 75% of the bacterial and 91% of fungal infections and had a low rate of false-positives. The test also identified the pathogens in seven of the 12 samples for which culture and PCR tests had been negative. Furthermore, the results could be obtained in as little as six hours. These findings demonstrate that an mNGS test could be used to accelerate diagnoses in hospitals. “More timely and rapid diagnosis has the potential to improve outcomes by providing actionable information to guide management and treatment of infectious diseases,” says Chiu. “We are now performing formal clinical validation of the assay in a clinically licensed laboratory and clinical trials to evaluate the utility of the body fluids assay in clinical practice.” Gu, W., Deng, X., Lee, M., Sucu Y.D.,Arevelo, S. et al. Rapid

pathogen detection by metagenomic next-generation sequencing of infected body fluids. Nature Medicine 27, 115–124 (2020).

VC H A L/ I S TOC K / G ET T Y I M AG ES P LUS

Sequencing of microbial genetic information can quickly identify the pathogen behind an infectious disease.

MEDICAL BIOTECHNOLOGYPARK

The Medical Biotechnology Park is a strategic project of KAIMRC/MNG-HA to contribute to the Saudi Vision 2030 through: • The development and commercialisation of biomedical R&D products, technologies and services • The contribution to economic and health improvement through science and innovations in medical and health sectors

WEBSITE: KAIMRC-BIOTECH.ORG.SA E-MAIL: KAIMRC-KMBP@NGHA.MED.SA PHONE NUMBER: +966-11-429-4516 TWITTER: @MEDICALBIOTECH

COVID-19

June 2021

YOUSS EF K H A LI L/ N AT UR E 20 21

Covid-19

A Global Challenge Assessing the response to the COVID-19 pandemic: How science won the race to develop a host of vaccines and is now tackling the challenge of emerging ‘variants of concern’ as mutations cause surges of infections around the world, spurring efforts to update vaccines.

innovations.kaimrc.med.sa

Issue No.9

COVID-19

A triumph for science: Hastening the race toward a COVID-19 vaccine

n the opening keynote of the COVID-19 Vaccine Forum that there is no single global regulatory body for vaccines, which hosted by KAIMRC in November 2020, Bali Pulendran of would simplify the currently cumbersome process of dealing Stanford University declared that he was “in awe” of the with regulators in different countries who often take different rapid pace at which COVID-19 vaccines have been devel- views on the same clinical data. oped. He explained how the many phases of vaccine research, The crucial basic research itself was accelerated by researchtrials, regulatory approval and large-scale manufacturing ers being well primed by existing work and by the novel nature had often previously taken 10 years or more. But in the case of of the first vaccines. Rather than the traditional approach of COVID-19, the first large administering viral proscale vaccinations began teins directly, these are In the case of COVID-19, the first large scale on 8 December 2020, based on RNA or DNA just under a year since that instructs the body’s vaccinations began on 8 December 2020, just the first case of the discells to manufacture a under a year since the first case of the disease ease was reported to the key immunogenic part World Health Organizaof the viral coat’s spike was reported to the World Health Organization. tion. protein. At the KAIMRC Forum, Researchers working Adrian Hill of the University of Oxford summarised the key fac- on these vaccines say they could be developed quickly in part tors behind the astonishing success of what he called “the grand- because we already had the technology to rapidly and routinely est global experiment in vaccine technology ever undertaken.” synthesize RNA or DNA of a desired sequence. RNA and DNA vacHe emphasised the unprecedented collaboration involving thou- cines have never previously been licenced for use in humans, sands of different specialists worldwide, all focusing their multi- although they have been used in veterinary applications and in disciplinary attention on one target. They worked at record speed many laboratory tests on animals. to sequence the viral genome, analyse its structure and explore The Pfizer/BioNTech and Moderna vaccines use synthetic sinthe options for vaccine development. gle-stranded messenger RNA (mRNA) molecules that contain the Hill then turned to the role of unprecedented levels of funding genetic instructions to directly induce the body’s cells to make from governments and other bodies, saying that for the first time the proteins that stimulate immunity. The Oxford-AstraZeneca in his career almost “unlimited funding” has been available. vaccine achieves a similar outcome using double-stranded DNA, He also talked of a new willingness by regulators to work much which is transcribed into mRNA by the normal metabolic activity faster than normal, which he views as one of the major lessons to within a cell. be learned for vaccine development in the future. Hill explained The Oxford team point out that DNA is more robust than mRNA

June 2021

YOUSS EF K H A LI L/ N AT UR E 20 21

An unprecedented international response by researchers, funders and regulators made it possible to develop COVID-19 vaccines in record time

A vaccine in a year Vaccine development timeline

November 2019

Retrospective studies suggest the first confirmed case of Covid-19 came on 17 November, in Wuhan, China

1st December 2019

First cases of the disease that would later become known as Covid-19 revealed by authorities in China (2 December)

January 2020

Chinese scientists isolate a novel coronavirus (7 January)

March 2020

US NIH begins Phase 1 clinical trial of an experimental vaccine developed in collaboration with Moderna Inc.

May 2020

Human trials of Pfizer/BioNTech vaccine begin, along with trials of many other vaccine candidates

July 2020

Phase 1/2 clinical trial results announced by Moderna

August 2020

Phase 1/2 clinical trial results announced by Pfizer

90%

October 2020

Submission of trial results data to regulators begins

November 2020

Phase 3 clinical trial results from Pfizer and Moderna indicate effectiveness rates above 90

January 2021

Vaccination programmes with Oxford-AstraZeneca and Moderna vaccines now also underway

December 2020

Several countries grant emergency authorizations for Pfizer/BioNTech, Oxford-AstraZeneca and Moderna vaccines to be used

COVID-19

Robust vaccination drives have meant shorter hospital stays around the world.

and the adenovirus’s tough protein coat also helps protect the genetic material inside, which makes their vaccine stable at significantly higher temperatures than mRNA-based vaccines—a significant benefit.The researchers behind the Oxford-AstraZeneca vaccine credit the “head start” they got through their many years of research on DNA vaccines as a key factor behind their rapid response. Sarah Gilbert, who designed the vaccine, explained to the KAIMRC Forum that the COVID-19 vaccine delivers DNA using a system which had already been developed in their laboratory. A harmless, modified adenovirus carries the DNA in their vaccine. “We had used this to make many different vaccines in the past,” Gilbert said, some of which were already in phase 1 clinical trials. All that is required to adapt this versatile system to a new disease is to change the DNA sequence being delivered. Together with an intensive research effort, this head start made it possible for the vaccine to move into clinical trials in April 2020, a mere 104 days after the researchers 22

June 2021

first received the genetic sequence of the SARS-CoV-2 virus responsible for COVID-19. This feature was also a key factor in accelerating the production of the Pfizer/ BioNTech and Moderna vaccines. Pfizer, which made the first COVID19 vaccine to get regulatory approval, emphasised the significance of their partnership with German company BioNTech in meeting the challenge so quickly. They say this brought together BioNTech’s specialist expertise in developing mRNA vaccines with Pfizer’s more broad expertise in vaccine technology, regulatory issues, and manufacturing and distribution. Most of the researchers placed particular emphasis on the unusually quick efforts of regulatory bodies worldwide to assess the results of fast-tracked clinical trials, in many cases, granting Emergency Use Authorizations for the earliest vaccines. These allow the vaccine to be used based on preliminary data provided that further surveys of efficacy follow as vaccination gets underway. The phases of vaccine trials normally

proceed consecutively and usually take several years. In the case of COVID-19, the massive funding available and the urgency of the situation made it possible to overlap some of the clinical trial phases. The researchers also pointed out that the vast number of infections worldwide made it easier and faster to run trials with many participants in a shorter time while still getting sufficient evidence to demonstrate efficacy. “Vaccines are good for pandemics, but pandemics are good for vaccines,” Hill told the Forum. The fact that COVID-19 rapidly became a pandemic helped get vaccines quickly developed and tested. For example, the Oxford-AstraZeneca team report that their vaccine “will have been tested on almost five times as many volunteers as is usually required for licensing a vaccine.” Hill also calls for regulators worldwide to come together to simplify and accelerate the regulatory process, which currently involves multiple national regulatory bodies and the ensuing complexities. According to him, this is the major change needed to improve vaccine development in the future. The key players in academia and industry generally agree that the experience of developing COVID-19 vaccines is likely to significantly improve the process in the future. If the new and quicker technology of RNA and DNA vaccines proves effective in the long term, it could accelerate vaccine development overall. The vast funding thrown at the COVID-19 challenge is unlikely to be available again, but the lesson that regulatory bottlenecks can be overcome may also bear fruit. If these lessons are learned, “developing new vaccines in three years instead of 10 years would become a bit more realistic,” says Hill.

JON N Y W EEKS /T H E G UA R DI A N - P OOL/G E T T Y I M AG E S

In the case of COVID-19, the massive funding available and the urgency of the situation made it possible to overlap some of the clinical trial phases.

KAIMRC EXPERIMENTAL MEDICINE

Three state-of-the-art vivarium facilities are located in Riyadh, Jeddah and Al Hasa. The vivariums are planned and designed according to international standards. They aim to assist biomedical research by providing animals and veterinary expertise. Moreover, they offer training and education in animal use for research. The facilities also work on the development and implementation of institutional policy, animal care and use policy including animal husbandry and veterinary care.

EMD@NGHA.MED.SA

COVID-19

Global accessibility: the path from vaccine trials to patients The unprecedented efforts and challenges to produce and allocate COVID-19 vaccines all over the world

ince the genetic sequence of SARS-CoV-2 was made public on 10 January 2020, researchers all over the world have raced to develop COVID-19 vaccines, backed by an unprecedented level of financial support. Vaccination programmes have started in about 50 mostly high-income countries, but the crisis demands a major global effort. At the ‘COVID-19 vaccine: Global challenges and prospects’ conference held by KAIMRC in November 2020, Saudi and international speakers discussed strategies to fast-track COVID-19 vaccine development and promote their equitable distribution worldwide.

COVID-19 in the Eastern Mediterranean region

Over one year after the start of the pandemic, COVID-19 has killed more than two million lives across the world and 24

June 2021

disrupted healthcare systems, economies and societies. In the Eastern Mediterranean Region, the World Health Organisation (WHO) reported more than 5 million cases and 125,000-plus deaths since the first case was reported in the region on 29 January 2020. Some countries, including Saudi Arabia, Jordan, the United Arab Emirates and Bahrain, have already signed bilateral deals with pharmaceutical companies and begun the vaccine rollout. However, other countries in the region and around the world have difficulty purchasing COVID-19 vaccines.

A global solution for equitable access

The Access to COVID-19 Tools (ACT) Accelerator was launched in April 2020 as a WHO & G20 initiative to support one of the biggest efforts to develop and

distribute new biomedical tools. The goal of the ACT-Accelerator is to reduce COVID-19 mortality and hospitalisation through the allocation of 2 billion doses of vaccine across the globe by the end of 2021, in addition to 245 million courses of treatment and 500 million diagnostic tests by mid-2021. The Covid-19 vaccines Global Access Facility (COVAX) within the ACT-Accelerator promotes the development and equitable distribution of COVID-19 vaccines, to try to prevent vaccine nationalism. This challenging project works on global solutions through a diversified portfolio of COVID-19 vaccines, strategic manufacturing, pooling of financial and scientific resources, and economies of scale. It is co-led by the Coalition for Epidemic Preparedness Innovations (CEPI), the Vaccine Alliance (Gavi), and the WHO, alongside key delivery partner

benefits and production costs. Furthermore, CEPI is also evaluating a second wave or generation of vaccines which could address the drawbacks of the first-generation vaccines. For example, they might be easier to deliver, cost less, provide protection after a single dose, have longer-lasting effects, or be stable at higher temperatures.

Most COVID-19 vaccines are manufactured in the US, India, China, the UK and Europe.

The Covid-19 vaccines Global Access Facility (COVAX) promotes the development and equitable distribution of COVID-19 vaccines, to try to prevent vaccine nationalism. UNICEF, and is possible thanks to the collaboration of governments, global health organisations, vaccine manufacturers and other private sector partners, universities, the Bill & Melinda Gates Foundation, civil society and philanthropy.

Ambitious timelines and broad portfolios

In total, the WHO lists more than 230 candidate vaccines against SARS-CoV-2 innovations.kaimrc.med.sa

in development, including 64 undergoing human trials. “The COVID-19 vaccine development process was crushed from 12 years to 12 months thanks to the effort of the different manufacturers across the globe, the support that has been given by different funding agencies and non-governmental organisations, like CEPI and the WHO, and the coordination that’s happening between private and governmental sectors,” said Ziad Memish, director of Research and Innovation Center at King Saud Medical City. At the conference, CEPI’s Richard Wilder explained that COVAX has invested in research and development portfolio that currently consists of nine candidate vaccines, and the programme is evaluating additional candidates. These vaccines are based on four different technological platforms with differing

Producing billions of vaccine doses is a gargantuan task. Normally, suppliers would be reluctant to scale-up their manufacturing facilities until they have received approval for a vaccine. However, COVAX is working with manufacturers to ensure that vaccine production starts ahead of regulatory approval. “Making vaccines on a large scale while clinical development is ongoing, is obviously risky, but it is really required to get a portfolio of vaccine candidates quickly,” said Holger Kanzler, programme officer at Bill & Melinda Gates Foundation. Most COVID-19 vaccines are manufactured in the US, India, China, the UK and Europe. Currently, aside from some facilities in Iran, the Eastern Mediterranean region lacks the capability to produce vaccines. At the conference, Peter Hotez from the Baylor College of Medicine in the US highlighted the fact that Saudi Arabia is extremely vulnerable to emerging infectious diseases due to its location and the high rates of non-communicable diseases such as diabetes. “Making the investment in biotechnology infrastructure for vaccine development is going to be essential. Saudi Arabia has universities, biotechnology companies, venture capital, and business sophistication: all the pieces are in place, and I think this needs to be a priority,” said Hotez. Yasser Al Obaidaa, CEO of Sudair Pharma, is of a similar mindset. “We need to build the infrastructure and capability to prepare for the next pandemic or epidemic. It should be a public and private partnership. We should work together Issue No.9

DH I R A J S I N G H /B LOOM B ER G VI A G ET T Y I M AG ES

A need for manufacturing capability in the Eastern Mediterranean region

COVID-19

The problem of affordability

More than 180 countries joined COVAX, including 92 low and middle-income countries that need funds to purchase the vaccine. COVAX needs to secure such funds via Advance Market Commitment (AMC) donors, Official Development Assistance (ODA), contributions from the private sector, and philanthropy. In this regard, the Kingdom of Saudi Arabia pledged US$150 million to support the COVAX-AMC initiative. Furthermore, countries could also donate any surplus vaccine doses. COVAX countries which can afford the vaccine provide the financial resources to buy vaccines for 10-50% of their population. However, they will initially only receive enough doses to vaccinate 20% of their population, with the remainder following once all of countries in COVAX have been offered this amount. By pooling resources, the self-financing countries not only help other countries in the fight against the SARS-CoV-2 but also increase their negotiating power and their chance of securing vaccines even if their own bilateral deals or negotiations fail. COVAX is also using its collective purchasing power in order to negotiate vaccine prices. Adrian Hill from the University of Oxford and the Jenner Institute explained that he and his colleagues insisted the company awarded the rights for their vaccine meet two requirements. It had to aim for global supply, finding manufacturing partners in low and middle-income countries, and it had to ensure a low price, as close to production costs as possible. “During a pandemic, vaccine developers have a duty to have a public health impact that’s as global as possible. We also need a structure in place like COVAX to make sure that vaccines are distributed equitably,” said Hill, who oversaw the Oxford-AstraZeneca COVID19 vaccine research and development and also collaborated with Naif Alharbi and other KAIMRC researchers to produce a candidate vaccine for Middle East Respiratory Syndrome. 26

June 2021

The challenges facing unprivileged populations

COVID-19 has exposed societal inequalities affecting minorities, indigenous peoples, migrant workers, refugees, and internally displaced persons. In light of this, the WHO recently congratulated Jordan for including refugees and asylum seekers in their national vaccination programme. With these inequalities in mind, COVAX has reserved about 5% of its available doses for acute outbreaks and humanitarian support. Countries participating in COVAX need to be ready to receive, store, and distribute the vaccine as well as to administer it. However, reaching vulnerable populations in war-torn countries and areas of political and social instability will be particularly challenging. Some of the COVID-19 vaccines need to be stored and transported at ultra-cold temperatures, which may not be available in remote areas and resource-limited countries. Furthermore, most of the approved and promising vaccines require two doses, which may be challenging to coordinate in some circumstances.

COVID-19 has exposed societal inequalities affecting minorities, indigenous peoples, migrant workers, refugees, and internally displaced persons. “The key solutions are collaboration, kindness and generosity,” says Mariwan Baker, founder and chairman of Bring Hope, a humanitarian foundation that helps refugees and people in poverty, partly by distributing medicines and hygiene items. “Before any nations, we are human beings. If you want to combat a human crisis, we have to take humanity as a base,” he says. Baker also highlighted the importance of collaborating with tribal and religious leaders, who play a major role in decision-making in some communities. Ultimately, the crisis will not be over until the coronavirus is under control everywhere, a sentiment captured in the Gavi slogan: “Nobody wins the race until everyone wins.” C HI N E N O UVELLE/S I PA /S H UT T ER S TOC K

to protect our countries against the next pathogen,” he said.

COVAX has reserved about 5% of its available doses for acute outbreaks and humanitarian support.

Masks, lockdown and vigilance attributed for curbing infection rates among healthcare workers across Saudi Arabia.

esults from a study in May 2020 of healthcare workers at the frontline of the battle against the COVID-19 pandemic in Saudi Arabia reveal that the seropositivity rate was low overall, though it varied across different regions and hospitals. Seroprevalence studies track the proportion of a population infected by a pathogen over a period of time. This is accomplished via immunoassays that measure the presence of antibodies in their blood serum. The prevalence of virus-neutralizing antibodies (NAbs) is an indicator of past infection as well as of immunity post-infection. The survey, the first of its kind in the kingdom, was conducted across 85 hospitals: 61 COVID-19 referral hospitals with confirmed COVID-19 patients, excluding those who were symptomatic, and 24 non-affected hospitals with no COVID19 patients. The latter did not report any innovations.kaimrc.med.sa

K I YOS HI TA K A HAS E S E G U NDO / A L A M Y S TOCK P HOTO

COVID-19 infection rate was low among healthcare workers early in the pandemic Serosurveys typically track detectable antibodies against SARSCoV-2 in a geographical population.

outbreaks among healthcare workers and were used as the control group. Blood serum samples tested from more than 12,600 healthcare workers had seropositivity rates from 0% to 6.31%. As expected, healthcare workers operating in case-hospitals with high COVID-19 exposure had a higher rate. In 8% of the tested samples, there was a lack of Nab due to the low level or presence of antibodies against coronaviruses. The low SARS-CoV-2 seropositivity could be an indication that vigilance in personal protective equipment and a nation-wide lockdown were successful in keeping the rate of asymptomatic COVID19 in healthcare workers at low levels, says Naif Alharbi, study co-author, and head of the KAIMRC Vaccine Development Unit. “This study is only part of the whole picture of COVID-19 epidemiology in KSA and needs to be taken in totality with other key studies and findings,” says co-author Jaffar A. Al-Tawfiq of Johns Hopkins Aramco Healthcare. The seropositivity rate varied between regions and also with the number of

community cases. “The variation in the seropositivity is likely to be related to the variability in the cases in that community or city. Healthcare workers are part of any community and they could be exposed to SARS-CoV-2 in the community,” explains Al-Tawfiq. Other studies have since been conducted to measure seroprevalence among the wider community in Saudi Arabia. Al-Tawfiq says that a study of blood from healthy donors found that the prevalence of antibodies to SARS-CoV-2 was low, although higher among non-citizens. Alharbi says that another survey showed that NAb is induced at a higher level in severe cases and peaks for three months post-infection. He has also been working on a more representative national seroprevalence study with over 11,000 samples collected between June and November 2020, which he hopes to publish soon. Alserehi H.A., et al. Seroprevalence of SARS-CoV-2 (COVID-19) among healthcare workers in Saudi Arabia:

comparing case and control hospitals. Diagn Microbiol

Infect Dis. 99, 115273 (2020).

Issue No.9

COVID-19

Vaccines vs variants: An ongoing race What does the rapid spread of SARSCoV-2 variants that affect vaccine potency mean for the fight against COVID-19?

s emerging COVID-19 ‘variants of concerns’ and mutations cause surges of infections around the world, pharmaceutical companies and researchers are racing to update and adapt their vaccines. The future may be unclear, but some scientists say the unprecedented scale of vaccine development and global collaboration give reason for hope. A myriad of COVID-19 vaccines were produced at record speed and authorized for emergency use, including mRNA-type vaccines and adenovirus vector vaccines. With the emergence of variants, the idea of developing boosters or creating seasonal or variant-proof vaccines has gained urgency and momentum. The emergence of variants—descendent viruses with errors in their RNA and consequently a different genetic code than the original virus—has raised concerns about the effectiveness of vaccination efforts. Some vaccines seem to fare better against some variants, but there are few absolutes.

June 2021

According to the US Centers for Disease Control and Prevention (CDC), last fall saw the birth of multiple variants, the most notable of which are B.1.1.7, commonly called the UK variant; B.1.351, the so-called South Africa variant, which emerged independently from B.1.1.74; and P.1, known as the Brazil variant, which the CDC reports has 17 unique mutations, including three in the receptor binding domain of the spike protein. B.1.1.7 is more contagious than other known variants and is associated with increased disease severity and possibly increased risk of death—a risk that, in late January, UK scientists were still trying to evaluate based on new analyses. Earlier this year, a medRxiv preprint—a paper that hasn’t been peer reviewed and thus has yet to be thoroughly evaluated— reported that a new variant of concern, tagged B.1.526, had been identified in New York, spreading among older and more frequently hospitalized people. The paper7 suggested that this variant has

found footing in the northeast of the US. Scientists are now rushing to understand how these variants cross react with each other, as well as how they interact with our immune system and, more specifically, with monoclonal (or laboratory-made) antibodies as well as antibodies produced naturally as a result of infection. Understanding these dynamics is an important step towards finding ways to neutralize the variants2. Penny Moore is among the scientists studying the characteristics of some of these variants in relation to monoclonal antibodies. In a March 2021 study in Nature Medicine,1 she was the first to show that the South Africa variant B.1.351 has the ability to resist convalescent plasma and completely evade three classes of neutralizing antibodies. When the data about B.1.351 first came out, Moore says she and her colleagues “were worried that the level of protection for people who were previously infected would be much less than we had hoped. The second major thing that we were very concerned about was that it might have implications for the efficacy of vaccines that were being rolled out in South Africa. Unfortunately, that did come to be.” Moore’s study suggested that reinfection was possible. A Nature paper5 by Alex Sigal and others published a few weeks after Moore’s confirmed that antibodies from recovered COVID-19 patients from the first wave of the epidemic in South Africa were less effective at neutralizing B.1.351. Moore’s work also indicated that vaccines targeting the SARS-CoV-2 spike may not be as effective against emerging variants of the virus. A separate study led by Michael Diamond looked at how antibodies fared against several variants. The study investigated monoclonal antibodies and

YOUSS EF K H A LI L/ N AT UR E 20 21

With the emergence of variants, the idea of developing boosters or creating seasonal or variantproof vaccines has gained urgency and momentum.

SARS-CoV-2 Variants Around the world, "variants of concern" are emerging

Scientists are tracking SARS-CoV-2 to identify variants that may pose increased risks or challenge vaccination efforts. Identifying the mutations in these variants and determining their effect on transmissiblity, severity, and immune response is critical to stay ahead of the virus.

B.1.1.7

B.1.351

B.1.617

P.1

Alpha

Beta

lncluding Kappa, Delta and other sub-lineages

Gamma

Sept 2020, UK

Oct 2020, South Africa

Oct 2020, India

Dec 2020, Brazil

More contagious

Greater Disease severity

Evade neutralizing antibodies

Possible Increased risk of death

Greater Disease severity

Evade neutralizing antibodies

Possible Increased risk of death

samples of serum from convalescent patients with COVID-19 and people who received the mRNA Pfizer-BioNTech vaccine, testing them against a panel of naturally occurring and synthetic SARSCoV-2 variants. Published in Nature Medicine 3 in March, the study found that current neutralising antibodies are less effective against the South African variants and other variants with specific mutations. The researchers recommended adjustments to the spike sequence used in some of the vaccines, as well updating monoclonal antibody cocktails to target highly conserved regions of the virus. A third study in Nature Medicine6 came to a similar conclusion: antibodies from people vaccinated against COVID-19 can neutralise B.1.1.7 but may partially or completely fail to neutralize B.1.351. This study used real viral strains instead of lab-engineered proxies. It is not surprising that the coronavirus is mutating—for the virus itself, this is business as usual. “Viruses are really very good at mutating to get away from anything that impacts them negatively, and in this case, it’s neutralizing antibodies which are a subset of your antibodies,” says Moore. “There’s a lot of pressure on the virus to change to get away from those.”

While the vaccine infrastructure has improved, testing of updated vaccines will have to be as elaborate as the trials of the original vaccines. In fact, Moore says that SARS-CoV-2 is not particularly mutating fast, noting that it mutates much slower than HIV, which she researched for most of her career. “What creates all these opportunities for the virus to pick up these mutations is the fact that there’s so many millions of people across the world who are infected.” However, there is a silver lining to the evasive tactics of B.1.351: a person infected by the variant produces broadrange antibodies that potentially inoculate against other variants, as per Moore. This was confirmed by Sigal’s Nature study5, which demonstrated that plasma taken from patients infected with B.1.351 during the second wave of the epidemic in South Africa was effective at neutralizing the strain that circulated during the first wave. Moore, and her colleagues are still trying to understand why antibodies from this variant are special. They are also still

uncertain about how future-proof these antibodies are. “Genetically, we do not know how the virus will mutate in the future. It’s a dead certainty that it will mutate, and new variants will emerge, but it is very hard to predict how that might happen,” Moore explains. According to Mark Zeller, who is part of the Andersen lab at the Scripps Research Institute that is investigating how viruses such as SARS-CoV-2 emerge and cause outbreaks: “We’ve proven that we can really make these vaccines pretty quickly. There’s a possibility that we end up in a situation where we just have to update vaccines regularly—it could even be every year,” he says. While the vaccine infrastructure has improved, Zeller cautions that tests of updated vaccines will have to be as elaborate as the trials of the original vaccines. “It will still take months, and then obviously [new vaccines and boosters] will have to be produced and distributed. But it can go faster than the first time around. And it almost certainly will,” he says. Moore notes that the pandemic has led to has spurred the development of vaccines and vaccine platforms. Some platforms, such as mRNA vaccines, “are very amenable to quick switches,” she says. “But understanding how well they will work requires a little bit more work.” 1. Wibmer, C.K., Ayres, F., Hermanus, T. et al. SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID19 donor plasma. Nat. Med. (2021).

2. Luchsinger, L.L., Hillyer, C.D. et al. Vaccine efficacy probable against COVID-19 variants. Science (2021).

3. Chen, R.E., Zhang, X., Case, J.B. et al. Resistance of SARSCoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies. Nat. Med. (2021).

4. Tegally, H., Wilkinson, E., Giovanetti, M. et al. Emergence of a SARS-CoV-2 variant of concern with mutations in spike glycoprotein. Nature (2021).

5. Cele, S., Gazy, I., Jackson, L. et al. Escape of SARS-

CoV-2 501Y.V2 from neutralization by convalescent plasma. Nature (2021).

6. Planas, D., Bruel, T., Grzelak, L. et al. Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies. Nat. Med. (2021).

7. Annavajhala, M.K. et al. A Novel SARS-CoV-2 variant

Studies have shown that current neutralising antibodies are less effective against variants, particularly those with specific mutations. 30

June 2021

of concern, B.1.526, identified in New York. medRxiv (2021).

M Y B OYS. M E/ /S H UT T ER S TOC K

COVID-19

BIOSTATISTICS & BIOINFORMATICS

It focuses on conducting stateof-the-art biomedical research SERVICES • Novel statistical and bioinformatics methods/tools • Biostatistics, mathematical modeling, protein modeling, next generation OMICS analysis, and artificial intelligence • Large collaborative initiatives that cover several disease areas • Independent research projects

• Outreach program for general technical advice as well as systematic educational activities

KAIMRC-DBB@NGHA.MED.SA

B L AC KJ AC K3 D / I S TO C K / GE T T Y I MAG ES P LU S

• Collaborations with mega projects that align with KAIMRC strategic initiatives

COVID-19

AZD1222 was among the first vaccines created to protect against COVID-19.

June 2021

ChAdOx1: More than a coronavirus vaccine

ZD1222, developed by the University of a simian adenovirus because “if you use a human Oxford and licenced to AstraZeneca, was adenovirus to immunise humans, you run into the among the first vaccines created to pro- problem of pre-existing immunity,” says Sarah Giltect against COVID-19. A non-replicating bert, professor of vaccinology of the University of viral vector vaccine which was approved for emer- Oxford and co-founder of the spin-off Vaccitech, gency use in several countries, it was later put on which patented the ChAdOx1 technology. Followhold because of links with the formation of danger- ing successful collaborations with other institutions ous blood clots. While the clinical trials and author- using other simian adenoviruses, Gilbert says “we isation procedures have received significant press wanted our own. We managed to acquire a chimcoverage, less has been panzee virus that had been said about the trailblazing described in the literature, “The host immune system technology that underand then a student in the pins AZD1222—a modified lab converted it to a vaccine learns to recognise chimpanzee adenovirus vector”—and ChAdOx1 and respond to the called ChAdOx1. was born. To create the platform, expressed protein.” Viral delivery Gilbert’s team modified the Viruses hijack infected cells viral genome to remove its and force them to produce copies of the virus itself. ability to replicate and to optimize its manufacture. Scientists have long leveraged this ability to create They can then insert the gene encoding a desired non-replicating ‘viral vector’ vaccines, in which a viral protein. The end result is an injectable soluvirus is genetically engineered to reduce or elimi- tion that infects cells around the injection site and nate pathogenicity but still prompt cells to produce causes very high expression of the target protein. the immunogenic proteins of another virus. This In the case of AZD1222, “something like 80% of the method exposes a host’s immune system to specific protein expressed from the adenovirus is spike proproteins from a target virus but not the virus itself, tein,” says Gilbert. enabling the host to safely build immunity . In the The host immune system learns to recognise and case of AZD1222, this protein is the spike protein of respond to the expressed protein, but because the SARS-CoV-2, the virus that causes COVID-19. virus can’t create new copies of itself, the shortIn 2012, researchers at the University of Oxford lived infection doesn’t proliferate around the body created ChAdOx1, a virus vector vaccine based on a and cause disease. This makes the platform very safe modified simian adenovirus. The researchers chose to use, even in people with a compromised immune

innovations.kaimrc.med.sa

Issue No.9

DES I G N C ELLS / I S TOC K / G ET T Y I M AG ES P LUS

At the core of a COVID-19 vaccine is a highly adaptable technology with the potential to protect against a range of viruses

COVID-19

since 2000, such as swine flu, avian flu, SARS, MERS, Zika, and Ebola, which have offered lessons in preparedness. In this context, it’s clear that the global research community needs to continue to prepare for what may come next.

Building for the future

The technology behind the COVID-19 vaccine has the potential to protect against a range of viruses.

system, says Gilbert. “It’s as if you have a coronavirus infection in your arm, but it’s not coronavirus, it’s the adenovirus and it can’t replicate.”

ChAdOx1 as platform rather than product

Gilbert describes the modified simian adenovirus as a “true platform technology” which can be modified to cause the expression of different viral proteins without any alterations to manufacturing or safety. Oxford researchers are using their platform to investigate vaccines for many diseases, such as tuberculosis, rabies, MERS, Dengue, and Zika virus. Ahmed Salman, a senior vaccinologist and immunologist at the University of Oxford, adds that ChAdOx1-based vaccines are easy to produce and stable once made, saying that large quantities can be produced “at a really low cost in a short amount of time.” The platform is also very effective at inducing a strong response from both B cells and T cells, whereas competing technologies often generate a skewed response. At the virtual KAIMRC conference “COVID-19 Vaccines: Global Challenges & Prospects Forum,” Gilbert described how her team managed to reach their first trials 34

June 2021

in humans just 103 days after receiving the genetic sequence of the spike protein. Vaccine sceptics believe that such rapid development means that these therapeutics must be poorly understood or poorly tested. Salman argues that vaccine research is normally hampered by slow bureaucratic processes and time wasted waiting for grants, approvals, and publication—all while people are suffering from a disease. With COVID-19, he says, we have a “good example” that things can be more streamlined. “I work on malaria, which doesn’t get [the same attention as COVID-19]. We’ll be in clinical trials in a few weeks, but we started research more than seven years ago.” Furthermore, vaccines such as AZD1222 weren’t created from scratch for COVID19; rather, they build on decades of existing research. Scientists also did not have to face the pandemic blindly—it was anticipated. In 2016, Salman says, the University of Oxford started its “Pandemic X” project. Scientists prepared plans based on anticipating what diseases might cause a global pandemic, what therapeutics might help, and what infrastructure should be put to work to abate disaster. Salman adds that there have been many regional epidemics

For Gilbert and Salman, work hasn’t stopped with the rollout of the Oxford/ AstraZeneca vaccine. “We’re really busy,” says Gilbert, adding that the trials are ongoing. The researchers will follow up with trial participants six months and one year after their second dose to collect blood samples and generate long-term data. Gilbert and her team have extended their studies to include an HIV-positive cohort in the UK and South Africa. However, many of these trials have been halted because of fears that the vaccine can cause dangerous blood clots in rare cases. The concerns appeared after the vaccine’s rollout, when several countries reported that it appears to be linked with dangerous blood clots in very rare cases. Despite the rarity, this led some regulators to temporarily suspend use of the vaccine and later to authorize its use only by some groups, such as older people. Overall, the consensus among health officials is that the benefits still outweigh the risks, but research is being done to under the mechanism behind the clotting in the hope that this will make it possible to reduce the risks further, as well as helping guide the evaluation of other vaccines. “We’ve got approval in 15 countries so far, but there are other regulators still making their assessments and sending through questions that we need to answer very quickly,” says Gilbert. “And once there’s any time to do anything else, I’ve got all the other vaccine projects that I should have been working on last year.”

M Y B OYS .M E/ /S H UT T E R S TOC K

“Since 2000, regional epidemics such as swine flu, avian flu, SARS, MERS, Zika and Ebola have offered lessons in preparedness.”

Better animal models for COVID-19 needed The lack of severe illness in animal models of COVID-19 suggests a wide gap between the disease in humans and animal models.

he significant differences in COVID-19 outcomes between humans and animal models mean that different models should be used depending on the questions asked, say KAIMRC researchers. They also propose that genetic engineering might create more accurate models to assist research efforts. The authors analysed 27 original research papers from January 1 to May 20, 2020. using a variety of primate species, mice, ferrets, and hamsters as models of the human disease. They hoped to identify one or more animal models that effectively mimicked the full range of consequences of COVID-19 in humans. “Our findings were not what we hoped for,” says Salleh Ehaideb of KAIMRC, explaining that the variety of outcomes in humans was poorly replicated by the innovations.kaimrc.med.sa

model systems. The animal models tended to replicate mild cases of COVID-19 with full recovery phenotype, while researchers aim to help develop therapy and assess vaccines for human that prevent severe disease and fatality. “We were not surprised by this disappointing finding,” Ehaideb adds, “as studies of other viruses in the same family reached similar conclusions.” However, the response of animals to experimental vaccines and anti-viral drugs more closely matched the desired response in humans, so they may nevertheless be valuable for proof-of-concept drug trials. The authors suggest that one reason for the mismatch may be that the virus binds tightly to the ACE-2 receptor on human cells, but less well to the structurally different ACE-2 receptors in animals,

particularly rodents, which are the most common laboratory animals. They also note that although the virus binds well to the ACE-2 receptor of nonhuman primates, which is similar to the human ACE-2 receptor, the animals do not develop severe COVID-19 or die. This is partly because ACE-2 and other receptors which are essential for entry and spread of the virus differ in the lungs, liver, and kidney between human and primates. “This changes the types of tissues and organs that will be severely infected,” says Ehaideb. Another likely factor is significant differences in the immune response in humans and animal models. This work could help guide other researchers in choosing the best animal model, with its advantages and limitations, for their research, as well as helping clinicians interpret the effects of drugs or vaccines before applying them to humans. Genetic engineering, may also help make the models closer to humans although this might be difficult for coronavirus studies. The KAIMRC team does not have the approved biosafety facilities to develop new models, but they hope other researchers will follow up on their findings and suggestions. Ehaideb, S. N., Abdullah, M. L., Abuyassin, B. & Bou-

chama, A. Evidence of a wide gap between COVID-19 in humans and animal models: a systematic review. Criti-

cal Care 24, Article number: 594 (2020).

Issue No.9

F OTOG R A F I X X / I S TOC K / G ET T Y I M AG ES P LUS

Genetic engineering might create more accurate models to assist research efforts.

Computed tomography (CT) chest scan showing changes in both lungs of a confirmed COVID-19 patient.

COVID-19 impact does not end with hospital discharge Hospital discharge could still mean a long way to full recovery for severe COVID-19 patients

June 2021

hospital discharge is not always the end of the disease for COVID-19 patients, according to recent research. A team in China has examined COVID patients six months after discharge and reported long-term health effects. The ongoing COVID-19 pandemic has infected many millions since its emergence in December 2019. Although most infected people experience mild symptoms, severely ill patients require hospitalisation. While the main aspects of COVID-19 during the acute phase have been extensively investigated, the long-term consequences of the disease remain unclear. Bin Cao of the China-Japan Friendship Hospital and Capital Medical University in Beijing, who led the new study, explains that lasting physical and psychological effects have been seen in patients with severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which suggests that COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)could similarly affect discharged patients. “These long-term

sequelae urgently need to be understood,” he says. Cao says that this study includes the largest cohort with the longest follow-up time for potential sequelae in COVID-19 adult patients. The researchers examined 1733 patients released from the first COVID-19-designated hospital in Wuhan, China between January and May 2020. The follow up visit occurred on average about six months after symptom onset and five months after discharge. To investigate long-term effects in detail, the researchers used multiple diagnostic tools to evaluate new and persisting symptoms, changes in lung function and physiology, and quality of life. For the first time, they also determined how the disease impacts other organs. They observed at least one symptom in 76% of the patients, predominantly fatigue or muscle weakness, anxiety or depression and sleep difficulties. Reduced lung function and abnormal chest images reminiscent of SARS sequelae were seen in over one third of the patients, especially those who received oxygen support and mechanical ventilation. Some COVID19 survivors exhibited emerging signs of impaired kidney function, diabetes, and blood clots. “This means that many people have not recovered completely six months after symptom onset,” Cao says. “We should continue follow-up and monitor the recovery of these patients after discharge.” Certain patients showed a dramatic drop in SARS-CoV-2-targeting antibody levels after discharge. The protective ability of these antibodies is unknown, but “their decrease definitely raises concern about COVID-19 reinfection,” Cao says. “We still do not know how long it takes to recover fully or whether complete recovery is possible,” Cao says. The team is currently extending the follow-up of these patients to 12 months to further assess COVID-19 consequences and better understand recovery. Huang, C. et al. 6-month consequences of COVID-19 in

patients discharged from hospital: a cohort study. The

Lancet 397, 220–32 (2021).

M OHA M E D A BDE L R A ZE K / A L A M Y S TOCK P HOTO

COVID-19

INFECTIOUS DISEASES RESEARCH

Is dedicated to enhancing prevention and treatment of infectious diseases through diversified basic, translational, and clinical research activities, surveillance programs and reference laboratory services. It aims to become the underpinning of the infectious disease public health research for the Kingdom of Saudi Arabia.

THE LABORATORY IS DIVIDED INTO • Microbial Genomics and AMR Unit, • Virology and Vaccine Development unit, and • Biosafety Level 3 laboratory (BSL3).

KAIMRC-ID@NGHA.MED.SA

KNOWLEDGE ECONOMY

Turning scientific discoveries into commercial solutions Abdelali Haoudi, Managing Director of the Medical Biotechnology Park at KAIMRC, discusses the barriers and possible solutions to commercialising academic research in Saudi Arabia and other Arab countries 38

June 2021

Innovations: Why do you feel Arab nations lag behind in converting promising research into commercial and clinical applications? Haoudi: One reason is the lack of coherent national research and development strategies. The research is often more focused on the needs of education programmes. Those dedicated research centres or institutes that have been established are not really well equipped for translating research findings into products and solutions that can have a direct impact on society, health and the economy. Most of the universities in Arab countries lack active technology transfer offices, and their research findings end up being disseminated—and perhaps languishing—only in academic research

AS HR A F HA B I B 20 20

The Medical Biotechnology Park at KAIMRC offers solutions to commercialising academic research in Saudi Arabia.

publications. We can see from the experience of other countries’ approaches that technology transfer offices play a critical role in supporting and guiding researchers towards patent filing and licensing deals. Innovations: You are MD of the KAIMRC Medical Biotechnology Park, but are such science and technology parks relatively rare in Arab countries? Haoudi: Yes, very few Arab countries possess truly dedicated science and technology parks or research incubators. We know these can play an extremely important role in the commercialisation of research findings and supporting start-up companies based on academic research. Innovations: What is being done to address these problems? Haoudi: Some countries, such as Saudi Arabia and Qatar, have recognised the importance of developing national strategies for R&D. There are increasing opportunities for R&D and commercialisation in many Arab countries. Innovations: So is it mainly a question of national governmental policy that needs to be addressed?

when the inventor or the entrepreneur is affiliated with an academic institution, and most of the time it is extremely difficult. At the same time, most of the academic institutions in Arab and developing countries are sponsored by the government and are not often well equipped to accommodate the entrepreneurial requirements needed to establish start-up companies. There are also still a lot of policy gaps in some of these countries. For example, in order to translate research findings in the health sector, it is necessary to go through clinical trials to test the safety and efficacy of novel products, but in some countries, there are no laws or policies to support and govern the conduct of clinical trials. This can present a tremendous handicap towards developing a thriving health economy. Innovations: Is funding for researchbased start-ups also hard to find? Haoudi: Yes, in most Arab and developing countries, less than 1% of overall government spending goes to R&D. Start-up companies resulting from innovative research need funding to be able to develop their research findings into products or solutions. There are few or no opportunities from angel investors,

Haoudi: The current government policies don’t usually go hand in hand with the setup of a thriving innovation and commercialisation ecosystem. The translation of academic research into commercial products needs to proceed through the creation of start-up companies to commercialise findings or through academic-commercial partnerships. But in most situations, government policies are not really permissive of this fast translation of research findings.

innovations.kaimrc.med.sa

Innovations: What are the best ways to tackle these problems? Haoudi: Given the scarcity of research funding in Arab and developing countries, the most promising way forward is to plan science and technology clusters or parks for start-up companies, with shared enabling platforms and shared support services. This will allow these fledgling companies to save tremendous costs in initial investment and optimize their resources towards better outcomes. Arab and developing countries should also focus their R&D strategies on research targeting critical and urgent challenges facing them. R&D is very costly, especially in areas such as health, energy and the environment. It’s time to focus on forging collaborations and partnerships, in particular public-private partnerships, in order to translate results from public research institutions into impactful outcomes. There are tremendous opportunities for regional and global R&D collaborations and partnerships. Innovations: Are you hopeful that the situation will soon improve?

Innovations: So does this cause difficulties even for individual researchers with interesting results that could potentially be developed? Haoudi: Yes. It is not clear how to obtain a commercial license to set up a start-up

venture capital, research foundations, or other private sources of funding. This poses a serious limitation to these companies, preventing most of them from growing and having an impact on economic development.

KAIMRC’s Dr. Abdelali Haoudi is confident there are increasing opportunities for R&D and commercialisation in many Arab countries.

Haoudi: I am hopeful that the situation will improve for some countries, such as Saudi Arabia, Morocco, and possibly others. These countries in particular have recognised the importance of developing and investing in all facets of the R&D continuum. A successful R&D enterprise represents an integrated ecosystem with multiple factors to ensure a successful economic impact, with a sound vision and strategy, sufficient and sustainable funding support, talented personnel, supportive regulatory frameworks, strong public-private partnerships, and true visionary leadership. This interview has been edited for length and clarity.

Issue No.9

AGEING AND THE BRAIN

Reducing chronic maladaptive inflammation rejuvenates brain cells in mice Scientists pinpoint a single molecular signalling pathway that could be used to reverse age-associated metabolic and immune dysfunction in mice.

he quest to slow down or reverse the mental decline triggered by age-related inflammation in the brain has been vigorously pursued. A discovery by scientists at Stanford University School of Medicine offers insights into cellular ageing and the promise of restoring cognitive functions. Ageing is associated with excess, chronic, low-grade inflammation, a process that specialists refer to as ‘inflammaging’ and believe is involved in many diseases, from Alzheimer’s to cancer. Inflammaging involves changes in the activity and biology of macrophages, specialised cells that detect and destroy bacteria and which form the first line of defence against disease-causing organisms and pathogens. Aged macrophages store energy differently to young and

June 2021

Ageing is associated with excess, chronic, low-grade inflammation.

healthy ones; for instance, instead of using it for fuel, they save up glycogen to use it in launching a stronger immune response during acute inflammation. But this stronger immune response, an overreaction of sorts, carries a hefty price in the aged brain; it damages normal tissue, tires the immune system, and exacerbates degenerative conditions. Katrin Andreasson, a professor of neurology at Stanford Medicine, is investigating the link between metabolic activity and maladaptive inflammation. In a new study published in Nature, her team showed that microglia—the resident macrophage cells inside our brains—are highly sensitive to changes in the levels of an inflammatory molecule called prostaglandin E2 (PGE2), which they sense via the cell-surface receptor EP2.

Microglia effectively reign over the brain’s active immunity. When they are not busy battling pathogens and suppressing inflammation, they’re clearing the misfolded proteins associated with neurodegeneration,1 removing old or dead neurons and cellular debris, and promoting neurogenesis by protecting and nourishing healthy and youthful neurons. But microglia—as central as they are to brain health—can also accidently turn against the very organ they protect by going into overdrive in response to distress signals that the receptors on their surface pick up. As a result, they end up killing neurons as they try to limit infections or damage.2

Slowing down cognitive decline

The team led by Andreasson used human myeloid cell cultures and aged mouse

glucose as glycogen, starving them of glucose. This problem is exacerbated by another property of aged macrophages which Andreasson and colleagues uncovered in the study. Cells can usually turn to other fuel sources for energy, such as glutamine or lactate, but Andreasson’s team discovered that aged macrophages lack that ability. They have a ‘fundamental dependence’ on glucose as a fuel source. Together with the increased conversion of glucose into glycogen, this puts macrophages in an energy-depleted state that drives an inflammatory response.

Pinpointing a molecular pathway

brains to investigate the links between metabolism and inflammaging in microglia. Blood-forming myeloid cells are a type of immune cell that also encompasses tissue-based macrophages. “The levels of PGE2 increase quite significantly with ageing in both the blood and the plasma,” says Andreasson. “Obviously, we could not do a trial on thousands of human subjects, looking at different ages, but we could look at the cells. We could look at the macrophages, young and old.” Andreasson and her colleagues found a significant difference in the level of production of PGE2 not only in young versus old macrophages, but also in young versus old serum and brain tissue. Higher levels of PGE2 and EP2 in older microglia make them lock up their innovations.kaimrc.med.sa

The EP2 receptor came to the team’s attention in 2015 when they linked it with Alzheimer’s in a mouse model. “That got a fair bit of press,” says Andreasson. She and her team had discovered that reducing EP2 in microglia affected the Alzheimer phenotype. In fact, knocking out EP2 by 50% yielded “dramatic effects,” she says, which, together with other evidence “kind of identified this pathway as an important one in ageing.” Treating mice with EP2 inhibitors that block PGE2 signalling reversed metabolic suppression and restored normal cell function. “The first conclusion is that you could probably reverse brain ageing by some sort of peripheral intervention,” says Andreasson. “The second is that you can reverse brain ageing by restoring youthful metabolism to your immune cells.” By fixing the glitch in metabolism that leads to energy-deficient states in macrophages, Andreasson and her colleagues

have managed to whittle down a complex cell disorder to a single molecular switch that they can toggle. Eyal Amiel, a University of Vermont associate professor of medical laboratory science who was not involved in the study, calls this an impressive piece of work. “What is really paradigm shifting is the simplicity of identifying a single metabolic access, a single inflammatory mediator, and a single receptor that underlie both the inflammatory and metabolic functionality of the cells, with a direct and impressive impact on neurodegeneration,” he says. “To have all of those things line up and work out is really breathtaking.” The million-dollar question, according to both Amiel and Andreasson, is what this means in terms of mitigating or reversing neurodegenerative diseases in humans. While human trials may still be far down the pipeline for the Stanford Medicine team, the immediate next step, says Andreasson, is to find more pathways that work in similar ways then take it from there. “I’m not sure if there are going to be that many pathways that are going to be like this, but there might be more,” she says. “We are looking at another one right now. There might be another pathway very similar to this one that could be increasing with ageing, that suppresses myeloid metabolism, and which basically promotes these maladaptive ageing inflammation responses.” In the meantime, other approaches could help people avoid or reverse inflammaging, says Andreasson. “Keeping a healthy lifestyle, exercising, eating right—this is all associated with inflammation, and I wonder if that actually might help correct the changes in metabolism that occur with ageing,” she says. “That is something we would like to test.” 1. Minhas, P.S., Latif-Hernandez, A., McReynolds, M.R.

et al. Restoring metabolism of myeloid cells reverses cognitive decline in ageing. Nature 590, 122–128 (2021).

2. Brown G.C., Vilalta A. How microglia kill neurons. Brain

Res 2, 288-297 (2015).

Issue No.9

S T EVE G S C H M EI SS N ER /S C I EN C E P H OTO LI B R A RY / G ET T Y I M AG ES

“Keeping a healthy lifestyle, exercising, eating right— this is all associated with inflammation, and I wonder if that actually might help correct the changes in metabolism that occur with ageing,”

AGEING AND THE BRAIN

Depression linked to premature brain ageing

Evidence is accumulating that depression and premature brain ageing are closely linked

t’s not unusual to feel older than your years, but that might be more true for some people than they realise. There’s growing evidence that mental illnesses such as depression are somehow related to a sufferer’s brain resembling that of an aged person. But does depression cause a brain to age prematurely or does premature ageing precede the onset of disease? Researchers use physical, cellular, and molecular markers to predict an individual’s ‘biological age.’ With these tools, they are trying to understand why biological age differs from actual age in some people. Research into accelerated brain ageing is an offshoot of this line of investigation. An individual’s chronological age can be predicted by the metrics of their brain. As humans age past 30, their brain starts slowly deteriorating over the remainder of their life. These changes are both physical, such as grey matter atrophy, and functional, such as a decline in cognitive flexibility, memory, and visual processing speed. However, some things, such as vocabulary and some verbal skills, survive the ageing process. With accelerated brain ageing, a person’s brain metrics belie their actual age. The changes may be slight, but a person’s brain looks and behaves closer to that of an older brain. Some researchers, such as Katharine Dunlop of Weill Cornell Medicine, are working to delineate the relationship between accelerated brain ageing

June 2021

and depression. In 2021, together with a team of researchers in the US and Canada, she published a paper on the subject in the journal Neuropsychopharmacology. They used images of more than 700 healthy adult brains to create a model that predicted age. When the model was used to predict the age of depressed patients, it predicted an age that was, on average, two years older than the patients’ actual age. Dunlop and her team also found that patients with older-looking brains were more likely to be impulsive, and males with older brains tended to have more severe symptoms. “We found that if you were more impulsive regarding financial decision-making, you tended to have an older-looking brain,” says Dunlop. This finding echoes a much larger study from the ENIGMA major depressive disorder consortium. In this large, multinational study, led by Laura Han from Amsterdam UMC, the Netherlands, the ENIGMA consortium found structural variation in depressed patients’ brains that made them appear to be approximately one year older. Dunlop says that prior to the ENIGMA MDD working group study, a few smaller studies showed “conflicting but not incompatible results” regarding whether brain ageing and depression were linked. Dunlop also remarks that although some conditions, such as schizophrenia and dementia, show “clear-cut” accelerated ageing,

things are a “little fuzzier” when it comes to depression. The ENIGMA study goes some way to settling the debate, however, as the largest study to date on the topic. In an effort to boost the study of accelerated brain ageing and depression, Han and her team also produced a web-based tool that allows other research groups to test their own data. “There are 77 structural brain features like thickness and surface area and volumes of the brain,” says Han. If another research team acquires these metrics and plugs them into the consortia’s web tool, it will offer up a prediction of brain age. Dunlop says she believes that brain ageing research is a stellar example of collaborative research done right. “The spirit of collaboration is exemplified in a lot of the brain ageing work because it requires a lot of data from multiple sources. That ENIGMA paper is a really good example of that,” she says.

KON DOR 8 3 / A L A M Y S TOC K P HOTO

Depression is linked to physical and functional brain changes otherwise associated with ageing.

It’s too early to tell, says Han, if being able to detect or predict accelerated brain ageing will prove useful for patients. However, one of the “hopeful messages,” according to her, is that there’s a lot of variation and overlap between healthy controls and patients with depression, and the ENIGMA study found an average deviation of just over one year in those with accelerated brain ageing. Dunlop adds that other factors also greatly influence behavioural and structural metrics associated with brain ageing, such as sex and socioeconomic status. Dunlop and her team also had access to outcome data in their study, as all participants underwent transcranial magnetic stimulation (TMS) therapy to treat their depression. “Earlier studies said ‘if you’re older, [TMS] doesn’t work,’” says Dunlop. Now it’s known that this isn’t the case. Instead, structural atrophy increases the distance innovations.kaimrc.med.sa

from the stimulator to the brain—something that can be remedied by a simple equipment adjustment. Dunlop’s study found no significant link between accelerated brain ageing and TMS response. Interestingly, they found that older looking brains responded better to placebo stimulation. But studies are ongoing—Han and her colleagues went on to publish a follow-up paper that showed a potential neuroprotective effect of antidepressants on brain age. For now, research efforts such as Han’s and Dunlop’s continue to try to untangle the relationship between depression and brain ageing. One key question, says Dunlop, is figuring out which happens first and which causes which—depression or brain ageing? “That’s the million-dollar question. I don’t think we have the answer to that just yet” she says. The link is more clear for some other

conditions: a previous study tracked people with mild cognitive impairment and found that brain ageing predicted who would go on to develop full-blown dementia. There are examples of brain ageing coming before certain diagnoses, but for psychiatric disorders, it’s a more complex story, and “probably not a unidirectional relationship,” Dunlop says. It’s likely that depression and brain ageing feed back into each other and involve mechanisms of chronic stress and inflammation. “The chicken and the egg discussion, it’s a real hurdle. And to answer these questions takes time and money,” Dunlop says. 1. Dunlop, K. et al. Accelerated brain aging predicts

impulsivity and symptom severity in depression. Neu-

ropsychopharmacology (2021).

2. Han, L.K.M. et al. Brain aging in major depressive disorder: results from the ENIGMA major depressive disorder working group. Molecular Psychiatry (2020).

Issue No.9

AGEING AND THE BRAIN

KAIMRC’s Medical Genomics Research Department is the only unit of its kind in Saudi Arabia, taking patients from initial genetic testing to a formal diagnostic report.

Uncovering the genetic roots of rare developmental disorders Clinical genomics experts are profiling patients and their families to diagnose childhood diseases that derail healthy neurological development

olicy-makers and researchers use ‘rare disease’ to describe a disorder that affects a small percentage of the population, but the term is slightly misleading—collectively, these

June 2021

disorders are estimated to affect roughly 5% of the world’s population. However, this collective figure comprises thousands of debilitating disorders and syndromes that are each very uncommon,

some arising in fewer than one in a million newborns. Discovering the basis of these diseases not only offers the possibility of screening for them – and perhaps developing treatments – but also improves understanding of human development. These conditions can often be traced to malfunctions in just a single gene, and Majid Alfadhel’s team at the Medical Genomics Research Department (MGRD) at KAIMRC is actively engaged in tracking down these causative mutations. “The conditions that most interest me are known as ‘inborn errors of metabolism’,” says Alfadhel, chairman of the MGRD referring to a category of genetic disorders that interfere with essential enzymatic pathways underlying the manufacture and digestion of fats, proteins and other biomolecules. A subtle mutation in an enzyme can have far-reaching consequences. For example, it could lead to the accumulation of toxic chemical intermediates, or deficiencies in necessary cellular building

Seeking a syndrome’s signature

Most rare genetic disorders are recessive, which means they only produce symptoms in children who have inherited mutations affecting both copies of a gene. To identify these, it is ideal to also perform genomic analysis of unaffected siblings and parents, because these can help researchers quickly home in on genes that are doubly mutated only in the patient. For example, in one study from February 2020, the MGRD team performed whole-genome sequencing on the full immediate family of a young boy with global developmental delay (GDD), axial hypotonia, and impaired neurological function, including extremely limited speech.1 This allowed them to identify a mutation that alters the amino acid sequence of an enzyme called UDP-glucose dehydrogenase (UGDH), which contributes to the production of certain complex carbohydrates. Several studies in animal models have indicated that UGDH is essential for healthy development, with malfunctions having particularly severe consequences for the heart, brain and skeletal system, but this study was the first time that a mutation innovations.kaimrc.med.sa

in this gene had been directly linked to human disease. Alfadhel and his colleagues predicted that the mutation they discovered destabilizes the UGDH enzyme and impedes its normal catalytic activity. In a second study from September 2020, Alfadhel’s team uncovered the mutation underlying a syndrome affecting a brother and sister who exhibited mild intellectual disabilities, GDD, and distinctive dysmorphic features including a ‘triangular’ facial structure.2 The initial diagnosis was made by whole exome sequencing of the young girl—the subset of the genome comprising protein-coding genes—which led the investigators to a causative mutation in a gene called EMC10. They subsequently confirmed this mutation’s role through targeted genetic analysis of the parents and the girl’s affected brother. EMC10 encodes one subunit of a complex that facilitates the folding of other proteins. Defects in other components of this complex are known to have far-reaching effects, producing a spectrum of neurological problems, but this was the first description of a clinical effect of mutations in EMC10. “This gene plays a key role in developmental milestones, with the potential to cause neurodevelopmental disorders,” says Alfadhel. Unlike in the case of UGDH, this mutation did not affect the protein-coding region of the gene, but rather one of the regulatory elements involved in splicing. Splicing is the biochemical process that cells use to prepare newly-transcribed RNA molecules for translation, and defects here can lead to proteins that are truncated or contain jumbled sequence features. Splicing abnormalities were also the culprit in a third study, where the MGRD team investigated four individuals from two different families affected by GDD3 that describes children born with clear deficits in motor function, social behaviour, speech, or other neurological functions. Whole-genome sequencing showed that all four patients had the same mutation in both copies of a gene called RAP1GDS1, an important signalling molecule that facilitates a wide range of cellular activities. Alfadhel notes that this particular

syndrome—which may now acquire his name, as its discoverer—highlights a potentially important developmental role for a broader class of signalling proteins. “Our observations add to the diverse and multi-symptomatic group of Mendelian disorders caused by variations in the RAP1GDS1 gene and related pathways,” he says.

Accelerating genome-guided medicine

The broader goal of the MGRD is to go beyond discovery, to translate their findings into meaningful changes in clinical practice and patient care. To this end, the department is building ties with other research centres, hospitals, and pharmaceutical companies to develop more sophisticated diagnostics and drugs based on their genetic findings. But Alfadhel and his team are also looking into opportunities to further streamline their workflow and achieve an even higher diagnostic success rate. “We need to improve the genome databases and our ability to differentiate between pathogenic and benign variants, and minimize the variants of unknown significance,” he says, referring to mutations for which the functional impact is insufficiently clear to indicate a role in disease. More sophisticated computation could play a role here, and Alfadhel is keen to make use of artificial intelligence and other algorithmic tools that could enable faster and more accurate interpretation of complex genomic data from many individuals. 1. Alhamoudi, K.M., Bhat, J., Nashabat, M., Alharbi, M., Alyafee, Y., Asiri, A., Umair, M. & Alfadhel, M. A missense mutation in the UGDH gene is associated with developmental delay and axial hypotonia. Front. Pediatr. 8, 71 (2020).

2. Umair, M., Ballow, M., Asiri, A., Alyafee, Y., al Tuwaijri,

M., Alhamoudi, K.M., Aloraini, T., Abdelhakim, M., Althag-

afi, A.T., Kafkas, S. et al. EMC10 homozygous variant

identified in a family with global developmental delay, mild intellectual disability and speech delay. Clin. Genet. 98, 555–561 (2020).

3. Asiri, A., Aloyouni, E., Umair, M., Alyafee, Y., Al Tuwaijri, A., Alhamoudi, K.M., Almuzzaini, B., Al Baz, A., Alwadaani, D., Nashabat, M. et al. Mutated RAP1GDS1 causes a new

syndrome of dysmorphic feature, intellectual disability & speech delay. Ann. Clin. Transl. Neurol. 7, 956–964 (2020).

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AS H R A F H A B I B 20 20

blocks, which could stunt normal development and lead to lifelong disabilities or even early death. To uncover such mutations, Alfadhel’s team works with patients and their families, using genome sequencing to identify potentially causative mutations that are subsequently validated through computational analysis and functional testing in the laboratory. The MGRD is the only unit of its kind in Saudi Arabia, taking patients from initial genetic testing to a formal diagnostic report, and Alfadhel says that his team has achieved a roughly 50% success rate in finding causative mutations. In just two years, they have characterized 20 new genes and gene variants, and established formal diagnoses for six diseases. These achievements pave the way for developing molecular diagnostics that could help doctors recognize such syndromes earlier and could even suggest therapeutic interventions that might halt or slow disease progression.

How melanoma manipulates its way to metastasis A growth factor secreted by melanoma cells makes the immune system ignore metastasis

ertain cancers can take control of elements of the body’s immune system, tricking immune cells into favouring the growth of cancer cells rather than attacking and destroying them. The deadliness of melanoma comes from its ability to metastasize rapidly to other organs if it is not treated early, and a new study indicates this process may involve manipulation of the immune system. A certain proportion of melanoma patients do not respond to immune checkpoint blockade therapy, suggesting that their immune system may be hijacked by melanoma cells. Now, María Soengas and her colleagues at the Spanish National Cancer Research Center (CNIO) in Madrid, Spain, have shown that a growth factor protein called midkine (MDK), which is secreted by melanoma cells, manipulates the immune system

June 2021

microenvironment. This causes immune cells to ignore the cancer threat and allow melanoma to spread. The team had previously shown that midkine plays multiple roles in metastasis, not just in melanoma but also in other tumours, including gastric and liver cancer. In their latest study, the researchers conducted RNA-sequencing and proteomics analyses of patient biopsy samples to examine how midkine affects gene expression profiles. In addition to showing that patients with a poor prognosis had high levels of midkine expression, the researchers identified a suite of genes affected by changes in midkine levels. Soengas and her team then turned to mouse models of melanoma to further investigate midkine and its mechanism of action. The team found that high levels of midkine secretion by melanoma cells create an inflamed microenvironment enriched in cytokines (proinflammatory proteins) and other tumourigenic molecules. This environment makes immune cells such as macrophages and T cells ignore the cancer cells, creating a suppressed immune microenvironment that favours metastasis. Mice with high midkine expression were more likely to suffer metastasis and to be resistant to immune checkpoint blockade therapies. When the team blocked midkine expression, macrophages and T cells began to function normally again, attacking and killing the melanoma cells and reducing cancer spread. The team identified several midkine-related genes that were linked to high midkine expression levels, and these could provide valuable biomarkers to identify patients less likely to respond to immunotherapies. As they wrote in their Nature Medicine paper, “this data not only links MDK signalling to poor prognosis and sets the proof of principle for dual MDK-ICB [midkine-immune checkpoint blockade] inhibition in melanoma, but also serves as a platform for future studies in other tumours and inflammatory diseases.” Based on this, the researchers believe that treating metastatic melanoma with a dual therapy that targets midkine and the immune checkpoint blockade could dramatically improve patient chances of survival. Cerezo-Wallis, D. et al. Midkine rewires the melanoma microenvironment toward a tolerogenic and immune-resistant state. Nature Medicine 26 1865-1877 (2020).

innovations.kaimrc.med.sa

Issue No.9

S TOC K T R EK I M AG ES , I N C . / A L A M Y S TOC K P HOTO

The 3D structure of a melanoma cell. Midkine, which is secreted by melanoma cells and linked with immunotherapy resistance, trains immune cells to turn a blind eye to cancer spread.

Skin cancer diagnoses could be improved by human-computer collaboration in clinical settings.

AI-supported decision-making improves skin cancer diagnosis

Researchers showcase a framework for image-based AI systems to assist doctors deliver more accurate diagnoses

achine learning improves the diagnosis of skin cancer when humans and artificial intelligence (AI) work together, according to a new study in Nature Medicine. Diagnostic AI has become more accurate and reliable in recent years. Medical researchers have been mining it for opportunities to support research in clinical settings. Now, Harald Kittler of

June 2021

the Medical University of Vienna, together with Philipp Tschandl and Christoph Rinner, show how human–computer collaboration through AI-based support can help physicians and clinicians interpret images of skin lesions. “In skin cancer diagnosis, collaboration improves diagnosis significantly,” says Kittler. “It’s also better than AI or a human alone, which means that the future should be directed into getting

Tschandl, P. et al. Human–computer collaboration for skin cancer recognition. Nature Medicine 26, 12291234 (2020).

P E T E R S CHAT Z / A L A M Y S TOCK P HOTO

humans and artificial intelligence to work together, to get the best of both worlds.” The researchers first trained a convolutional neural network on an open-source dataset of pigmented malignant and benign lesions. In tests, their algorithms outperformed both human-acquired results and other machine-learning algorithms that had been developed and tested with the same image dataset. Next, the researchers developed a web-based interface for clinicians to view the output of the algorithms using different classifications, representations, and levels of engagement. One provided multiclass probabilities for each of the possible diagnoses, the second provided malignancy probability, and the third was a content-based image retrieval model that allows physicians to search databases and dig up similar images with known diagnoses. Finally, people from 41 different countries (‘raters’) were asked to diagnose batches of images, with and without AI-based decision support. The results show that the availability of AI-based multiclass probabilities increased the accuracy of the raters’ diagnosis from 63.6 to 77 percent. This type of AI-support also influenced raters to change their initial diagnosis to align with the AI prediction—though less often if they were confident—and the support was especially useful for less experienced clinicians. This paradigm of human-AI collaboration is particularly useful in a postCOVID-19 world, in which physical access to clinicians and healthcare providers has become restricted, according to the researchers. Although the focus of the study is on skin cancer recognition, the researchers say that their conclusions are applicable to similar research in image-based diagnostics, though the algorithms first need to be tested rigorously in real-life settings. “The real world is always more complex than a confined situation of an experiment,” says Kittler.

MEDICAL GENOMICS RESEARCH

Is equipped with the latest technologies and poised to carry out cutting-edge research aimed at addressing medical problems with an emphasis on the people of Saudi Arabia. The major areas of research are in the fields of human genetics, medical and cancer genomics, hepatology besides cellular/gene therapy.

SERVICES • Next-generation sequencing • Microarray • Sanger sequencing • Prevention genetics technology • Functional studies & real-time PCR

KAIMRC-MGRD@NGHA.MED.SA

A KAIMRC study has found that support from family members vastly improves chances of recovery from serious injuries.

Family support hastens recovery Family ties are key for successful recovery from injuries that can lead to temporary or permanent disability

June 2021

trong family ties improve our ability to recover from serious injuries, according to new research from KAIMRC. Injuries, primarily from road traffic accidents, are the second leading cause of death in Saudi Arabia. Although mortality rates are declining due to improved treatment, the number of people discharged with some form of disability is rising. “Identifying the factors that affect recovery from long-term disability after injury is crucial to guide planning for interventions aimed at improving trauma outcomes,” says KAIMRC researcher, Sarah Almarwani. Previous studies have identified a range of factors that influence rehabilitation after injury, including age, type of disability and family support. To gain insight into the role of family cohesion in patient recovery in Saudi Arabia, Almarwani and her colleagues interviewed 249 adults who were hospitalised at the King Abdulaziz Medical City following blunt trauma. In the first interview, the researchers asked patients in the hospital about their occupation, income, marital status and quality of life before the injury, using the

Almarwani, S. M., Hijazi, L. O., Alamer, M. A., Alnwaiser, J. M., Aldakheel, R. A., et al. The association between

family cohesion and disability following blunt trauma: findings from a level-I trauma center in Saudi Arabia.

Injury epidemiology, 7, 40 (2020).

ZM S / S TOCK / G E T T Y I M AG E S P LU S

validated EQ-5D-5L disability scale. In addition, a family support scale was used to measure the strength of the relationship between the patient and their immediate family and to assess family cohesion. The researchers determined the extent of recovery through a follow-up interview conducted three months after discharge They found that patients with poor family cohesion reported greater disability in the first interview. These patients reported more pain, difficulties with mobility and self-care, and an inability to perform usual activities, such as driving and house chores, as well as significantly higher levels of depression and anxiety compared to those with stronger family ties. After three months, 165 patients responded to the follow-up interview. Most of them (88%) continued to report disability, with approximately 75% reporting pain or discomfort and 50% reporting difficulties in performing usual activities. However, patients with poor family cohesion were significantly less likely to recover from depression or experience improvements in mobility, regardless of age, sex or length of hospitalization. “Our results are consistent with other studies showing that strong family support has a positive impact on both physical and mental recovery after injury,” Almarwani says. By identifying patients with suboptimal family cohesion in hospital, it may be possible to offer them additional support and counselling aimed at strengthening emotional ties with family members to help improve their recovery. In light of the findings, Almarwani calls for more investment in the prevention of road traffic accidents; increased awareness among health care providers about the role of family cohesion and mental health in post trauma care; and more rehabilitation centres and public health guidelines to decrease the burden of injuries.

Investigating the factors affecting burn patient survival Data from patients on mechanical ventilation offers insight into factors affecting survival

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To ensure a patient’s vital signs are stable, intensive care treatment typically starts with intubation and mechanical ventilation, which are essential to ensure that severely burnt patients can breathe without difficulty. 2019. Eighty of these patients received mechanical ventilation because of inhalation injury. More than 95% of the admitted patients

Ismaeil, T., et al. Survival analysis of mechanically ventilated patients in the burn unit at King Abdulaziz Medical City in Riyadh 2016-2019. International Journal of

Burns and Trauma 10, 169–173 (2020).

PH AN I E / A L A M Y S TOC K P H OTO

more effective and tailored treatment for sufferers of severe burns could soon be available. KAIMRC researchers have assessed the mortality rates of burn patients in need of mechanical ventilation and identified factors contributing to their survival. Burns affect the skin or other tissues to various degrees. Minor burns, which involve the surface of the skin and some underlying layers, can heal rapidly with simple pain medication. Major burns spread to all skin layers and to deeper tissues, such as muscles, organs and bones, and often lead to the loss of the burned area. These life-threatening injuries require intensive and prolonged treatment in a specialised unit. State-of-the-art critical care methods and dedicated teams have substantially reduced the mortality rate of burn patients. To ensure that a patient’s vital signs are stable, intensive care treatment typically starts with intubation and mechanical ventilation, which are essential to ensure that severely burnt patients can breathe without difficulty. Nonetheless, mortality rates remain quite high. Fatmah Othman, who led the study, says that data on the survival of burn patients admitted to intensive care units and requiring mechanical ventilation varies widely, and information on this topic is also scarce at the national level. The researchers evaluated the mortality rate of 356 patients admitted to the burn units of King Abdulaziz Medical City and King Abdullah Specialist Children’s Hospital between January 2016 and July

survived their injury, a better rate than in other developing countries. “This can be explained by our highly advanced practices and specialised team,” Othman says. Unfortunately, 20% of the mechanically ventilated cohort died. Patients older than 14 had a higher mortality rate than younger patients, probably due to differences in physiological mechanisms and immune responses. Othman says that comorbidities, which are more prevalent in the non-survivor group, can also increase mortality rates in older patients. Burns exceeding 60% of the body resulted in a higher mortality rate than minor injuries. Inhalation injury and medical complications extending the hospital stay also aggravated the mortality rate. In particular, ventilator-associated pneumonia, organ failure, and sepsis—a body’s severe response to infection that destroys its own tissues and organs—were the most significant causes of death in mechanically ventilated patients. The team plans to expand this study to other centres around the Kingdom.

Data on the survival of burn patients admitted to intensive care units and requiring mechanical ventilation varies widely.

Issue No.9

A fatty diet disturbs circadian brain metabolism A high-fat diet changes metabolic oscillations in brain regions that control circadian rhythms

June 2021

K IR I LL KUR AS H OV/ S H UT T ER S TOC K

he circadian rhythms that keep processes such as the sleep/ wake cycle, body temperature and hormone levels in step with light/dark cycles are tightly linked with the oscillation of metabolites during a 24-hour period. An international study led by researchers in the US showed that a high-fat diet (HFD) can disturb circadian metabolic rhythms in the brain, revealing an unexpected susceptibility of brain clocks to nutritional choices. Diet affects the function of many organs, such as the liver, intestines or pancreas, by modifying their endogenous clock. This alters the daily production cycles of important molecular factors and metabolites. However, little is known about the effects of diet and changes in metabolite production on the master clock in the brain, the suprachiasmatic nucleus (SCN), which keeps our other biological clocks in sync. Paola Tognini and her colleagues examined the complete set of metabolites in the SCN and medial prefrontal cortex (mPFC), a brain area related to higher cognitive functions and emotional behaviour. “Understanding how diet impinges on the metabolism of these two brain areas is relevant for the health of the body and the mind,” she says, explaining that the researchers compared metabolites in these tissues in mice fed either a HFD or a normal diet. They found that a HFD altered the number, type and oscillation phase of circadian metabolites. “We saw how metabolites, which were not oscillating upon consumption of a balanced diet,

A high-fat diet in mice altered the number, type and oscillation phase of circadian metabolites.

started to oscillate after high-fat feeding,” Tognini explains. The effects differed drastically between the SCN and mPFC. The metabolic profiles of these regions were also consistent with changes in their gene expression profile, confirming that a HFD affected the oscillation of metabolites in a region-specific manner. “We were surprised at both the extent of the effect of a high-fat diet on oscillating metabolites in the brain and its specificity,” says Tognini. Some of these changes involve metabolites with established roles in neuronal plasticity, communication and survival. “Our results raise the possibility that

prolonged consumption of high-fat foods could have deleterious effects on various aspects of brain function and behaviour,” says Tognini. An improved understanding of how diet affects circadian regulation and the function of the SCN and mPFC could point the way towards novel therapeutic approaches for a range of chronic diseases associated with the disruption of circadian rhythms, such as mood disorders and dementia. Tognini, P. , Samad, M., Kinouchi, K., Liu, Y., Helbling, J.C.

et al. Reshaping circadian metabolism in the suprachiasmatic nucleus and prefrontal cortex by nutritional challenge. PNAS 117, 29904–29913 (2020).

Liposomes carrying the right drug combination could help in the fight against drug-resistant microbes

ombining the antibiotic azithromycin with a mucous-clearing drug called N-acetylcysteine within lipid bubbles could provide a new treatment for drug-resistant bacterial infections. Tests by researchers at KAIMRC and King Saud bin Abdulaziz University for Health Sciences suggest the formulation has the potential to improve the ability of azithromycin to inhibit and kill antibiotic-resistant E. coli. Harmful strains of E. coli, gram-negative bacteria found in the lower intestine of warm-blooded organisms and in fecal matter, can cause urinary tract infections, respiratory illnesses and fatal diarrhoea. Antibiotic-resistant strains are on the rise globally. “Drug-resistant bacteria are a major problem that threatens many lives,” says Alaa Eldeen Yassin, who led the study. “Clinicians need more treatment options.” Previous research has shown that N-acetylcysteine can be combined with antibiotics to prevent the formation of treatment-resistant microbial biofilms on surfaces such as dental implants and catheters. It is also known that the antibacterial activity of azithromycin and other antibiotics can be increased when encapsulated in lipid-based drug delivery systems called liposomes. The researchers tested azithromycin alone, within a liposome (LA) and combined with N-acetylcysteine within a liposome (LAN). These three formulations were evaluated against an E. coli strain

innovations.kaimrc.med.sa

with some resistance to antibiotics and a multi-drug resistant (MDR) strain. The lowest concentrations needed to prevent growth of the antibiotic-resistant strain and to kill it were 21 times lower for the LA formulation than for azithromycin in its own. Likewise, these formulations were effective against the MDR strain at one-fifth of the concentration needed for azithromycin. The inclusion of N-acetylcysteine caused a 17% reduction in the lowest concentrations needed to prevent growth of the MDR strain and to kill it but provided no benefit against the antibiotic-resistant strain. The researchers then tested the lowest concentrations of azithromycin, LA and

Aljihani, S.A. et al. Enhancing azithromycin antibacterial activity by encapsulation in liposomes/liposomal-N-ace-

tylcysteine formulations against resistant clinical strains of Escherichia coli. Saudi Journal of Biological Sciences 27, 3065-3071 (2020).

Experimental formulations in lipid bubbles could help combat drugresistant bacteria.

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I BR E A K M E DI A / A L A M Y S TOCK P HOTO

A properly packaged mix overcomes antibiotic-resistant bacteria

LAN needed to prevent growth of biofilms of the bacteria. Azithromycin was no more effective against the MDR strain when in the LA and LAN formulations than when alone. However, the LA and LAN formulations were better at reducing biofilm formation by the antibiotic-resistant strain. Yassin adds that he expects LA and LAN will prove to be effective against other drug-resistant bacteria, not just E. coli. Despite the fact that LA and LAN were stable at biological temperatures, further tests found that their formulations were unstable when exposed to sputum and blood plasma. The researchers believe this problem can be overcome by changing the lipid content of the liposomes. The group plans to change the formulation in an effort to further increase its antibacterial activity, and also hopes to test it in animals and, ultimately, in clinical trials.

Animating the inanimate

Molecular crystals are rarely dynamic and their ability to move is limited.

olecular crystals are not known for their dynamism, according to Rabih Al-Kaysi. Chemists pay them little interest, because they’re not generally thought of as exciting substances. Al-Kaysi, a professor at King Saud bin Abdulaziz University for Health Sciences and KAIMRC, has recently published a paper which bucks this trend. The study, carried out with a team from Saudi Arabia, Japan and the USA, reports a ‘smart’ molecular crystal that continuously oscillates when illuminated with two wavelengths of light, a discovery the researchers hope will lead to further developments in microrobotics.

June 2021

Motile materials are not new. Other researchers have previously demonstrated that certain materials can be made to change form in response to external stimuli, such as light or an electrical or magnetic field. However, this capability has mostly been demonstrated in soft materials such as polymers. Examples of hard molecular crystals that move are few, and their ability to move is limited. Light causes a change in the geometry of individual molecules in these crystals. However, these hard photomechanical crystals tend to only do one thing when activated, says Al-Kaysi. Whether it’s a jumping motion, a twisting one, or bending, “you shine a light on them, they do

that action, it’s gone,” he says. In contrast, the crystalline microwires developed by Al-Kaysi and his team oscillate continuously. The microwires are composed of the compound (Z)-DVAM. When exposed to a continuous source of UV and visible light, they oscillate, moving forward at a speed of 7 micrometers per second (0.007 millimeters per second). This mimics the behaviour of flagella, the whip-like apparatus that some biological cells use to move. This discovery is the fruit of methodical effort to find a crystal structure with such properties, says Al-Kaysi, as theory predicted that one should exist. “With a lot of experiments, eventually you find that ‘sweet spot,’” he

says, where the “thickness, length, and the photochemistry [of the crystal microwires] all work together and give you this autonomous motion.” The (Z)-DVAM flagella not only exhibit superior properties compared with other molecular machines but are also significantly smaller than polymer ones, expanding their potential uses. With the discovery of these crystalline microwires, researchers now have a light-activated actuator that needs no wires. Al-Kaysi describes this as “a quantum leap forward.” Tong, F. et al. Light-powered autono-

mous flagella-like motion of molecular crystal microwires. Angewandte Che-

mie International Edition 60, 24142423 (2020).

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Swimming crystalline microwires could be the progenitors of futuristic microrobotics systems

Seatbelt use in Saudi Arabia remains low A survey reveals that young adults, women and people suffering from depression and anxiety are less likely to buckle up

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The Saudi population has a lower level of seatbelt compliance and a higher rate of fatal road traffic crashes than other developed countries, leading to a burden on the economy and public health. reported depression and anxiety were 26% less likely to wear seatbelts than those who did not report a mood disorder. Women were 86% less likely to fasten

Alghnam, S. et al. Predictors of seatbelt use among Saudi adults: Results from the National Biobank Project. Fron-

tiers in Public Health 8 (2020).

F I LI P P O BAC C I / E+ / G ET T Y I M AG ES

Saudi survey reports that around 40% of participants regularly fasten their seatbelt when in a car, and the compliance rate is correlated with age, gender, mental health and other habits. These findings can support the Kingdom’s efforts to improve traffic safety. Seatbelt usage is an effective method to reduce road injuries and fatalities. However, the Saudi population has a lower level of seatbelt compliance and a higher rate of fatal road traffic crashes (RTCs) than other developed countries. In the United States, 2% of RTCs are fatal, but in Saudi Arabia the proportion is 23% according to one study and 15% according to a more recent study. Nevertheless, these high estimations can reflect the number of losses in the workforce, hospital resources and human capital, leading to a significant burden on the Saudi population, economy and public health. Wearing seatbelts became compulsory for drivers and front-seat passengers in 2000 and has been enforced with surveillance cameras since 2018. In this study, KAIMRC researchers surveyed 5,790 adults affiliated with the Ministry of National Guard Health Affairs in Riyadh. The survey was conducted between 2017 and 2019, and the data is part of the Saudi National Biobank, an ongoing project that evaluates the health behaviours of the Saudi population. The analysis showed a higher compliance rate among older individuals. Respondents between 26 and 45 years of age were nearly 50% more likely to fasten their seatbelts than those who were 18-25 years old. Interviewees who

their seatbelt than men. However, many women sit in the rear of the car, where the use of the seatbelt is not compulsory in KSA. Seatbelt compliance among Saudi women who have obtained their driving licenses since 2018 needs further studies. Furthermore, cancer patients were twice as likely to buckle up as those without cancer, and people who brush their teeth more than twice a day were also in the habit of fastening their seatbelts. The researchers say that this demonstrates that people who follow a healthy lifestyle may tend to adopt safe habits in the car as well. “This study highlights the need for further investment in public health programmes that target specific groups and focus on seatbelt compliance for injury prevention,” says public health researcher Suliman Alghnam of KAIMRC and KSAU-HS. “A significant commitment is required to curb road deaths as KSA works to reduce the RTCs mortality rate by 7% annually in alignment with the Saudi Vision 2030.”

Wearing a seatbelt significantly improves traffic safety, but compliance with seatbelt laws varies between different groups in Saudi Arabia. Targeted interventions to increase compliance could help.

Issue No.9

Mice treated with mucus-penetrating nanosuspensions of HDAC inhibitors showed improved rates of full-term delivery. Drugs formulated using nanocrystals (seen at left) help prevent preterm births in mice.

Nanotechnology prevents preterm birth in mice Formulation helps overcome mucus barriers for targeted drug delivery

new nanomedicine strategy for delivering drugs to the female reproductive tract could help prevent women from going into labour prematurely. Each year, around 1 in 10 babies worldwide are born before 37 weeks of gestation, resulting in more than 1 million deaths due to complications resulting from preterm birth. The steroid hormone progesterone is sometimes used to prevent early delivery in at-risk women, but current treatment formulations often have little effect because they fail to deliver the hormone to the appropriate tissues of the cervix and uterus. A team from Johns Hopkins University in the USA designed a nanosuspension system that enables vaginally

June 2021

dosed drugs to overcome the mucus barrier of the female reproductive tract and reach uterine tissues, where they can forestall labour. The system involves grinding drugs into miniature crystals about 200 to 300 nanometers in diameter—smaller than the size of a typical bacterium. A stabilizing agent is then added to keep the nanoparticles from getting stuck in the vagina’s protective mucus, which normally traps foreign particles such as microbes—but also medicines—and prevents their entry into the body. The researchers tested the system in mice experimentally induced to develop uterine inflammation, an unpredictable major condition that often leads to premature labour in humans and results

The researchers found that mice treated with mucus-penetrating nanosuspensions of HDAC inhibitors, both with and without progesterone, showed improved rates of full-term delivery. Large litters of healthy, normal pups were born. By comparison, mice injected with the drugs in their body cavity—like untreated mice— went into labour prematurely, with no surviving offspring. “Delivery matters,” says Laura Ensign of Johns Hopkins, who led the research. “And we must sometimes think outside the box of pills and injections to develop effective treatments.” In other mouse studies, Ensign and her colleagues have used their nanosuspension system to enhance drug delivery in the gut, in the airways and at other mucosal surfaces. Kala Pharmaceuticals, a company cofounded by Ensign’s close collaborator and mentor, Justin Hanes, has licensed the technology and developed two topical eye treatments for people, one for dry eye disease and one for post-operative ocular inflammation and pain. “There are many diseases affecting mucosal surfaces that would benefit from more targeted local and sustained drug delivery,” Ensign says. Fortunately, her technology now makes that possible. Zierden, H.C. et al. Enhanced drug delivery to the reproductive tract using nanomedicine reveals therapeutic

options for prevention of preterm birth. Science Trans-

lational Medicine 13, eabc6245 (2021).

HA N N A H ZI E R DE N

in nearly 4 million global premature births annually. They focused on vaginal administration of two types of drugs: histone deacetylase (HDAC) inhibitors, which they showed can help to inhibit the contractility of the uterine wall in human cell experiments, and progesterone, which has known anti-inflammatory effects.

An artificially intelligent route to better prediction of diabetes risk A neural network model developed at KAIMRC can identify patients at risk of diabetes with unprecedented accuracy

he use of artificial intelligence (AI) to predict risk of certain diseases could not only save lives but also reduce the workload of over-burdened medical staff. Now, KAIMRC’s Riyad Alshammari and his co-workers have developed a highly accurate model to identify patients with diabetes based on simple test results and details about lifestyle. Diabetes cases are on the rise worldwide, bringing associated risks of complications including heart disease and strokes. In Saudi Arabia alone, experts predict that there will be 2.5 million more diabetes patients by 2030. While genetic factors account for only a small fraction of diabetes risk, it is established that the disease is more closely associated with obesity and other lifestyle parameters. This means that models based on personal data can be innovations.kaimrc.med.sa

successful without the need for complex laboratory tests. “AI can help healthcare providers redefine their strategies to prevent and manage diabetes,” says Alshammari. “This will save medical expenses for both patients and healthcare authorities.” Alshammari and a team at KAIMRC, King Saud Bin Abdulaziz University for Health Sciences, and Simon Fraser University in Canada used a cloud computing service to build and test four algorithms based on machine learning. They also acquired data on more than 66,000 patients from Ministry of National Guard Hospital Affairs between 2013 and 2015 who had undergone hemoglobin A1c (HgbA1c) tests to determine whether they were diabetic. The dataset included 17 attributes per patient, such as age, body mass index, blood pressure, and several lab tests.

To test each algorithm, the researchers used a 10-fold cross-validation process. “We divided the original data randomly into ten equal-sized sub-datasets,” Alshammari explains. “One of the ten was used to train the model, and the rest were used to validate the model. We repeated the process until every sub-dataset served as the training set.” The most successful model was a neural network algorithm called Deepnet, which correctly identified 88.5% of patients as diabetic or non-diabetic. “Deepnets are an advanced form of AI that mimic the human brain. They can be trained to learn about data and pick out patterns,” says Alshammari. The researchers are hopeful that such accurate predictions from routine health checks will lead to earlier detection and allow for improved initial management of the disease. If so, Deepnet could help healthcare authorities save some of the billions of dollars that are currently spent on managing diabetes. Alshammari plans to explore how models such as Deepnet could empower individuals to monitor their own health risks using the Internet of Things. “AI could be deployed in small devices attached to the body and connected to smart phones,” he says. Alshammari, R, Atiyah, N., Daghistani, T. & Alshammari,

A. Improving accuracy for diabetes mellitus prediction by using Deepnet. OJPHI 12(1):e11 (2020).

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SA N JER I / E+ / G ET T Y I M AG ES

Algorithms that can predict an individual’s risk of diabetes will play an important role in managing the increased worldwide prevalence of the disease.

Microglia are thought to play a key role in childhood glaucoma.

June 2021

A key role for microglia in childhood glaucoma

utation of a gene linked with primary congenital glaucoma (PCG) alters the performance of cells that surround, protect and maintain the optic nerve. The progression of glaucoma is not completely understood, but these findings shed some light on the molecular mechanisms behind the disease and its complications. PCG affects children younger than four and is responsible for 5% of childhood blindness worldwide. A mutation in the CYP1B1 gene is responsible for 63% of PCG cases in the western region of Saudi Arabia. However, how this mutation results in damage to the optic nerve is still unclear. Researchers at KAIMRC, King Saud Bin Abdulaziz University for Health Sciences and King Saud University used CRISPR to introduce the mutation into cultured microglia, astrocytes and mesenchymal stem cells isolated from rats. They found that the mutation has particularly severe consequences in microglia, which are known to

innovations.kaimrc.med.sa

play a vital role in the immune defence of the central nervous system. The growth of microglia dropped by around 60% three days after induction of the mutation. In addition, many of the mutated microglia died prematurely, leading to an elevated inflammatory response. Together with an increase in cellular stress and a decline in mesenchymal stem cells, this could cause damage to the extracellular matrix, which provides structural and biochemical support to the optic nerve, as well as the trabecular meshwork, which controls the pressure inside the eye. “Microglia keep surprising scientists with their activities. I would like to understand whether keeping them alive helps treatment or medical management,” says KAIMRC’s biomedical scientist Bahauddeen M. Alrfaei, leading author of this study. In addition, monitoring microglia in glaucoma animal models will lead to new and better therapies.” The researchers also reported an increase in the expression

of several pro-inflammatory proteins. In particular, MMP-2 production was increased in mutated astrocytes, cells which are involved in the maintenance and survival of neurons. This could further damage the extracellular matrix surrounding the optic nerve. Altogether, these findings show that CYP1B1 mutation may disrupt eye development through the loss of microglia, degradation of the extracellular matrix and increased cellular stress. The researchers suggest that the resulting inflammation might explain why some types of eye surgery for glaucoma patients fail. “We hope that this and future studies will help us to understand whether the inflammation in childhood glaucoma is preventable via anti-inflammatory treatments or other non-invasive procedures,” says Alrfaei. Alghamdi, A., Aldossary, W., Albahkali, S.,

Alotaibi, B. et al. The loss of microglia activities facilitates glaucoma progression in association with CYP1B1 gene

mutation (p. Gly61Glu). PloS One 15.11 (2020).

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P. B O G DA N OV-C . SO L A- J. SA M P EDR O- M . VA LER I /VA LL D’H EB R ON I N S T I T UT DE R EC ER C A ( VH I R )

The mutation in most Saudi children with primary congenital glaucoma disrupts optic nerve development through its effect on microglia

Sequencing immune system genes for stem cell transplant success Sequence data from immune system genes of nearly 29,000 Saudi stem cell donors will help match them to patients

n improvement in the Saudi Stem Cell Donor Registry (SSCDR) means that patients in need of stem cell transplants will have a lower risk of complications. The addition of sequence data from the immune genes of potential donors reduces the chance of a mismatch. SSCDR, launched in 2011 by King Abdullah International Medical Research Center(KAIMRC) and the Ministry of National Guard Health Affairs, lists more than 75,000 registered potential donors who are willing to donate their blood-forming hematopoietic stem cells (HSCs) to patients around the world with life-threatening diseases such as leukaemia. Transplanted HSCs can reboot the production of healthy blood cells, but they need to be compatible with the patients’ immune system.

June 2021

Human leukocyte antigen (HLA) genes play a key role in determining the success of HSCs transplantation. HLA genes produce cell surface proteins that bind to bacteria, viruses and cancer cells, and activate the immune system to attack them. The frequency and distribution of HLA alleles differ widely between different ethnicities and geographical areas. “Matching HLA alleles between patient and donor in stem cell transplantation is an important factor for a successful outcome,” says KAIMRC’s Ali Hajeer, founder of the SSCDR, and lead author of the new study. A mismatch between donor and recipient HLA alleles can lead to organ rejection, graft failure and cause graft versus host disease, a major post-transplant complication in which donated cells recognise the host’s cells as foreign and attack them. The new study describes the frequencies of HLA types in nearly 29,000 Saudi stem cell donors. “By sequencing such a large population, we found many new alleles that were not known before and were first reported in the Saudi population, and we identified new associations between different genes of the HLA system that are not seen in other populations,” Hajeer explains. These data can be used to predict the chances of finding a compatible unrelated donor for patients who need a stem cell transplant but don’t have an HLA-compatible relative. Although the chances of finding an HLAmatched relative are quite high in Saudi Arabia due to the high rate of consanguineous marriages, it is estimated that up to 40% of patients cannot find a matched HSCs donor within their family. The results also provide a useful starting point for investigating associations between particular HLA alleles and autoimmune diseases such as type I diabetes, rheumatoid arthritis and celiac disease, among others. “We will continue sequencing HLA and other polymorphic genes in our donors creating a larger Saudi cohort to further understand the genetic basis of the immune response in Arabs,” Hajeer says. KAIMRC researchers are assembling DNA fingerprints of immune genes in Saudi stem cell donors to help find a match.

innovations.kaimrc.med.sa

Jawdat, D., Uyar, F.A., Alaskar, A., Müller, C.R., Hajeer, A. HLA-A, -B, -C,

-DRB1, -DQB1, and -DPB1 allele and haplotype frequencies of 28,927 Saudi stem cell donors typed by next-generation sequencing. Front Immu-

nol. 11, 544768 (2020).

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“By sequencing such a large population, we found many new alleles that were not known before and were first reported in the Saudi population.”

A molecular link between diabetes, obesity and cellular ageing Obese people and type-2 diabetes patients have high levels of LMNA, a protein associated with cellular ageing

June 2021

besity and type-2 diabetes tumour suppressor protein p53 and cycare known to increase the risk lin-dependent kinase inhibitors p16INK4a of cardiovascular disease, a and p21CIP1/WAF1 have been shown to be leading cause of death. Some upregulated in atherosclerosis patients. In experts believe that inflammation trigthe current study, the researchers found gered by premature ageing of immune that p53, p16INK4a, p21CIP1/WAF1 and cells might be the primary mechanism LMNC (a transcriptional variant of LMNA) driving obesity and type-2 diabetes. were all downregulated in type-2 diabetes However, the molecular mechanisms patients. In contrast, LMNA was highly underlying this relationship remain upregulated in obese individuals and poorly understood. type-2 diabetes patients. To investigate this question, MohamThe researchers found that LMNA, med Al Dubayee and his co-workers LMNC, p53, p16INK4a and p21CIP1/WAF1 at KAIMRC, King Saud bin Abdulaziz were expressed normally in type-2 diabeUniversity for Health Sciences, and tes patients who were taking the anti-diAlfaisal University in Riyadh obtained abetic drug metformin. The researchers blood samples from 110 people, includhypothesise that metformin works by ing lean individuals, obese individuals, modulating LMNA transcription. and diabetes patients, whether newly LMNA is best known for its role diagnosed or on Hutchinson-GilMetformin, and f o rd P ro g e r i a LMNA protein was highly then quantified S y nd rome , a the expression of genetic condition expressed in obese people several proteins characterised associated with the dramatic, and type-2 diabetes patients by premature agera p i d a p p e a r ing of peripheral ance of ageing in but not in lean individuals. blood mononuchildren. Studies clear cells. They have shown that found that the LMNA protein was highly defects in LMNA could result in growth expressed in obese people and type-2 retardation, shortened lifespan, and diabetes patients but not in lean indiplaques building up in blood vessels in viduals. The result suggests that LMNA young patients. A better understanding might be a key mediator in the inflamof the role of LMNA in obesity and type-2 matory processes underlying obesity and diabetes might yield new insights on celtype-2 diabetes, as well as a promising lular ageing and other diseases. biomarker for these metabolic diseases. Earlier studies have already demonAl Dubayee, M. et al. Metformin alters peripheral blood strated that proteins associated with celmononuclear cells (PBMC) senescence biomarkers gene lular ageing can be useful biomarkers expression in type 2 diabetic patients. Journal of Diabefor metabolic diseases. For example, the tes and Its Complications 35, 107758 (2021).

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R C S B P DB OF P DB 1 I VT / K R I M M ET A L ., S T R UC T UR E VOL .1 0 , I SS UE 6 JU N E 2 0 0 2

Researchers take blood tests to examine biomarkers associated with the premature ageing of immune cells.

A scanning electron micrograph of prostate cancer cells.

Pinning down a genetic cause of increased prostate cancer risk Propensity hinges on the regulatory role of a rare genetic variant 64

June 2021

en of African ancestry are more than twice as likely as other populations to develop prostate cancer. Genetic components partly contribute to this disparity, but their role is ill-defined. An international team has now determined how a rare genetic variant prevalent in men of African ancestry increases their risk¹. Several variants at chromosome region 8q24 have been linked with different types of cancer. The region is home to various genes that are more strongly expressed in prostate tumours, including multiple long non-coding genes (lncRNAs) and the protein-coding proto-oncogene MYC, a gene that can contribute to cancer when mutated. The non-coding region of 8q24 also contains rs72725854, a rare genetic variant with a pivotal role in the elevated prostate cancer risks in men of African ancestry. However, the relationship between rs72725854 and its neighbouring genes has been unclear.

Walavalkar, K., Saravanan, B., Singh, A.K, Jayani, R.S., Farooq, U. et al. A rare variant of African ancestry acti-

vates 8q24 lncRNA hub by modulating cancer associated enhancer. Nature Communications 11, 3598 (2020).

S CI E NCE P HOTO L I BR A RY / A L A M Y S TOCK P HOTO

The team devised an approach relating three-dimensional chromatin structure to transcriptional regulation in order to establish the functional relevance of rs72725854. This enabled them to reveal a mechanism behind the heightened prostate cancer risk. “This is the first functional study that mechanistically links a rare variant in non-coding genome with disease susceptibility,” says team leader Dimple Notani, from the Tata Institute for Fundamental Research in India. DNA-protein interaction analysis revealed that the region containing rs72725854 acts as a prostate cancer-specific enhancer. The region was inactive in healthy cells and turned into an extremely active androgen-responsive enhancer in prostate cancer cells. The researchers found that, unlike its non-risk counterparts, the risk allele of rs72725854 amplified the activity of the enhancer by binding to the transcription factor SPDEF, a sequence-specific DNA-binding protein that controls transcription rate. This promoted the response of the enhancer to androgen stimulation. Structural analysis showed that the enhancer physically interacted with lncRNAs and MYC promoters by forming chromatin loops, which increased the expression of the genes. The proximity of allele-bound SPDEF augmented the activity of the enhancer, boosting the expression of nearby lncRNAs and MYC. “This study helps us better understand the causes of complex diseases, such as prostate cancer, which is valuable for designing diagnostic tools and therapeutics,” Notani says. The team is currently planning to apply their approach to understand risk factors to other complex diseases, such as the susceptibilities of the Indian population to metabolic diseases like diabetes. “That would pave the way for more efficient diagnostic tools and, ultimately, treatments for these diseases,” Notani says.

Diverse disorders from a single source Investigation of a complex developmental disorder gives researchers deeper insight into a multi-functional protein linked to many essential cellular processes

innovations.kaimrc.med.sa

Cell culture experiments demonstrated that MADD deficiency disrupts several critical cellular signalling pathways and impairs cell physiological survival. development of speech and motor skills and susceptibility to seizures. The researchers analysed the impact of these mutations in skin cells donated by some of the patients. This allowed them to determine how different alterations in MADD give rise to truncated or otherwise aberrant forms of the encoded

Schneeberger, P.E., Kortüm, F., Korenke, G.C., Alawi, M.,

Santer, R. et al. Biallelic MADD variants cause a pheno-

typic spectrum ranging from developmental delay to a multisystem disorder. Brain 143, 2437–2453 (2020).

ASH R A F H A B I B 20 20

he mutation of a single gene that contributes to a wide range of physiological functions throughout the body can produce complex multi-organ syndromes. A recent investigation of 23 patients with mutations in a gene called MADD illustrates this phenomenon, revealing how different genetic alterations give rise to a spectrum of disease manifestations and severities. The study began when Kerstin Kutsche of the University Medical Center Hamburg-Eppendorf in Germany encountered two siblings with a range of respiratory, endocrine, neurological and other developmental abnormalities. These were linked to a mutation in the MADD gene, and Kutsche subsequently contacted other researchers around the world who had experience with cases of such mutations. “Our group had previously discovered this gene mutation and published it in a manuscript,” says KAIMRC’s Majid Alfadhel. He shared his clinical data with Kutsche’s team, whose collaborative effort ultimately gathered data on a total of 23 children with 21 different mutations in MADD. These diverse mutations gave rise to equally diverse disease states, which the researchers classified into two broad groups. The first, comprising 14 patients, faced an especially poor prognosis, with high mortality risk early in life, severe developmental delays, haematological anomalies and hormonal and neurological dysfunction. The second group, which had 9 patients, exhibited relatively milder neurological impairments, with delayed

protein. Subsequent cell culture experiments demonstrated that MADD deficiency disrupts several critical cellular signalling pathways and impairs the ability of cells to survive stressful physiological conditions. These analyses also revealed some potential mechanisms underlying the diverse symptoms seen in the 23 patients, although it remains unclear how specific mutations contribute to particular disease phenotypes. This collaborative advance in understanding the clinical impact of MADD mutations would not have been possible if clinicians around the world had not published their findings from individual patients. “We have learned that you should not underestimate the impact of single case reports in research,” says Alfadhel. His team remains actively engaged in discovering other such disorders as part of KAIMRC’s Genetics and Rare Diseases programme. “We aim to characterise their clinical phenotypes, delineate genetic and molecular mechanisms, and discover future potential treatments,” he says.

Genomic analysis revealed a diverse range of mutations in the MADD gene that can contribute to different combinations of developmental deficits.

Issue No.9

Researchers are beginning to understand how a single mutation can lead to early childhood diabetes.

How a single mutation causes diabetes

A single mutation shifts the expression of several genes and induces hereditary diabetes in young children

June 2021

onogenic diabetes is a rare, potentially devastating form, that is usually identified in infants and children under 15 years of age. Unlike the more common type 1 and 2 diabetes, monogenic diabetes is purely hereditary — and only one genetic mutation is needed to trigger the condition. However, the mechanisms by which single-gene mutations induce diabetes symptoms are not well understood. A team led by Yazeid Alhaidan, who is affiliated with the King Abdullah International Medical Research Center in Riyadh and Odense University Hospital in Denmark, have now identified a gene, EDEM2, behind the diabetes symptoms of two members of a single family. The researchers also showed how changes in EDEM2 cause monogenic diabetes, which may point the way towards therapeutic interventions. The first person, a lean Caucasian girl, was presumed to have type 1 diabetes at the age of 2.5. The second, her lean father, was presumed to have type 1 diabetes at the age of 11. They were recruited to the study at the age of 23 and 54, respectively. Subsequent antibody tests showed that the girl and her father were negative for

Alhaidan, Y., Christesen, H.T., Hojlund, K., Al Balwi, M.A. & Brusgaard, K. A novel gene in early childhood diabe-

tes: EDEM2 silencing decreases SLC2A2 and PXD1

expression, leading to impaired insulin secretion. Molec-

ular Genetics and Genomics 295, 1253–1262 (2020).

FE R T NI G / E + / G E T T Y I M AG E S

type 1 diabetes. However, both displayed diabetes symptoms, including high fasting blood sugar levels, low serum insulin levels, low fasting serum C-peptide levels and low fasting serum proinsulin levels. Whole-exome sequencing analysis revealed that they both had a paternally inherited mutation in EDEM2. Gene knockdown assays using rat pancreatic cell lines showed that the deletion of EDEM2 led to suppressed insulin secretion. Further tests showed that downregulation of EDEM2 led to a huge decline in the expression of INS1 and INS2, which regulate insulin secretion, as well as – PXD1 and GLUT2, which control the development of insulin-producing beta cells and their glucose uptake. The findings have important implications for the treatment and diagnosis of monogenic diabetes. “Monogenic diabetes is often mistakenly diagnosed as T1DM,” says Alhaidan, adding that “correct diagnosis will lead to better treatment, management, and surveillance of complications, as well as having important implications for siblings and offspring.” The researchers suggest that targeting the actions of EDEM2 and the link with PXD1downregulation may help restore insulin levels in patients suffering EDEM2-related monogenic diabetes. The researchers carried out an extended family segregation study and showed that the EDEM2 mutation was present in two other family members — the paternal grandmother, aged 76, and the paternal sister, aged 56. However, unlike the girl and her father, these two family members had no history of diabetes and did not display symptoms of monogenic diabetes. The researchers therefore conclude that the EDEM2 mutation has limited penetrance, meaning that it is possible for some people to carry the mutation without ever displaying symptoms of monogenic diabetes.

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KAIMRC Innovations Issue 9

Articles inside

DIVERSE DISORDERS FROM A SINGLE SOURCE

PINNING DOWN A GENETIC CAUSE OF PROSTATE CANCER RISK

SEQUENCING IMMUNE SYSTEM GENES FOR STEM-CELL TRANSPLANTS

A MOLECULAR LINK BETWEEN DIABETES, OBESITY, AND CELL AGEING

A KEY ROLE FOR MICROGLIA IN CHILDHOOD GLAUCOMA

INVESTIGATING THE FACTORS AFFECTING BURN PATIENT SURVIVAL

AI-SUPPORTED DECISION-MAKING IMPROVES SKIN CANCER DIAGNOSIS

REDUCING INFLAMMATION REJUVENATES BRAIN CELLS IN MICE

THE GENETIC ROOTS OF RARE DEVELOPMENTAL DISORDERS

HOW MELANOMA MANIPULATES ITS WAY TO METASTASIS

FAMILY SUPPORT HASTENS RECOVERY

DEPRESSION LINKED TO PREMATURE BRAIN AGEING

TURNING SCIENTIFIC DISCOVERIES INTO COMMERCIAL SOLUTIONS

COVID-19 IMPACT DOES NOT END WITH HOSPITAL DISCHARGE

DNA SEQUENCING ACCELERATES INFECTION DIAGNOSIS

CHADOX1: MORE THAN A CORONAVIRUS VACCINE

COVID-19 INFECTION RATE WAS LOW AMONG HEALTHCARE WORKERS EARLY IN THE PANDEMIC

OPTIMISING INFLUENZA VACCINES TO HARNESS PRE-EXISTING IMMUNITY

ANTIBIOTIC RESISTANCE IN CIRCULATING BACTERIAL STRAINS

BETTER ANIMAL MODELS FOR COVID-19 NEEDED

FIGHTING THE PANDEMIC ON ALL FRONTS