KAIMRC Innovations Issue 6 by Nature Research Custom Media

DECEMBER 2019 - Issue No.6

ISSN 7901-2398 innovations.kaimrc.med.sa

FROM LAB TO HUMANS A L OOK IN T O T HE K INGDOM â&#x20AC;&#x2122; S JOUR NE Y T O WA R D S HOL DING T HE F IR S T P H A S E I C L INIC A L T R I A L , A ND C OMB AT T ING ME R S A L ONG T HE WAY P.5 4 , 5 6 & 60

Shared Enabling Platforms Shared enabling platforms is a key element to create a culture of cooperation. This approach is deeply engraved in KAIMRC to encourage collaborative environment between KAIMRC scientists and others to accelerate research outcomes and outputs. The Cord Blood Bank (CBB) at KAIMRC is a national non-profit project, responsible for recruiting, processing, testing, cryopreserving, storing, thawing and infusing cord blood units that will be used for patients in need of cord blood stem cell transplantation. The CBB activities are carried out within a quality control system up to international standards.

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TABLE OF CONTENTS

P.8 HUNGRY FOR HEART HEALTH

P.10 A ROCKING GOOD SLEEP

Study shows hunger hormone helps preserve cardiac muscle cells and reduce heart attack damage

Study reveals that gentle rocking helps adults sleep and keeps their memory strong

P.12 LAYING BARE THE SKELETON FOUNDATIONS

P.14 CURBING EXCESSIVE ANTIMICROBIAL USE

Research concludes that the organization of the cell skeleton during bone cell formation is regulated by TGFβ1

High levels of antibiotic use in ICUs in Saudi Arabia are exacerbating the antibiotic resistance problem

FEATURE

P.16 BIRTH WEIGHT ESTIMATES UPDATED

P.18 BRAINS OF BLIND PEOPLE ADAPT P.20 HIV STEM CELL THERAPY: WHY TO SHARPEN SENSE OF HEARING IT’S TOO EARLY TO DECLARE A CURE

Research provides more accurate charts for assessing birth weight based on updated information

People with impaired vision have sharpened and nuanced sense of hearing

innovations.kaimrc.med.sa

Gene-editing and stem cell therapy have emerged as potential treatment for HIV/ AIDS, but ideal recipients are rare Issue No.6

TABLE OF CONTENTS

P.24 THE PSYCHOLOGICAL TOLL OF MULTIPLE SCLEROSIS

P.26 ROTAVIRUS VACCINE COULD HELP PREVENT TYPE 1 DIABETES

Saudi researchers examine the severity of depression among multiple sclerosis patients

Rotavirus vaccine is correlated with a reduction in type 1 diabetes incidence among infants

FEATURE

P.27 HEARTENING FINDINGS ON AN AORTIC SURGERY ALTERNATIVE

P.28 SEEKING CURES FOR ALZHEIMER’S DISEASE

A minimally invasive alternative to heart surgery may offer better outcomes for a broader range of patients with aortic stenosis

A look at the advances in Alzheimer’s research over the past few years and identify bacteria as a possible cause

P.32 MAT DEFICIENCY: WIDER EFFECTS OF A RARE DISEASE P.34 AN INSTIGATOR FOR IMMUNODEFICIENCY A rare childhood disease reveals a new mutation as underlying cause

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A genomic survey of immunodeficient patients reveals key gene in fending off infection and controlling inflammation

TABLE OF CONTENTS

P.36 WHAT DOESNâ&#x20AC;&#x2122;T KILL YOUR ANCESTORS MAKES YOU STRONGER

P.37 GENE MUTATION ASSOCIATED WITH FERTILITY

Stressed-out fence lizards inadvertently give younger generations a better chance against predators

A mutation in gene encoding a cell surface receptor is linked to miscarriage

FEATURE

P.38 SLIM CHANCE OF DEFYING GENETIC ODDS IN THE WEIGHT GAME

P.40 SEARCHING FOR ANSWERS SURROUNDING AUTISM

New study shows that maintaining a healthy weight can be down to genetics

Replicating a gene linked to autism in a monkey model sheds light on its underpinnings

FEATURE

P.44 SLIGHTLY RAISED RISK OF RARE CHILDHOOD CANCERS IN IVF BABIES

P.47 STEM CELLS MARSHAL TROOPS AGAINST CANCER

Largest cohort study shows marginally increased cancer risk in IVF babies

A population of adult stem cells generates signals that could spur immunity against tumour cells

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Issue No.6

TABLE OF CONTENTS

P.48 SAUDI ARABIA GETS FAMILIAR WITH ITS SUPERBUGS

P.50 BACTERIA IN SPERM HINDERS FERTILITY TREATMENT

First study to examine genetic diversity of multidrugresistant strains in Saudi Arabia

The presence of bacteria in semen reduces sperm quality that might affect success of IVF treatments

FEATURE

P.54 THE RAPID JOURNEY OF A DEADLY MERS OUTBREAK

P.56 KAIMRC A STRONG PLAYER IN QUEST FOR A MERS-COV VACCINE

Analyzing the unusual outbreak of the MERS virus involving a ‘superspreader’ patient

The journey towards KAIMRC hosting the first phase I clinical trial in the kingdom

P.60 REVOLUTIONIZING THE CLINICAL RESEARCH LANDSCAPE IN SAUDI ARABIA Executive Director Ahmed Alaskar discusses how KAIMRC is spearheading the initiative to develop clinical trials

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TABLE OF CONTENTS

P.62 A SMART WAY TO BEAT THE HEAT FEATURE

KAIMRC researchers develop a system to help treat heatstroke patients

P.65 THE MENTAL TOLL OF CONFLICT FEATURE

WHO estimates that mental disorders are three times more common in conflict settings

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

KAIMRC Innovations Phone: +966 11 429 4516 Email: innovations@ngha.med.sa Web: innovations.kaimrc.med.sa

Springer Nature The Campus – 4 Crinan Street – London, N1 9XY, UK Email: nature@nature.com Web: www.nature.com

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

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Issue No.6

Myocardial infarction, more commonly known as heart attack, is a leading cause of death and disability worldwide.

December 2019

Hungry for heart health

Study in rats shows that hunger hormone helps preserve cardiac muscle cells and reduce heart attack damage

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Issue No.6

ZOON A R G M B H / A L A M Y S TOC K P H OTO

eople who have experienced a heart attack are the highstress. The tissue samples taken from the MI-induced rats’ left est risk group for future attacks. When a blockage occurs ventricles showed reduced expression levels of cell-death bioin the heart’s coronary arteries, the reduced blood flow markers and increased expression levels of a cell-death inhibitor. could cause swelling, cell death, and structural abnorThe researchers further used electron microscopy to exammalities in the heart’s left ventricle, particularly in areas surine tissue samples from control and MI-induced rats, and found rounding the blockage. These microscopic changes result in chest that control rats administered saline solutions containing ghrelin pain, shortness of breath and the formation of fibrous tissues, and for three consecutive weeks experienced no adverse effects. On weaken heart functions, increasing the risk of heart failure. the other hand, ghrelin reduced vascular formation, reversed Saudi researcher Refaat Eid and the formation of fibrous tissues, co-workers at King Khalid Univermitochondria struc“These results suggest that gherlin preserved sity in Abha, Saudi Arabia, have now ture, and prevented mitochondrial investigated the gut hormone ghreswelling in MI-induced rats. Taken lin and its protective effects against together, these results suggest that is safe and effective in preserving left ventricular damages in rats ghrelin is safe and effective in prewith induced myocardial infracserving cardiac muscle cells and tions (MI) via surgical procedure. reducing left ventricular damages. cardiac muscle cells and reducing Ghrelin is often termed the ‘hunger The researchers believe ghrelin hormone’ because it is produced in has important roles in regulating the gut and serves as a signalling left ventricular damages.“ cardiac functions and protecting molecule for telling the brain to be against cellular stress. However, it hungry. Recent studies have shown is unclear whether the administrathat ghrelin is produced in the heart and other organs, suggesttion of the hormone has the same curative effects on humans as ing that the hormone has wide physiological roles not limited to it does on rats. More experiments and further trials are needed hunger signalling. to confirm the safety and efficacy of ghrelin in the prevention of The Saudi researchers found that MI-induced rats that were future MIs. administered saline solutions containing ghrelin for three consecutive weeks had improved heart functions, increased cardiac conEid, R. A., et al. Subacute ghrelin administration inhibits apoptosis and improves ultratractility, as well as reduced serum levels of creatine kinase and structural abnormalities in remote myocardium post-myocardial infarction. Biomedlactate dehydrogenase — two enzymes associated with cellular icine & Pharmacotherapy 101, 920–928 (2018).

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A rocking good sleep

Study reveals that the gentle rocking motion that soothes children to sleep works just as well for adults, and also keeps their memory strong

Researchers offer an explanation to why humans sleep better in moving cars, trains, and in rocking beds.

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which play a role in sleep regulation and memory processing. They can be affected by state of mind, and factors such as noise, heat, drug or alcohol intake prior to sleep, as well as health conditions such as chronic pain. There are several frequency oscillations associated with sleep. Slow oscillation and spindles — bursts of brain activity that moderate responsiveness during sleep —have been linked with less wakefulness during the night and memory improvement in the morning. “Spindles and slow oscillations appear more or less frequently, depending on the sleep stage you are in,” explains Perrault. The data shows gentle rocking increases the prevalence of slow spindles and oscillations and synchronizes their timing to the rocking cycle, making participants fall faster into deeper sleep, and stay asleep for the whole night. It’s possible that these benefits can be extended to individuals with sleeping difficulties or insomnia, but a discussion of application is perhaps premature with the research still in its early stages. Perrault says that they first need to test the rocking bed on a larger sample of adults before results can be considered clinically significant. Perrault, A. et al. Whole-Night Continuous Rocking

Entrains Spontaneous Neural Oscillations with Benefits for Sleep and Memory. Current Biology 29, 402–411 (2019).

Issue No.6

A LEKSA N DA R N A K I C / E+ / G ET T Y I M AG ES

noozing on a rocking bed can foster better sleep and improve overnight memory recall, reveals a new study that monitored the brainwaves of several participants as they were rocked to sleep. The secret lies in inducing longer periods of ‘slow wave’ or deep sleep, according to a study published in Current Biology. “We naturally rock babies to sleep. Yet, we also have plenty of anecdotal reports of adults falling asleep faster when in a train or a car, as well as reported feelings of relaxation in a hammock,” says Aurore Perrault, research co-author. Researchers from the University of Geneva and the University of Lausanne recruited 18 participants who slept in the lab for three nights. The first night was intended to get them used to sleeping in a lab environment. They spent the second night on a rocking bed and the third on a stationary one. The researchers recorded the participants’ brainwaves using an electroencephalograph (EEG). . In the evenings and mornings, they gave them word pairing exercises to test memory recall. A whole night of gentle rocking made participants doze off faster, says Perrault. “[The motion] also boosts brain oscillations that are crucial for overnight memory consolidation processes.” Brain electrical oscillations are microevents that happen during sleep and

FEATURE

Laying bare the skeleton foundations

New research concludes that the proper organization of the cell skeleton during bone cell formation is regulated by TGFβ1, a key growth factor that the cytoskeleton became very organized, forming bundles like many ropes collected together,” says Mahmood. When the team added an inhibitor of TGFβ1, the actin “became completely disorganized — like someone had messed with all the ropes, leaving some pieces on top of each other and some laying in other places where they should not be.” To confirm the importance of actin in differentiation, the team treated the cell cultures with CYD, a chemical that disrupts the cell skeleton by interfering with the formation of actin filaments. Stem cells treated with CYD didn’t differentiate into bone cells, even when the culture was also treated with TGFβ1. Instead, CYD enhanced the differentiation of stem cells into fat cells, again regardless of whether TGFβ1 was added. Analysis of gene expression in these cultures uncovered 13,000 genes affected by CYD, including many actin-related genes and 218 genes that were upregulated

by TGFβ1, but downregulated by CYD. Mahmood believes that the effect of TGFβ1 on the cell skeleton makes cells more likely to become bone cells, whereas fat cell differentiation may be less sensitive to the actin distribution, since fat cells don’t need to be held in a specific shape. “I think the change in actin pattern leads to differentiation, which again makes changes to the actin, which further reinforces the differentiation process,” he says. These findings clarify the role of TGFβ1 in bone cell formation and highlight the importance of the cell skeleton in this process. The team hopes that TGFβ1 could be used as a treatment for diseases such as osteoporosis, an idea they’re now testing in mice. Elsafadi, M., Manikandan, M., Almalki, S., Mobarak, M., Atteya, M., et al. TGFβ1-Induced differentiation of human bone mar-

row-derived MSCs Is mediated by changes to the actin cytoskeleton. Stem Cells Inter-

national 2018, 6913594 (2018).

Issue No.6

A LF R ED PAS I EK A /S C I EN C E P H OTO LI B R A RY / G ET T Y I M AG ES

crucial growth factor, TGFβ1 reorganizes the cellular skeleton during bone cell differentiation, according to new research that may offer a path towards treating osteoporosis. A team of Saudi researchers, led by Amer Mahmood of King Saud University, investigated the activity of TGFβ1, which is key to the differentiation of bone and fat cells from bone marrow stem cells. The researchers treated stem cell cultures with TGFβ1 to induce differentiation, and analyzed which genes were affected. They identified around 3,000 genes which responded to TGFβ1. Genes related to a component of the cell skeleton known as actin were surprisingly common among TGFβ1-regulated genes, leading the team to suspect that TGFβ1 might influence differentiation by regulating the cell skeleton. The researchers examined the actin filaments in cells cultured with and without TGFβ1. “After treatment with TGFβ1, we saw

Curbing excessive antimicrobial use

High levels of antibiotic use in intensive care units across Saudi Arabia are exacerbating the antibiotic resistance problem

AIMRC researchers monitored five adult intensive care units (ICUs) over 33 months to help establish measures to reduce unnecessary use of antimicrobials, especially antibiotics, and control the emergence of antimicrobial resistance (AMR). The study shows that the use of some strains of antibiotics is six times higher in Saudi Arabia compared to European countries. For patients infected with pathogenic microorganisms, broad-spectrum antimicrobials can make the difference between life and death. However, because antimicrobials are readily available, generally affordable, and safe, they are often overused. Excessive antibiotic consumption has been associated with AMR and high levels of antibiotic consumption in hospitals have highlighted an urgent need to establish stricter guidelines. In 2015, the World Health Organization (WHO) issued the Global Action Plan for AMR. Based on this plan, Gulf Cooperation Council (GCC) countries have developed a national AMR plan to determine the baseline antimicrobial consumption. “Estimating the baseline antimicrobial consumption will serve multiple purposes; to identify hospital units or wards of highest consumption, to monitor the impact of future interventions, and to reduce inappropriate prescription patterns,” says Hanan H. Balkhy, former executive director of the infection and prevention program at the Ministry of National Guard Health Affairs, and lead author of this study. Balkhy and colleagues collected data on the daily dose, treatment length, and frequency of daily consumption of 16 antimicrobials in governmentally funded ICUs that provide healthcare services for approximately 1,800 patients per year. The authors monitored more than 40,000

December 2019

antimicrobial drug doses administered during 4,919 admissions. The average course of treatment was 9.5 days and the most consumed antimicrobial agents across all ICUs were the antibiotics meropenem (21.4 percent), piperacillin/tazobactam (16.8 percent), vancomycin (14.9 percent) and colistin (13.5 percent), and the antifungal agent caspofungin (8.0 percent). There was some variation in ICU-specific antimicrobial consumption, with carbapenems, the broad-spectrum antibiotic group that includes meropenem, being the most frequently consumed in medical and surgical, burn, and units providing transitional care between the ICU and the general ward. By contrast, piperacillin/tazobactam was the most frequently consumed antimicrobial in cardiothoracic ICUs. Although the study was unable to determine whether antimicrobial consumption was inappropriate or excessive, comparisons to similar reports from other countries indicate that the use of carbapenems in Saudi Arabia is considerably higher. It was up to six times higher than in some European countries, which might have contributed to the emergence of carbapenem-resistant Enterobacteriaceae and carbapenem-resistant Acinetobacter identified in hospitals in GCC states. “Our results indicate that the judicious use of antibiotics should become a priority,” says Balkhy. “Implementing specialised Antimicrobial Stewardship Programs will ensure that those who need such agents receive them in a timely fashion and those who do not need them will not.” Balkhy, H. H., El-Saed, A., El-Metwally, A., Arabi, Y. M., Aljohany, S. M. et al. Antimicrobial consumption in five adult intensive care units: a 33-month surveillance study. Antimicrobial Resistance and Infection

Control 7, 156 (2018).

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Issue No.6

Birth weight estimates updated

New research provides more accurate charts for assessing birth weight based on updated information to identify need for infant care A research led by the Harvard Pilgrim Health Care Institute has provided updated reference charts for birth weight for gestational age, used to determine the health of newborns, using a nationally representative sample of birth data and 16

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obstetric estimates of gestational age. This update could better reflect the current sociodemographics of the US population and identify infants who need additional care, according to researchers in the US. â&#x20AC;&#x153;Previous birth weight charts may not

reflect the current sociodemographic composition of the US,â&#x20AC;? explains Izzuddin Aris, who led the new study. â&#x20AC;&#x153;In addition, they rely on gestational age estimated from maternal reports of last menstrual period, which is often less accurate than

Birth weight reference for gestational age reference charts is essential to determine health of newborns

obstetric estimates that take into account ultrasound measurements, menstrual history, and laboratory tests.” Birth weight is an indicator of health for a baby and its mother, so it is important to know whether a newborn’s weight is healthy for the stage of pregnancy at which the infant is delivered, also known as gestational age. A birth weight at the extremes of the range for a given age indicates restricted or excessive growth and is associated with health risks. Reference charts are used to determine whether an infant’s birth weight is within the normal range. These charts indicate the proportion of infants born within ranges of weight at different gestational ages. However, current birth weight charts used in the US are based on old data, and innovations.kaimrc.med.sa

the standard approach of estimating the gestational age relying only on the mother’s reports of her last period. Aris and colleagues developed new birth weight reference charts based on the birth weights of more than 3.8 million infants born in the US in 2017 at gestational ages of 22–42 weeks, according to obstetric estimates. They then applied two modelling techniques to construct curves that show average birth weights of boys and girls and the percentage of infants within various weight ranges at different gestational ages. The two modelling techniques produced curves that overlapped considerably, indicating the validity of the approaches. Comparison of the new charts with charts from 2009 and 1999 revealed considerable differences. For infants born preterm,

the new charts classified fewer infants as small, and more infants as large, for their gestational age. For infants born postterm, the new charts classified more infants as small and fewer as large. The differences probably result from changes in sociodemographics and the accuracy of obstetric estimates of gestational age. “We expect clinicians to be able to use the updated reference to identify at-risk infants in need of additional monitoring or care,” says Aris. “The next step is to compare existing birth weight standards with our updated reference in predicting important health outcomes later in life.” Aris, I. M., Kleinman, K. P., Belfort, M. B., Kaimal, A. & Oken, E. A 2017 US reference for singleton birth weight

percentiles using obstetric estimates of gestation. Pedi-

atrics 144, e20190076 (2019).

Issue No.6

The brain adapts to blindness by developing a more selective response to sounds.

People with impaired vision have sharpened and nuanced sense of hearing

esearchers have found the first evidence in humans for increased plasticity in the auditory cortex as a result of early blindness or vision impairment. In the absence of visual information, functional sensory areas in the brain, such as those responsible for hearing, develop enhanced capacities, making a blind person’s hearing more sensitive to subtle differences in frequency, reveals the study published in the Journal of Neuroscience. “A voxel is a chunk of brain only three by three by three millimeters, but it contains almost 100,000 neurons. For each of these tiny chunks of the brain, we looked to see what auditory frequencies they responded to,” says Ione Fine, professor of psychology at the University of Washington, and the

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study’s principal investigator. Early blindness has generally been linked to sharper hearing. This study, however, provides evidence that blind people are not just good at auditory tasks, but that their perception of the auditory world is slightly more refined. They’re better at tuning in to slight variations in sounds and at tracking moving objects by sound alone. Fine and colleagues not only confirmed that people who were born blind or have become blind in childhood are better at making distinctions between two or more tones that are similar, but that these tones are also represented differently in the brain. The researchers used functional magnetic resonance imaging (fMRI) to measure how populations of neurons represent

Huber, E. et al. Early blindness shapes cortical representations of auditory frequency within auditory cortex. Journal of Neuroscience 39 (26), 5143-5152 (2019).

JOS E DA N I EL C OR T ES S EC O / EY EEM / G ET T Y I M AG ES

Brains of blind people adapt to sharpen sense of hearing

information about sound inside the brains of blind and sighted participants by detecting changes in blood flow and oxygen metabolism. “Instead of just looking at whether responses are bigger or smaller, we really looked at how sophisticated that representation is,” Fine explains. Their investigation showed that, in blind participants, the auditory cortex becomes better at extracting more information from sounds. This narrow frequency tuning is evidence of compensatory plasticity. Fine says that this type of plasticity, where an area inside the brain becomes more responsive as a way to compensate for deprivation in another area, has so far been understudied. She explains that scientists were more fascinated by crossmodal plasticity, in which an area of the brain takes on new functions. “A brain area getting slightly better at doing its normal function is less dramatic,” she says. The scientists plan on taking a deeper look. “Audition involves much more than pitch. It also involves things like timbre, tracking moving objects, and identifying objects from the sound they make. We’re interested in how blindness influences all these different tasks,” says Fine.

Translational Research Unit Is the Hub for clinical Trials with additional unique feature, phase 1 clinical Trials.

EMAIL: TRU@NGHA.MED.SA PHONE NUMBER: +966-11-429-4516

The Unit consists of: • • • • • • •

Reception Ward with 16 Beds Phlebotomy Room Volunteers Screening Room Volunteer Recreation Room Centrifuge and Freezer Room Chemistry Lab

FEATURE

HIV stem cell therapy: Why it’s too early to declare a cure Gene-editing and stem cell therapy have emerged as promising approaches to the treatment of HIV/AIDS, but ideal recipients are rare

ore than a decade after Timothy Ray Brown, an American man known as the Berlin patient, was cured of HIV following a bone marrow transplant, news of a similar case, the London patient, emerged last March. The case sparked hope, with reports suggesting that Brown’s case may be replicable, and that science is close to finding a cure to HIV. There are approximately 37.9 million people in the world living with human immunodeficiency virus (HIV), the virus that causes AIDS, according to the latest available data from UNAIDS. Over 23 million of those are on some form of antiretroviral therapy, a standard regimen that consists of a combination of two or more HIV drugs to suppress and control the progression of the virus. In March 2019, and coming on the heels of the news of the London patient, an anonymous Dusseldorf man, who stayed HIV-free for five years after a bone marrow transplant and for months after

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ceasing antiretroviral treatment, appears to be the third person who may have been cleared of HIV. His case is less celebrated since, at the time of announcement, he had only been in remission for three months, which is “an early stage” according to Björn Jensen, the doctor overseeing his case. His case study has also not been published yet. All three patients had leukaemia, an aggressive type of blood cancer, and they had undergone bone marrow transplants as part of their cancer treatment. Their transplants specifically came from donors carrying a rare CCR5 genetic mutation, known as CCR5-delta 32, which is resistant to HIV and which only appears in people of European descent. The London patient, for instance, had stage-four Hodgkin’s lymphoma and had failed multiple lines of chemotherapy. He then had to undergo stem cell transplantation, and was matched with a donor holding the CCR5-delta 32 mutation in both copies,

HIV affects nearly 38 million people around the world and until today has no cure, although patients who receive treatment to suppress the virus live relatively normal lives.

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

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Issue No.6

FEATURE against newspapers describing it as a cure, without reservations. “I think that the press release [we wrote] was cautionary. I think that if people interpret it in a certain way, that’s not good journalism. I’m hoping that people would read between the lines,” said Gupta. He is also a professor at the University College London and the University of Cambridge. The treatment is feasible, and modifica-

to consider it as a common treatment to people with HIV.“

Timothy Brown became the first ever patient to be cured of HIV/AIDS

replicating the Berlin patient’s profile. When it enters the body, HIV targets immune cells that fight infection, but carriers of the mutated gene CCR5-delta 32 are not susceptible to the attack. The transplanted ‘Gandalf’ cells, which the London, Berlin, and Dusseldorf patients received, cause CCR5 co-receptors, gateways which sit outside the cell, to shrink and collapse inwards, preventing the virus from passing through. In other words, the transplant from CCR5-mutation-carriers turns cancerous bone marrow cells into HIV-resistant cells, preventing the virus from returning. In 2016, the London patient was taken off antiretroviral treatment 16 months after his transplant and remains in remission. The Berlin patient has been in remission for more than 10 years. Neither experienced a relapse when they stopped their HIV medication.

HIV cure science: cautious optimism

The recovery process of stem cell therapy is lengthy and complex. It took about three years post-transplant for rigorous tests to confirm that the London patient 22

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was HIV-free, and five years for the Dusseldorf patient. Disruption of antiretroviral medications occurred months after that. Researchers must wait months before they can confirm that the patient has become HIV-free. The media was quick to brand the case a breakthrough and the treatment a win in the war against AIDS, a syndrome of HIV which causes irreparable damage to the immune system. And it seems to be a remarkable step forward, as many have noted. “In the three cases where CCR5-delta 32 transplantation was successfully performed, we have achieved an eradication,” Gero Hütter, the haematologist who pioneered stem cell therapy for HIV and who treated the Berlin patient, told KAIMRC Innovations. The evidence is suggestive that “CCR5 depletion is responsible for the comparable outcome.” But independent experts wonder if it’s too early to claim, unequivocally, that the second and third patients have been cured, as opposed to being in long-term remission. The leader of the research team, Ravindra Gupta, himself cautioned

tions to it can be as effective as the original transplants, according to Hütter. “Berlin, London, and Dusseldorf show us that the approach is reproducible,” Gupta said. “But it’s more a symbolic victory, it’s not an option for everyone.”

How repeatable are the cases of London, Berlin, and Dusseldorf?

The potential bone marrow donors who are eligible CCR5-mutation-carriers, and thus resistant to HIV infection, represent only 1 percent of the Northern European population. The mutation has not been found in people from Africa or East Asians, for instance. What complicate matters more is that donors must be homozygous carriers; in other words, they must have inherited a copy of the rare mutation from both parents. Can millions of HIV patients reboot their infected cells with this type of stem cell therapy? The short answer is that it’s not even nearly possible for most patients. “I think it’s impossible to consider it as a common treatment to people with HIV because people who were so-called cured all had an underlying leukaemia [and] lymphoma that required the chemotherapy for the leukaemia, plus a stem-cell transplant, plus immuno-suppression to prevent the rejection of it, so the process

P H OTO B Y T.J. K I R K PAT R I C K /G ET T Y I M AG E S

“I think it’s impossible

itself was quite dangerous,” said Anthony Fauci, Director of NIH’s National Institute of Allergy and Infectious Diseases, USA. “It can never be done for someone unless they really needed a transplant for another reason.” Islam Hussein, a virologist, drug discovery researcher, and senior scientist at Microbiotix, seconded that this type of stem cell transplant cannot become the method of choice for most patients. “[It] is a very expensive and risky procedure that might be justifiable only for HIV patients who are also suffering from lymphoma,” he said. “We already have an arsenal of HIV therapies that are safe, effective, and affordable.” When Hütter himself was asked if stem cell therapy can live up to its promise as a possible lifetime cure for HIV, he said, “not in the setting we did in Timothy Brown.” He agreed that stem cell transplantation from matching donors “is not an option for HIV patients without cancer” adding that, “the treatment related morbidity and mortality is too high. New developments use autologous cells or manipulated allogeneic cells with much fewer side effects.” In a paper evaluating 30 years of stem cell therapy in HIV patients, Hütter contended that the therapy is unlikely to achieve complete eradication of the virus. HIV persists in pockets of cells, and infected macrophages become stable reservoirs for the virus. It is why antiretroviral treatments could never finish the job.

likely be able to stop antiretroviral therapy and just have a person come in every four to six months for an antibody infusion.” After a year or less, Fauci explained, the person might not ever need further passive antibody transfers. Immune enhancement treatment targeting the immune system’s T-cells, is another potential option, although it’s still in the animal study phase. Discovered by University of California, Los Angeles scientist Scott Kitchen and his team, the T-cell-based therapy modifies blood-forming stem cells and safely engrafts them in the bone marrow. The therapy can potentially guard against rebounds by destroying HIV-infected cells that may reappear months or years following treatment. A study published in September focused on macrophage cells, the HIV dormant reservoirs. These reservoirs help the virus survive and later resurface, and typically have higher expressions of long non-coding RNAs (IncRNAs), which are tissues and cell-type specific genes. By genetically modifying IncRNAs in HIV-infected macrophages, scientists may have found

“a key switch that the HIV field has been searching for, for three decades,” said Tariq Rana, lead scientist of the study, according to a press release by the University of California, San Diego. There are also stem cell therapy and gene modification studies to treat HIV, but Fauci explained that “they’re so far into the experimental stage that you really can’t say anything about their practical use yet. “It’s impossible to give a timeline or to predict whether we’ll have a true cure to eradicate the virus from the body. In fact, it is conceivable that it would be impossible to do that.” But that’s not necessarily bad news; Fauci said that science is, in fact, closer than ever to replacing the daily need of antiretroviral pills. “With modifications, combination with gene therapy and autologous sources, I believe that some kind of cell therapy will impact HIV treatment in the future,” said Hütter. Gupta, R.K. et al. HIV-1 remission following CCR5Δ32/ Δ32 haematopoietic stem-cell transplantation Nature 568, 244-248 (2019).

Less risky interventions, such as the discovery that combining broadly neutralizing HIV-1 antibodies can replace antiretroviral medications and may result in longer remission, are in development, and are more realistic, according to Fauci. “We have monoclonal antibodies — broadly neutralizing antibodies — that you can modify genetically to make them last for a very long time,” he said. “If you can get passive transfer of a combination of antibodies that’s directed against the virus, we strongly anticipate that you’ll innovations.kaimrc.med.sa

TO W FI Q U PH O TO G R A P HY / M O M EN T / GE T T Y I M AG ES

Alternative pathways to HIV treatment and prevention

HIV/AIDS patients can live relatively normal lives with daily antiretroviral treatment to suppress the virus.

Issue No.6

December 2019

The psychological toll of MS Saudi researchers examine the severity of depression among multiple sclerosis patients

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Issue No.6

G C A /S P L/ G ET T Y I M AG ES P LUS

ultiple sclerosis (MS), a disease affecting the cenas treatment received and level of disability. The results of the tral nervous system (CNS), has been on the rise in patient health survey showed that almost a third of patients Arabian Gulf countries, reaching a prevalence rate (30.8%) were likely to suffer from mild depression, nearly a of 0.04 percent in Saudi Arabia. As with many other quarter (24.7%) suffered from moderate depression and almost debilitating diseases, depres10 percent (10.7%) suffered sion is common among MS from severe depression, while â&#x20AC;&#x153;A third of MS patients studied patients. In Saudi Arabia, a only about 2 percent (2.3%) cross-sectional study found appeared to have no signs of that more than 53 percent depression. suffered mild depression, a quarter of those studied were likely Depression rates were sigto have mild to moderate nificantly higher among depression, and that depreswomen, those who were suffered moderate depression, and sion severity is closely linked highly educated, and patients with the degree of disability with the lowest income. Sigcaused by MS. nificant differences in sever10% suffered severe depression.â&#x20AC;&#x153; MS is a chronic autoimity of depression were also mune disease where the reported according to the bodyâ&#x20AC;&#x2122;s immune system attacks the protective sheath covering medication they received, which may be attributed to the depresthe nerve fibers of the central nervous system, including the sion-related side effects associated with those drugs. brain, the spinal cord, and the optic nerve. This disrupts the flow There is also a significant correlation between level of disability of information within the brain, and between the brain and the and severity of depression; so early support of MS patients, esperest of the body, affecting movement control, sensory percepcially newly diagnosed ones is could ensure a better quality of life. tion, memory, and speech. The study was conducted on nearly a quarter of MS patients Alhazzani, AA. Depression severity and its predictors among multiple sclerosis patients in Saudi Arabia to analyze the link between severity of depresin Saudi Arabia: across sectional study. Neuroimmunology and Neuroinflammation. sion and sociodemographic characteristics and factors, such 10, 1-10 (2018).

Rotavirus vaccine could help prevent type 1 diabetes Rotavirus vaccines have been introduced in the regular immunization schedule since 2007.

As concern grows over social media anti-vaccination campaigns leading to possible outbreaks of preventable diseases, a new study points to the benefit of rotavirus vaccination. This study comes after previous research found an association between the development of type 1 diabetes in genetically predisposed infants and rotavirus infection. A recent study 1 in Australia found that with the routine administration of the rotavirus vaccination there was a 14 percent decline in the incidence of type 1 diabetes in infants from 0 to 4 years of age. The correlation, however, wasn’t significant in older children studied. The preliminary results then indicate that the rotavirus vaccine may be protective against the development of type 1 diabetes 26

December 2019

in early childhood. Rotavirus is a contagious virus and the most common cause of inflammation of the stomach and intestines in children. Severe cases could case dehydration and in some cases death. Rotavirus vaccines have been added to the regular immunization schedule in Australia in 2007, so the study compares incidence rates of type 1 diabetes in the eight years before and the eight years after the routine oral vaccine was introduced. According to Terry Nolan, head of the Melbourne School of Population and Global Health and one of the researchers in the study, “the findings provide preliminary evidence to strengthen the importance of rotavirus vaccine in early infancy as currently recommended.” However, the

1. Perrett, K. Association of Rotavirus Vaccination with the Incidence of Type 1 Diabetes in Children. JAMA Pedi-

atrics.173(3), 280-282 (2019).

2. Rogers, M.A., Basu, T. & Kim, C. Lower Incidence of Type 1 Diabetes after Receipt of the Rotavirus Vaccine in the United States, 2001-2017. Scientific Reports. 9 (2019).

3. Honeyman, M.C. et al. Association between rotavirus

infection and pancreatic islet autoimmunity in children at risk of developing type 1 diabetes. Diabetes. 49, 1319–1324 (2000).

VOI S I N / P H A N I E / A L A M Y S TOC K P H OTO

Rotavirus vaccine is showing a correlation with a reduction in type 1 diabetes incidence among infants

evidence does not show the importance of rotavirus vaccines to older children. This echoes the results of a more detailed cohort study2 that was conducted by a team in the US, showing a 33 percent reduction in the risk of type 1 diabetes among infants after the completion of a rotavirus vaccine series. According to Nolan, further detailed research will give more insight into the results seen in Australia and the significance of the effect of the vaccine on children who are genetically predisposed to type 1 diabetes. Research on the effect of rotavirus vaccines on incidence rates of type 1 diabetes was prompted by research3 conducted in 2000 in Australia, that found a correlation between the incidence of rotavirus infections and type 1 diabetes. The detailed study found that the virus contains highly similar peptide sequences to T-cells, which then triggers pancreatic infection by molecular mimicry.

Heartening findings on an aortic surgery alternative

A minimally invasive alternative to heart surgery may offer better outcomes for treating a broader range of patients with aortic stenosis

urgery has historically offered the best hope for preventing stroke or heart failure in patients with aortic stenosis, a serious condition where the aortic valve opening narrows, restricting blood flow from the heart to the main artery. New clinical trial data from a team led by Michael Mack, at Baylor Scott and White Health Heart Hospital in Plano, Texas, now indicate that a minimally invasive procedure known as innovations.kaimrc.med.sa

â&#x20AC;&#x2DC;transcatheter aortic valve replacementâ&#x20AC;&#x2122; (TAVR) may offer a simpler and more effective alternative for most patients. People with severe stenosis have dangerous constriction of the aorta valve, which prevents it from fully opening to let blood through. Surgical replacement of the aortic valve is the standard solution for repairing such damage and preventing cardiovascular complications. TAVR was developed as a treatment alternative for

Mack, M.J., Leon, M.B., Thourani, V.H., Makkar, R., Kodali,

S.K. et al. Transcatheter aortic-valve replacement with a balloon-expandable valve in low-risk patients. New

England Journal of Medicine 380, 1695â&#x20AC;&#x201C;1705 (2019).

Issue No.6

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

Valve-replacement surgery can be very effective for treating aortic stenosis, but a minimally invasive procedure known as TAVR may be a better alternative for many patients.

patients who are likely to fare poorly in surgery, and entails the use of a catheter to deliver an expandable valve that can directly unblock the aorta valve without the need for complete replacement. The new valve is similar to a stent, and once it expands inside the valve, it takes over blood flow regulation. Today, TAVR is commonly performed even in patients at low risk for surgical complications, but it has remained unclear how well this approach stacks up against conventional surgical replacement. Mack and colleagues embarked on the Placement of Aortic Transcatheter Valves (PARTNER) 3 clinical trial to answer this question. They enrolled a cohort of low-surgical risk patients with severe aortic stenosis, of whom 496 underwent TAVR and 454 received valve-replacement surgery, and then monitored both sets of patients over the course of a year. Strikingly, the researchers found that the risk of death, stroke, or hospitalization during that period was reduced by nearly half in the TAVR patients relative to those who underwent surgery. This minimally invasive procedure also offered better outcomes in the shorter term, with a considerably lower risk of death, stroke or other complications even within the first 30 days after treatment. This increased benefit from TAVR was apparent despite the fact that patients receiving surgery in this trial generally fared very well, with fewer than 3 percent experiencing death or stroke after a year. Mack and colleagues caution that this study is still too short to draw a decisive conclusion on the suitability of TAVR for all patients, and that they will be monitoring this cohort for at least a decade to track the durability of the implanted valves. Nevertheless, the findings from PARTNER3 are very encouraging, and suggest that this less aggressive treatment strategy could potentially offer a superior approach for treating a broader population of aortic stenosis patients.

FEATURE

Amyloid plaques on a nerverticale cell

Seeking cures for Alzheimerâ&#x20AC;&#x2122;s disease Advances in Alzheimerâ&#x20AC;&#x2122;s research over the past few years are increasing hopes of finding more effective treatments, while identifying bacteria as a possible cause 28

December 2019

S C I EP R O/S C I EN C E P H OTO LI B R A RY/ G E T T Y I M AG E S

esearchers at the State University of New York recently uncovered a possible route to restoring the memory loss and other cognitive functions that are the distressing hallmark of Alzheimer’s.1 The results come mainly from investigations in mice and cultured human cells, but the researchers report that the insights in mice are now being matched by early work with human cells. Their work focuses on changes in the regulation of the activity of key genes, rather than on the DNA sequence of the genes. Alzheimer’s has long been attributed to a mixture of genes that bestow susceptibility to the disease and subtler gene regulatory innovations.kaimrc.med.sa

processes, known as epigenetics. A common epigenetic control mechanism involves the addition of methyl groups (CH3) to proteins called histones that are bundled together with the DNA of chromosomes and control gene activity. The researchers’ first key finding is that in mice with a form of Alzheimer’s this histone ‘methylation’ process significantly reduces the levels and activity of proteins required for the normal transmission of nerve impulses in the brain. The proteins are receptors that sit in nerve cell membranes and bind to the neurotransmitter glutamate. Neurotransmitter molecules allow signals travelling along one nerve cell to influence Issue No.6

explore whether they could form the basis of a future treatment,” Voigt concludes.

A link with oral bacteria

the activity of other cells. This communication is the essence of how our brain cells work together to make our minds. The damaging methylation revealed in the research is catalyzed by two proteins, EHMT1 and EHMT2, the elevated activity of which was detected in the brains of the Alzheimer’s mice. Examining post-mortem tissues from human patients also suggested increased methylation activity of the type catalyzed by EHMT1 and EHMT2. This forges a crucial link between the mouse studies and the human disease.

Rescuing memories

The researchers speculated that the key to treating this specific aspect of Alzheimer’s might be to inhibit the methylation. Fortunately, chemicals that inhibit the two implicated proteins were already known, allowing the possibility to be readily tested. Injecting an inhibitor of EHMT1 and EHMT2 into affected mice achieved what the researchers describe as the ‘rescue’ of cognitive function, which was confirmed through tests of recognition memory, spatial memory and working memory. 30

December 2019

These included the ability of the mice to remember their way through mazes and to demonstrate recognition of previously encountered objects. “We were quite surprised to see such dramatic cognitive improvement,” says Zhen Yan of the research team. There is a long road to travel between preliminary results in a mouse model and the development, testing, and approval of a treatment for humans. Nevertheless, a new door has been opened and the Buffalo research team are already developing the work further. Yan reports that her team has conducted proof of concept trials in cultured human nerve cells, to confirm that the approach can lead to the recovery of signalling function in the human cells. She says that the “promising” results will be published soon. “One of the most exciting aspects of epigenetic research is that the changes are potentially reversible,” says Jana Voigt, head of research at Alzheimer’s Research UK, commenting on the paper. “These interesting findings in mice now need to be taken forward in studies in people, to

Looking back to the start of the trail of cause and effect in Alzheimer’s, researchers have recently uncovered surprising evidence that the disease may be linked to bacteria that cause gum disease.2 Research led by US biopharmaceutical company Cortexyme Inc. found Porphyromonas gingivalis, a bacterium associated with chronic gum disease, in post-mortem tissue from the brains of patients with Alzheimer’s. The researchers also found that the levels of this bacterial infection showed a correlation with those of two types of protein, called tau and ubiquitin, which malfunction and accumulate in the brain in Alzheimer’s disease. And when mice were infected with P. gingivalis the bacterium was found to colonize the brain alongside increased production of proteins that combine to form aggregates called amyloid plaques, which are strongly implicated in the damage found in Alzheimer’s-affected brains. There was no evidence of the transport of two other common types of oral bacteria into the mouse brains, suggesting the link to Alzheimer’s may be limited to specific bacteria, or perhaps to P. gingivalis alone. The bacterium itself produces toxic proteins called gingipains, and these were also found in the brain tissue of Alzheimer’s patients at levels that correlated with the tau and ubiquitin proteins. “We believe P. gingivalis and its associated gingipains cause the majority of what is currently being diagnosed as Alzheimer’s disease,” says Stephen Dominy of the Cortexyme team. If confirmed, that would surely be a startling advance in understanding. One obvious possible significance of the bacterial link is that poor oral hygiene may increase the risk of Alzheimer’s. Good oral hygiene may therefore offer a simple approach to reducing the risk of acquiring the condition. Dominy urges some caution on that issue, however. “It is very possible that P. gingivalis and the gingipains enter the brain without first causing gum disease,” Dominy

DR _ M I CR OBE / I S TOCK / G E T T Y I M AG E S P LU S

FEATURE

“Researchers have recently uncovered surprising

evidence that the disease may be linked to bacteria that cause gum disease.“

Other avenues

Another promising avenue of recent research is also focused on bacteria, but in the gut rather than the mouth. Researchers led by Sangram Sisodia at the University of Chicago, USA, used antibiotics to alter the bacterial population of the gut in mice with a form of Alzheimer’s. They found alterations that could reduce brain inflammation and amyloid plaque formation, but intriguingly so far only in male mice.3 Researchers elsewhere are exploring the ultimate preventive measure, in the form of vaccines that could prevent Alzheimer’s ever gaining a foothold in the brain. Kiran Bhaksar and colleagues at the University of New Mexico, USA, have developed a virus-based vaccine that provokes an effective immune response against the

tau proteins of Alzheimer’s, restoring some cognitive functions, but thus far only in mice.4 Research will surely push forward on many fronts to find treatment and preventive options better than the limited help that the currently available drugs can offer. 1. Zheng, Y., Liu, A., Wang, Z-J., Cao, Q., Wang, W. et al. Inhibition of EHMT1/2 rescues synaptic and cognitive

functions for Alzheimer’s disease. Brain 142, 787-807 (2019). DOI: 10.1093/brain/awy354

2. Dominy, S. S., Lynch, C., Ermini, F., Benedyk, M., Marczyk, A. et al. Porphyromonas gingivalis in

Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhib-

itors. Science Advances 5 : eaau3333 (2019). DOI: 10.1126/sciadv.aau3333

3. Dodiya, H.B., Kuntz, T., Shaik, S. M., Baufeld, C., Leibowitz, J. et al. Sex-specific effects of microbiome per-

turbations on cerebral Aβ amyloidosis and microglia phenotypes. The Journal of Experimental Medicine 216 1542-1560 (2019) DOI: 10.1084/jem.20182386

4. Maphis, N. M., Peabody, J., Crossey, E., Jiang, S., Ahmad, F. A. J. et al. Qß Virus-like particle-based vac-

cine induces robust immunity and protects against tauopathy. npj Vaccines 4 Article 26 (2019) DOI: 10.1038/s41541-019-0118-4

M IC RO G E N/ I STO C K / G ET T Y I M AG E S P LU S

points out. Tara Spires-Jones, deputy director of the Centre for Discovery Brain Sciences at the University of Edinburgh, also urges caution, saying: “People with Alzheimer’s disease also have disruption of their blood brain barrier, making them more susceptible to getting infections in their brains, so while these data are interesting, it is possible that the infection is a by-product instead of a cause of disease.” Nevertheless, Cortexyme is exploring the possibility of using drugs that inhibit the activity of the bacterial gingipain proteins to treat Alzheimer’s. They have performed preliminary tests in a mouse model of Alzheimer’s, using gingipain inhibitors that the company has designed and synthesized. The inhibitors significantly

blocked amyloid protein production, reduced nerve cell inflammation and led to reduced degeneration of nerve cells. The company has now begun a large clinical trial of one of their gingipain-inhibiting drugs. Dominy reports that they are also investigating whether P. gingivalis might also be involved in other neurodegenerative diseases.

innovations.kaimrc.med.sa

Issue No.6

A case of a rare childhood disease reveals a new mutation as an underlying cause and identifies unknown manifestations of the disease on the skin and hair.

esearchers at KAIMRC have established a link between a rare childhood disease and a newly identified gene mutation, as well as previously unknown complications. “This is the latest of more than 50 novel genes associated with diseases that we have discovered in the last few years,” says Majid Alfadhel, explaining how the research fits into a long history of achievement in the field of genetic disease. This latest work focused on a single specific case of a 40-month (3-year) old patient suffering from methyl adenosyltransferase I/III deficiency (MAT deficiency). This metabolic disease occurs in children whose genome has a mutation in the gene for the methyladenosyltransferase enzyme. The resulting deficiency in the enzyme leads to an accumulation of the amino acid methionine in blood. Methionine is required to make many of the body’s normal proteins, but too much can be harmful. Most cases of MAT deficiency nevertheless lead to minimal

December 2019

R CS B.OR G / CC BY 4 .0

MAT deficiency: Wider effects of a rare disease Researchers at KAIMRC have established a link between a rare childhood disease and a newly identified gene mutation.

symptoms, like a distinct breath odour but some severe cases are associated with neurological problems like impaired movement and intellectual disabilities. One of the most significant results of the KAIMRC research is to identify symptoms beyond the disease’s effects on the central nervous system . “Our patient had an unexplained zinc and iron deficiency, in addition to mild speech delay,” says Alfadhel. These problems were accompanied by skin lesions, hair whitening, and hair loss. The scientists identified the genetic cause of the 40-month old male’s MAT-deficiency as a previously unidentified mutation in the gene for the MAT enzyme. This adds to the range of mutations that can cause the disease. “As we conducted our research we were surprised by the lack of knowledge about this rare disease,” says Alfadhel. One major recommendation emerging from the investigation is that patients diagnosed with MAT deficiency should be further

screened in search of the less well-known consequences of the condition, beyond its effects on the central nervous system. In an effort to clarify what is known about these wider symptoms, the researchers reviewed previous reports of the consequences of the disease. They found that the reporting of symptoms other than effects on the central nervous system was “sporadic.” “Investigating effects of the disease beyond the central nervous system might lead to a better understanding of the disease and the function of the MAT enzyme,” says Alfadhel. With the KAIMRC team having looked at just one case, they emphasize that a much wider survey of cases from around the world would now be justified to yield deeper insights. Nashabat, M., Al-Khenaizan, S. & Alfadhel, M. Methio-

nine adenosyltransferase I/III deficiency: beyond the central nervous system manifestations. Therapeutics

and Clinical Risk Management 14, 225–229 (2018).

Leading Reliable Healthcare An outstanding, timely and much awaited contribution to the healthcare sector in the Kingdom of Saudi Arabia and globally.

Edited by Bandar Al Knawy, MD, FRCPC CEO, Ministry of National Guard Health Affairs Foreword by Dr. Paul Rothman CEO, Johns Hopkins Medicine Published by CRC Press, 2017

FEATURES

Contains contributions from recognized healthcare leaders from the UK, USA, Canada and South Korea/Singapore.

Describes how leadership can ensure reliable standards of care for patients and how excellence can be achieved.

Focuses on a different aspect of building a reliable healthcare system.

Relevant to global healthcare systems with key themes such as effective clinical practice and crisis management being universal.

An instigator for immunodeficiency

A genomic survey of immunodeficient patients reveals a gene with an important role in fending off infection and controlling inflammation

ecent findings from a cohort study of patients with a rare hereditary immunodeficiency disorder reveal insights into a geneâ&#x20AC;&#x2122;s role in immune function, as well as possible treatment avenues. The study

December 2019

is the first to characterize the effects of complete RIPK1 (a signalling protein) deficiency in humans. Hundreds of genes have already been linked to primary immunodeficiency (PID) disorders, and an international team

of researchers led by Sergey Nejentsev at the University of Cambridge embarked on a dragnet to identify additional causative mutations. They sequenced the full complement of genes from 48 patients who had experienced recurring, severe

N EP H R ON / C C B Y SA 3 .0

Patients lacking RIPK1 all manifested the gastrointestinal tissue damage associated with inflammatory bowel disease, demonstrating a lack of healthy immune system regulation.

infections throughout their lives as a consequence of PID. Four of these 48 people had mutations that essentially disabled the same gene, encoding a RIPK1. In addition to being infection-prone, all four also suffered from arthritis and inflammatory bowel disease (IBD) — conditions associated with immune dysfunction. Previous studies have indicated that RIPK1 acts as a master regulator that controls the inflammatory response and cellular survival, but this is the first report to date of humans with RIPK1 deficiency. Working with both patient-derived blood cells and genetically modified human cell lines, Nejentsev’s team found that RIPK deficiency debilitates the cellular response to molecules that normally innovations.kaimrc.med.sa

trigger a strong immune response. These findings, which were published in Science, could explain why the patients failed to fend off infection. The researchers also identified deficiencies in the production of certain signalling proteins that have previously been linked to the onset of IBD. These results are in striking contrast to previous data from RIPK1-deficient mice. The mice experience extensive inflammation and cell death early in development, and perish soon after birth. In contrast, two of the affected individuals had reached adolescence by the time of this study, illustrating the limitations of mouse models for predicting the clinical impact of genetic mutations. Importantly, the study also identified

potential avenues for the treatment of this form of PID. For example, one of the four patients achieved considerable — but not complete — recovery after receiving a stem cell transplant that enabled production of healthy, RIPK1-expressing blood cells. The researchers also determined that excessive production of an immune signalling protein called IL-1β is a common feature of RIPK1 deficiency. Based on this finding, they propose that drugs that inhibit this protein could potentially alleviate the immune symptoms in these patients. Cuchet-Lourenço, D., Eletto, D., Wu, C., Plagnol, V.,

Papapietro, O. et al. Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation. Science 361, 810–813 (2018).

Issue No.6

An experiment with lizards and fire ants shows that stress can have lasting effects across generations.

What doesn’t kill your ancestors makes you stronger

Stressed-out fence lizards inadvertently give younger generations a better chance against predators.

ence lizards whose ancestors were frequently exposed to extreme stress tend to develop better immune responses to stress in early life, according to new research. “When we think about how an organism responds to stress, we don’t always consider previous experience,” says Gail McCormick, first author of The Journal of Experimental Biology study, and biologist at Pennsylvania State University. “Our research reveals that an individual’s experience with stress in its lifetime, as well as its ancestors’ experience with stress, both play important roles in how the individual responds to it.”

December 2019

Animals typically react to stressors, including attacks from predators, through fight, flight or enhancing immune function to prepare for injury and trauma— the latter is the focus of the study led by Tracy Langkilde, head of biology at Penn State. To study transgenerational stress and its implications on early development, McCormick and her colleagues experimented on Sceloporus Undulatus or eastern fence lizards, native to southeastern United States. As of the 1930s, these lizards often shared their habitat with fire ants, an invasive species that can sting and leave victims open to fatal infections. For comparison, the researchers

McCormick, G.L. et al. Population history with invasive predators predicts innate immune function response to

early life glucocorticoid exposure. The Journal of Exper-

imental Biology (2019).

L A NG K I L DE L A B, P E N N S TAT E

collected pregnant female lizards from both low-stress sites that are free of fire ants, and high-stress sites where the reptiles had been under attack for more than 30 generations. They raised offspring from these lizards, varying their exposure to stress during their first year of life. The young were either made to endure attacks from fire ants, or received topical doses of corticosterone dissolved in oil, which causes a spike in their blood corticosterone levels, mimicking their physiological reaction to real-life attacks. Under stress, the body undergoes a series of physiological changes to help it survive and recover. This results in production of glucocorticoid stress hormones—cortisol in humans, corticosterone in lizards. The hormones interrupt inflammation and suppress the immune system. Lizards whose ancestors lived in highstress environments, however, showed a better adaptive response to glucocorticoid, by enhancing immune function instead of suppressing it. In the long term, having a more robust immune response to stress is more useful in helping lizards deal with a persistent stressor, says McCormick, since stress for a long time or at high intensities comes at a cost, such as reducing growth or compromising reproduction or immunity. McCormick and colleagues still found the results surprising considering their previous works have shown that early life stress in these lizards generally didn’t affect survival, yet stress experienced by their ancestors did. Researchers plan to study the maternal effects of stress. “Stress experienced by a mother can affect the stress hormones in the yolk of her eggs and can affect stress-physiology, morphology, and behavior of her offspring. We would like to investigate whether maternal effects play a role in the immune differences we saw in this study,” says McCormick.

Gene mutation associated with fertility A mutation in a gene encoding a cell surface receptor disrupts the growth of lymphatic vessels and is linked to miscarriage.

innovations.kaimrc.med.sa

“Studies in cells showed that mutated CLR failed to reach the cell surface, thus preventing the receptor’s ligand from binding and disrupting normal adenomedullinCLR signalling.“ as her husband’s revealed that they both carried a mutation due to the deletion of a single amino acid called valine 205. This mutation impairs the ability of the cell receptor CLR (calcitonin receptor-lie receptor) to interact properly with the helper proteins RAMPs (receptor activity-modifying proteins). This interferes with the normal cellular function. Studies in cells showed that mutated CLR failed to reach the cell surface, thus preventing the receptor’s ligand, adrenomedullin, from binding and disrupting normal adrenomedullin-CLR signalling. Interestingly, deletion of either the

genes encoding CLR, its partner protein RAMP2, or adrenomedullin in mice caused mid-gestation embryonic death due to disrupted growth of lymphatic vessels, mimicking the hydrops fetalis observed in humans. These results not only highlight a novel role for this conserved signalling pathway in the survival of mammals and female reproductive function, but they have also identified three new genes to study in large-scale genetic testing platforms for hydrops fetalis and other developmental vascular malformations. “In theory, females carrying the CLR mutation could benefit from therapies that maintain the normal adrenomedullin-CLR signalling,” says Al Mutairi. Drugs that selectively target and modulate the interaction of G-protein-coupled receptors with RAMPs have recently been approved for clinical use in the treatment of migraines. This study suggests that similar strategies targeting the CLR-RAMP2-adrenomedullin interaction may hold potential for improving fertility. Mackie, D.I., Al Mutairi, F., Davis, R.B., Kechele, D.O., Nielsen, N.R. et al. hCAL CRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia. JEM 9, 2339–2353 (2018).

Issue No.6

F UA D A L M UTA I R I

esearchers from Saudi, the UK, and the US discovered a genetic mutation associated with reduced female fertility and miscarriage due to abnormal fluid accumulation in fetal compartments. The condition, known as hydrops fetalis, can occur when the mother’s immune system destroys the red blood cells in the fetus. This type of hydrops fetalis can be prevented with an injection of anti-D immunoglobulin. However, there are many other causes, such as heart or lung problems, severe anaemia, and genetic or developmental problems associated with impaired growth of lymphatic vessels, most of which result in fetal death. Further understanding of the mechanisms leading to excessive fluid leaving the bloodstream and the fetus’ capacity to manage fluid could guide the development of new treatments or preventive measures. “Our discovery arose from [studying the case of] a 22-year-old healthy woman who was referred to the genetics clinic in King Abdulaziz Medical City after experiencing two second-trimester miscarriages due to hydrops fetalis, and one spontaneous miscarriage in the first trimester,” explains KAIMRC’s Fuad Al Mutairi, one of the study’s lead authors. Genetic analyses of all the mother’s protein-coding genes (exome), as well

KAIMRC researchers discovered that a mutation due to the deletion of a single amino acid impairs the ability of the cell receptor CLR

Slim chance of defying genetic odds in the weight game

Staying thin may not be the result of sheer willpower. A new study shows that maintaining a healthy weight can come down to genetics.

December 2019

The research shows that genes can help people keep a low body mass index (BMI), or make it difficult for them to lose weight.

innovations.kaimrc.med.sa

“Some people are just luckier in the genetic lottery, and that makes it easier for them to keep a low BMI. Some are unluckier and have a harder time losing weight.“ distribution need to be done before we start thinking about treatments. We still don’t know the way most of these genetic variants influence obesity or thinness,” explains Riveros-McKay. The researchers compared obese participants with healthy, thin individuals with a BMI lower than 18. Thin participants were examined to ensure they were healthy and had no eating disorders or any other diseases causing their thinness. They had to have been thin for most of their lives. Extensive research has been done on obesity and thin individuals with eating disorders, but no study of this size has been conducted on healthy, thin individuals who remain thin in obesity-inducing environments. According to the study, the results obtained have encouraged the researchers to continue studying and gathering information on “the biology underlying human energy homeostasis, and as an alternative approach to uncovering potential anti-obesity targets for drug development.” Riveros-McKay, F. et al. Genetic architecture of human thinness compared to severe obesity. PLOS-Genetics 15, 1 (2019).

Issue No.6

I M AG EB R OK ER / A L A M Y S TOC K P H OTO

recent study on 2,000 healthy, thin participants reveals that 74 percent of thin participants had a family history of being thin and healthy, concluding that thin people have a genetic tendency to keep the weight off. “There is a combination of genetic variants that makes you more likely to be really obese, and a combination of those same variants that makes you more likely to be really thin,” says Fernando Riveros-McKay, one of the lead authors of the research, which was conducted by researchers from the Wellcome-MRC Institute of Metabolic Science and the University of Cambridge. While previous research has shown many connections to obesity and genetics, little was known about the genetic relationship between thinness and any hereditary predisposition. The researchers sought to find hereditary explanations to healthy individuals who are resistant to obesity in environments that would otherwise tend to cause it, publishing the results of the largest cohort study of its kind to date in the journal PLOS-Genetics. “Some people are just luckier in the genetic lottery, and that makes it easier for them to keep a low body mass index (BMI). And some are unluckier and have a harder time losing weight,” says Riveros-McKay. The research can give insight for future studies to eventually reach a possible treatment for obesity, a leading cause of non-infectious diseases worldwide among children. “More studies on the functional aspects of the genetic influences on both extremes of the BMI

FEATURE

Genetically engineered macaques could offer researchers and clinicians new avenues to better understand autism and develop therapies for affected children

December 2019

Searching for answers surrounding autism

or Guoping Feng, one of the hardest aspects of his work is hearing the anguish of the parents of children with autism. As a professor of neuroscience at the Massachusetts Institute of Technology and a prominent researcher of the mechanisms that underpin neurodevelopmental conditions such as autism spectrum disorder (ASD), Feng hears their distress by email, phone, and visits to his office. “They ask what we can do, and I can’t help them right now,” he says. Feng’s response is a reflection of the current state of research into ASD, on which much work remains to be done. “You can’t give them false hope, but you want to give them some hope… Just, how do I tell them?” Despite these emotional struggles, the calls for help received by Feng act as a powerful call to action: “It really motivates me and the people in my lab to try and do something as quickly as possible to help them.” Feng, along with a large international

innovations.kaimrc.med.sa

collaboration of MIT scientists and researchers from China, has made a breakthrough that may open doors to a greater understanding of ASD by creating genetically modified macaques with one of the same genetic mutations common to people with autism. This newly-developed ‘model’ of autism now offers scientists more opportunities to study the disorder, and to bridge the understanding between its genetic basis and its debilitating symptoms. Armed with this knowledge, researchers will hopefully be able to devise new therapies for ASD.

The study of ASD

ASD is a neurodevelopmental disorder that manifests in many ways. The condition usually presents at a very early age; however, affected individuals can reach early adulthood before traits become evident. Autism can significantly affect the ability to communicate, or social functioning. Other symptoms include fixative, repetitive behaviour — including that which causes self-harm. Issue No.6

M EG A P R ESS / A L A M Y S TOC K P H OTO

Replicating a gene linked to autism in a monkey model could shed light on its underpinnings.

thousands of embryos to successfully create an edited one. With CRISPR, scientists can now get five edited embryos out of 10. Some teams have reported up to a 90 percent efficiency. The team created five macaques with damaged SHANK3 genes, producing lower levels of functional SHANK3 protein, and inducing autism-like symptoms. The macaques manifested repetitive behaviour, interaction issues, motor function issues, and an inability to fall into a deep sleep — all hallmarks of ASD in humans. But perhaps the biggest breakthrough in the team’s experiments was that the mutations induced in the monkeys were carried through germline transmission, meaning the mutations were hereditary, and could be passed on through reproduction to the next generation of macaques.

Empowering future science The global research community has discovered a list of almost 1,000 genes that are implicated in ASD, says Yang Zhou, a former researcher in Feng’s lab at MIT, and lead author of their newly-published Nature study. Zhou has extensively studied animal models for autism for around 10 years, and now continues his research at McGill University in Montreal, Canada. Autism can be caused by multiple genetic factors, or in some cases, a single, monogenic factor. Zhou and Feng’s study focused on a mutation in the SHANK3 gene, which is present in around 1.5 percent of all cases of monogenic autism. Despite this low percentage, SHANK3 actually constitutes one of the largest single-gene causes of ASD. “SHANK3 is a gene that encodes a key scaffold protein that forms synapses in the brain,” says Zhou. “The synapse is the main building block required for communication between individual brain neurons.” When SHANK3 is disrupted, neuronal connectivity is impaired, leading to brain circuitry changes that could contribute to the array of symptoms seen in autism. Zhou, Feng, and their team previously 42

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studied autism in rat models, in which gene editing tools have long allowed for inducing the condition. But rat models can only offer so much. As Feng explains, every animal’s brain, emotions, and behaviour develop through the process of evolution to best suit the particular needs of that animal. As a result, a rat’s brain is very different than a human brain. A monkey’s is closer. However, until just a few years ago, there was no reliable technique to genetically modify a monkey.

Enter CRISPR

The team’s big break came in the form of CRISPR-Cas9, a gene-editing tool discovered and refined over the last 10 years. CRISPR gene editing involves the DNA-cutting protein Cas-9 bound to a guide RNA — a short sequence of genetic material that seeks and binds a complementary section of DNA, which Cas-9 then cleaves. Through the selection of specific guide RNAs and the alteration of the Cas-9 complex, scientists can now disable certain genes, increase their expression, or introduce new genes entirely. In the past, Zhou says, they’d need

The model devised by Zhou, Feng, and their team can now be leveraged to gain greater insights into the cause and effects of ASD. For instance, says Zhou, research efforts are now underway to develop artificial intelligence-powered systems to observe ASD model macaques and better understand the details of autism’s impact. Future studies may use this model to study the effects of gene therapies that might revolutionize the treatment of autism. Using MRI and EEG scans, researchers may be able to identify signatures of the disease in brain activity, providing clinicians with a reliable set of biomarkers to more easily and objectively diagnose ASD in children. With these prospective future discoveries, the parents who contact Feng may be able to see their children benefit from the treatments they seek. Until then, they remain supportive of his work, “many of them help us,” he says. “They fundraise for donations, seeing that science is the way to give hope to their kids.” “We’re very grateful, and very motivated by them,” he adds. Zhou, Y., et al. Atypical behaviour and connectivity in SHANK3-mutant macaques. Nature 570 326–331 (2019)

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Medical

BIOTECHNOLOGY Park The Medical Biotechnology Park, a new company at KAIMRC/MNG-HA is a strategic project of MNG-HA to contribute to the Saudi Vision 2030 through:

The development and commercialization of biomedical R&D products, technologies and services

The contribution to economic and health improvement through science and innovations in medical and health sectors

EMAIL: KAIMRC-KMBP@NGHA.MED.SA PHONE NUMBER: +966-11-429-4516 TWITTER: @MEDICALBIOTECH

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Hepatoblastoma, the most common form of liver cancer in children, is slightly more common among children conceived via IVF

Slightly raised risk of rare childhood cancers in IVF babies

Largest cohort study to date shows marginally increased cancer risk among IVF babies, but researchers say overall numbers very low 44

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hildren born through in vitro fertilization (IVF) are slightly more likely to develop early childhood cancers, especially of the liver and central nervous system, according to a new study by researchers in the US. The study, conducted by the University of Minnesota, has concluded that, compared to the occurrence rate in naturally conceived children, the overall cancer rate in children from IVF may be 17 percent higher, and hepatic tumour occurrence may be 2.5 times higher. However, the researchers emphasize that the increased risk is too small to worry people considering IVF treatment, with an occurrence rate of 252 cancer cases per million IVF births, or 0.025 percent. In 1978, in Manchester, UK, Louise Brown was the first child born after IVF conception. The procedure accounted for 1.7 percent of US births in 2015, according to a recent survey. Livestock produced through IVF are at a higher risk of developing an overgrowth disorder, and

innovations.kaimrc.med.sa

Issue No.6

OG P H OTO/ I S TOC K / G ET T Y I M AG ES P LU S

IVF-conceived babies have greater inciamong children conceived via IVF. Howto have a child who is at a higher risk of dence of the analogous human disorder, ever, the overall rate of these tumours is cancer, that needs to be known wherever Beckwith-Wiedemann syndrome, which extremely low. Spector uses the analogy of the risk comes from.” predisposes children to certain types of lottery tickets to help communicate this. “A However, understanding the origin cancer. doubling in risk is scary to hear about. But of any increased risks would be the first “There wasn’t a huge amount of eviif you buy two lottery tickets, even though step towards dealing with it. If the IVF dence saying that this should be of conyou have twice the chance of winning, process is the source of the problem, cern, but it was enough for us to want everyone would agree that your chances practices could be changed to reduce or to investigate,” says the study’s lead are still infinitesimal,” he explains. eliminate risks caused by the procedure. author Logan Spector, a paediatric can“We didn’t identify anything that IVF cer epidemiologist at the Univerclinics would have to do differsity of Minnesota. Spector’s team ently,” says Spector, commenting “They found a small association has conducted the largest cohort on the results of his current study. study to examine the occurrence He has started a new project, between IVF and overall cancer of cancer in IVF-conceived chilhowever, to look for differences dren, studying a sample that is 2.5 between tumours from children larger than previous studies, and conceived with and without IVF. rates, with about 252 cancers per publishing the results in JAMA “That might help us distinguish Pediatrics in April 2019. the biological effect of IVF,” he million IVF births, compared to Together with researchers says. around the US, Spector collected “Building on this work, DNA 193 per million non-IVF births.“ data from the Society for Assisted methylation analysis of children Reproductive Technology Cliniconceived by IVF may identify cal Outcomes Reporting System (SART Identifying risk factors at birth those who have higher risks of CORS) to find IVF births in birth regisMarie Hargreave, a senior researcher developing specific cancers,” says Andrea tries in 14 states. They then matched these at the Danish Cancer Society Research Riccio a genetics professor at the Univerwith 10 times as many non-IVF births and Center who was not involved in the study, sity of Campania ‘Luigi Vanvitelli’, who used the combined list to study childhood points out that childhood cancers are very was not involved in the study. cancer rates based on data in cancer regrare, especially liver tumours. She adds, istries. They found a small association however, that “childhood cancer is the Building on knowledge between IVF and overall cancer rates, leading cause of death due to disease This is the latest in a series of cohort studwith about 252 cancers per million IVF for children in Western countries” and ies investigating potential links between births, compared to 193 per million nonthat even those who survive will face an IVF and childhood cancer, including the IVF births. increased risk of cardiovascular disease, 2013 UK study and a 2014 study in the “The most important takeaway from our endocrine disorders, or secondary canNordic countries. All three studies had research is that most childhood cancers are cers. “Identifying risk factors is imporsimilar findings. Alastair Sutcliffe, a paenot more frequent in children conceived tant for understanding the underlying diatrics researcher at University College by IVF,” says Spector. He explains that the mechanisms.” London who led the UK study, calls the slight link between IVF and overall cancer While the study measured an increase accumulated results “reassuring to date,” rates is largely driven by a small increase in in cancer rates, the researchers were unaand Spector underlines the importance of the incidence of embryonal tumours and a ble to determine whether this was due to carrying out parallel studies in different doubling in the rate of liver tumours in IVFthe IVF treatment or underlying fertility countries since IVF practices differ from born children. This is consistent with a 2013 problems which led the parents to IVF. place to place. UK study, which found that liver tumours “On a practical level it doesn’t matter,” In addition to difference in IVF procewere roughly three times as common says Spector. “If IVF enables somebody dures, the population with ready access

ZU M A P R E SS , I NC. / A L A M Y S TOCK P HOTO

FEATURE

In 1978, Louise Joy Brown became the world’s first test tube baby

to IVF differs between countries, depending on whether and how it is supported by healthcare programs. In the US study, IVF was much more common among white, educated, older women, a skew which might have biased the results. “It’s a really thorny issue,” says Spector, but after further statistical analysis to test for this he says “I don’t think that it had a large impact” on the conclusions. Hargreave adds that differences can also arise if studies include other fertility treatments alongside IVF, or even because of differences in the hormones used during fertility treatments. “This has changed over time and may be different between clinics and countries,” she says, which could affect childhood cancer risk. The findings of all three cohort studies also overlap with the results of a meta-analysis carried out by Hargreave and others at the Danish Cancer Society Research Center in 2013, which combined data from 25 earlier studies and found a significantly increased overall risk for cancer, as well as greater risks for specific 46

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types of cancer, such as leukaemia, and central nervous system cancers. However, the researchers interpret these results differently. For Hargreave, “the increased risk of a serious life-threatening disease in children is worrisome, aside from the other more frequent and well-established health consequences of IVF.” But Spector urges people to focus on the absolute risk, rather than the relative increase. “I don’t think that these numbers warrant a parent changing their consideration of whether they should use IVF. I would not recommend anybody change their behaviour based on this,” says Spector, adding the greater pathology during pregnancy and higher risk of birth defects associated with IVF are more likely complications for people considering the treatment. Looking forward, Spector hopes to pool the data from this study with others in the hope that a larger data set will lead to more robust conclusions and enable further research. “It’s going to be a lot easier to pool existing studies than to try

creating more,” he says, explaining that assembling the data can be a long and difficult process. The University of Minnesota study concludes by recommending continued monitoring for cancer in IVF-born children. Spector explains that this is because different cancers peak at different ages, and the study only followed IVF-born children for seven years — long enough to cover childhood cancers such as leukaemia, which nearly always occur in the first five years, but too short to catch cancers which become more likely closer to or during puberty. But although continued surveillance is warranted, Spector hopes this study will reassure paediatricians and prospective parents that the overall risk remains extremely low. “We intentionally published this in a journal where paediatricians would notice it,” he adds. Spector, L.G. Brown, M.B., Wantman, E., Letterie, G.S., Toner, J.P. et al. Association of In Vitro Fertilization With

Childhood Cancer in the United States. JAMA Pediatrics 173 (2019).

Stem cells marshal troops against cancer A recently identified population of adult stem cells generates signals that could spur immunity against tumour cells

onventional wisdom on the potential of stem cells is about treatments that directly replace unhealthy tissues — but new research suggests certain stem cells can actually wage a war against cancer cells. A team led by Mohamed Abumaree at KAIMRC has demonstrated that mesenchymal stem cells (MSCs) may have the capacity to marshal a potent antitumor immune response.1 MSCs are derived from certain innovations.kaimrc.med.sa

connective tissues in the body. These adult stem cells can form bone, fat, and cartilage, but are also known to release a host of powerful biological signals that may prove valuable in treating diseases. In a paper published in Stem Cell Research & Therapy, Abumaree and colleagues identified a new subpopulation of MSCs in a section of the human placenta known as the decidua parietalis (DP), and he was intrigued by their potential clinical use.

Abumaree, M.H. et al. Characterization of the interaction

between human decidua parietalis mesenchymal stem/ stromal cells and natural killer cells. Stem Cell Res. Ther. 9, 102 (2018).

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A culture of placentally-derived decidua parietalis mesenchymal stem cells, or DPMSCs.

“We found that these DPMSCs produce factors that are known to modulate the functional activities of immune cells, and to induce the expression of anticancer molecules by these immune cells,” explains Abumaree. In order to evaluate the physiological effects of these signals, his team assessed the way selected subpopulations of human immune cells respond when cultured in the presence of DPMSCs. They focused on natural killer cells, which play a pivotal role in defending against tumours and viral infections, and also coordinate the broader immune response. When these natural killer cells were already biochemically activated, they attacked and destroyed the DPMSCs. But when these cells were inactivated, the DPMSCs promoted natural killer proliferation and helped switch them on by acting on a signaling protein called interleukin-18 receptor (IL-18R). When these stem-cell-activated natural killers were transferred into cancer cell cultures, they swiftly moved to attack and destroy the diseased cells. “These DPMSCs enhance the anticancer activity of natural killer cells via mechanisms that may involve IL-18R,” says Abumaree. However, these same immunity-stimulating properties would most likely make these cells a poor choice for the treatment of autoimmune disorders such as multiple sclerosis — an indication for which other MSC subtypes are now being tested in the clinic. Immunotherapy has proven a powerful weapon against intransigent cancers, but it can be a challenge to rouse an effective immune response. Abumaree is therefore looking to explore whether these stem cells might be used to ‘coach’ freshly-harvested immune cells to attack tumours more aggressively. “We’re looking to educate natural killer cells in culture with DPMSCs, and then infuse these educated cells back into cancer patients,” he adds.

Saudi Arabia gets familiar with its superbugs

First study to examine the antibiotic resistance, virulence factors, and genetic diversity of multidrug-resistant strains in Saudi Arabia

genetic analysis of dangerous antibiotic-resistant bacteria in a Saudi hospital (King Abdulaziz Medical City) has uncovered new associations between resistance genes and bacterial strains, which are useful for monitoring infections. A global spread of the multidrug-resistant Klebsiella pneumoniae (K. pneumonia) is a pressing healthcare concern. K. pneumoniae are bacteria that live in the intestines and faeces, and that are usually harmless unless they spread to other parts of the body through human contact. An infected person can develop severe infections in the lungs, bladder, brain, liver, eyes, blood or open wounds. The risk of infection is higher when a person is sick, which makes it especially difficult to control in hospitals, where patients have a weaker immune system. Another risk factor for contracting infection is longterm antibiotic use, a common problem throughout the world, but especially in the Arab world. In Saudi Arabia, K. pneumoniae is one of the most challenging pathogens to control in hospital-acquired infections of the urinary tract, respiratory tract, and bloodstream. It is becoming resistant

December 2019

to antibiotics, including carbapenems, which are considered last-line antibiotics against superbugs. Researchers at King Abdulaziz Medical City collected 71 samples from patients in 2011-2012. All samples of the bacteria studied were resistant to more than three types of antibiotics, and genetic analysis revealed the genes responsible for such antibiotics resistance. Among the genes that provide resistance to carbapenems, the researchers identified OXA-48 as the most prevalent, present in 67.6 percent of the sample studied, followed by NDM1, present in 12.7 percent of the isolates. Around 8.5 percent of the samples carried both genes, and 11.2 percent had neither of the two genes. Remarkably, none of the samples carried one of the most prevalent carbapenem-resistance genes in the US and other countries (K.pneumoniae carbapenemases). Further analysis classified these bacteria samples into 18 genetic profiles, known as sequence types (STs), and showed new correlations between some resistance genes and some sequence types. For example, all samples belonging to the most abundant sequence type (ST199) were positive for the OXA-48 gene,

but not NDM-1. The study also showed that the samples belonging to the ST-152 are a rare subspecies of K. pneumoniae called ozaenae, and are frequent carriers of the NDM-1 gene. This the first report to describe the presence of NDM-1 gene in this subspecies. The researchers also identified the mobile pieces of DNA that allow bacteria to acquire and exchange antibiotic-resistance genes. By looking at the factors that aid bacterial growth and invasion, the scientists also found that the samples may not have been hypervirulent (variants linked to more aggressive type of infection), supporting the idea that antibiotic resistance and hypervirulence are independent of each other. Since bacteria with certain genetic profiles are more prone to acquire multidrug resistance, keeping track of correlations between resistance genes, the DNA responsible for acquiring and exchanging that gene, and strains could help monitor this phenomenon to combat superbugs. uz Zaman, T. et al. Clonal diversity and genetic profiling

of antibiotic resistance among multidrug/carbapenem-resistant Klebsiella pneumoniae isolates from a tertiary care hospital in Saudi Arabia. BMCInfectious dis-

eases 18 (2018).

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Bacteria in sperm hinders fertility treatment The presence of bacteria in semen reduces sperm quality with a knock-on effect on the success of IVF treatments

any people undergoing fertility treatment face the disappointment of unexplained failure. Recent research indicates that semen can harbour high levels of bacteria that reduce the function and fertility of individual sperm, suggesting it is crucial to test for and treat bacterial infection in sperm before undergoing fertility treatment. Now, Mohamad Eid Hammadeh and co-workers at the University of Saarland

December 2019

in Germany, along with Mohammed Hamad at King Saud Bin Abdulaziz University for Health Sciences in Saudi Arabia, have shown that bacteriospermia appears to play a key role in the failure of a reproductive therapy called intracytoplasmic sperm injection (ICSI). ICIS involves injecting a single sperm into a mature egg, and if a viable embryo is generated, it is then transferred into the uterus. However, the sperm used must have the correct ratio of two

Zeyad, A., Hamad, M., Amor, H., & Hammadeh, M.E. Rela-

tionships between bacteriospermia, DNA integrity, nuclear protamine alteration, sperm quality and ICSI outcome. Reproductive Biology 18 (2018).

M OR SA I M AG E S / DI G I TA LVI S I ON / G ET T Y I M AG ES

Bacteria in sperm can interfere with sperm quality, reducing fertility and leading to the failure of IVF treatment.

proteins, protamines P1 and P2, to provide tight packing for sperm DNA. Otherwise DNA can fragment, leading to poor embryo quality. The ability of sperm to move independently (sperm motility) also impacts on overall sperm quality. Hammadeh and his team enrolled 84 couples due to undergo ICIS treatment at the University of Saarland infertility clinic. They collected semen samples from every male participant and analysed features including sperm bacterial content, protamine levels, DNA integrity, and sperm motility. They found that 34.5 percent of samples were infected with at least one type of bacteria at concentrations high enough to have an impact on sperm quality. The bacteria present in samples included three species of Staphylococcus, along with Escherichia coli, Enterococcus faecalis and Streptococcus. Alongside reduced sperm quality, the bacteriospermia samples had imbalanced protamine levels compared with non-infected males. This was reflected in significant differences in fertilization rates following ICIS treatment. In total, 34 out of 84 females became pregnant after the ICIS course. The team found that infected males who had higher P1 levels than P2 in their sperm were less likely to make females pregnant. Their results suggest protamine balance is a vital part of male fertility. Precisely how bacteria influence sperm composition and concentration is not clear, but Hammadeh’s team believe it may be connected with increases in inflammation and reactive oxygen species triggered by the immune system in response to infection. “Male partner patients should do a semen bacterial investigation and then treat the bacteriospermia before the patients undergo ICSI treatment,” state the authors in their paper published in Reproductive Biology. They add that more research on this issue is necessary.

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

Combatting

MERS KAIMRC has made it its mission to focus on strategic projects that are relevant to the Saudi population, and answers a need that is unmet by international research on more generic areas of disease. Their collaborative efforts have now led to developing a potential MERSCoV vaccine, and holding the very first phase I clinical trial in the kingdom to test its efficacy.

December 2019

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The rapid journey of a deadly MERS outbreak

Citing an unusual outbreak of the MERS virus involving a ‘superspreader’ patient, scientists urge better point-of-care diagnosis.

n 2017, one Middle East respiratory syndrome (MERS) patient in Riyadh was responsible for directly infecting 16 patients, leading to an outbreak that infected 44 people in the surrounding area in just over a fortnight. Recent research into the outbreak indicates that it is often difficult to diagnose pneumonia, one of the key symptoms of the disease, in patients suffering renal and cardiac failures. This delays identification of the virus, and proper infection control procedures. The Middle East respiratory syndrome (MERS) is a viral illness included in the World Health Organization’s priority list of diseases that need to be closely watched due to their potential to cause an epidemic. Caused by a type of coronavirus, MERS-CoV, was first identified in 2012, and is transmitted through contact with infected camels or people. There is no known cure and 35 percent of the reported patients have died. There have been at least 845 MERS-CoV-related deaths in 27 countries since September 2012. Approximately 80 percent of the reported cases are from Saudi Arabia. Learning from past outbreaks is essential to improve infection control. A team of researchers, from universities and researcher centres affiliated with the Saudi Ministry of Health, and the Ministry of National Guard Health Affairs, have

December 2019

now examined the factors that led to an outbreak in Riyadh in 2017. Between 31 May and 15 June of that year, 44 cases of MERS-CoV were reported at three healthcare centres. Eleven patients died from their infections. Of the total number of people infected, 29 were from King Saud Medical City (KSMC), the largest hospital in Saudi Arabia. Focusing on those affected at KSMC, the researchers describe how a single patient became a ‘superspreader’ — an individual who infects a much greater number of people than average. The outbreak was traced to a 46-yearold Yemeni man who, after arriving at the hospital by ambulance, spent 14 hours in the emergency department. His symptoms included coughing and shortness of breath, and the doctors noted that he had diarrhoea for the two previous days. Blood tests initially indicated that he was suffering from kidney failure. To undergo haemodialysis (a routine process of cleansing the blood for patients whose kidneys are not functioning), he was transferred to a medical ward, where he shared a room with four other patients for two days. His condition did not improve. He had trouble breathing and was admitted to an intensive care unit. At this point the medical team suspected a MERS-CoV

infection, and a nose and throat swab sample confirmed their suspicions. The man was isolated and transferred to Prince Mohammed bin Abdulaziz Hospital, a referral centre for MERS patients where he died 22 days later. By mapping the patient’s journey from the ambulance to the different sites in the hospital, the study showed he came into direct contact with 120 people: 107 health care workers and 13 patients. Nine of the 107 health care workers and seven of the 13 patients tested positive for MERS-CoV. It took 30 days for the outbreak to be brought under control. The researchers conclude that “In MERS-CoV endemic countries, there is an urgent need for developing rapid point-of-care testing that would assist emergency department staff in triaging suspected cases of MERS-CoV to ensure timely isolation and management of their primary illness and prevent major MERSCoV outbreaks.” They also recommend that continued training of the growing number of expatriate healthcare workers in Saudi Arabia is needed to help prevent future outbreaks. Amer, H., Alqahtani, A., Alzoman, H., Aljerian, N. and

Memish, Z. Unusual presentation of Middle East respiratory syndrome coronavirus leading to a large outbreak in Riyadh during 2017. American Journal of Infec-

tion Control 46 1022–1025 (2018).

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December 2019

KAIMRC a strong player in quest for a MERS-CoV vaccine

The medical hubâ&#x20AC;&#x2122;s research into a singledose vaccine for the lethal Middle East respiratory syndrome coronavirus (MERSCoV) is promising, but more evaluation and trials are needed, scientists say. C E NT R E F O R I N F E C T I O N S / P U B LI C HE A L T H E N G L AN D / SC I E N C E P HO TO LI B R A RY

he search for a vaccine that would curb the threat of Middle East respiratory syndrome (MERS) and stop the virus in its tracks has been central to KAIMRCâ&#x20AC;&#x2122;s clinical research efforts. Now, a new vaccine developed by the centre and tested successfully in camels carries a lot of promise. The new vaccine, ChAdOX1, is now being tested in humans, marking the first phase I clinical trial to be conducted in Saudi Arabia. The kingdom was the site of the first MERS-Corona virus (MERS-CoV) infection and has reportedly experienced the worst outbreaks of the virus. MERS-CoVrelated fatalities have reached 851 globally, with 773 in Saudi Arabia alone, according to figures released by the World Health Organisation (WHO) this September. So far, MERS-CoV infections have reached a total of 2,468 worldwide, including 2077 infections in Saudi Arabia. MERS-CoV, a viral disease caused by a novel

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A FP P HOTO/ FAY E Z NU R E L DI NE VI A G E T T Y I M AG E S

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coronavirus, was first identified in a pneumonic patient in Saudi Arabia in 2012. Patient zero died shortly after contracting the virus, whose symptoms ranged from fever, cough and shortness of breath to diarrhoea and other gastrointestinal symptoms. MERS-CoV is endemic in dromedary camels¬¬¬¬ — possibly the virus’s only intermediate animal host, although scientists believe that bats may be putative reservoirs. Saudi Arabia’s research into MERS risk factors, transmission techniques and potential treatments had been at the forefront over the past few years. KAIMRC intensified its own research drive after experiencing a hospital outbreak in 2015, forming collaborations nationally and internationally, including with Oxford University. The hospital “epidemic led KAIMRC to prioritize MERS-CoV and make it one of its 58

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strategic projects,” said Ahmed Alaskar, KAIMRC’s executive director. “The MERS-CoV crisis has led to a drastic strategy to promote research and development to reduce the health and economic burdens of this emerging pathogen,” added Majed Alghoribi, Chairman of KAIMRC’s infectious diseases research department. “And the best way to prevent and tackle the dissemination of the MERS-CoV is to develop camel and human vaccines.”

Enter ChAdOX1

As of now, there are no proven antiviral or vaccines to treat or prevent MERS, and none of the vaccines proposed, have yet been licensed for use against the virus. According to Abdelali Haoudi, head of strategy and business development at KAIMRC, there are about 40 potential vaccine candidates worldwide, four of

which were developed in Saudi Arabia. Among the strongest contenders was an MVA-based vaccine that has been tested in infected camels and which requires two doses to reduce the viral load and provide partial protection. A joint study by KAIMRC’s associate research scientist and virologist, Naif Alharbi, Oxford University and the Ministry of Agriculture now proposes a -single-dose vaccination, based on a chimpanzee adenoviral viral vector known as ChAdOX1. Successful vaccination of camels would reduce viral circulation in this host and thereby reduce human exposure,” said the study authors. “In addition, developing a vaccine for humans and vaccinating humans at risk, such as camel keepers and healthcare workers, would further control the number of human infections.”

The ChAdOX1-based vaccine has been “We are expecting to see results in so we’re going for a push for regulation initially tested in mice, with encouraging 2020,” said Alharbi. to control vaccines in animals.” results, then later in seropositive dromAccording to Alharbi, the scientists Alhrabi explained that while MERS can edary camels. will also conduct another small study to be transmitted to anyone around the world, The new vaccine has provoked a optimise the vaccine dose and the way it’s which can potentially cause outbreaks, the strong immune response and proved to administered. “There is still a chance to endemic areas are limited to a few counbe both effective and safe, according to optimize the single dose to achieve even tries, which is not typically a strong market a study in Scientific Reports1. It has also stronger immune responses in camels.” incentive for vaccine research and develsuccessfully reduced virus replication Alaskar and Alharbi both said that opment. Promising research could build a in camels, according to Alharbi, stronger case, however, for biopwho describes the outcome of harma to get on board. “There’s no regulatory pathway the research as “remarkable.” KAIMRC’s Mohammad Bosaeed, The vaccine can also potentially the clinical trial’s phase I principal to approving a vaccine for camels, protect both camels and humans investigator, shared his concern — a huge turning point for virolthat endemic countries still need not internationally and not in ogists and scientists desperately to prepare for worst-case scenarthis country, so we’re going trying to develop effective antiios. “When you have an outbreak, MERS vaccination. you need to have a vaccine that is for a push for regulation to Alharbi’s team’s study is ready to use,” he said. reportedly the first of its kind to Alharbi is hopeful, however, control vaccines in animals.“ evaluate a MERS vaccine in dromthat the country will see at least edaries in endemic countries. one or two vaccines passing phase “It is also the first to utilise naturally KAIMRC plans to expand the vaccine triII clinical trials in the next five years. infected camels to assess vaccine effials to include a greater number of camels, Finally, once a vaccine is approved for cacy,” said Alharbi. and they are now working on developing veterinary use, explained Alharbi, public According to the scientists involved, it the best protocol for that. “We also need to health authorities in endemic countries has covered considerable ground in only wait longer to see how long the immunity would need to convince camel farmthree years, a brief time considering that lasts in these camels,” Alaskar added. ers to immunize their animals, which, research into infectious diseases can take There are challenges, however. Alharbi despite being hosts of the disease, are decades to yield results. said that aside from the logistical chalnot harmed by it. lenge of sampling 40 camels per day and The first phase I clinical finding the optimum way for vaccine 1. Alharbi, N.K., Qasim, I., Almasoud, A. et al. Humoral trial in the kingdom delivery, the mechanisms of transmisImmunogenicity and Efficacy of a Single Dose of ChAIn collaboration with Oxford University sion of MERS-CoV among hosts, and its dOx1 MERS Vaccine Candidate in Dromedary Camels. scientists, Alharbi is currently worktipping point, are largely mysterious, Sci Rep 9, 16292 (2019) DOI:10.1038/s41598-019ing on a human phase I clinical trial leaving the scientists in the dark about 52730-4 for the single-dose vaccine, which is a risks and modes of infection. 2. Alharbi, N. K., Padron-Regalado, E., Thompson, C. P., first in Saudi Arabia. A phase I trial has Application and pushing the vaccine to Kupke, A., Wells, D., Sloan, M. A. et al. ChAdOx1 and MVA already launched in Oxford, and is set to the market, following successful trials, based vaccine candidates against MERS-CoV elicit neustart in the kingdom imminently. The could also prove problematic, according tralising antibodies and cellular immune responses in structure is set in place, and the Saudi to the scientist, making it difficult to start mice. Vaccine 35 (30):3780-3788 (2017) DOI: 10.1016/j. Food and Drug Authority (SFDA) has much-needed vaccination. vaccine.2017.05.032 already given the green light, accord“It’s not easy to conduct these stud3. Modjarrad, K., Roberts C.C., et al. Safety and immuing to Alaskar, and they are now in the ies and so we have to be very clever in nogenicity of an anti-Middle East respiratory syndrome recruiting phase. This will be the firstdesigning the next experiment,” said coronavirus DNA vaccine: a phase 1, open-label, sinin-human vaccine to be developed in Alharbi. “There’s no regulatory pathway gle-arm, dose-escalation trial. The Lancet Infectious Saudi Arabia or in an endemic country, to approving a vaccine for camels, not Diseases 19 (9): 1013-1022 (2019) DOI: https://doi. according to Alharbi and peers. internationally and not in this country, org/10.1016/S1473-3099(19)30266-X innovations.kaimrc.med.sa

Issue No.6

Revolutionizing the clinical research landscape in Saudi Arabia Ahmed Alaskar, executive director of KAIMRC, discusses how his institute is spearheading an initiative to develop clinical trials in the kingdom 60

December 2019

The drug development and clinical trials ecosystem in Saudi Arabia is nascent but growing strongly; how far has the kingdom come on that front?

Saudi Arabia is transforming in all aspects; the economy, medicine, healthcare, research and education. In alignment with Vision 2030, a knowledge-based economy becomes a must, and as such we realized early on that medical R&D and clinical trials play a pivotal role in improving healthcare, with a direct impact on patients, and making the latest developments in the pharmaceutical industry available and accessible to the larger pool of patients in Saudi Arabia. We have positioned KAIMRC to lead an initiative at the national-level to improve and coordinate the setup for clinical trials and make it attractive to the international industry. We set up various agreements with local and international partners to build capacity internally, and we have government support. We’re working closely with the Saudi Food and Drug Authority (SFDA) to align regulations with the fast pace of clinical trials considerations and draw ethical guidelines. Recently, the SFDA gave us our first accreditation to establish a phase I clinical trial unit at KAIMRC. That is the first in the country. We have also received approval on our phase I clinical trial project at the national level, testing a MERS-CoV [Middle East respiratory syndrome-coronavirus] vaccine that is developed in collaboration with the University of Oxford.

What are some of the challenges that KAIMRC has faced developing the MERS-CoV vaccine?

In 2015, our hospital saw a MERS-CoV outbreak, which led to the closure of the hospital for a few days to minimize the spread of the infection. This led KAIMRC to prioritize MERS-CoV as a strategic project, which led us to send one of our scientists to the University of Oxford to co-develop a vaccine with scientists there. That vaccine went to various pre-clinical trials in animals. Over three years, we successfully completed trials of the vaccine in camels in Saudi Arabia. It was proven safe and promisingly effective. Our next step would be to expand this study to a greater innovations.kaimrc.med.sa

number of camels and wait longer to see how long the immunity lasts in these camels. We published the findings in Scientific Reports and our first human trial conducted first in Oxford. The second part just started in KAIMRC this December.

A 2019 study showed that there are positive attitudes towards clinical trials in the kingdom, but relatively low level of knowledge. What are you doing to change this? We’re trying to raise awareness about the importance of clinical trials and change some of the misconceptions in the community, like the idea that a research subject is “a guinea pig” to experiment on. Instead, we want the public to look at clinical trials as an opportunity to benefit from an otherwise non-exiting treatment. We have also launched an informational website that has a database for what we call “research friends” where people can register as ambassadors to promote clinical trials in their respective communities.

What are some of the understudied areas related to drug discovery and clinical trials that you believe KAIMRC should prioritize?

We have identified several strategic projects and diseases based on the prevalence of these diseases in the country, and the unmet need in general. We focus on breast cancer, leukemia, lymphoma and colorectal cancer. Diabetes is another focus, and so are infectious diseases, like MERS-CoV, and anti-microbial resistance. Another area of focus is cardiovascular diseases like ischemic heart disease, which is a common cause of mortality in the country and worldwide. We have a trauma registry because motor accidents are one of the top causes of death, especially among youth, in this country. We currently have a biobank with more than 2,000 strains of bacteria available for researchers. We have also decided to focus on hyperthermia, as heat stress is a devastating health challenge for the pilgrims.

Are results from clinical trials, bio-bank data and the genome sequencing data open source or are they available to other researchers across Saudi Arabia?

It is indeed open and we encourage collaboration with other institutions from the country and internationally and to attract scientists who are interested to work with us. Perhaps not all the universities have the funding and the resources available to KAIMRC. We definitely open our doors to collaborators, and we invite scientists who have a successful research record to be part of KAIMRC, including offering them joint appointments. Issue No.6

ASH R A F H A B I B 20 1 9

rom the lab bench to the market, King Abdullah International Medical Research Center (KAIMRC) wants to transform basic research, drug discovery and clinical research in Saudi Arabia and the region. The center has already been namechecked as a promising hub for offshoring clinical research by pharmaceutical giants. KAIMRC is also spearheading a national command center to develop clinical trials in the kingdom. Ahmed Alaskar, executive director, says it is only the start of a major medical overhaul, powered by government backing, a solid research framework and selected and focused international partnerships.

FEATURE With Hajj coinciding with the hottest season of the year, Saudi researchers are developing techniques to combat heatstrokes

December 2019

A smart way to beat the heat

eatstroke is a major concern in Saudi Arabia, especially when the pilgrimage coincides with the hottest months in the kingdom, as it does this year. In 1985, for instance, when pilgrimage came in similarly hot conditions, heatstroke killed more than 1,000 people in just a few days. KAIMRC researchers have developed a multisensor-based system that mimics the thermoregulatory functions of the hypothalamus. It is set to transform the way life-threatening heatstroke is treated. Heatstroke expert Abderrezak Bouchama has established a research programme to better understand the impact of heat, and develop effective preventative and therapeutic measures against heatstroke. With co-inventor Ali Almuntashri, his team has devised a method that relies on a hypothalamus-like smart control system to optimize temperature regulation in real time. “We anticipate that this invention will set a new standard for cooling therapy,” Bouchama says. The hypothalamus is a part of the brain that acts as the body’s thermostat. It continuously monitors and adjusts the core temperature to 37 degrees Celsius according to environmental temperature changes to ensure normal cellular function. This is done through various responses, including regulating sweat and heat production by the muscles to respond to heat or cold.

innovations.kaimrc.med.sa

Failure of the body’s regulatory system can increase the risk of heat illnesses, particularly heatstroke. Heatstroke involves a rapid increase in body temperature above 40 degrees Celsius, associated with neurologic alteration such as delirium, convulsions, or coma. Heat can irreversibly damage cells, causing multiple organ failure and ultimately death. “This is a true medical emergency because if not withdrawn from the heat and cooled rapidly, the victims will die in just a few hours,” says Bouchama. Heatstroke results from strenuous physical exercise or exposure to extremely high temperatures. It is a major public health problem in Saudi Arabia, especially when the annual pilgrimage to Mecca enters the hot cycle. “Immediately after my arrival in this country [more than 30 years ago], I discovered how devastating heatstroke can be,” says Bouchama. According to epidemiological predictions based on 2 million pilgrims, several hundred cases of heatstroke could present during the Hajj, of which approximately 50 percent could die every year. This projection could underestimate the actual prevalence of this heat-related morbidity and mortality because under climate change forecasts, temperatures are expected to soar to extreme levels across the Middle East change, Bouchama adds. Heatstroke has also become an important

health concern across the world as a result of global warming.

Beating the heat

Existing measures against heatstroke typically involve reducing heat exposure and physical cooling. Specifically, the patients are immersed in cold water, covered with cold packs or ice slush, or sprayed with cold water and continuously fanned to promote heat evaporation. However, rapid cooling can cause adverse effects, such as discomfort, severe shivering, and skin vasocontraction, which can promote heating instead of the desired effect. Current state-of-the-art cooling devices, such as cooling pads, endovascular catheters, and blankets, rely on materials that accelerate heat transfer, instead of ice or cold water. Yet, these new devices have brought little improvement compared to conventional methods because they have overlooked the complexity of thermoregulatory response mechanisms, Bouchama explains. Bouchama’s system, however, relies on a hypothalamus-like smart system to prevent the adverse effects of cooling associated with actual cooling techniques. The artificial hypothalamus can simultaneously monitor several physiological parameters, such as core and skin temperatures, cutaneous circulation, and muscle activity, using multiple sensors. Issue No.6

OM A R C H AT R I WA L A / M OM EN T / G ET T Y I M AG ES

KAIMRC researchers develop a system that can regulate body temperature in real time to help treat heatstroke patients.

ZEP H Y R / S C I EN C E P H OTO LI B R A RY / G ET T Y I M AG ES P LU S

FEATURE

Researchers developed a smart system to act like the hypothalamus (the part highlighted in green) and regulate the body’s temperature

By combining these data, it can react more rapidly than its natural counterpart. “As soon as these sensors detect a drop in skin temperature, an increase in muscle activity, or a decrease in blood flow before any signal reaches the hypothalamus, the system will stop cooling and activate a warming of the skin until all these data normalize,” Bouchama says. In this example, the smart control system helps optimize cooling by bypassing the patient’s thermoreceptors and preventing the hypothalamus from triggering adverse effects, such as vasoconstriction and shivering. Once the skin is warm, the system resumes cooling. The artificial hypothalamus functions via a feedback loop, in which it records the information detected and processed by the sensors, determines whether this information is within a predetermined normal range, and converts this information into so-called fuzzy values if it does not lie within the normal range. Next, it evaluates a set of predetermined rules and 64

December 2019

combines these rules to generate a precise value, which is transmitted to a set of cooling devices, such as a fan, a cooling blanket, a water circulation device, and an intravascular heat exchange system. These next-generation cooling techniques equipped with artificial hypothalamus achieve predictable and fast cooling, eliminate shivering, maintain skin blood flow, and reduce the need for sedation or anaesthesia often required to control the adverse effects of current cooling techniques. The artificial hypothalamus uses a machine-learning algorithm that relies on a network of sensors that include skin blood flow as well as surface and core temperatures and neuromuscular activity measured in real time. This physiology-based cooling system allows the physician to immediately treat a heatstroke patient by programming the device using a temperature profile adapted to the patient’s pre-existing health condition, such cardiovascular disease, and modify the program once a final diagnosis is provided.

Bouchama’s team, in collaboration with a Saudi company, is currently at the proof-of-concept stage in the development of their artificial hypothalamus. “When this is completed, we will develop a prototype that will be incorporated in any cooling devices,” he says. The anticipated impact in terms of commercialization can be international. At the national level, the impact is immediate because the new cooling bed is a needed component of the public health response to heatstroke, especially as the pilgrimage coincides now with the hottest season. Beyond Saudi Arabia, it can also respond to the need of military, outdoor workers, and athletes who are at risk for heatstroke. 1. Bouchama, A. and Almuntashri, A. Method for regulating body temperature. US Patent 10307287B2, Published June 4, 2019.

2. Bouchama, A. and Almuntashri, A. Artificial hypothal-

amus for body temperature regulation. US Patent 10188548B2, Published January 29, 2017.

Updated WHO estimates show mental disorders are three times more common in conflict settings.

new study by the World Health Organization (WHO) shows that people in conflict settings are approximately three times more likely to have depression, anxiety disorder, post-traumatic stress disorder, bipolar disorder, or schizophrenia. Researchers updated the WHOâ&#x20AC;&#x2122;s 10-year-old estimates for prevalence rates of mental disorders in conflict-affected settings using more modern tools of statistical analysis, and by reviewing a wider range of previous research. The statistics were gathered through a close innovations.kaimrc.med.sa

search and review of different mental health research conducted in conflict areas, including 45 new studies published over a four-year period. The results of the review indicate that approximately one in five people in post-conflict settings had been diagnosed with one of these disorders, compared to a global average of one in 14. The researchers found there was a higher prevalence of severe mental disorders than was previously estimated, with a current estimate of 5.1 percent, compared to the previously estimated

Standardizing conflict

The stigma and mental health culture, as well as the nature of conflict, affect diagnosis and the reporting of data in an emergency setting. For example, Jabr explains that the psychiatric definition of trauma does not accommodate political settings where humiliation, objectification, forced helplessness, and daily exposure to toxic stress Issue No.6

P H OTOTA LK / E+ / G ET T Y I M AG ES

The mental toll of conflict

3 to 4 percent. They also found a higher prevalence of mild to moderate mental disorders. The estimates of years living with disability per 1,000 for depression and post-traumatic stress disorder were five times higher than the global burden of disease estimate. These findings are essential for action plans and a closer look at conflict settings. According to Samah Jabr, psychiatrist and director of the Mental Health Unit at the Palestinian Ministry of Health, â&#x20AC;&#x153;the results can help us understand the increased mental health burden and its relationship to war and violence.â&#x20AC;?

FEATURE

The study shows that anxiety, as well as other mental disorders like depression, are more common in conflict areas

are daily realities. The review of cultural variations then is not only essential at a contextual level but from a clinical perspective. “We attempted to control for contextual differences where possible by testing a range of variables such as intensity of trauma exposure, time since conflict, political terror scale rating and world region—significantly associated variables were incorporated into our models,” says Fiona Charlson, the study’s first author and a researcher at the Queensland Centre for Mental Health Research, in Australia. However, conflict settings vary strongly. “Fully accounting for cultural and contextual variations is extremely challenging and was a limitation of our study,” she adds. Defining what was considered conflict was essential for the research. For this review, conflict was defined as “the existence of opposing forces and stipulate a violence threshold described in terms of number of deaths [and] level of state terror according to state-perpetrated human rights violations.” Natural disasters and disease outbreaks, such as Ebola, were not included in the study. The researchers used the Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Classification of Diseases (ICD) criteria, as well 66

December 2019

as variables known to be associated with prevalence (such as exposure to trauma) as a reference for the disorders and their diagnostic traits to measure the prevalence rates. The research reviewed criteria such as age, comorbidity, years living with disability (YLD) and the severity of the disorder. The DSM and ICD were updated repeatedly within the time of the study, between the year 2000 to 2017. Due to cultural variations and changes in diagnostic criteria, the study advises a revision of anxiety and post-traumatic stress disorder prevalence.

What do we do with the numbers?

In May 2012, the World Health Assembly adopted a resolution to implement a global mental health action plan. Prevalence rates of mental disorders are essential in the goals the action plan set to carry out. According to the WHO document, the plan “is global in its scope and is designed to provide guidance for national action plans. It addresses, for all resource settings, the response of social and other relevant sectors, as well as promotion and prevention strategies.” The findings shed light on the increased mental health burden and its relationship to war and violent context, Jabr argues. They also make

a compelling case for global humanitarian, development, health, and mental health communities to prioritize development of mental health services in conflict and post-conflict settings. In Palestine, for example, Jabr says the study “motivates us to further integrate mental health in school settings where we can find a third of the Palestinian population, and in primary healthcare that is accessible to most people.” She adds that it also rings the alarm bell about human rights and political oppression, a root cause for this increased incidence of mental disorders. It is important to acknowledge that despite its importance, the study is limited by its basis on published research, not readily available in many countries, especially those undergoing conflict. Jaber says there is a shortage of comprehensive mental health research in Palestine, for example. “We have therefore a long way to go before we can draw reliable conclusions about mental health in our community. Until that time, we should examine with a critical eye the results of epidemiological surveys conducted under emergency conditions,” she says. Charlson, F. et al. New WHO prevalence estimates of mental disorders in conflict settings: a systematic review and meta-analysis. www.thelancet.com (2019).

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