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APRIL 2016 • ISSUE 16

I D E A S • M A L T A • R E S E A R C H • P E O P L E • U N I V E R S I T Y

DIGITAL EDITION

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University of MaltaValletta Campus

28 April 20168 June 2016

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Some research can change how a society perceives itself. Such discoveries do not happen often. Over the last few years DNA samples from hundreds of Maltese people have been sequenced.

The data has set in stone the origin of the Maltese people. Read about it in the first article (pg. 19) of our focus on The Maltese Genome.

The other focus articles talk about genes for health. A University of Malta team found a novel mutation in local families connected to the blood disorder thalassaemia (pg. 26), which can lead to death in the worst cases. The researchers are trying to determin how to use this knowledge in patients suffering from the condition. Other work focuses on heart disease (pg. 32). Malta has one of the highest rates of heart attack-related deaths in Europe. A Maltese study is trying to determine which gene alterations common in Malta increase risk. Knowledge is power for treatment.

Marijuana is a controversial drug. Research worldwide, including in Malta, has shown that it can potentially treat several conditions, explains Prof. Giuseppe Di Giovanni (pg. 38). Malta has double the EU average of early school leavers. Cassi Camilleri writes about local research seeking solutions to this problem that is destroying communities (pg. 52).

Marie Claire Gatt talks about sea birds around the Maltese Islands (pg. 44). These are vital for the Mediterranean Sea’s health. She reports on research performed to see which areas are in dire need of protection.

In this issue, students talk about digital art (pg. 16) and testing octopi for heavy metal levels (pg. 15). While alumni discuss their work building security apps. The fun section rounds up the issue with reviews, fun science questions, and a 100 word idea to change Malta (pg. 67–71).

MALTESE ORIGINSE D I T O R I A L

Edward DucaEDITOR

edward.duca@um.edu.mt @DwardD

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THINK is a quarterly research magazine published by the Communications & Alumni Relations Office at the University of Malta To subscribe to our blog log into www.um.edu.mt/think/subscribe and fill in your details. � For advertising opportunities, please call 2340 3475 or get in touch by email on think@um.edu.mt Advertising rates are available on www.um.edu.mt/think/advertise

TOOLKIT ARTICLEDr Noel AquilinaWilliam Hicklin

WITHOUT BORDERS ARTICLESDr Edward DucaProf. Victor Grech

DESIGN ARTICLEDr Edward DucaNikki PetroniDr Giuseppe Schembri Bonaci

OPINION ARTICLESDr Jean ButtigiegAlan Saliba GauciProf. Victor Grech

STUDENT ARTICLESJoshua GiliMatthew Galea

RESEARCH ARTICLESarah Spiteri

MALTESE GENOME FOCUSDr Stephanie Bezzina-Wettinger

Dr Joseph BorgProf. Alex FeliceClint MizziScott Wilcockson

FEATURE ARTICLESProf. Carmel BorgCassi CamilleriProf. Giuseppe Di GiovanniMarie Claire GattStephen GrixtiDr Milosh RaykovDr Ing. Nicholas Sammut

ALUMNI ARTICLEDr Nicholas MIcallefVeronica Stivala

CULTURE ARTICLEValletta 2018 Foundation

FUN ARTICLESDr Mario AquilinaDavid ChircopDr Jurgen GattAlexander HiliDr Philip M. MagriCostantino Oliva

COMIC STRIPDr Ġorġ Mallia

PHOTOGRAPHYDr Edward DucaJean Claude VancellElisa von Brockdorff

ILLUSTRATIONSSonya HallettMarie Claire GattJean Claude Vancell

WEBSITELars LorenzJean Claude Vancell

COVER STORY

C O N T E N T S

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The Maltese Genome

I S S U E 1 6 � A P R I L 2 0 1 6

Hundreds of Maltese people have had their DNA sequenced. The research is trying to identify the root of rare diseases common in Malta. The data has also revealed the origins of the Maltese people.See editorial on pg. 18

CONTRIBUTORS

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OPINION

Science, art, academia: Star Trek 6Malta Global Game Jam 8

Why practise Taijiquan? 12Who owns you? 13The enduring appeal of Star Trek 14

10DESIGNModern European sculpture

TOOLKIT

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Octopus around Malta: safe to eat? 15Transform everything 16

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How art is being used to fund research at the University of Malta 17Art for research's sake

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EDITORIALEdward Duca EDITOR-IN-CHIEFScott Wilcockson FOCUS EDITOR

DESIGNJean Claude Vancell DESIGNER

COPYEDITINGVeronica Stivala

PROOF READINGPatricia Camilleri, Daphne Pia Deguara

PRINTINGGutenberg Press, Malta

THINKI D E A S • M A L T A • R E S E A R C H • P E O P L E • U N I V E R S I T Y

ISSN 2306-0735Copyright © University of Malta, 2016

The right of the University of Malta to be identified as Publisher of this work has been asserted in accordance with the Copyright Act, 2001.

University of Malta, Msida, MaltaTel: (356) 2340 2340Fax: (356) 2340 2342www.um.edu.mt

All rights reserved. Except for the quotation of short passages for the purpose of research and review, no part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the publisher.

The publisher has used its best endeavours to ensure that the URLs for external websites referred to in this magazine are correct and active at the time of going to press. However the publisher has no responsibility for the websites and can make no guarantee that a site will remain live or that the content is or will remain appropriate.

Every effort has been made to trace all copyright holders, but if any have been inadvertently overlooked, the publishers will be pleased to include any necessary credits in any subsequent issues.

APRIL 2016 - ISSUE 16

MALTESE GENOME FOCUS

FEATURE

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FUNReviews (Books, Film, Games) 67–70100 word idea: Think critically, think Malta 71What is more addictive: cannabis or coffee? 71

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Seabirds around Malta are critical for the Mediterranean Sea's health

Time, space, & the ocean wanders

FEATURE

58Testing software to prevent disasters like the 1996 Ariane 5 rocket launch

Rockets that fail safely

FEATURE

Maltese research on how the drug can be used to treat epilepsy

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Marijuana for epilepsy?

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Malta has twice the number of early school leavers as the rest of Europe. How can this problem be solved?

FEATURESystematic failure, persistence and success

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Security apps for good health

ALUMNIShiny 'appy people

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The results are in on the Malta cultural participation survey

CULTUREMaltese cultural participation: What do the people want?

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The hidden history of the Maltese genome 19Blood, genes & you 26Heartbreakers 32

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Photography by Jean Claude Vancell

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The Mobile Air Quality Laboratory (MAQL) is the first of its kind on the Maltese Islands. Run by a

team of geoscientists at the University of Malta, the MAQL can assess the quality of the air by continuously monitoring particulate and gaseous air toxics.

The particulates it can detect vary in size. The finer particles (PM1 and PM2.5) are usually the most dangerous respirable fraction but the instrumentation can also measure coarser sized particles (PM4 and PM10). The suite of gaseous pollutants that can be checked are sulfur dioxide, oxides of nitrogen, carbon monoxide, ozone, Volatile Organic Compounds (VOCs), organic and elemental carbon, and radon.

The MAQL is able to compare the air in indoor and outdoor spaces while recording meteorological conditions onsite. The comparison helps scientists understand from where the pollution originates. Is there so much pollution in our environs because of all the cars

outside our window? Or is it because of the new sofa the family next door just bought? Or perhaps it is a result of the redecoration the building down the road recently underwent. Such data is vital for scientists to be able to figure out the root of a problem, to create a model of personal exposure to the pollutants, and to develop safer measures for the general public.

The MAQL facility will help scientists develop a clearer picture of the indoor air quality across the Maltese Islands. It will help other scientists interpret older data, and enable them to design new studies. Medics can match such data with population studies and assess disease rates around Malta. The MAQL can determine the sources of pollution inside buildings with the help of lifestyle and meteorological data, providing enough information for the construction of dwellings which have cleaner and safer air for everyone.

MAQL

QUICK SPECS

• Power consumption (including cooling system): 2.5 kW

• Particulate limit of detection: 1 ug/m3

• VOCs measurement frequency: 1 sample/30 minutes

• Gaseous pollutants measurement frequency: 1 minute

• Gaseous pollutants limit of detection: < 0.5 ppb

• Cost: €0.60 million

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Science, art, academia: Star Trek

The Star Trek academic symposium will be held at the Faculty of ICT, University of Malta, on

15 and 16 July 2016. This event will be a platform for both academics from various disciplines as well as Star Trek fans to meet and explore the intersection between the humanities and the sciences. There will be inspirational presentations from national and international speakers, with the programme tailored to attract a wide audience. Contributors will be encouraged to explore contemporary issues in medicine, science, and technology as well as philosophical, psychological, and sociological issues connected with the science fiction entertainment franchise Star Trek.

A similar symposium was held in 2014 and which proved to be a worldwide first that successfully

drew participation from many international scholars including American philosopher Jason Eberl, UK-based neonatologist and ethicist Neena Modi.

As a result of its success, this second event that marks the 50th anniversary from the launch of Star Trek: The Original Series is being organised. The event will be held under the auspices of the Humanities, Medicine and Sciences Programme (HUMS), a University of Malta programme set up to explore and encourage the interfaces between the humanities, medicine, and sciences. The Science Fiction Symposium will appeal to scientists and fans of science fiction alike..

For more information, visit:www.startreksymposium.com

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Art by Prof. Victor Grech

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Malta Global Game Jam

Indie games are seemingly unstoppable. As mainstream blockbuster AAA games stutter,

new niches are opening up with nearly half of gamers being female and mobile revenue increasing rapidly. In Malta, an important piece in the indie game developer puzzle is the Malta Global Game Jam, which brings coders, designers, artists, writers, and other creatives together to create a game from scratch in just 48 hours.

Run in Malta by the Institute of Digital Games since 2013, the yearly event has grown considerably since its inception, pulling an international crowd from all over Europe. The January event this year included London-based games and pop-culture writer Philippa Warr and Milan-based indie design duo We are Müesli.

After keynotes and workshops to hone participants’ skills, 14 different games were created. The worldwide theme was ‘ritual’. In third place was the create-your-own-god game, Godowbows, and the self-explanatory non-fun game, IKEA supply assistant. In second place the beautifully designed The Passage immersed players into an

ancient temple’s rite of passage. Hashtag Master Race won the local event with a game about angels and demons. Internationally over 28,000 people participated.

Apart from a fun weekend, the event is an opportunity for one to practice and learn skills, to build networks and, in a few cases, build promising new IP (Intellectual Property). Participants form a small indie development team every year. Back in the 2013 Malta Global Games Jam, the game And Then We Held Hands saw success and as it was distributed internationally following a $60,000 Kickstarter campaign. The experience can be used to help those already in the industry, or for those wishing to enter the industry, gain confidence to make more indie games or for them to join a big company with proven experience.

Intense events like this play a vital role in the building of a local game development scene that can soon see Malta join its international peers in producing top-notch, international and lucrative games.

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DESIGNModern European sculpture

French sculptor Auguste Rodin (1840–1917) is the progenitor of modern sculpture. He

rebelled against idealised forms in order to express the inner truths of humanity in his artworks. His successors went on to challenge his work, continuing to explore the aesthetic revolution he had started. key examples include Henry Moore (1898–1986), Alberto Giacometti and the largely undiscovered Swiss sculptor Hans Josephsohn (1920–2012).

These artists were studied alongside Maltese sculptor Josef kalleya (1898–1998) at the conference entitled ‘Peripheral Alternatives to Rodin in Modern European Sculpture’ (December, 2015). The international speakers created significant links between works by renowned sculptors and kalleya, who has been poorly understood by his contemporaries and is unknown outside Malta. kalleya developed unique methods of creating photomontages alongside the innovative use of a knife to create powerful visceral incisions

as a means of moulding his sculptures. He managed to create a new aesthetic.

The conference brought scholars from all over Europe to discuss these and other European sculptors. The scholars debated topics from the mutation of the human form to an artist’s sense of heritage. The event focused on pioneering sculptors who went beyond their current socio-political context. It also helped place Malta’s own kalleya deservedly on the international map.

The conference and exhibition were organised by the Department of History of Art, Faculty of Arts, University of Malta. The events were convened by Dr Giuseppe Schembri Bonaci and curated by Nikki Petroni. Other participants included Dr Sophie Biass-Fabiani (Musée Rodin, Paris), Dr Jon Wood (Henry Moore Foundation, Leeds), Barbara Vujanović (Atelijer Meštrović, Zagreb), Dr Julia Kelly (Loughborough University), and, Ulrich Meinherz (Kesselhaus Josephsohn, St Gallen).

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Top: Josef Kalleya, Study for City Gate, Valletta. Photograph of plaster model (image courtesy of the Kalleya Family Archives)

Left: Josef Kalleya, L'Abbandono della Casa Materna. Photograph of lost work (image courtesy of the Kalleya Family Archives)

Right: Josef Kalleya, I Santi, Bronze. Photo by Elisa von BrockdorffOpposite page: Josef Kalleya, Pierrot, Bronze. Photo by Elisa von Brockdorff

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Why practise Taijiquan? Alan Saliba Gauci

In the 12th century, the Shaolin Monk Chang San Feng witnessed a battle between a snake and a crane, during which the snake managed to conquer its opponent with its grace. The monk went on to formulate a set of movements,

which have become the basis of Tai Chi, a martial art based on the pillars of Taoism, Confucianism and Buddhism. Taoism upholds the importance of being one with nature and the universe.

Taijiquan shares concepts with Confucianism, a system of philosophical teachings that stresses that all under the sky is one family. Everyone can be part of this great family regardless of their social status, political or religious creed. By practising Tai Chi together and sharing knowledge, participants learn and develop respect and obedience; qualities stressed by Chinese teacher and founder of Confucianism, Confucius.

During my Tai Chi classes, I like to first develop the technical aspects of a student’s movements in order for them to have a solid foundation. This is then followed by an emphasis on self-expression through movement and concentration on these movements. In the film Enter the Dragon, Bruce Lee tells his apprentice ‘like a finger pointing away to the moon. Do not concentrate on the finger or you will miss all that heavenly glory.’ At first a movement is just a movement. However, after constant practice and analysis, the practitioner realises that the movement has a rhythm behind it and this charges them with feeling, a process that resembles the way a musician feels the beat/the rhythm when performing.

THE BENEFITS OF TAIJIQUAN

Taijiquan is a good method to alleviate stress and achieve good health. Rather than going to a gym, where a lot of energy and effort are required, with Tai Chi, a lot can be achieved without any force,

and like Taoism, Tai Chi is based on the principle, known as Wu Wei (effortless effort). This means that those who practise Tai Chi should be soft and flexible in the same way that water flows smoothly. Water can take the form of any container yet on its own it is formless and shapeless.

Some scientific studies have shown Tai Chi’s benefits. One study concluded that moderate Tai Chi practice helps older people maintain fitness, while other studies showed that Tai Chi was good for a healthy and well-functioning heart, as well as to regulate blood pressure levels.

Taijiquan is based on the principle of Yin and Yang, an element of Chinese philosophy that describes how two contrary forces can be complementary. Building on this belief, those who practise the discipline try to achieve harmony which in turn brings with it good health.

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Who owns you?Dr Jean Buttigieg

One fifth of human genes have already been claimed as US Intellectual Property. But should anyone own our genes? And what happens

when gene ownership can drastically prevent the advancement of life-saving cures?

The US Patent Office’s most controversial patents are on BRCA1 and BRCA2, both linked to the high risks of ovarian and breast cancer. They are now owned by Myriad Genetic Laboratories. In 1996, Myriad Genetics developed and began marketing a predictive test for the presence of possible cancer-causing mutations: the ‘BRCAnalysis’ test. The price of the test was US$3,000 but the company promised that it would eventually drop the price to US$300. This never happened because its patent holder had the right to stop any other party from duplicating the patented sequences. This single test accounted for over 80% of Myriad Genetics’ multibillion dollar business.

In 2009, the American Civil Liberties Union (ACLU) decided to challenge the patenting of human genes on legal grounds. The ACLU was the representative of 20 medial organisations, geneticists, women’s health groups, and patients unable to be screened due to the prohibitive patents. The ACLU’s position was that Myriad’s patents violated the patent law on the issue of patent-eligibility.

The case went before the Supreme Court. By 3 June, 2013 it was declared that the Myriad patents

were invalid because they did not create or alter any of the genetic information encoded in the BRCA1 and BRCA2 genes. The location and order of the nucleotides existed in nature before Myriad found them. The company simply discovered what was already there and did not create anything new.

There is no worldwide consensus on whether parts of the human genome should be granted intellectual property protection. The Myriad patents should alert us to the injustice of having a pharmaceutical company make money out of cancer predictive tests that could cost 10 times less than what is charged. The same patents stifled diagnostic testing and research that could have led to cures as well as limiting women’s options regarding their medical care in Malta as in all other parts of the world. There are various international and regional agreements that have described the human genome as being part of humanity’s ‘common heritage’, including the 1998 UN Declaration on the Human Genome and Human Rights. The Myriad patents controversy has shown that gene patenting does not work to stimulate more research—one of the prime arguments Big Pharma uses. It is time to explore other avenues that will both promote scientific progress and technological development but at the same time protect the special nature of human genes that make us who we are. No one should own our genes—they should be exploited in the interest of everyone.

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I am often asked why Star Trek appeals to me and so many others. For me, the answer lies with its founder, the humanist Gene Roddenberry. Humanism is defined as ‘a faith in and commitment to shared humanity’. Secular Humanism is not an ideology or

fixed ethical system but a collection of general guidelines that should allow humanity to increase its knowledge to further its collective wellbeing. The philosophy seeks to establish moral principles that are independent of any mystical sources, though they remain conducive to the freedom and wellbeing of the populace based on ethical reasoning. The term Secular Humanism explicitly rejects the supernatural and the primacy of moral codes based solely on religious convictions. Secular Humanist philosophy offers an alternative to more traditional ethical and moral concepts.

Humanism is rooted in the oeuvre of the philosopher John Locke, who asserted that everyone has the natural right to ‘life, liberty, and property’ as well as in the work of philosopher Adam Smith, who addressed the importance of private property and free trade.

Star Trek’s brand of secular Humanism appeals to all since no deities are invoked. When people invoke God or gods this almost inevitably precipitates arguments on which religion is correct or true. Such conflicts are a principal source of past, present, and future contention.

Television aliens can be read as ciphers and metaphors for humanity. Humanism could be interpreted as a belief system that is a useful point of reference to explore human differences. The medium of science fiction combines these two, leading to open dialogue and self-insight to bridge the artificial gulfs that separate us as individuals and as races.

The Star Trek universe continues to offer ‘an alternative, liberal future that not only has eliminated poverty, racism, sexism, jingoism, and colonialism, but also challenges contemporary society to rectify such unacceptable states of affair’.

Star Trek, like other science fiction, has an unshakeable ‘belief in the liberating power of the imagination’ to optimistically create utopian worlds that help us realise ‘our limitations, and thereby to move beyond them toward a more inclusive awareness’ of humanity’s potential.

The enduring appeal of Star TrekProf. Victor Grech

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Octopus around Malta: Safe to eat? Joshua Gili

STUDENTS

Heavy metals can be toxic to humans. They need to be monitored to ensure environmental levels do not go

above dangerous levels. The European Commission has set acceptable maximum levels of metals allowed in food since most metals end up in humans through their diet.

But how do metals find their way into our food in the first place? Heavy metals can enter the environment in a number of ways, including through volcanism, fossil fuel burning, and antifouling paint use. The heavy metals bind with biomolecules inside living tissue, and can build up to dangerous levels. One prime example of how such metals end up in the food we eat can be seen in the case of the common octopus (Octopus vulgaris). The octopus is susceptible to accumulating high levels of heavy metals due to its high ingestion rate of benthic fauna.

Joshua Gili (supervised by Prof. Victor Axiak) recorded the concentrations of cadmium, copper, lead, and zinc

in the common octopus. Specimens were collected from

around Malta during summer and winter. The analysis was performed on

two of the species’ tissues—the tentacles

and the digestive glands— which function

in a similar way to the human

liver. Each tissue was gathered into one pool by site, then homogenised, dried, and acid-treated. Afterwards a technique called polarography was used to determine the levels of each metal. This data helped Gili decide whether metal accumulation in the tissue of octopi is affected by biometry, season, or geography.

In Malta, metal levels depended on where the octopus was caught. In general, the concentrations were lower than other Mediterranean regions. The levels of cadmium and lead in the tentacles were below toxic levels as stated by the European Commission, indicating that local octopus is safe to eat.

This research was performed as part of Joshua Gili’s Bachelor of Science (Honours) in Biology and Chemistry, which he is reading at the Faculty of Science, University of Malta.

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Transform everythingMatthew Galea

Digital technology opens up new possibilities for the visual arts. It allows artists to

go beyond the traditional constraints of art. Sculpture is a centuries-old tradition reliant on the relationship between the artefact, and its material and space around it. In the past, sculpture was confined to being a physical act; it produced three-dimensional tangible objects that had little to do with the digital world.

But this is just one side, if you would forgive the pun, to sculpture. Sculpture can be viewed as a mental process. It is the act of remediating things, or rather reassigning meaning to objects. Marcel Duchamp’s infamous sculpture ‘Fountain’ (1917) is perhaps a perfect example of this. Meaning is a social and cultural construct created through interactions by people with the objects and their environment. Since meaning is fabricated by society, then it stands to reason how the same objects have held multiple interpretations through time.

Matthew Galea (supervised by Dr Vince Briffa) explored these social and cultural constructs to create novel artworks. To do so, he employed skills from different disciplines including drawing, painting, sculpture, music, and the other performing arts. But instead of expressing them individually he fused them into one art form. The various art forms could be experienced collectively, for example, as a musical instrument, or a painting, or even through movement.

The multidisciplinary approach also allowed Galea to investigate chemistry and physics as ways of generating content and engaging with the artefact. Galea produced an art installation that made use of the night sky, which itself has held multiple interpretations by humankind throughout time. The artwork transformed movement into audio and visual content.

Thanks to his research, Galea helped show how hyperdisciplinary artefacts that fuse various art forms are possible through digital technology. Computers can transform data into an image, audio, or text. Software can transform anything. Digital technology can enhance artworks' interactivity with the audience, making visitors part of the artwork.

To see the project’s outcome visit: www.behance.net/gallery/27174125/Map-of-the-HeavensThis research was performed as part of a Master of Fine Art in Digital Art which Matthew Galea completed at the Faculty of Media and Knowledge Sciences (MaKS), University of Malta. It is partially funded by Master it! scheme. This scholarship is part-financed by the European Union—European Social Fund (ESF) under Operational Programme II—Cohesion Policy 2007–2013, ‘Empowering People for More Jobs and a Better Quality of Life’.

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Art is no stranger to science and research. When it comes to raising funds for medical research, artists

and art lovers around the world have always been at the forefront. Concerts, art exhibitions, and art auctions have long been effective platforms for raising funds for research, particularly medical research.

Over the past four years, since the inception of the the University of Malta’s Research, Innovation and Development Trust (RIDT), a growth has been observed in terms of support for and contribution towards research from the art industry. This growth in support comes from both the artists themselves as well as the producers of artistic events. It is encouraging to see a culture change whereby research is being recognised as a cause worthy of support.

Noteworthy examples of this are two music events that took place in December 2015. The 18th edition of Teatru Unplugged was held at the Manoel Theatre, Valletta and raised funds for cancer research. The initiative also honoured Nirvana Azzopardi, one of the co-founders of

the event, who passed away in 2013. Jonathan Shaw, the producer of

Teatru Unplugged, explains that ‘a part of the proceeds or the money raised through initiatives associated with Teatru Unplugged has always gone to good causes,’ but ever since Nirvana passed away, Teatru Unplugged has focused specifically on cancer-related causes.’ This year the organisers decided to go one step further, and collaborated with RIDT. Shaw adds that ‘we believe that investing in research to help find possible or potential solutions to a problem is just as important as helping those who are currently facing that scenario. It is important to channel support to the long-term solution at the root.’

The 25th edition of Prelude to Christmas, a concert for Christmastime held at the Mdina Cathedral by the Amadeus Choir, raised funds for cancer research conducted at the University of Malta. Mro Brian Cefai, director of the Amadeus Choir comments that ‘as a choir we have been raising funds for charitable causes for decades. This year we decided to support RIDT because we recognise

the importance of supporting the work that is being carried out in the field of cancer research […], work that may not have an immediate result, but by supporting it we are supporting a long term plan.’

The most recent event was held on Easter Sunday. RIDT presented Vivaldi’s The Four Seasons at St Publius Church, Floriana, featuring internationally acclaimed violinist Carmine Lauri together with a 14-piece string ensemble, under the direction of Prof. Mro Michael Laus. The concert was supporting Brain Awareness Week that aims to raise funds for research in brain-related studies, and was supported by APS Bank and the ADRC Trust.

Art for research’s sakePerforming artists support medical research through the University of Malta’s Research, Innovation and Development Trust

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S P E C I A L F E A T U R E

DNA is what life is made of. Found in every cell of the human body, it has sent criminals to jail and been the focus of controversial court cases. Dr Jean Buttigieg discusses these legal and ethical issues (pg. 13). DNA has also

transformed the meaning of being human, with traits from disease to intelligence all linked to it. DNA is changing the world.

Malta has not lagged behind in genetics research. one of the largest local research groups has been investigating for decades the genetics behind haemoglobin switching and the blood disorder thalassaemia. Their research is recognised worldwide (pg. 26). They recently discovered a mutation, in some Maltese families, that led them to a master regulator that could help bone marrow alleviate the disease. They are trying to turn this knowledge into a treatment for sufferers worldwide. In the worst cases thalassaemia is fatal.

Another large scale study is looking into heart disease (pg. 32). The mortality rate in Malta is higher than the European average. This is partly our lifestyle but there is also a genetic component. The Maltese Acute Myocardial Infarction (MAMI) study is focused on finding the genetic component behind three key heart-disease related problems.

The local studies on Maltese genetics are very ambitious (pg. 19). They have already partially sequenced tens of people and plan to map the genomes of 4,000 Maltese people, around 1% of the population. Malta would suddenly become one of the best genetically documented in the world. This research has already borne fruit with a public health genomics database, a biobank, and the origin of the current Maltese population finally nailed.

The Malta Human Genome Project (MHGP—Grant Agreement R&I 2013-041) is funded by the Malta Council for Science and Technology in the Health & Biotechnology sector. Research consortium lead: University of Malta. Partners: Mater Dei Hospital, Erasmus MC, Rotterdam, The Netherlands and Complete Genomics Inc., California, Silicon Valley, USA.

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By reading someone’s DNA one can tell how likely they are to develop a disease or whether they are related to the person sitting next to them. By reading a nation’s DNA one can understand why a population is more likely to develop a disease or how a population came to exist. Scott Wilcockson talks to Prof. Alex Felice, Dr Joseph Borg, and Clint Mizzi (University of Malta) about their latest project that aims to sequence the Maltese genome and what it might reveal about the origins and health of the Maltese people. Illustrations by Sonya Hallett.

In 1990, geneticists all over the world launched the largest biological project in history. Over the course of 13 years, the Human Genome Project sought to decipher the sequence of human DNA;

the chemical code found in every cell of our bodies that contains the information to create an entire human being. The completion of this project, and the subsequent boom in the field of genetics, has turned the 21st century into the age of genetics.

The first draft of the Human Genome has been invaluable to researchers all over the world who sought to understand the intricacies of human biology and evolution. Another major outcome was the rapid surge in DNA sequencing technologies. The first human genome took over 200 scientists 13 years and $3 billion to complete. The newest technology, known as Next Generation Sequencing (machine-based sequencing technologies), now allows a small group of scientists to sequence one person’s genome in a few weeks for around

The Hidden Historyof t h e ma lt e s e g e nom e

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$1,000. Such a low price has fuelled innovation—from reimagining medicine (into precision medicine that considers a person's gene variations, environment, and lifestyle) to teasing out the origins of humankind through projects like The Cancer Genome Atlas and the International 1,000 Genome Project.

While useful, the first draft of the human genome does not paint a complete picture of every person alive today. While 99.9% of the sequence of every human’s DNA is the same, the 0.1% which is slightly different (called variations or mutations) makes us unique. Borg explained, ‘all of our traits, such as eye colour and height, boil down to small variations in our DNA sequence. Importantly, diseases are also attributed to [gene] mutations and variants.’ While every person is genetically different, so are large

groups of populations. Caucasians have particular DNA variations that make them unique from East Asian populations and vice versa.

Thus, the current data on the human genome falls short when one attempts to study a specific population’s genetics. Researcher Clint Mizzi explains, ‘there have been a number of [genome sequencing] projects but how many Maltese people were included? […] Populations from different countries have different variants that appear in different percentages of the population, thus some [gene variants] may be found mainly in the Maltese population [while] others are absent.’ This is why many countries worldwide are initiating their own genome projects. Now Malta has entered the foray with the Maltese Genome Project and a partial genome has already been completed.

A GENOME FOR THE PEOPLE

The three-year Maltese Genome Project was launched in 2015, based on nearly 25 years of human genomic research in Malta. It will map the genomes of around 4,000 Maltese people, or 1% of the population, in order to obtain an averaged or referenced Maltese genome sequence. This means that the end result will not be the sequence of any one person’s genome but a representative example of the entire Maltese population.

Having this kind of information will be invaluable to geneticists and clinicians to diagnose rare diseases and investigate new therapies. Borg describes how ‘if they embark on their own genetics project and uncover a mutation […], instead of having no idea how frequently it occurs [in the

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Maltese population] or what it does, they will now have a reference they can look to.’ This knowledge will vastly improve the understanding of how particular gene variants affect the Maltese population when studying disease mechanisms.

FORGETTING PAST TECHNOLOGY?

Malta has a long history of genetics research. Older genetics technologies were less focused and much more labour intensive. They looked at one gene at a time, forcing the researcher to choose particular genes, possibly missing the gene linked to a disease or condition. Modern whole genome sequencing (next generation sequencing) is fast, relatively inexpensive, and allows researchers to look at every single gene and all the DNA in between.

So does this mean that next generation sequencing technology will signal the end for old technologies? On the contrary, Borg explains that ‘we are at a stage where we usually sequence the whole genome […] but if we can obtain enough data [about the Maltese population], researchers no longer need to sequence everything. Once we have the thousands of unique and non-unique [gene] variants, a researcher can study a Malta-specific [range of genes] that can be more precise and less time consuming.’ Far from replacing the old technology, whole genome sequencing can work alongside it to streamline research. ‘[Genome sequencing] will help direct research to specific genes,’ Borg explains, ‘[so a scientist can] tailor design experiments rather

than exploring […] work that might be futile, which can be very frustrating.’

CONVERTING PEOPLE INTO BIG DATA

Getting hold of a person’s DNA is quite easy: a cheek swab or some blood is all you need. Once the DNA has been prepared—which involves cutting it up into tiny fragments—it is placed in one end of a DNA sequencing machine and left to run. These machines essentially make a copy of the DNA fragments and

monitor which molecules are added in sequence to the growing chain of new DNA. This then allows you to determine the original sequence. Then it is someone else’s job to make sense of what comes out the other end. Say 'hello' to the bioinformaticians!

Clint Mizzi is a bioinformatician at the University of Malta working on the Maltese Genome Project. He explains that ‘bioinformatics encompasses multiple disciplines […] involving an understanding of biology, computer science, mathematics, statistics, and some engineering. We apply mathematical sciences to biological data.’ A single person can equate to 200–400 gigabits of raw data and Mizzi needs to make sense of it.

Once Mizzi has the DNA sequence fragments he aligns them to a

reference genome to match everything up like a giant jigsaw puzzle. By comparing the genomes, any variations in the DNA sequence specific to the Maltese population can be singled out.

With this information, the researchers can then focus their efforts on the specific gene variants or mutations that are affecting the Maltese population. Mizzi stresses ‘that bioinformatics does not stand alone. […] The machines are not 100% perfect, although there are a number of [methods we use] to minimise the

errors. […] So it is important to go back to the laboratory to confirm results and do experimental functional studies.’ It is imperative to check that the variants or mutations have an effect on our biology. By working together, researchers from different fields are putting this knowledge to good use.

The age of genetics heralds a bright future for our understanding of human physiology and what treatment is best when our genes turn against us. But the field of genetics is not only about working towards a better future. Hidden deep within our DNA are clues of our distant past. By reading the Maltese genome one can understand the origins of the contemporary Maltese population and the evolutionary forces that shaped their genome.

This knowledge will vastly improve the understanding of how particular gene variants affect the Maltese population when studying disease mechanisms.

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MALTESE ORIGINS

The Mediterranean has enjoyed a turbulent past with more civilisations and empires rising and falling than a year's hot dinners. This question of ‘where did the Maltese come from?’ has been debated for centuries. To understand how this modern nation arose needs a bit of history.

A long time ago in South-East Africa, the environment was just right for the beginning of humankind. Modern humans (Homo sapiens) entered the world stage around 200,000 years ago—exact dates are still unknown. Evolutionary genetics studies that look into our distant past rely on two genetic markers.

The first is mitochondrial DNA. This DNA is distinct from the rest of our DNA found in the cell nucleus. Mitochondrial DNA is found in small energy producing factories known as mitochondria—if they stop working, death follows quickly. These are inherited only from one's mother and only transmitted through daughters. By looking at

specific parts of the mitochondrial DNA (known as haplogroups, that remain largely unchanged over time so are shared worldwide) researchers are able to trace ancestry through the female lineage.

The second is the Y chromosome. Human DNA is broken up into 46 chunks known as chromosomes, with each parent contributing half. Gender is determined by two chromosomes known as X and Y. XX makes a female, XY makes a male. The combination depends on one's father. The Y chromosome also has haplogroups, making it a useful genetic marker for evolutionary studies on men's origins.

THE VOYAGE OF HUMANITY

Around 80,000 years ago humans embarked on the most important journey in humanity’s history. They left Africa. From the analysis of mitochondrial DNA, humans 'exited from East Africa as a small group of male and female modern humans,’ explains Prof. Alex Felice. Two splinter groups of the Eastern African

population, known as M and N, moved into the Middle East and made their first steps toward global colonisation.

By 40,000 years ago, humans had entered Continental Europe. Felice explains that ‘over a relatively short period of time […] humans replaced the pre-existing humanoids, mostly Neanderthals in Europe, due to some kind of Darwinian advantage.’ Some cross-breeding took place between the two humanoids but gradually Homo sapiens took over the planet (except Antarctica). Malta was only colonised around 7,000 years ago.

THE FIRST PEOPLE OF MALTA

The first humans in Malta are presumed to have been Sicilian farmers, who brought cattle and crops over that changed the Maltese landscape. After more than a millennium, the culture of this people took an interesting turn. They built over 30 temple complexes, the oldest free-standing stone structures in the world. This Temple Period saw the rise of a complex civilisation with a ritualistic and artistic

Lebanese DNA contributed less than 5% to today's Maltese DNA

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culture (see Death of the Temple People in THINK, Issue 10, pp. 34–41).

For one and a half millennia the Temple People flourished, leaving behind their distinctive mark on the Maltese and Gozitan landscape. However, their departure left us with Malta’s greatest mystery: why did they suddenly disappear around 2500 bc? A number of theories have been proposed, including environmental stress and their own religious fervour. The real reason is being unravelled by the FRAGSUS project involving archaeologists, biologists, engineers, and others from the Universities of Cambridge, Belfast, and Malta.

Events like this seem to echo throughout Malta’s history. ‘The archaeological record is such that [humanity’s presence in Malta] is like that of the dinosaurs. The Temple People were here but they seem to have been replaced by others,’ comments Felice. For the next four millennia Malta constantly changed hands, closely following the rise and fall of the great Mediterranean Empires. ‘It is not correct to say that the island was

completely uninhabited; there is not a very good record, but in principle there was not a substantial population [...]. It was probably a mixture of the main populations of the time,’ he continues.

The Temple People were replaced by Bronze Age settlers. Then came the Phoenicians around 700 bc, followed by the Carthaginian Empire in 332 bc, then the Romans during the First Punic War in 218 bc. Malta's population was thought to be very small, Felice adds how there was ‘maybe a small urban presence in modern Mdina and [a few other places], but apparently only a couple thousand at most.’

DESCENT FROM PHOENICIA OR SICILY?

In 2004, a National Geographic magazine interview sparked exciting revelations on the origins of the Maltese people. Early results of a Y chromosome study showed that 50% of Maltese men are of Phoenician origin. In 2008 the study was published in The American Journal of Human Genetics. The researchers looked for Phoenician DNA in modern

day colonial areas based on haplogroups in modern day Lebanese people. Late Stone Age farmers in Greece, Crete, and Southern Italy had the same piece of DNA. The Maltese population did too, but this small genetic footprint could have been left behind by others like the Stone Age ancestors. The methodology of this study turned out to be flawed. Maltese history does not reflect a large Phoenician population that could have lasted till today

So where do the contemporary Maltese come from? Research carried out in Malta points to just a few hundred miles north. A study published in the Annals of Human Genetics in 2004, on which Felice collaborated, looked at Y chromosome haplogroups found throughout the Mediterranean and identified common population groups. ‘Data on Mitochondrial DNA [from the ongoing Maltese Genome Project] is also nearly complete but what we have also points in the same direction [as the previous study]: that most contemporary Maltese males and females can trace their ancestry to Sicily and [Southern]

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Italy around 1,000 years ago,’ reveals Felice. Middle Eastern DNA, including Lebanese DNA, contributed less than 5% to today's Maltese DNA.

NORMAN DOMINION

History reflects the DNA evidence. The decline of the Roman Empire was followed by Arab rule of the Islands for at least two centuries from around ad 870. First under the Aghlabid Emirate and then the Fatimid Caliphate. Malta was either uninhabited or there were very few people. The turn of the first millennium brought a documented influx of people from Arab-ruled Sicily.

At the turn of the 11th century a new set of players entered the game. Adventurers from Northern France had gained a foothold in Southern Italy and sought to expel the Arab and Byzantine occupiers. By 1091, Count Roger I landed in Malta and established Norman rule.

Malta continued to be governed by the Arab administration until 1127 when Count Roger II of Sicily, the son of Roger I, finally displaced the Arab governors and established complete Norman dominion. Over the next few centuries, the Maltese population grew with an influx of Sicilian and Norman settlers. Felice explains ‘there was [still] a strong Arab subculture in Sicily and Southern Italy […]. If you go to the small villages outside [Sicilian] towns today they speak very differently to modern Italians, not too different from what we call Maltese. These [people] began to re-inhabit Malta, although there were only around 20,000 people up to ad 1500.’ Once again, Malta was colonised by Sicilians who gradually latinised the island and brought their unique Siculo-Arabic language that evolved into modern Maltese.

THE PRICE OF PROSPERITY

‘So this is the [genetic and historical] data on the recent origins of the contemporary Maltese. This is important for a number of reasons. Firstly it addresses questions such as: Who am I? Where am I going? Where did I come from?’ Felice observes, adding, though, that ‘there are also important questions [for Malta today] regarding public health’ that must be asked. For millennia ships have dropped anchor along the Maltese shore and the ripples can still be felt today.

The current population of Malta stands at just over 420,000 and originates from a small population that settled here after the first millennium. Felice explains, ‘these [people] were visited by small groups, military details of young men who stayed for a short time […] and left genetic memories in the form of gene variants and mutations […].’ This, he notes, is what we now recognise as Founder Effects. As the small population expanded over the centuries, these newly introduced Founder Mutations became widespread across the population for better or worse.

The history of Malta continued to become more and more interesting with various groups and nations visiting over the centuries, which provided ample opportunities for these Founder Mutations to arrive and mix with genomes from distant countries. Felice describes two major events that occurred after 1500: ‘first was the arrival of the Order of the knights

of St John and second, as in the rest of Europe, this was the beginning of a certain degree of public hygiene and prosperity […]. The populations of Europe and Malta started to grow exponentially. It was during this time that rare diseases accumulated’.

In 1528 the population of Malta was estimated at 12,000 with 5,000 residing in Gozo. Within 10 years, the estimate had almost doubled to 22,000 in Malta and 6,500 in Gozo, including the knights. Despite sieges and depopulations of Gozo, by 1814 the Island's population boomed to 41,000.

EXPERIMENTING WITH NEW MASTERS

Nothing lasts forever; the knights had fallen out of favour with the Maltese toward the end of the 18th century due to the opulence of Grandmaster Pinto’s reign. On 9 July, 1798 Napoleon Bonaparte landed in Malta and, by the 12th of the month, Malta was added to the French Empire.

Despite the Maltese collective memory of their evil French overlords, rule under France was not all that bad. Napoleon planned the building of hospitals and invested in education. Unfortunately, the new rules did not sit well with the clergy who stood to lose their significant power over the Maltese. So they initiated a rebellion. The Maltese were induced to revolt 82 days after accepting French rule (see Malta: Stockholm Syndrome in THINK, Issue 13, pp. 48–55).

The two-year-long siege resulted in great suffering. Malta's population plummeted by 18.7% around this time from 114,000 to 93,000 due to war, famine, and disease. By 1800, the French relented and the Maltese won their freedom back. Without

Who am I? Where am I going? Where did I come from?

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Malta being involved in the negotiations, it was handed back to the knights with the British acting as protectorate. The British amalgamated Malta into their empire. The Maltese were deemed incapable of governing themselves leaving Malta to enjoy 164 years of British rule.

BOTTLENECKS AND FOUNDER EFFECTS

Events over the last millennia have shaped the modern Maltese people. The rise and fall in population numbers created genetic bottlenecks. These events impacted genetic diversity so much that rare DNA mutations became common spreading disease.

The problem is evident today. ‘There are a number of mutations that give rise to rare diseases, those [found] in less than one in 10,000 people. […] So, there is this genetic burden,’ explains Felice. ‘In the 1990s we set up, with the Department of Health and the late Dr Joe Louis Grech, the Laboratory of Molecular Genetics [at the University of Malta] and the Thalassaemia Clinic at St Luke's Hospital, now at Mater Dei Hospital, and we began to identify some of these mutations.’ Interestingly, the research on these disease-causing mutations supports the Y chromosome and mitochondrial DNA studies carried out in Malta: most of the Islands' genetic mutations are shared with Sicily and Southern Italy.

Some mutations that cause rare diseases are disproportionately high in the Maltese population and include gangliosidosis, coeliac disease, and

blood disorders like thalassaemia. One study in 2007 by Felice and his team focused on a mutation in the SPR gene that leads to a rare disorder known as Segawa’s Disease, a motor neuron disorder with some similarities to Parkinson’s Disease. A single mutation in the SPR gene was found in a high proportion of the population. Because of this discovery, babies are diagnosed at birth and treated immediately preventing severe disability.

Genetics is making great strides. Felice adds that ‘because of the efficiency and costs of the new

technology, over the next few years research and diagnostics shall be moving to whole genome sequencing.’ With the Maltese Genome in hand, researchers will be able to figure out how to treat diseases widespread locally while helping others worldwide. Researchers will generate a complete picture of where the Maltese came from and who they are today.

The study’s co-principal investigators are Prof. Alex Felice and Dr Joseph Borg with Clint Mizzi and Dr Nikolai Pace as close associates.

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BLOOD, GENES,& YOU

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Over the course of nine months, an entire human body is sculpted from a few cells into a baby. The blueprint is the information written into our DNA. But what happens if there is a mistake in these blueprints? Decades worth of research carried out in Malta and abroad have aimed to understand how these errors lead to a disease common in Malta and prevalent worldwide. Scott Wilcockson talks to Dr Joseph Borg (Faculty of Health Sciences, University of Malta) to find out more.

You are unique. This is not just saying that to make you feel good about yourself. Everyone is unique. Every person is moulded by their upbringing, experiences, and genes.

By fusing together their DNA, our parents have made a distinct person with a unique DNA sequence, randomly passing on the best and worst of themselves to the next generation.

The information written into your DNA, or genome, supplies the embryonic ‘you’ with the instructions to build your entire body and then to maintain it throughout your life. While all human beings possess a common set of genes—around 23,000 of them—our DNA is not exactly the same for all of us. We are all riddled with small variations, or mutations, throughout our genomes. Many of these mutations result in biological quirks that play a role in our individuality. For example, mutations in the OCA2 gene are a major determinant of eye colour. Other mutations can have more profound effects on health and well being.

Most diseases have some sort of genetic element, though the exact cause can vary. Some diseases, like diabetes or cancer, are due to many genes malfunctioning and are known as multifactorial. The multiple genetic mutations acting in concert trigger disease progression. Others on the other hand are monogenic as they are triggered by one gene mutation. One such disease is Beta

Thalassaemia, which has become the focus of Dr Joseph Borg’s research after he joined Prof. Alex Felice's research group that has studied how a genetic quirk could be used to treat this illness.

WHEN BLOOD TURNS BAD

Borg explained that ‘thalassaemia is an inherited blood disorder caused by an inability to produce sufficient amounts of haemoglobin, the [molecule] in red blood cells that binds and transports oxygen to our various tissues and organs.’ The most prominent form in the Mediterranean is Beta Thalassaemia. This is caused by mutations that affect the production of the beta-chain sub-unit of the haemoglobin molecule in blood cells.

There are around 300 known mutations that cause thalassaemia worldwide. In Malta, a single mutation in the beta-globin gene was found to be the main culprit in the late 1980s by Prof. Christian Scerri (Faculty of Medicine and Surgery, University of Malta) and had been designated the very catchy name of β+ IVS-I-6 (T→C). This mutation is common throughout the Western Mediterranean and accounts for two thirds of all Maltese cases.

Unfortunately, treatment options are limited. Borg explains that ‘adult patients have to undergo lifelong blood transfusions every month, or a bone marrow transplant in rare cases.’ Hope is in sight, however. Studies are now focusing on a biological

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quirk that could hold the key to treating patients. In the 1990s, a study on the Maltese population carried out by Prof. Alex Felice (Faculty of Medicine and Surgery, University of Malta) and his team identified another common mutation within the gamma-globin gene. This gene contains the blueprints needed to make another haemoglobin protein known as the gamma-chain. In adults the beta-chain is used to make haemoglobin. In babies the gamma-chain is used instead in the developing foetus and up to six months after birth.

A QUIRK OF NATURE

When a foetus is developing, oxygen is provided through the mother’s blood supply. Oxygen diffuses through the mother’s placenta in the womb where it is picked up by the baby’s red blood cells. The foetus needs to be able to absorb as much oxygen as possible and therefore uses a different type of haemoglobin (foetal haemoglobin) that has a stronger attraction toward

oxygen molecules. Following birth, babies are able to obtain plenty of oxygen on their own and switch from primarily foetal to adult haemoglobin.

Intriguingly, the switch is not always complete. Borg described how a small portion (less than 1%) of all our haemoglobin is foetal even in adulthood. However, some adults can have much higher levels because of certain genetic mutations. This phenomenon is known as Hereditary Persistence of Foetal Haemoglobin (HPFH). Felice first discovered a Maltese person with HPFH, and now whole families have been found.

Earlier, Prof. Maurice Cauchi (now Melbourne, Australia) had discovered the Hb F Malta I variant in the gamma-globin gene. The mutation is found in around 2% of Maltese newborns. Together with other variants they are the most valuable quantitative markers of the foetal to adult globin gene switch unique to Maltese families.

Individuals who have two mutant genes, one from each parent, can have

The relative ease with which researchers can sequence all of a person’s genes is paving the way for a much greater understanding of how diseases develop and how to treat them.

Left to right: Dr Joseph Borg, Jeanesse Scerri, Stefanie Inguanez

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around 58% of their total haemoglobin to be foetal. One mutant gene leads to between 15–34% foetal haemoglobin. This particular quirk of biology does not cause any ill effects, as foetal haemoglobin functions well and individuals with the mutation usually do not find out until they have it tested.

This biological peculiarity is of great interest to researchers like Felice and Borg. ‘We wanted to use the knowledge of this mechanistic imbalance [in the switch] to understand how best to treat those who suffer from blood disorders like thalassaemia and sickle-cell disease.’ People with these disorders usually have normal foetal haemoglobin but abnormal or insufficient adult haemoglobin. Increasing the level of foetal haemoglobin in adulthood effectively cures these diseases. Borg added how ‘if you can augment higher levels of foetal haemoglobin [in adults] you can render [patients] independent of transfusions. No more

treatment. No more medicine. It would give them a better quality of life.’

In 2010, this team published (together with ERASMUS) a seminal work in the world-leading journal Nature Genetics. The work identified a key factor that caused the haemoglobin switch in the first six months of a baby’s life. The study looked at an entire Maltese family, where ten out of 27 members exhibited HPFH with varying degrees of foetal haemoglobin production ranging from 3–20% of the total haemoglobin. Borg and his colleagues sequenced the recruited family’s DNA to identify the genetic mutations causing this imbalance. They found that a single gene called kLF1 was mutated in all family members with HPFH and, to date, this mutation seems Malta-specific.

This gene provides the blueprint to make the kLF1 protein. kLF1 is a transcription factor. It binds to specific parts of the DNA and turns genes on or off. kLF1 switches on genes involved in red blood cell production.

This study revealed how the mutation in the Maltese family blocks the kLF1 protein from binding to DNA and doing its job. kLF1 normally switches on the adult beta-globin gene and turns off the foetal gamma-globin gene. By stopping kLF1 from doing so the Maltese mutation causes a lot more foetal haemoglobin to be produced in adults.

This exciting discovery identified a major regulator of the switch. Borg cautions however, that ‘after our publication, other groups identified similar and also conflicting results because of different kLF1 mutations [...]. This [suggested] that kLF1 is not acting alone.’ Another puzzle was that foetal haemoglobin levels varied greatly in family members. They ranged from 17–20% to only 3–5%. The kLF1 mutation alone did not explain the difference, which means it was not capable of driving high foetal haemoglobin levels on its own. Other factors and gene mutations must be at play.

This leads us to the next stage of the research. ‘We have now identified three other Maltese families with the same kLF1 mutation but with normal [foetal haemoglobin] levels, less than 1%.’ Felice, Borg, Ruth Galdies, and their team sequenced all of the DNA (a genome) of over 50 individuals. They are now comparing the genomes of these new families with the earlier study. ‘kLF1 is a common factor [in all families]. We can cancel it out and see what [genes] we are left with. […] We suspect we will be left with the ‘friends’ or ‘foes’ of kLF1 controlling the [foetal haemoglobin] levels.’

The relative ease with which researchers can sequence all of a person’s genes is paving the way for a much greater understanding of how diseases develop and how to treat them.

MIMICKING BIOLOGY

Gene therapy is a possible method to treat diseases like thalassaemia. The idea is to change the gene’s sequence or activity within living people. Borg describes new methods known as gene editing that could be used to

INHERITANCE OF THALASSAEMIA

PARENTS

Fathera carrier

Childa carrier

Childhealthy

Childa carrier

Childwith Thalassaemia

Mothera carrier

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correct genetic defects to treat these disease types. ‘This could be used in the form of a vaccine [injected into the patient which] then can home in [and] turn off the [gene].’ Gene therapy is still experimental, due to health and safety concerns, but Borg believes that ‘we are not too far away [from a treatment].’

The advances in gene sequencing technology are rapidly turning science fiction into science fact. Once developed, gene therapy is a giant leap over traditional drugs. ‘What is beautiful is that with today’s technology, you can either choose to fully or partially [turn off a gene],’ Borg explains. ‘This may be very important because the complete absence of a gene can have dire consequences.’ For now, humanity will have to wait till this technology develops.

Luckily, gene sequencing has started to be used alongside conventional medical treatment. Attempts to mimic the effects of HPFH by elevating foetal hemoglobin levels in adults using drugs have been going on for a while. Sickle-cell disease (a disease similar to thalassaemia) is already being treated. The drug Hydroxyurea

reactivates the production of foetal haemoglobin in adults and blocks the formation of mutant haemoglobin, which keeps the disease in check.

Hydroxyurea has similarly been tried to treat thalassaemia. The results have been mixed, with some responding better than others. The drug can also have serious side effects and can kill blood cells. It seems that the bone marrow of thalassaemia patients is inflamed and highly sensitive to hydroxyurea. The dosage needs to be carefully regulated to minimise these effects, but also to ensure that individuals are not needlessly exposed to the drug if they do not respond to it. This is where genetics comes back to save the day.

MEDICINE MADE JUST FOR YOU...

Personalised medicine is a rapidly growing idea that uses a person’s genetic information to determine the best drug cocktail. By knowing a person’s genetics, an individual’s drug response can be estimated. The right treatment can be matched to the right patient without wasting time and money, while reducing threats to the patient’s health—a dream that needs more research to be realised.

The enormous wealth of information studied by geneticists is migrating from labs into clinics. Thanks to researchers like Felice, Borg, and the rest of the team the ways in which diseases develop are being understood. The aim is to tailor treatments for individual patients. We all share the same 99.9% of DNA. But that 0.1% makes a big difference.

The study’s principal investigator is Prof. Alex Felice with Jeanesse Scerri, Ruth Galdies, and Dr Joseph Borg as close associates.

By knowing a person’s genetics, an individual’s drug response can be estimated.

Ruth Galdies

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Illustration by Jean Claude Vancell

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By this time next year, around 17 million people will have been lost to heart or cardiovascular disease. Almost half of these deaths will have been due to coronary heart

disease, commonly resulting in heart attacks (myocardial infarction)—the world’s leading cause of death. While mortality rates are steadily declining throughout Europe, the death rate in some countries, including Malta, remains much higher than the EU average.

Unfortunately, our modern way of living threatens to turn the tide against reducing deaths. A growing love for junk food and a loathing for vegetables is leading to high rates of obesity and diabetes, while alcohol, tobacco, and other drugs are abused of regularly. Altogether, these lifestyle factors account for around a third of all cardiovascular disease in the developed world. But this information is nothing new. We have known about this for years.

PREDISPOSED TO A BROKEN HEART?

These lifestyle factors act on our genetic make-up. Like most other conditions, cardiovascular disease has a genetic element. Back in 1994, a study into death by coronary heart disease in twins showed that genetics plays a role in our susceptibility and accounts for 40–60% of the variability between individuals. Research being carried out by Dr Stephanie Bezzina-Wettinger and colleagues is looking into how genetics can have a hand in driving heart attacks in the Maltese population.

‘Many years before a heart attack, the artery wall develops what is known as an atheroma plaque,’ Bezzina-Wettinger explains. ‘This is where cells from the blood start to accumulate, begin taking up fat, and secrete a lot of inflammatory molecules [which have a number of roles, including attracting more blood cells and promoting blood clotting]. At some point the plaque can rupture, liberating its contents into the bloodstream [which] can trigger blood clotting. This can then either heal […] or end up causing a [heart attack] because heart tissue dies off [as] it is starved of oxygen and nutrients.’

Now a large collaborative study headed by Bezzina-Wettinger is investigating the genetics that leave the Maltese susceptible to plaque formation, known as atherosclerosis, and subsequent heart attack. The Maltese Acute Myocardial Infarction (MAMI) study is focused on three key topics: inflammation, fatty lipid and cholesterol deposition, and blood clotting. The idea is to search for genes that could in some way contribute to each of these three processes.

IT'S ALL IN THE GENES

So genes are the instructional element of DNA and can be imagined as a specific sequence of letters. These letters are read to provide the blueprints for the construction of proteins that regulate every aspect of our biology. While we all share the same set of genes, the exact sequence of letters can vary from person to person resulting in different variants of the same genes. ‘All of us have literally tens of thousands of [gene] variants,’ clarifies

Every person possesses the same genes within every cell. Their DNA provides the information to first create an entire functioning body and then keep it running. While all humans share more than 99.9% of their DNA, it is the subtle differences in our DNA that ensure individuality. Many differences are superficial effects, like hair colour, but some can have disastrous health effects. Scott Wilcockson talks to Dr Stephanie Bezzina-Wettinger (Faculty of Health Sciences, University of Malta) about her research on these subtle differences and how they can contribute to heart attacks.

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Bezzina-Wettinger, and the effect that these variants have on us, if any at all, depends on multiple different factors. ‘The genetics of [heart attacks] is very complicated. We talk about it as a complex disease, [...] one caused by a mixture of genes and [variants] that interact with one another as well as with the environment, such as lifestyle and physiological factors like diabetes.’ These interactions can make identifying the gene variants to blame for complex diseases harder than usual and this is further complicated by the fact that many of these gene variants are quite common. These variations are known as polymorphisms. This is the idea that a single type of object

or animal can come in multiple different forms or shapes. The most dramatic biological example is the existence of males and females. Genetic polymorphism refers to the same gene existing in a population in multiple variations. For example, there are a small group of polymorphic genes that determine your hair colour and so, whether your hair is blonde, brown, black, or red depends on which gene variants you receive from your parents. Bezzina-Wettinger explains that many of the genes we know are linked to heart attacks are polymorphic. These are the focus of her research.

DISSECTING THE MALTESE HEART

Previous studies carried out on other nationalities worldwide have identified groups of gene variants associated with an increased risk of heart attack. Malta has its unique genetic mix so these studies could not be blindly applied to the Maltese population. Bezzina-Wettinger explains that ‘we knew a lot about the epidemiology but in terms of the genetics, there was nothing when we started.’ To study the Maltese population they had to start from scratch.

Collecting all the material necessary for population-based studies can seem like a mammoth task and the MAMI study is a substantial project that involves collaboration over many disciplines. The team consists of clinicians, technicians, and cardiologists from Mater Dei Hospital, as well as geneticists from the University of Malta. Just over 1,000 participants were involved, including around 400 who

Malta has its unique genetic mix so these studies could not be blindly applied to the Maltese population.

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had had a heart attack, 400 ‘control’ participants who did not, and 200 relatives of heart attack victims. A lot of data was obtained for every single patient, starting off with each answering an extensive questionnaire that delved into all aspects of their daily lives. This was accompanied by a number of biochemical tests to gauge their general health, such as whether liver and kidney were functioning correctly. These tests provided an overview of the general lifestyle and health of the patients involved in order to determine the lifestyle risk factors that predispose the Maltese people to heart attack.

The study’s early results have shown that the Maltese are not immune to the conventional risk factors for heart attack including

smoking, diabetes, high blood pressure, and high cholesterol. Regular consumption of alcohol can be associated with decreased risk of heart attacks, but before running to the bar to get another drink, you should only be having a few drinks a week. Too much alcohol has the exact opposite effect. Binging on six drinks or more on a daily basis greatly increases your risk. Moderation is key.

The next step will be to look into the genetics. To do this, the team are using Next Generation Sequencing technology that vastly decreases sequencing costs. Since the advent of the Human Genome Project in the 1990s, our ability to sequence DNA is becoming increasingly easier, cheaper, and readily accessible,

along with the power to process, store, and analyse the vast amounts of data this technology produces. Bezzina-Wettinger’s team are using a method known as Whole Exome Sequencing that focuses specifically on genes and misses out the DNA in between. ‘We take one group of proteins that we think are involved [in heart attacks] and look at all their genes—there can be something like 100–200—and then we look for the variants.’ This technology has enabled Dr Ritienne Attard, a former Ph.D. student of Bezzina-Wettinger, to compare the variation in sequences between members of the same family. By doing this, Attard hopes to identify gene variants that could predispose individuals to heart attack.

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ADDING COMPLEXITY: THE GENE-LIFESTYLE LINK

What you have to keep in mind when studying the genetics of complex diseases, like heart attack, is that you can be looking at very common gene variants. ‘If you study the genetics alone you don’t really get anything conclusive [….] You could start to see a genetic [variant] that has no effect in the general population. But, for example, in smokers with this [variant, you find] they will have a higher risk. So we do see these kinds of gene-lifestyle interactions’. This phenomenon is prevalent in all complex diseases, including the plethora of cardiovascular diseases, type 2 diabetes, and many common cancers. Thus we can introduce the idea of one being predisposed to a particular illness.

The initial results of the MAMI genetics study show just this. Bezzina-Wettinger describes one of the team’s results whereby a single letter is changed in the sequence of one gene. ‘In [people] who are non-smokers,

non-diabetic, and have low cholesterol, the risk is the same as the base line population. But in smokers, diabetics, or [people with] high cholesterol the risk goes up 6.6-fold. Now, only a part of this is due to the [lifestyle factors] because someone with the same lifestyle factors but without this [gene variant] only has a four-fold increased risk.’ The difference between these two is down to the gene variant which does nothing at all in a healthy individual. Inherited genes play a role, but there is a chance to change the outcome with the lifestyle you choose for yourself.

THE BEATING HEART OF MALTA

So is the Maltese population particularly predisposed to heart attacks? Answering this question is not straightforward. The genetic information obtained so far relates to single families and is not representative of the entire population. While the genetic variants, or polymorphisms,

Inherited genes play a role, but there is a chance to change the outcome with the lifestyle you choose for yourself.

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that have so far been studied are common, the frequency can vary greatly from one population to the next. In addition, lifestyle factors can also vary. For example, one nation’s average diet can be very different to that of the neighbouring country. Bezzina-Wettinger adds that ‘the prevalence of diabetes is higher here and this [provides] a background within which some of these gene variants have an effect.’ The results of the MAMI study have yet to be fully published and proposed future work includes the sequencing of the exomes of all 1,000 participants. This will markedly increase the team’s ability to identify the gene variants that increase risk to disease and link them to the environment and lifestyle of the Maltese population.

According to the World Health Organisation, there are over 300 risk factors associated with coronary heart disease including depression, low socioeconomic status, and illicit drug use. This information could be useful to policy-makers when aiming

to reduce the incidence of heart attack in the general population. However, we know the major risk factors in the developed world with well-founded gene-lifestyles links (smoking, obesity, alcohol use, high blood pressure, and high cholesterol) and so these will remain key targets in the fight to reduce heart attack incidence. The advent and growth of this field of research now presents new possibilities when it comes to patient treatment or the application of preventative measures.

Accompanying the arrival of cheap Next Generation Sequencing technology, there has been an explosion in the field of personalised medicine. This is the idea of tailoring a patient’s treatment to the individual. Everyone has a unique genetic makeup that can influence how they react to treatments and drugs. This is already being applied in some cases, particularly in certain types of cancer, to determine the best course of treatment for that individual. However, Bezzina-Wettinger believes we are

not there yet when it comes to heart attacks. ‘The very fact that the influence of a gene can change depending on the lifestyle of that individual makes it far more complex... Eventually the major drivers [of heart attack] will be identified and treatments, either direct or preventative, will be developed.’ So while the age of personalised medicine may have already begun, our knowledge of the genetics of disease still has a way to go yet.

Annoyingly, complex diseases are quite complicated.

This research by the University of Malta forms part of the IAAMI and NGS projects conducted in collaboration with Mater Dei Hospital and funded through the National Research and Innovation Programme (Malta Council for Science and Technology). The study’s principal investigator is Dr Stephanie Bezzina-Wettinger with Dr Rosienne Farrugia and Dr Ritienne Attard as close associates.

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Marijuana has been used for centuries for medical reasons. In the early 20th century it was first linked to treatment for epilepsy. Over the last few decades researchers have been unravelling the truth behind the

drug. Prof. Giuseppe Di Giovanni tells us more about using marijuana for medical research and his own research on this controversial drug.

MARIJUANA FOR EPILEPSY?

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When I was a high school student my dream was to become a university professor and carry out brain research. I achieved my

dreams but I did not plan to end up as a marijuana researcher.

I only recently started studying the effects of chemicals found in Cannabis sativa, better known as marijuana. A few years ago, I was trying to establish a scientific collaboration with a friend and colleague of mine, Dr Roberto Di Maio (Neurology Department, Pittsburgh University), who is interested in epilepsy and marijuana. While researching the topic I found out that many epileptic patients have turned to marijuana to try to control their seizures. I had no idea of the extent of medical use of marijuana in the U.S.

Medical marijuana has many powerful uses. Apart from reducing epileptic seizures, medical marijuana can treat glaucoma, pain, and nausea in cancer and HIV patients, but it also protects the brain from the effects of trauma, eases the spasms of multiple sclerosis, slows the growth of tumours and reduces brain damage in Alzheimer’s disease. It appears that marijuana is effective for all sorts of disorders of the body, mind, and soul.

Considering the bounty of treatments linked to the drug, it is unsurprising that today 23 U.S. states allow the use of medical marijuana. Other states are expected to follow suit and other countries will probably also follow in America’s steps.

The situation is very different for the recreational use of marijuana. The drug has been decriminalised in many countries including Malta (up to 3.5 gr) but legalised in only a few parts of the world (four U.S. states, the Netherlands, and Bangladesh) and is ‘tolerated’ in many others. This is probably due to generalised governmental policy. Marijuana is still listed by the U.S. federal government as a Schedule 1 drug, alongside LSD and heroin. This class has no other drug that has already been accepted for medical use.

Marijuana is moving onto centre stage. Understanding the neurobiology and chemistry

behind the increasingly claimed medical benefits of marijuana is vital for scientists and now governments worldwide. At present, the medical uses of marijuana as treatments are still controversial and anecdotal. All pharmaceutical drugs on the market need gold standard large double-blind controlled clinical studies that make sure a drug is safe, or at least safe enough. To date, no such clinical studies have been carried out to examine the beneficial effects of cannabis in different disorders.

Anecdotal evidence is not good enough for treatments. In my laboratory, I am imposing some scientific rigour on what has become a very big ad hoc experiment (Medical School, University of Malta). In Malta, the use of marijuana for research or medical reasons is allowed, but is strictly controlled by national legislation. To get some solid data, I focused part of my research on the effect of cannabinoids (after the plant’s formal name) on different types of epilepsy. I did not use the chemical found in marijuana called delta-9 tetrahydrocannabinol (Δ9-THC), which induces marijuana’s psychotropic effects, but a synthetic analogue named win 55,212-2, that is many times more powerful than Δ9-THC. To understand how this chemical can help epilepsy sufferers I will explain how the condition arises.

WHAT IT IS EPILEPSY?

Around 60 million people have epilepsy worldwide—in Malta, the number is 3,000. The common neurological condition is caused by recurring disruptions to the brain’s usual activity. The disruption is usually short-lived. The outward signs of epilepsy are known as seizures. Some go unnoticed while others lead to involuntary muscle spasms and loss of consciousness. The type of spasm depends on the part of the brain affected and how far the disruption has spread. The brain is made up of billions of nerve cells that process information from our senses, thoughts, memories, emotions, and actions, and any (or all) of these activities can be affected by a seizure.

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Most seizures are over within a few minutes or less, and the person recovers quickly. Epileptic syndromes are classified as either generalised seizures, which affect the entire brain, or partial seizures, which occur within specific brain regions. Conventional drugs are not fully effective in 30–40% of patients meaning that research is needed to find new treatments.

During my time in Palermo I started to study temporal lobe epilepsy (TLE), the most common form of epilepsy that results in partial seizure in humans. We showed the anti-epileptic role of nitric oxide—a gas produced naturally in our brain. When I moved to Cardiff, I joined Prof. Vincenzo Crunelli’s (University of Cardiff and now also University of Malta) group. We unexpectedly discovered that absence epilepsy is not largely a neuronal disease, but a defect in glial cells (the part of the brain that supports and modulates neurons)—work we published in Nature Medicine, one of the world’s most important journals. When I moved to Malta in 2009 I brought this research with me.

CANNABIS TO TREAT EPILEPSY?

Cannabis has been used to treat epilepsy for centuries (see table).

Unfortunately, marijuana can have some serious cognitive side effects that have been the major obstacle in its medical use. Marijuana impairs perception, reaction time, and short-term memory. Marijuana can be addictive but only mildly so: 9% who try it will become addicted, according to a recent study. The same study listed alcohol at 15%, 17% for cocaine, 23% for heroin, and 32% for nicotine. So although marijuana may be addictive for some, 91% of those who try it do not get hooked.

For our study, we first focused on status epilepticus, a life-threatening condition in which one epileptic fit follows the other without the sufferer recovering consciousness. Dr Roberto Colangeli, a researcher in my group, (now at the University of Calgary, Canada), conducted many

experiments that led to one important unexpected discovery. Synthetic cannabinoids only had a modest effect on the development of seizures. When another chemical called serotonin was activated, their effectiveness multiplied, stopping the fits.

Not all types of epilepsy are created equally. In temporal lobe epilepsy, synthetic cannabinoids were even more effective than the epileptic drug phenytoin. The only problem that we found with this treatment was that the dose of cannabinoid impaired the hippocampus, an important part of the brain. The process it blocks is needed for learning and memory. This side effect was very frustrating; our treatment was effective but could harm patients. Dr Stefania Butini (University of Siena, Italy) synthetised a new compound that could block the breakdown of the natural cannabinoids our brain normally makes. The new drug boosted the amount of our own marijuana in epileptics’ brains. The new compound was less effective in stopping epilepsy but was longer-lasting without major memory side effects. We are currently following this line of intervention, trying other drugs that increase the levels of our own cannabinoids when and where they are needed to avoid any possible

We unexpectedly discovered that absence epilepsy is not largely a neuronal disease, but a defect in glial cells.

Epileptic seizure with the new drug

Epileptic seizure without the drug

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MEDICAL MARIJUANA FOR EPILEPSY: THE EVIDENCE

MEDIEVAL TIMESArab writer Ibn al-Badri Hashish reportedly uses marijuana to cure the sick son of the Caliphate Council’s chamberlain in Baghdad.

16TH CENTURY German physician Leonhart Fuchs names the plant Cannabis sativa (A.D. 1542).

19TH CENTURYBritish army surgeon William Brooke O’Shaughnessy introduces marijuana into medical practice as a treatment for pain, nausea and convulsions (A.D. 1842).

MODERN TIMES• In a 1967 study by Martin Keeler and Clifford Reifler marijuana

smoking was associated with an increase in seizure frequency.

• In the 1980s, Δ9-THC (active ingredient in marijuana) was characterised as an anticonvulsant in animal studies. Convulsions are a common symptom in epilepsy.

• A 1990 epidemiological study by Mervyn Susser and colleagues found that chronic marijuana use protects against seizures.

• According to a 2001 questionnaire conducted by Elisabeth Gordon and Orrin Devinsky and completed by 215 epileptic patients using marijuana regularly, 7.4% experienced a reduction, 2.3% an increase, and 90.2% no change in seizure frequency.

• Recent studies by Robert DeLorenzo’s group (Virginia Commonwealth University) show that endocannabinoids can block epilepsy (status epilepticus and temporal lobe epilepsy) in cell culture and animal models.

• In a 2014 survey, conducted by Orrin Devinsky on parents who had children with epilepsy and who were at the time using cannabis products, 16/19 respondents reported a reduction in seizure frequency while taking medical marijuana; others reported beneficial effects such as improved sleep and mood.

• In a 2015 retrospective survey, conducted by Craig Press and colleagues on paediatric patients with different types of epilepsy who were taking oral cannabis extracts, 57% of respondents reported improvement in seizure duration and frequency.

side effects. This research could treat millions of epilepsy patients safely.

THE BRAIN’S OWN MARIJUANA

The active ingredient in marijuana comes from a plant, whose extracts would not normally have any affect on the human brain. However, this active ingredient is different. Why? The answer is simple; it happens that the active ingredient in cannabis is very similar to that which the human brain produces naturally. By taking the drug you elevate the chemical levels, switching on the brain to abnormal highs. Other drugs like LSD, opium, caffeine, and nicotine also have analogues that are produced naturally in our brains.

It seems incredible that everyone produces a form of these drugs in their own brain. As mentioned previously, the brain’s own marijuana compounds are called endogenous cannabinoids or endocannabinoids. In 1992 Raphael Mechoulam (Hebrew University, Israel) discovered the first endocannabinoid, naming it anandamide (n-arachidonoylethanolamine or AEA) after the Sanskrit word ‘ananda’ (bliss) and ‘mide’ (chemical). In 1997 Daniele Piomelli (University of California, USA)

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discovered lipid 2-arachidonoyl glycerol (2-AG), the other major endocannabinoid in humans. The endocannabinoids (classified as neurotransmitters) pass on signals in our brains and bind to proteins called receptors found in neurons. These two cannabinoids bind to the CB1 and CB2 receptors that help to regulate appetite, mood, memory, and many other functions.

CB1 receptors, the more common type, are widely distributed in the brain, with high concentrations in regions of the brain linked to epilepsy, and are involved in pain perception and forming new memories (the cortex and hippocampus). There are low levels of CB1 in the brainstem, where cardiac and respiratory functions are regulated. This is one of the reasons

why cannabis does not threaten your heart or breathing with no overdoses ever recorded from cannabis use.

CB2, the other main cannabinoid receptor, is found mostly in the immune system. The immune system triggers inflammation and studies show that marijuana can reduce inflammation. Its presence there interests scientists because the immune system triggers inflammation, and studies show marijuana can have an anti-inflammatory effect.

The active ingredient in marijuana, Δ9-THC, can bind to these CB1/CB2 receptors to artificially trigger the same mechanisms in the brain. The cascade of events releases neurotransmitters (the molecules that brain cells use to communicate with

one another). Suddenly, they make the world seem hilarious and normal foods taste delicious. Under the influence of marijuana, people generally feel happy, relaxed, and introspective, although paranoia and

irritability are common, undesirable side effects. This is because the brain concentration of Δ9-THC reached – after smoking a joint or eating marijuana – is much higher than the normal level of endocannabinoids and greatly magnifies the effect. The result is the well-known marijuana high.

I find it difficult to answer the question: is marijuana good or bad for you? I do not think there will ever be a black or white answer, and it will always be somewhere in between. Although many scientists agree that marijuana is safe enough to temporarily alleviate the symptoms of certain medical conditions, both the short- and long-term use of the drug may harm the body and mind. Marijuana’s continued popularity among teenagers raises particular concern because the drug might hinder the ongoing maturation of the adolescent brain.

For medical use, trying to boost our own marijuana (endocannabinoids) levels will probably be safer. The best approach will probably be by blocking the enzymes that break it down. Research is needed to develop these new drugs to treat a host of different brain disorders. Several research groups in the world, including mine in Malta, are seeking answers to reinvent marijuana uses.

Prof. Giuseppe Di Giovanni (giuseppe.digiovanni@um.edu.mt) is the Coordinator of the Malta Neuroscience Network, who organised the first Brain Awareness Week, from 14–20 March 2016, the global campaign engaging the public with brain research. Prof. Di Giovanni is also the Editor-in-Chief of Xjenza Online, the journal of the Malta Chamber of Scientists www.mcs.org.mt/index.php/xjenzaThis is the first article in the Malta Neuroscience Network (MNN) series.

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POTENTIAL APPLICATIONS OF MEDICAL MARIJUANA

EPILEPSYMultiple animal studies have suggested that Δ9-THC may inhibit the brain processes thought to cause seizures. High-quality human studies are lacking and this leaves many questions unanswered.

CANCERThe active ingredient in marijuana, Δ9-THC, and its synthetic derivatives have been approved by the U.S. Food and Drug Administration to control nausea in cancer patients undergoing chemotherapy and to stimulate appetite in patients with AIDS. Yet it may not be as effective as other recently developed drugs, so marijuana is not considered as a first-line treatment for these symptoms. Numerous recent studies have suggested that cannabinoids might directly inhibit cancer growth.

MULTIPLE SCLEROSIS (MS)A large trial published in 2012 found that a cannabis extract significantly decreased muscle stiffness and other symptoms associated with multiple sclerosis (MS). A smaller study found that smoking cannabis reduced spasticity and pain in participants resistant to other treatments. Given the few therapies available for MS, a 2011 review concluded that medical marijuana might help manage certain symptoms.

GLAUCOMASeveral studies have found that smoking marijuana lowers pressure inside the eye, relieving glaucoma-related discomfort for about three to four hours. Other pharmaceutical drugs have now been found to be a better treatment than medical marijuana.

PARKINSON’S DISEASE (PD)Recent studies do not offer a complete understanding of the role of endocannabinoids and cannabinoid receptors in Parkinson’s disease (PD). Research supports the notion that the endocannabinoid system plays an important role in movement disorders like PD. The studies can lead to novel therapies.

STROKEThere is conflicting evidence on the usefulness of cannabinoids in the treatment of stroke—more research is needed.

PAIN AND INFLAMMATIONMarijuana is only slightly better than a placebo in reducing acute inflammation, and it may even increase the perception of pain in some patients. When taken in combination with other medications, various cannabis-derived drugs are moderately effective in reducing chronic pain.

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Malta is one of the bird migration hotspots in the Mediterranean. As an archipelago, the Maltese Islands have been a hotspot for seabird nesting since time immemorial. Marie Claire Gatt talks about her research and a major EU project determining sea bird colony location and which areas need to be saved. Photography by Jean Claude Vancell.

Sitting in pitch darkness on a hidden cliff ledge at l-Aħrax tal-Mellieħa (Malta), I listen intently to the ghostly calls of the seabirds, Yelkouan shearwaters (Garni, Puffinus yelkouan), as they

return to their nests after a day foraging at sea. Like albatrosses in the southern hemisphere, shearwaters and petrels spend their life roaming the seas and oceans, feeding on fish, squid, and other marine animals, only approaching land during the breeding season to nest. Even then, these birds cover hundreds of kilometres at sea every day just to feed.

Back to the cliff ledge. I have just been slapped in the face by the wing of an unsuspecting Yelkouan as it returns to its nest hole. I pick up the confused bird and pass it to Ben Metzger, who reads out the identification number on the metal ring on its leg: EE01105. It is 2013 and Metzger is the Head of Research at the EU LIFE+ Malta Seabird Project, a conservation research project led by BirdLife Malta. This male bird was first handled in Malta in 2007 and fitted with this ring by seabird researcher John J. Borg; it has been breeding yearly at the same location ever since. Metzger and a team of colleagues and

Time, space, & the ocean wanders

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volunteers (such as me) have been building on past efforts by monitoring the three seabird species which nest on Malta’s coasts and islands: the Yelkouan shearwater, its close relative, the Scopoli’s shearwater (Ċiefa, Calonectris diomedea), and the tiny Mediterranean Storm petrel (Kanġu ta’ Filfla, Hydrobates pelagicus melitensis). Around 10% of the world’s population of the Yelkouan breed in Malta, while as much as 50% of Mediterranean Storm petrels breed in the rock scree of Filfla. I have been involved in this project since its start in 2011, and this experience inspired me to study the lives of this group of birds.

A year later and 2,850 km due west, I am standing outside the remote research station on Deserta Grande, Madeira, surrounded by Bulwer’s petrels (Bulweria bulwerii) swiftly manoeuvring around me to join their partners in nest burrows among the rock scree. I have flown out to the Madeiran archipelago from Manchester Metropolitan University to join the research group of two biologists from Lisbon studying the ecology and behaviour of the Bulwer’s petrel—a

small, soot-coloured petrel which the Portuguese call Alma-negra—black soul!

LIFE AT SEA

Seabird behaviour is closely tied to the rhythms of marine life. The Bulwer’s petrel feeds on fish and squid species that occupy greater depths of the sea during the day compared to the night. These fish and squid follow plankton along their vertical migration up and down the water column. The plankton seem to sink to the darker waters to hide from predators, while returning to the surface at night to feed. They are at their most abundant at the surface during the new moon period when there is no moonlight. Their predators seem to follow them. Likewise, the Bulwer’s petrel. It can only feed from the sea surface so it hunts mostly

at night. While on Deserta Grande, I investigated whether the Bulwer’s petrel’s hunting efficiency was being influenced by this predicted difference in food availability across the lunar cycle. To our surprise, it appeared as though these birds were managing to catch just as many fish and squid, no matter the moon cycle, during their breeding period. This raised more questions than it answered, as is typical of ecological studies, and more investigations were needed to figure them out. Other studies on bird activity outside the breeding season seem to suggest that Bulwer’s petrels can adjust their behaviour to get food when they need it most.

Seabirds are top predators in the marine environment. They hold an important place in the food web and reflect the health of the seas in their success. Unfortunately, they are also very vulnerable. Albatrosses, shearwaters and petrels pair with a single mate throughout their life and lay no more than a single egg every year. Both pair members take turns to incubate the egg for days at a time while the other parent is foraging.

Seabird behaviour is closely tied to the rhythms of marine life

The number of seabirds estimated to die globally as fisheries bycatch every year

700,000

Light pollution from Madeira

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Marie Claire Gatt

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They nest in the same site all their life, returning every year to the same spot from halfway around the world. The chicks that make it then take between two to 12 years to reach sexual maturity in the different species. All these facts add up to a low birth rate and a high dependence on a stable habitat. The loss of just a few birds can have a big impact on the population.

While attached to their breeding colony, seabirds depend on food being relatively close to their nest to be able to regularly swap the incubation shift with their partner. When the chick hatches they need to bring back food at an even faster rate. While

on Deserta Grande Island, I came across several Bulwer’s petrel’s eggs that had been abandoned by their parents; the birds may have either not found enough food in time to exchange incubation duties or died at sea. The major cause of incidental death is fishing gear. Fishermen do not intentionally target birds but the birds become entangled in their gear as they try to catch baited fish. A number of modifications to fishing gear are starting to be implemented in the southern hemisphere. These adjustments do not badly hamper fishing fleets. For example, in South Africa streamer lines on trawl cables were introduced that

discourage the birds from approaching the fishing gear, reducing seabird bycatch by up to 99%. Other simple mitigation measures include weighting lines to quickly sink beyond the reach of foraging seabirds. Conservatively, 700, 000 seabirds are estimated to die globally as fisheries bycatch every year. The situation in the Mediterranean is not yet known.

Seabird numbers are also hit by overfishing; 80% of fish stocks are overexploited. Overfishing, pollution, and the degeneration of our seas result in increased stress for seabirds—and fishermen—to catch enough fish. Ship traffic, dumping, sea pollution, and

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offshore windfarms can also harm seabirds where these activities overlap with critical seabird areas.

Metzger’s team at the Malta Seabird Project have been tracking the movements of Malta’s breeding seabirds to map important flyways, feeding areas, and other communal hangouts which need attention. Each EU country is responsible for protecting and managing marine habitats under the Natura2000 framework. In 2015, the LIFE+ Malta Seabird Project presented the areas around Malta on which Maltese breeding seabirds depend in various stages of their lives. Those that fall within Malta’s exclusive economic

zone (EEZ) will hopefully soon be incorporated into Malta’s Natura2000 network. But seabirds have no regard for national boundaries so their conservation depends on international research teams and intercontinental initiatives to halt threats.

RISKS ON LAND

Let us have another look at coastal seabird colonies. Deserta Grande is much like an oversized Filfla—it is a 16km-long ridge of stratified volcanic rock and bays of loose boulder scree. Both islands are uninhabited nature reserves, with strict access control and negligible direct human disturbance. And both still belong to seabirds. The Bulwer’s petrel colony on Deserta Grande is probably the biggest in the Atlantic, much like how Filfla likely hosts the biggest population of Mediterranean Storm petrels in the world. If the quality of these land areas deteriorated, the populations could suffer a fatal blow. Shearwaters and petrels only approach their coastal breeding colonies under the cover of darkness to escape predation and harassment by gulls. However, the lighting up of promenades has exposed some cliff lines and made

HOW TO FOLLOW SEABIRDS

Large-range at-sea movements are difficult or impossible to trace visually. Cutting edge technology can come to the rescue. Remote data loggers are relatively small devices that can be attached to animals and use one of a range of techniques to record their position. Device applications change depending on their size and weight, level of accuracy, and battery life. The smallest devices available use the time of sunrise and sunset to approximate seabirds’ position on the globe. The most accurate devices record GPS location via satellite connection. As data loggers continue to become smaller, more accurate, and cheaper, their applicability to new questions and smaller species increases.

Seabirds hold an important place in the food web and reflect the health of the seas in their success. Unfortunately they are also very vulnerable

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Scopoli at sea. Photo by Ben Metzger

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them unattractive to seabirds. Several historic breeding colonies in Malta have probably been abandoned because of light pollution. Chicks ready to fly the nest also wait for night-time to take off, unaided towards the horizon, but street lights can, instead, attract many fledglings to fly inland.

Alien invasive species are a huge threat on land, particularly on islands. Rats are the most notorious. With no natural predators in Malta, their numbers can quickly explode by feeding on our litter. Rats are intelligent, curious, and agile, and are able to swim several hundred metres. Their presence at breeding colonies spells disaster, as the rodents prey on eggs and chicks and can easily wipe out a breeding season.

But it is not all doom and gloom. It is now 2016, and as the LIFE+ Malta

Seabird Project draws to an end, BirdLife Malta has just launched a new LIFE project—Arċipelagu Garnija—which will aim to protect birds on land. Metzger is now heading a fresh team to identify threats to the Yelkouan Shearwater colonies scattered across the Maltese Islands. Arċipelagu Garnija also wants to engage with the public and bring them on board. Small changes like not leaving litter for rats, reducing light pollution, and keeping sound disturbances low near colony sites will go a long way to help preserve seabird populations.

These ocean wanderers captivate me. They have attuned themselves to the ways of the seas for the past 35 million years. Now they are one of the most endangered groups of birds in the world. The only way to stop

their disappearance is for worldwide research to go hand in hand with political and social willpower to make sure that seabirds keep shearing the seas.

Members of the public can learn more about the Maltese Islands’ seabirds and enjoy them in their natural habitat during yearly pelagic trips organised by BirdLife Malta: www.birdlifemalta.org.

Marie Claire Gatt’s Master degree was partially funded by the Master it! Scholarship Scheme (Malta). This scholarship is part-financed by the European Union—European Social Fund (ESF) under Operational Programme II—Cohesion Policy 2007-2013, ‘Empowering People for More Jobs and a Better Quality Of Life.’

FLEDGING RECOVERY

In June and July many disoriented young Yelkouan shearwaters are found, and in September and October, Scopoli’s shearwaters—sitting ducks for anything that wants an easy kill. Should you come across a disoriented seabird fledgling, please get in touch with BirdLife Malta on 21347 645/6. The bird will be collected by a licensed bird handler, ringed, and released in a safe place at the coast, giving it a second chance to roam the sea.

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Ben Metzger

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Systematic Failure, Persistence and SuccessA tale of early school leavers

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There was once a time when a certificate meant a secure job. But that time is long gone. Education is increasingly expensive and time consuming. Many a time,

graduates enter the job market with little to no experience, with most taking entry-level jobs that do not pay nearly enough to compensate for the work they put into their studies.

From this perspective, the high number of dropouts and poor update of tertiary education is unsurprising. It is a worldwide phenomenon. The premise is simple: why not get on the job ladder early and work your way up through dedication and experience?

In Malta, however, 20.4% of students become ‘early school leavers,’ meaning they finish their education with five ‘O’ levels or less under their belt. Does the same reasoning above still apply? Are the long-term effects of such a decision as negligible as some might think?

Prof. Carmel Borg and Dr Milosh Raykov (Faculty of Education, University of Malta) joined forces about a year ago to answer these questions. They looked into the effects of early school leaving on individuals’ emotional, social, and financial wellbeing.

A pioneering study, Borg and Raykov’s work was supported by the Observatory for Living with Dignity, one of five research entities within the Maltese President’s Foundation for the Wellbeing

of Society. But this is not to say that the journey did not bring challenges with it—far from it. Hurdles were present from the word go. ‘There is a dearth of research when it comes to the correlation between early school leaving and wellbeing,’ says Borg, hence work had to start from scratch. Piles of data from copious surveys conducted by local and major European and International Institutions, needed to be sifted through and analysed. What’s worse was that ‘they were not even meant to study this correlation,’ says Borg.

Despite the difficulties, however, the project has been going on for over a year and the first phase has been completed. Published in December 2015, the report outlines a series of emerging trends. Sadly, they are not positive.

STAY IN SCHOOL

The truth is that early school leavers are struggling. According to the study, the low incomes prevalent among this group are resulting in serious financial difficulties for families, even restricting access to important learning tools, such as computers and the Internet, for their own children. Money problems are just the tip of the iceberg. Negative emotions and a lack of optimism are widespread in their lives. They are less optimistic about their futures and experience exhausting time-pressures. They have little to no time to do things they actually enjoy, and as a result they feel less

In Europe, around one in 10 students (18-24 years old) is an ‘early school leaver’. For Malta, it is one in five. A fifth of our local student population is neither in school, nor in training, and with less than five SEC exams under their belt, Malta’s public education investment (~6% GDP) is not seeing much fruit. Cassi Camilleri speaks to Prof. Carmel Borg about what is needed to abandon the antiquated system our communities are being marred by. Photography by Elisa von Brockdorff.

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happy, less calm, and less peaceful. Feelings of social exclusion have also been reported, a direct result of their perception of a low social status.

This is ‘a struggle which cannot be taken lightly,’ says Borg, especially when looking at the state the current student population is in. By international standards, around 5–6% of pupils are doing exceptionally well. But a staggering 45% are doing very badly. This is a ticking time bomb of early school leavers just waiting to go off. What is even more worrying is that the majority of the people making up the 45% cohort are students from a lower socio-economic status. To have these staggering gaps across social strata in such a small country is ‘ethically and morally unacceptable,’ says Borg.

This is what has made education a personal mission for Borg. ‘Those who know me well are aware that my agenda is focused on social justice, equity, and inclusion in education,’ says Borg. ‘I believe in social justice and I believe education is a very important instrument in achieving it.

The urgency is obvious but

the problems in our education system are multi-faceted.

In his famous TED talk titled ‘Changing Education Paradigms,’ ken Robinson deconstructs current models, pointing out how we are trying to fit within an educational ideal conceived during the industrial revolution. Schools function like factories, Robinson explains, and this system is out of date. This kind of schooling is about conformity, not learning, and Borg agrees wholeheartedly. Different children have different needs and skills and most institutions, both in Malta and other countries, operate within a standardised curricular regime, streaming, and testing that ignore individual needs. ‘How can you speak of inclusion, social diversity, and justice when you have an educational process that is largely informed by an anti-educational routine?’ he asks.

Interviews with a number of former students, though not early school leavers by definition, reinforced the above. Now 22 years old, Adam* was frustrated in school because he felt classes were too easy for him and his teachers failed to challenge him. As

a result, he left when he was 16 as soon as a business opportunity arose. Twenty-one year-old Elisa*was not ready to make decisions about which subjects she wanted to pursue at the age of 11. She ended up making the wrong decisions then abandoning her course to start work at 19.

‘Our schooling system is short-changing its pupils,’ says Borg. And this statement refers to both early school leavers and the students who stay on. The bulk of our education system is devoted to exam preparation and regurgitating information. Even at University level, ‘there is [generally] very little critical thinking,’ Borg claims, with ‘very little happening beyond accumulating knowledge’.

All this being said, early school leaving is not a problem to be placed squarely on the shoulders of educational institutions. The issues leading up to early school leaving are complex and lead down many avenues.

There can be personal reasons for leaving school such as chronic health issues and genuine learning difficulties which might have been inadequately addressed. One’s community also

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‘Education is simply the soul of a society as it passes from one generation to another’ Gilbert Chesterton Prof. Carmel Borg and Dr Milosh Raykov

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contributes. An economically or socially depressed community sees greater numbers of early school leavers. Family is another factor. Chronic intergenerational unemployment, very low expectation from parents—all these play a role in an individual’s decision whether to stay on at school or not.

‘Many times,’ Borg says, ‘all of these issues are present in their own right and combine, creating dropouts and early school leavers. There isn’t just one reason.’

One more element contributes considerably to early school leaving.

The economy. When economies do well, early school leaving rises. This might seem counterintuitive but it is not. A prospering economy is able to absorb many more people with low level skills and competencies because there are more jobs.

However, such early school leaving levels cannot be sustained. Eventually, skill gaps emerge which need to be filled by foreigners. The currently booming e-gaming industry in Malta is the perfect example. Struggling to find local talent, foreigners are brought in to take up the new roles. But this is a band aid, a temporary solution. A powerful economy cannot grow and prosper on low skill, low income, and precarious jobs.

A RAY OF HOPE

Malta’s current status with regards to early school leaving is far from enviable, but it is not all bad. As a result of Borg and Raykov’s work, long-term, steadfast solutions are being proposed. The approach is three-pronged

involving preventative, intervention, and compensatory measures.

Preventative measures see professionals in communities working directly with families. This would help deal with problems like chronic intergenerational unemployment and very low family expectations. Such

ASKING THE RIGHT QUESTIONS

The research undertaken by Prof. Carmel Borg and Dr Milosh Raykov is multidimensional in nature, trying to shed light on the social, economic, and emotional wellbeing of early school leavers. It attempts to answer the following questions: What are the work experiences, job characteristics and social status of early school leavers? How does the decision to leave school early affect happiness levels and quality of life? And what is the impact of early school leaving on mental and physical health?

The work also has a wider scope, determining the economic repercussions of early school leaving and how that would affect not only an individual’s living conditions but also the country as a whole. Can a country and its economy progress with high levels of early school leaving?

Around 5–6% of pupils are doing exceptionally well. But a staggering 45% are doing very badly

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conditions can be countered by high quality day care and preschool. As children grow older, schools need to remain relevant. This means that vocational education will have to occupy a prominent position within secondary education to cater for people who want to work in more practical fields. The needs of high academic achievers need to be met through alternative programmes within mainstream schooling.

Intervention measures come into play when an individual risks leaving school. These students, such as teen mothers, need solid support networks. Investing in student and parent after-school programmes would greatly help.

Compensatory measures focus on reintegrating people back into some form of education after leaving school. MCAST has a second chance element

in its programme already, thanks to its foundation courses, allowing those with no qualifications to start school again. In itself, this is a great initiative

but more work needs to be done to retain students. ‘A high percentage of the people who sign up for MCAST foundation courses are gone by the end of the year,’ says Borg.

‘We need to break that cycle of failure and disappointment. What we cannot do is continue reproducing the same systems and hoping that they will lead to a different result.’

Change is sorely needed. The good news is that the wheels are already in motion to make that happen.

The Youth Guarantee programme, launched in April 2014 by the Maltese government, is the first port of call. The programme, which is also being implemented throughout Europe, works with young people to provide support, motivational training, and guidance on employment. It also recognises the effectiveness of

Malta has now hit a plateau. This could have something to do with the fact that the number of females becoming early school leavers is rising fast

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a combination of off-the-job and on-the-job training, giving trainees the opportunity to garner practical training either in a simulated workshop or in a real working environment.

According to the programme’s report on the 2015 scheme, dropouts were prevalent. Of the 606 applications received, 418 opted out. What was noted from the scheme echoes Borg’s words: ‘the rates still highlight how essential it is to further invest in similar initiatives to try and reach this cohort and re-engage them in education, training, or employment.’ But the task is far from easy.

Malta is trying. It ranks high in education investment. In fact, according to the latest figures from the World Bank (2012), about 6.8% of its GDP (Gross Domestic Product) goes towards education.

‘Education authorities are highly aware and genuinely concerned about

early school leaving,’ notes Borg. In fact, their research is being welcomed with open arms by the Directorate for Lifelong Learning. Borg is also certain that these authorities will step up to the plate and sponsor more studies in the years to come. This is essential. In Malta, research gaps go hand in hand with policy gaps. ‘We need to produce more knowledge upon which we can design good policy.’

Across Europe, the aim is to bring down early school leaving to 10% by 2020, but Malta will not achieve this goal, according to Borg. While figures show that the rate declined considerably over recent years, 2004

saw it at 43.1%, Malta has now hit a plateau. This could have something to do with the fact that the number of females becoming early school leavers is rising fast. ‘At best, we might hit the 10% mark by 2025. But this too seems unlikely,’ says Borg.

So where does this leave the Maltese public?

At the second phase of Borg and Raykov’s research, popular wisdom and research will come together as the pair interview a number of early school leavers. ‘We will be digging deep, excavating narratives, and biographies,’ Borg says. They will be looking into personal experiences and mining for further solutions to reduce early school leavers.

This three-year project has a long way to go, but it has the legs to go the distance fuelled by the deep-rooted sense of duty in Borg and Raykov. ‘We are structurally responsible for the predicament of early school leavers’ says Borg, ‘and if we don’t act now by investing in quality primary and secondary education for our children, then we will pay for it at a later stage.’

FURTHER READING

• Eurostat. (2015). Early leavers from education and training. Retrieved from http://ec.europa.eu.

• Ministry for Education and Employment (MEDE). (2014). A strategic plan for the prevention of early school leaving in Malta. Malta: Ministry for Education and Employment.

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ROCKETS THAT FAIL

SAFELY

Ariane 501 a few seconds before break up

ROCKETS THAT FAIL

SAFELY

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Spacecraft failures are spectacular. These unfortunate events are seared into the public memory. One reason why rockets can fail are software bugs. If a rocket’s computer system fails, that infamous blue screen leads to lost work hours, billions of Euro, and lives. Researchers from the Faculty of ICT and Faculty of Engineering (University of Malta) tell THINK about their collaboration with the European Space Agency (ESA) to test novel satellite software architecture to prevent rocket failure.

June 1996, Ariane 5 Flight 501. Twenty years ago, the world braced itself for the very first flight of a giant rocket that was capable of hurling a pair of three-tonne satellites into orbit. Standing proudly

at the European spaceport in French Guyana, the rocket represented ten years of progress in launcher technology and was meant to catapult European space science to the forefront.

Less than a minute into the flight, the mighty Ariane 5 suddenly veered off course and broke up. Naturally, when rockets fail, they fail spectacularly. They always do. Ariane 501, the Titanic of European launchers, turned into a massive fireball on its maiden voyage—a sad day for European space science.

The crash inquiry report, published a few months after the incident, revealed that the launcher broke up when it abruptly swerved off course under the command of the flight control system. The culprit was a small bug in its Inertial Reference System (IRS), the system that calculates the altitude of the launcher: a few erroneous lines of code had tried to stuff a 64-bit number into a 16-bit space. This resulted in invalid altitude information being communicated to the flight control computer, which interpreted it as valid altitude input causing three powerful nozzles to swing to an extreme

position. The control system was compensating for a wrong turn that had not taken place, which destroyed the launcher in the process.

A little bug and a big bang: around €6b worth of research and development had fallen victim to a few wrong lines of code. This glitch is infamously considered to be one of the most expensive software bugs in history. Garbage in, garbage out, as fiery bits of debris ended up littering the swamps of French Guiana.

The crash inquiry concluded that the development programme ‘did not include adequate analysis and testing of the inertial reference system or of the complete flight control system.’ Suitable testing could have detected the potential failure and the appropriate fixes would have contributed to a more robust control system—perhaps robust enough to gracefully deal with unanticipated situations, such as a misleading altitude input.

SYSTEM ROBUSTNESS AND THE SPACE SECTOR

Some bugs do not fly, and this was definitely one of them. Designing robust systems that can deal with such glitches pays off. These software issues are, of course, not just limited to the space sector. The same vulnerabilities may crash your word

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processor. The worst scenario in our everyday lives is hours lost leading to a very bad day. In space, things are a bit different. Considering the number of man-hours of delicate and intricate work involved in design and development, it sometimes means that, kilo for kilo, satellites would cost less were they to be made out of solid gold. Provided the spacecraft has surpassed the critical phase of launch, unrecoverable satellite subsystems may result in the loss of control of the orbiting satellite. Years of work and millions of Euro are turned into a lump of orbiting junk—now that really is a bad day.

Nowadays, spacecraft software design needs an extensive dependability and robustness testing campaign. The stakes in the space sector are too high to get it wrong. But how would you check how robust a piece of software is?

Simply put, the answer is: by making it fail. And by ‘causing it to fail’, software glitches can be detected before they lead to failure during space flight. Developers may detect and fix bugs they had overlooked during the initial design phase. One way of doing this is to intentionally inject faults within the software being tested and observe how it responds or stops responding.

SPACE FLIGHT MALTA

To try to make rockets fail safely, Stephen Grixti (supervised by Dr Ing.

Nicholas Sammut and Prof. Ing. David Zammit Mangion) spent six months at the ESA (European Space Agency) working on the research project. He tested the robustness of ESA’s novel satellite software architecture as part

of a collaboration between the Faculty of ICT, the Faculty of Engineering (both at the University of Malta) and the European Space Research and Technology Centre (ESTEC).

At ESTEC, the research heart of

Considering the number of man-hours of delicate and intricate work involved in design and development, it sometimes means that, kilo for kilo, satellites would cost less were they to be made out of solid gold

Top: Grixti (second from the left) together with other ISU colleagues at the RF Testing chamber at MDA, Montreal. Below: Grixti with the Artemis Jr lunar rover prototype designed by the Neptec Design Group for NASA and the Canadian Space Agency

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Space science and technology research projects open unique opportunities. Sammut reminisces about a unique experience when a collaborator from the Centre National D’Etudes Spatiales (CNES) invited him to a free parabolic flight. These flights are performed by aircraft such as the Airbus A300 aircraft that briefly leads to near-weightlessness as they shoot up to very high altitudes simply to hurtle back down to earth. They are used to conduct microgravity experiments for scientists to understand the behaviour of matter in the absence of gravity. Apart from research, such flights usually serve as training for astronauts.

‘During the microgravity flight, you first feel twice your weight, and you can hardly lift your own hand. Then all of a sudden you are completely weightless, floating around freely and upside down. If you just hit the wall a little, you are sent hurtling towards the other side of the cabin,’ comments Sammut as he reminisces about his wonderful experience.

Microgravity Parabolic Flights on the CNES Airbus A300 Zero-G plane last approximately 2.5 hours with 15 parabolas totalling five minutes of weightlessness. Parabolic arcs are performed to create a weightless environment, allowing passengers to float, flip, and soar as if they were in space.

‘It has been a lifelong dream to be an astronaut,’ states Sammut. ‘Now I know what it feels to be an astronaut for a day, or rather, for five minutes.’

WEIGHTLESS AT LASTthe ESA in the Netherlands, and later at UoM, ESA’s satellite software was tested by scientists trying to make it fail—and unfortunately (or fortunately) it actually did fail! Grixti found a number of critical design flaws that led ESA contractors to re-evaluate their systems to avoid the same kind of fault that had led to the destruction of the Ariane 501.

Through this study, a black-box robustness testing methodology was tailored to inject faults within the separation kernel of a Time and Space Partitioned (TSP) spacecraft on-board software. The devised testing architecture was then used to investigate the robustness of ESA’s own EagleEye spacecraft. EagleEye is an ESA testbed representative of typical Earth observation satellites—that is, the satellites that snap those beautiful Earth photos from around 800 km. The case study detected a number of issues with robustness at the satellite’s software core. It picked up on a glitch that led to the system’s catastrophic failure.

A PASSION FOR SPACE TECHNOLOGY

Grixti looks back at his research experience and recollects many fulfilling memories. Every time an ESA satellite was launched, a large crowd would gather and the event was streamed live from the launch site. Those present could sense a mixture of tension, passion, and excitement

Dr Ing. Nicholas Sammut during the parabolic flight on the CNES Airbus A300 Zero-G plane

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among the onlookers. These researchers felt responsible for that spacecraft; it was their baby.

But perhaps the best cocktail of passion, pride, and champagne came in November 2014 with the Rosetta mission making the news all over the world. Philae, a lander the size of a washing machine, was released from the Rosetta satellite and made the first ever comet landing. Rosetta and Philae had been travelling for 10 years in space and Grixti was fortunate enough to be stationed at ESA when this landing happened. The Rosetta control room was streamed live in the auditorium and once the landing was announced the tense, never-ending silence broke into cheers, claps, and the winning sound of popping champagne bottles. Again, there was an infectious sense of achievement and belonging. This was one small step for the Rosetta

mission, but one giant leap for science.There was more to come. Half-

way through his project, Grixti was sponsored to attend a two-month space studies course in Montreal, Canada. This was organised by the International Space University (ISU), a community of space professionals from all over the world that harbours a healthy network of influential space experts, which includes political figures and numerous astronauts.

THE RESEARCH EXPERIENCE

The whole research project was a memorable journey. The value gained does not only come from the technical experience and the excellent results achieved, but from meeting people from different cultures in an international setting. By venturing outside of their comfort zone up and

coming scientists can learn and be inspired by world renowned specialists and astronauts within an environment of collaboration.

Reading about satellites and space technology is exciting, but actually living it through such collaborations takes the experience to an entirely different level. That is what successful rocket launches do all the time, and once they lift off they are difficult to access. Robust systems are critical for space travel. Finding critical flaws through testing like those found by UoM researchers could have saved the Ariane 5 Flight 501 in 1996.

The University of Malta research team would like to thank Prof. Edward Gatt from the Faculty of ICT, and the Flight Software Systems section in ESTEC for their support throughout the research project.

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Dr Nicholas Micallef grew up in a family of four and despite his having lived in Scotland for the past six years

they have always been a very close family. ‘Our parents always pushed us to study and to do well in school’, Micallef notes, adding how grateful he is knowing that ‘if it wasn’t for their constant support, we would not have made it to University or been so successful in our careers’.

While his twin brother pursued a successful career as a lawyer, Micallef embarked on an academic path: a B.Sc. in Information Technology—Computer Science and Artificial Intelligence (Faculty of ICT, University of Malta) followed by a Ph.D. on phone security and sensors (Interactive and Trustworthy Technologies, (ITT) Glasgow Caledonian University). His research team’s work quickly caught the attention of the media and has been featured on the BBC, New Scientist, and the Daily Mail. In short, they had developed an app

which gets to ‘know’ its user and realises if someone else is using the phone. The app has opened up a series of opportunities for Nicholas, but, he reveals, while his fascination for technology has never waned, his ideas were not always well-received and he first experienced a series of disappointing rejections.

When he was in secondary school learning Computer Studies, Micallef became fascinated with how people interact with tech. ‘At that stage we were taught about the technicalities of computers and we also had our first experiences with programming languages. However, I always felt that there was more to it and that people’s perceptions of technology were quite different to those of the technical people that designed them’, he explains.

The link between people and technology continues to be a thread in Nicholas’s scientific oeuvre. But then Nicholas is a people person. He doesn’t quite fit the bill of the stereotypical, introverted, misanthropist scientist

and ‘always likes to meet people. Also’, he adds, ‘I’m always up for a pint’.

In between his degrees, Micallef spent six years as a software engineer. In this position he focused on enhancing and supporting e-commerce solutions. This saw him improving the way computer systems worked, by tailoring them to people’s needs as well as fixing the problems they encountered.

He later took the difficult decision of leaving home for Scotland to read for an M.Sc. in Computer Science (University of Edinburgh), followed by a Ph.D. The decision to leave was fueled by a desire to find new opportunities so when he encountered a plethora of rejections, he was understandably left feeling disappointed.

‘I think the most difficult moments were accepting all the setbacks we encountered when trying to publish our work. We faced fierce criticism from traditional security researchers because our research was redefining the boundaries of the area that they were not open to. In the end

Shiny, ‘appy people

Dr Nicholas Micallef is fascinated by technology and has an outgoing personality. He recently made a name for himself thanks to his invention of a security app. Veronica Stivala writes about how he fought disappointment and skepticism to reach new heights.

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we managed to overcome this problem and published some of the work, but we still have some work which is unpublished’, he notes.

But these reactions all served to make Nicholas a stronger person: ‘at the beginning this was difficult to accept, but as time went by this helped me learn to accept rejections. Also, these situations helped me to look for positive criticism, take it on board, and always continue working hard without giving up.’

And so he did. While at the ITT, he developed the famous mobile app called Ambient Unlocker that ‘watches how you use your phone to build a portrait of your ‘normal’ behavior’ (BBC). To start, he had to first identify the research gap in the field. Followed by throwing himself hook, line, and sinker into mountains of reading and a large amount of analysis, Nicholas identified a lacuna in the protection of phones from unauthorised access.

They first tested the app. They collected three weeks of sensor data from 10 users in an empirical study. Next they ran security studies to understand the strengths and weaknesses of the app. This strengthened the app’s safeguards. Finally, to assess how the app works under real life conditions they conducted a three-week user study on 20 users. Ambient Unlocker was born.

The most rewarding moment came when Micallef was analysing the feedback he had collected from his last user study, because this supplied him with the evidence required to prove that this app can actually improve people’s everyday interaction with technology.

Micallef and his team have

discussed how this app could be implemented in our phones. They also plan to have a long-term study of about three months to understand whether using the app over a longer period of time would change users’ perceptions. These discussions are still at an early stage and their feasibility is still being discussed. They are now looking into other uses for the app. He explains, ‘right now, we are

mostly interested in researching how it could be used in different health-related scenarios. One example is to find the right time to remind Type 2 diabetes patients to check for foot ulcers and infections, which, if left untreated, could lead to amputations.’

Apart from this, he is working on a post-stroke exercise rehabilitation app to help stroke survivors remember to exercise frequently. This app can improve the state of post-stroke rehabilitation and plans to evaluate whether it can actually help improve stroke survivors’ arm impairments.

Becoming an expert in improving people’s everyday interactions with technology is Nicholas’s ultimate goal. ‘Eventually, as I start getting more senior positions I expect the focus of my work to shift from implementation and evaluation to designing and defining the overall user experience strategy.’ This means his role will eventually shift from a hands-on role to a more managerial one.

Perhaps one day, we will all be using Micallef’s app to keep thieves at bay or to remind us when to take our medication?

We faced fierce criticism from traditional security researchers because our research was redefining the boundaries of the area that they were not open to

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Malta is rich in culture—that is a fact beyond contention – and whose vast range of cultural activities attract different people with varied interests. But how

does this fit in the context of Valletta being the European Capital of Culture (ECoC) in 2018?

Before delving into the many questions that surround this, one needs to perhaps address what we understand by the term ‘culture’ – are we talking about traditions or art? Cultural participation in Malta is often believed to be low, and a Eurobarometer survey carried out in 2013 confirmed that the Maltese are among the least active participants in culture in Europe. However, culture is not something that can be given a clear-cut definition. The term can refer to anything from art exhibitions to the more popular, traditional festi (feasts). Such feasts are not taken into consideration by many surveys like the Eurobarometer.

The Valletta 2018 Foundation’s research department has therefore embarked on a five-year research process (2015–2019) whereby it aims to understand the factors that affect cultural

participation to create a body of research that will shed light on participation in the sector. The research will help artists, cultural practitioners, and policy makers.

Last year, the Valletta 2018 Foundation conducted the first in a series of surveys that are looking into cultural participation in Valletta. The survey, carried out in collaboration with the National Statistics Office, asked 1,138 respondents about their preferred cultural activity. The top three cultural activities the Maltese public enjoyed were citywide activities such as Notte Bianca, followed by Carnival, and visits to museums and historical sites.

The events took place in Valletta and registered more active participation from residents than from those living outside the city’s walls. Valletta residents are more likely to have attended artistic exhibitions and events when compared to non-Valletta residents (18% vs 12%). People from the island’s Northern Harbour region (the area around Marsamxett Harbour and neighbouring areas) placed second after Valletta residents in their likelihood to have attended some form of cultural event in the capital. On average, 35% of residents from the Northern Harbour region

MALTESE CULTURAL PARTICIPATION:

What do the people want?

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have attended some form of cultural activity in Valletta, compared to an average of 15% from other regions. These statistics give the impression that physical proximity plays an important role in the degree of cultural participation. People commented on the pleasant atmosphere and the sense of unity events created while others said that such events make for a different kind of family outing.

The Maltese people also seem to enjoy the performing arts. Other popular activities include going to the cinema or attending film screenings, artistic exhibitions and events, live music and live theatre events. These are followed by the Valletta parish feasts—more traditional activities tied to the city itself. Dance is not as appreciated as other performing arts disciplines, with a staggering 94% of respondents claiming they had never attended a dance performance. The only other activities less well-attended are passion plays in Easter time (95%

never attended) and the Regatta (96% never attended).

The general consensus of the respondents was that Valletta is a cultural city which is improving in terms of its cultural offerings as well as its image. However, attendance for Valletta’s cultural events is still relatively low with people showing a lack of interest in cultural activities (38% of respondents claimed that they do not attend cultural events as they are simply “not interested”). This statistic is a concern in the light of the fact that Valletta will be capital of culture in just two years. It is the role of the Foundation to use these findings to find new opportunities that can boost cultural participation and encourage engagement with cultural activities. This data can also help other entities and practitioners in the sector.

The Foundation has developed a varied cultural programme, which is open, engaging, and accessible. To complement the aforementioned

Valletta Participation Survey, the Foundation has also carried out an in-depth, qualitative analysis of its cultural programme. This research shows that the Valletta 2018 Cultural Programme not only includes projects related to the visual arts and feasts in Valletta, but also other community projects, aiming to eliminate barriers that prevent cultural participation and that allow for the co-creation of cultural activities and audience development. The study shows how the Foundation is taking a contemporary approach in developing cultural projects, by looking at a long-term development process and aiming for a long-lasting legacy. This research shows how that, to date, the Valletta 2018 Cultural Programme has focused on community and interdisciplinary projects, as well as projects involving music and film.

Both the Valletta Participation Survey and the qualitative analysis of the Valletta 2018 Cultural Programme will continue to be carried out in the coming years. Such studies explore the relationship between the cultural programme and participation countrywide in order for changes in the level of cultural participation in the Maltese Islands can be compared.

The Valletta 2018 Evaluation and Monitoring research process is a five-year project (2015–2019) that is looking into the impacts of Valletta 2018 on the country. The Valletta Participation Survey is a study carried out in collaboration with the NSO that takes place on a biannual basis. The qualitative study, titled ‘A Comprehensive Analysis of the Valletta 2018 Cultural Programme’ is being carried out by Daniela Blagojevic Vella.

REASONS FOR ATTENDING CULTURAL ACTIVITIES*

Nice atmosphere and unity

Other

Different outing for the whole family

National pride/tradition

Well-organised

Enjoy arts and culture

Don't know (2.5%)

42.2%

18.8%

16.9%

8.2%

6.5%

5%

* Graph taken from the Valletta Participation Survey

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The State of AfricaMARTIN MEREDITH

by Dr Jurgen GattBOOK REVIEW

Let me start this book review with a prediction. As your eyes ran over the title of this page

just a few seconds ago, a flurry of thoughts and images raced through your mind: hunger, illness, HIV/AIDS, Boko Haram, migrants, elephants, gazelles, and lions, slavery, Joseph Conrad’s novel about the horrors of the Belgian Congo, Heart of Darkness. These images, I argue, are about as representative of Africa as the moustache and the baguette are of France. While clichés might hold an element of truth, they surely reflect a profound unfamiliarity with France if one thinks only of these caricatures. The state of our ignorance about Africa—a continent of some 30 million square kilometers that houses well over a billion people—is immeasurably worse.

Martin Meredith’s excellent book The State of Africa has an easy-to-read style and a fast pace, and it attempts to remedy this all-too-common deficiency in our understanding of the continent. The book reviews the history of some 70 years of African history. Starting with the first uneasy and bloody stumbling steps toward decolonisation, the work chronicles the first experiments with one-state African socialism, the burgeoning

private coffers of corrupt officials, and the tyrants who replaced them. Finally, the book leads to an unbiased account of the emergence of Africa onto the world stage and discusses the various problems which still plague most of its countries.

The State of Africa is at its most enjoyable in its stark portrayal of the characters of the early African liberation movement. The image of Senghor—a poet cum politician of Senegal—is particularly powerful. The author does not shirk from recounting, often in great and painful detail, the ensuing downfall of most of Africa’s early heroes as they assumed political power. The account is highly selective. Yet, in a series of powerful stories and stark images, the book effectively conveys—in just over 700 pages—exactly what its title promises: a picture of the current state of the African continent and enough historical depth for one to conceive how it came about.

This book fulfils an important function. As the vast continent struggles to find its footing, the nations of Africa are gaining greater relevance in our ever-shrinking world. The North’s ignorance of its southerly neighbours has for too long been lamentable. Now it is becoming inexcusable.

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A n artist often works to break down the boundaries of a medium.

The artist’s only tools are personal vision, an unrelenting belief in their work, and the need to convey it to an audience. Then again, an artist must also understand that the shock-value of their work might not only lie in the artistic content but in the manner in which they technically attempt to rewrite the rules, regulating their mode of expression. Today’s cinema is focused on the spectacular, from the competitive use of special effects to weak plots meant for sheer entertainment. And yet, the cinematic medium has so much more to offer and to express.

Following on from Tree of Life (2011; winner of the Palme d’Or Cannes Film Festival), and To the Wonder (2012), director Terrence Malick’s recent Knight of Cups is a portrait of Rick (played by Christian Bale), a scriptwriter in Los Angeles. Malick continues his artistic discourse by progressively breaking down all of cinema’s constitutive elements that audiences are used to, thanks to most Hollywood movies: is it possible to produce a long feature

shorn almost entirely of dialogue, which progresses only through voice-overs? Is it possible to deliver a love story exclusively through its poetic spirit, providing the illusion that the camera possesses a life of its own by allowing it to flow freely around the characters? Is it possible for cinema to draw a bridge between the intimate microcosm of a particular man and the impersonal macrocosm of the collective? Is it possible for cinema to still ponder upon existential notions such as reality, freedom, destiny, religion, and astrology?

Malick is one of the few contemporary directors who willingly leads the audience down this unbeaten track. Impressively, Malick enlisted big-budget actors like Bale (in a role that is in diametric opposition to his ‘Dark knight’), Cate Blanchett, and Natalie Portman. The movie includes cameos by Antonio Banderas and Joe Manganiello. This is a movie about Hollywood, with a cast list of Hollywood A-stars, which seeks to corrupt the very world it seeks to portray and inhabit. Malick famously

worked without even providing a script, allowing the actors to play themselves in some of the scenes.

The result is an expressionistic and highly self-reflexive portrait of a decadent character inhabiting a decadent world. Rick reads like a character penned by Bret Easton Ellis, whose Patrick Bateman was also portrayed by Bale in Mary Harron’s filmic adaptation of American Psycho (2000). More than Sorrentino in his La Grande Bellezza, Malick is here clearly concerned with how even intimate emotions can be misleading. His character Rick craves love and yet is destined to emerge, solitary and broken, from all his relationships. Rick treats his own life as a movie script, merely seeking from his love interests a temporary element of drama that might set the ball rolling for something more meaningful, which never manifests itself. Love appears and disappears, randomly, uncontrollably. In both form and content Malick clearly tells us that this is the life of the working artist—damned, romantic, aestheticised, and yet excruciatingly beautiful.

by Dr Philip M. MagriFILM REVIEW

Knight of CupsYear of release: 2015

Director: Terrence MalickProduction company: Dogwood Films, Waypoint Entertainment Certification: 18

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Overcoming the ‘limits’ of movies and books through digital media remains a daunting

task. After all, traditional media is perfectly fine at narration. Her Story is a brilliant example of what digital games can bring to the table.

The game revolves around a murder and the player is the detective. The case has recently been re-opened and the player is left examining old VCR tapes containing snippets of interviews with a single person. During this solitary, meditative

experience the player’s search for the truth is guided by database queries. The player will feel uncomfortable as they become more and more eager to explore a disturbing past. Only by letting curiosity get the better of them can the detective put the pieces back together.

Her Story uses a minimalistic interface, hiding its mechanics under a masterfully crafted visual presentation. At the same time, the game mixes narrative techniques borrowed from movies and TV series. It is reminiscent of forgotten laser disc games, or clunky interactive novels from the 1990s. Somehow, the interactive game blends everything together in a unique masterpiece. For decades, digital storytelling remained a chimera; Her Story might very well be the medium’s most accomplished realisation.

www.herstorygame.com

by Costantino OlivaGAME REVIEW

HER STORY Platforms: PC, Mac, iOSDeveloper: Sam Barlow

EveMalta evemalta @evemalta

Your daily sin!

Only by letting curiosity get the better of them can the detective put the pieces back together

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Malta Playing Arts

by David ChircopGAME REVIEW

It would be easy to dismiss this nifty card game as a simple tourist

souvenir, but a closer look reveals a somewhat deeper meaning than a mere deck of Maltese Playing Cards.

Reviewing this set of cards is outside my immediate comfort zone. I spend so much time thinking about mechanics, group dynamics, table talk, design, and replayability of games, that when presented with something that cannot really be critiqued for any of those game dynamics, I stumble. Truth is, there is no game here. There is a tool for a game, the motives of which aren’t really related to games at all. The ‘game’ part of this product is used more as a vehicle to deliver an ideal, a message, and a story.

At their core, the Malta Playing Cards are just a set of playing cards. Their particular characteristic is that each single card features a unique piece of art from a local artist, and each one has some sort of connection to Maltese history or culture. That in itself is already a great idea but the card makers didn’t stop there: the deck comes with a small booklet called Walkthrough and Compendium. The booklet shows how every single card was thoughtfully and meticulously matched with the artwork. The cards tell a story. They are riddled with connections to one another, one linking

to the next like an intricate hyperlinked web. By the time I had reached the the end of the booklet, I felt like I had gone through some sort of hybrid between a curated gallery and guided walkthrough of Maltese culture. One is free to walk wherever they like, and the deeper one digs the more connections are uncovered.

Now, I must retract what I said about this pack of cards not being a game. I was wrong. Few other ‘games’, especially tabletop ones, have so rewarded my curiosity and desire to explore. Of course, the ‘game’ can be read once and then it is over, but then the cards can be reused for any other game you would like to play, and whenever you do, the images on the cards have all now been imbued with meaning. They act as reminders of the little journey you experienced when you went through the deck in one hand, and the booklet in the other, discovering a beautiful story.

One final note, the cards are premium plastic. Not paper, which is awesome. I highly recommend Malta Playing Arts.

See the artworks at Malta Playing Arts: The Exhibition curated by Marika Azzopardi, Palazzo Ferreria, 310, Republic St, Valletta, 18–29 April (Mon–Fri, 0830–1630hrs).

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Let us strengthen Malta’s democratic system by thinking critically. We need to learn how to avoid blindly accepting or rejecting ideas and opinion

based on our political affiliations or unquestioned, long-held beliefs. Let us actively go against the dualistic thinking that dominates local public

debate. Let us, for example, phase out media outlets financed by political parties; amend the constitution

to facilitate the entry of a third political party to parliament; and put critical thinking at the centre of our educational system by strengthening subjects

that enhance it (literary and rhetorical analysis, logic, philosophy and the scientific method).

MY 100 WORD IDEA TO CHANGE MALTAThink Critically, think Malta

Dr Mario Aquilina

Don't THINK by Ġorġ Mallia

The answer is coffee. Coffee is drunk by around 80% of Americans. The large numbers call for extensive studies

on the effect of this drug on the brain. Caffeine is a stimulant. It has a similar molecular structure

to adenosine, a chemical linked to us feeling tired. Caffeine binds to adenosine and stops it from working. Coffee does not wake you up but makes your body forget it is tired.

Taking that espresso in the morning makes your body increase the number of receptors to caffeine in the brain. This increase makes us dependent on that cup of coffee in the morning to reach normal functional levels. On the other hand, cannabis has minimal risk of long-term addiction.

Read more about cannabis on pg. 38 Send in your science questions to think@um.edu.mt

WHAT IS MORE ADDICTIVE: CANNABIS OR COFFEE?Alexander Hili

MEMECULTURE GENES

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