Iceland (population: 320,000) is proud of writer Halldor Laxness; the even smaller Faroe Islands (pop: 50,000) celebrates its physician and scientist Niels Ryberg Finsen.The combined population of these countries is smaller than Malta’s, yet they have each managed to secure Nobel Laureates: Laxness in Literature in 1955; Finsen in Medicine in 1903. Small size may be a handicap, but—as the Iceland and Faroe examples attest—it is not an insurmountable obstacle. Small size should not prove to be a cheap excuse. So the question is: can Malta produce a Nobel Laureate?
Thinking big can be a powerful motivator. Grand ideas can push publics, enterprises, and governments to achieve the unthinkable. Believe in the impossible, advised the historian Max Weber, and then the possible might just become true. Landing a man on the moon before the end of the decade inspired the US Space Programme in the 1960s. The Live Aid Concerts in 1985 delivered £150 million in famine relief. And the One Laptop Per Child (OLPC) Initiative has equipped 2.5 million children, and counting, across the world.
Malta needs ‘think big’ projects to galvanise the nation. Securing a Nobel Laureate could be one. Developing an underground subway system (and linking Malta to Gozo in the process) could be another. Such projects need not be mutually exclusive. Their trademark would be their ability to engage public opinion, foster national pride, and raise the game to the next level. Naturally, people will continue to talk about politics, the weather, the traffic, the guy or gal next door… but also about these grand accomplishments. Of course, these projects will be controversial; they will have as many sympathisers as dissenters and critics. So? What’s new? That is how it should be.
Securing our political independence was one such dream for the 1960s. Bringing an end to our fortress economy was another aspiration for the 1970s. Joining the European Union was a third. Valletta Capital of Culture for 2018 may be a fourth and is an active project. What’s cooking in the Kitchen of Big and Bold Ideas for Malta for the next few years?
We need to think ahead. Apathy is dangerous, and we need big ideas to keep it at bay.
By the way, St Lucia (population: 150,000) has not one, but two Nobel Laureates: Arthur Lewis for Economics in 1979 and Derek Walcott (born in 1930, still alive at the time of writing) for Literature in 1992.
It was a cold and grey February afternoon. Snowflakes were pelting the dreaming spires of Oxford. This gloomy weather did nothing to impede the warmth and buzz exuding from the laboratories crammed in the iconic Sherrington building. Less than a century earlier, this labyrinthine edifice was the habitat of Sir Charles Sherrington whose experiments shaped our understanding of the ‘synapse’ or the minute gaps between one brain cell (neuron) and another. The Sherrington building (part of the Department of Physiology, Anatomy, and Genetics at Oxford University) has undergone several expansions over the years. In its newest wing, nowadays it houses the research group of Dr Ji-Long Liu, a rising star in the field of genetics and cell biology.
For me, this was no ordinary afternoon. Together with Liu’s lab teammates, I was perched on a stereomicroscope whilst holding a delicate brush in my hands. On one side was a tray jammed with vials populated with fruit flies and the usual good strong cuppa. Fruit flies are no house flies: each adult fly is only a few millimetres long, their beautiful bodies are pale with black zebra-like stripes and their eyes a bright apple-red colour. I grabbed a vial, fired a puff of carbon dioxide gas through its fluffy plug and then firmly rapped the upended vial to shake its sleepy occupants onto an illuminated pad. I took a deep breath before peering at them through the eyepieces.
At the time, I was more than mid-way through my doctoral studies, and the results of my experiments were far from extraordinary. I was researching the most common genetic killer of human infants, a neuromuscular degenerative disease known as spinal muscular atrophy or SMA in short. I was exploiting the tiny fruit fly to gain new insight into this catastrophic disease.
I decided to up my efforts by generating a series of mutants or faults in Gemin3, the gene that I was investigating. I was targeting these mutants to different organs such as brain, muscle, or gut. The results of this screen were due today. With a few flicks, I deftly flipped and sorted the minuscule fly bodies into neat piles taking note of differences that are invisible to the untrained eye. The mutants did not produce any dramatic effect. Damn! Another experiment down the drain! Frustrated by the result, I mistakenly knocked over a vial, dislodging its plug. Usually, released flies would happily escape by flying. Strangely, my flies were jumping as if attempting flight but just couldn’t make it into the air — an unexpected but interesting trait or phenotype. I checked the tag on the vial. In these flies the mutant was targeted to that part of the body that powers movement, the so-called ‘motor unit’. Following that afternoon, which will remain forever etched in my memory, the results just flowed in and a few months down the line I would find myself donning my subfusc (Oxford-speak for academic dress) to defend my doctorate.
The rise to biological stardom for the fruit fly, scientifically known as Drosophila melanogaster, began in 1907 when my great-great-grandfather (by academic lineage) Thomas Hunt Morgan adopted this organism to understand heredity or genetics. Morgan was the first to harness the major advantages of working with this organism: they have an insatiable sexual appetite and a speedy development (only 10 days) from embryo to adult. This means that large-scale experiments are doable in record time. Morgan’s infamous ‘Fly Room’ at Columbia University in New York set the stage for a new ‘religion’ practiced and preached across the globe.
Morgan spent years searching unsuccessfully for flies with clear, heritable differences so that he could investigate how they are inherited. A breakthrough happened in April 1910 when he discovered his first mutant, a white-eyed male fly amongst many red-eyed flies. Morgan took great care of this special fly: he kept it in a bottle and after a day’s lab work he used to take it home! At the same time his wife Lilian, who also became a famous geneticist, gave birth to a child. And such was the excitement surrounding Morgan’s discovery that on his first visit to the hospital, Morgan’s wife said: ‘How’s the fly?’ To which, Morgan replied: ‘How’s the baby?’.
When the white-eyed fly was bred or crossed with a virgin red-eyed female, their offspring were all red-eyed. When sisters and brothers were crossed, half of the male progeny gained back their white-eye colour. This hereditary pattern is typical for a sex-linked (recessive) variation, since the gene for eye colour in Drosophila, named by Morgan as the white gene, is on the X chromosome which determines sex. Similar to us, male flies are XY whereas females are XX. This key experiment and numerous others that followed expanded on the knowledge gained through the ingenious cross-breeding experiments of pea plants by the Austrian monk Gregor Mendel half a century earlier. Importantly, this fly-based work found that characteristics like eye colour are inherited from parents through chromosomes — large structures which package DNA in our cells. Furthermore, Morgan and his gifted students uncovered that the thousands of genes in our genome are arranged along chromosomes in a precise order, like beads in a necklace. Each gene can be identified by its specific location on a chromosome.
“Flies could be used as models of human disease”
In 1933, Morgan won the Nobel Prize for these great discoveries. The first of six awards was to recognise seminal insights into our biology through this tiny fly. Hence, in 1946 one of Morgan’s protégés, Hermann Muller, was recognised for his fly research demonstrating that X-rays can damage chromosomes. Then in 1995, Ed Lewis, Christiane Nüsslein-Volhard, and Eric Wieschaus shared the Nobel Prize for their herculean efforts in discovering the genes that controlled early development in Drosophila. In the embryo, waves of master genes are triggered that lead to eyes, brains, and the body’s patterning. Similar genes were later found in humans doing the same function. In 2011 Jules Hoffman received the Nobel Prize for finding how the body’s inbuilt immunity works through the use of the fly model organism. I suspect that there is still room for more trophies in the fly triumph cabinet.
At the dawn of this century, the genomics revolution led to the complete DNA sequencing of an organism including fly and human. These monumental projects revealed that an astonishing number (more than two-thirds) of human genes involved in disease have counterparts in the fly. This development meant that flies could be used as models of human disease. It sparked off a renaissance of Drosophila research. The fly was good at modelling neuro-degenerative conditions because their nervous system has stunning similarities to ours. Neuro-degenerative diseases including Alzheimer’s, Parkinson’s, Huntington’s, and Motor Neuron Disease occur when neurons in the brain and spinal cord begin to die slowly. Patients may lose their ability to function independently or think clearly. Symptoms progressively worsen and ultimately, many die. Most neuro-degenerative diseases strike later in life, so we should expect their frequency to soar as our population ages — Alzheimer’s disease may triple in the US alone by 2050.
Malta: the right time to fly?
Together with my students in my lab at the University of Malta I am working with flies to learn more about neuro-degenerative disease. We continue to focus on SMA, a genetic disorder arising from the deterioration of motor neurons which are nerves that communicate with and control voluntary muscles. As the motor neurons die, the muscles weaken with drastic effect on the walking, crawling, breathing, swallowing, and head and neck control of unfortunate children afflicted by this condition. The child’s intellectual capacity is unaffected but vulnerability to pneumonia and respiratory failure means that many patients die a few years after diagnosis.
The underlying cause of SMA is usually a gene flaw that results in low levels of a protein called SMN for survival of motor neurons. Inside cells, SMN is bound to other proteins called Gemins. The SMN-Gemins alliance is involved in building the spliceosome, which is the chief editor of messenger RNA molecules. Messenger RNA carry the DNA code that instruct cells how to fabricate proteins. If SMN is absent spliceosomes do not form, correctly-edited messenger RNA are not produced and protein synthesis is heavily disrupted — the cell should shut down. Spliceosomes are required in each of the 120 trillion cells forming our body. Yet, in the disease SMA only motor neurons die. The reason has baffled researchers for decades and remains unsolved.
Is it possible that SMN has another function in motor neurons? And does it act alone? Our flies were crucial in providing some answers to these questions. Our work showed how the SMN-Gemins family is tightly-knit. In this regard, we recently demonstrated that both SMN and Gemins can be detected in prominent spherical specks in different cellular compartments. Within the cytoplasm, these organelles are known as U bodies because they probably are the factories of spliceosome components, which themselves are rich in the chemical Uridine. In the nucleus, the structures containing the SMN-Gemins family hug the mysterious Cajal bodies — discovered over a century ago by Spanish Nobel laureate Santiago Ramón y Cajal.
“We are feeding these flies the Mediterranean diet derivatives to see whether Alzheimer’s can be stopped in flies, which will bring us one step closer to treating it in humans”
And what about the flightless flies? Think about it. Considering that SMA is a neuromuscular disease, it makes perfect sense that on loss of SMN, muscles become so weak that flies are unable to flap their tiny wings fast enough to fly. Our latest work reveals that flightlessness is seen in flies without enough Gemin proteins. This means that SMN does not function alone but hand in hand with the Gemins. Our next step was to find out the pathway connecting the SMN-Gemins family to the motor defects. We linked the Gemin mutant which did not work properly to a tag called green fluorescent protein or GFP. GFP glows under the right light in cells. We managed to create genetically-modified flies with this modified gene — a first for Malta and a powerful tool to solve the mysteries of this disease.
Fluorescent proteins let researchers figure out a protein’s location. And by knowing the location of proteins we gain of lot of information about what they do. Consider this analogy with a VIP. If we tagged the Prime Minister of Malta we would find that he is most probably found in Valletta most time of the year. If we were aliens from another planet, this knowledge would allow us to refine our understanding of the Prime Minister’s function. Therefore, we can eliminate a function in the entertainment industry (weak signal from Paceville) but we cannot exclude a function in government (strong signal from Valletta). Likewise, we found that our GFP-Gemin mutant is mostly found in the cell’s nucleus. The nucleus houses life’s instruction manual: DNA. Our work now needs to zero in on the other proteins the SMN-Gemins family works with in the nucleus. Doing so will open new therapies to halt neuro-degeneration in children. Back to our analogy, we need to zoom in on Valletta until Auberge de Castille, the Prime Minister’s office, is clearly in focus.
Several neuro-degenerative diseases occur because of sticky protein clumps that wreak havoc inside, and outside, neurons. This is typical in Alzheimer’s disease, Parkinson’s disease and Motor Neuron Disease. With Dr Neville Vassallo’s research group, and local industry (Institute of Cellular Pharmacology), we are testing chemical derivatives of the Mediterranean diet and flora on fruit flies to see whether they can curb the protein clumps’ toxicity. They definitely do in a test tube. Flies mutated to be remarkably similar to human Alzheimer’s lose their ability to climb up the sides of their vial habitats and die prematurely because of neuro-degeneration. We are feeding these flies the Mediterranean diet derivatives to see whether Alzheimer’s can be stopped in flies, which will bring us one step closer to treating it in humans.
Through flies we have understood human biology. Apart from choosing Mr and Mrs Right, a good geneticist must learn to focus and listen to what flies are really saying. This is easier said than done but achievable. Flies have spurred me to pursue unexpected but interesting paths. In the years to come I, together with my students, will continue to flip, sort, screen and tag, looking for fly mutants who will continue to teach us about ourselves. And yes, we will be all ears!
The author is indebted to colleagues at the UoM and worldwide for their constant support and inspiration. The research of Dr Ruben Cauchi (Department of Physiology & Biochemistry, UoM) is funded by the Faculty of Medicine and Surgery, the University of Malta Research Fund and the Malta Council for Science & Technology (MCST) through the National R&I Programme 2012 (Project R&I-2012-066). For more about Dr Cauchi’s research click here.
People do not always act rationally. They overeat, overspend, and find it difficult to plan for the future. THINK met Prof. Liam Delaney to talk about how a new branch of economics might solve the pension crises, the obesity epidemic, the financial situation, help science, and make us feel better. Words by Edward Duca
We experience gravity everyday, but how it works is one of the biggest questions in physics. Einstein’s theory of relativity means that we don’t understand over 90% of the Universe. A team at the University of Malta is trying to put that in order.
I do not know what I may appear to the world, but to myself I seem to have been only like a boy playing on the seashore’, said the famous Isaac Newton. Humanity has progressed in its search for answers by always searching for the next smooth pebble, the next pretty shell. In Malta, a small group of students is trying to understand gravity through the observation of stars and galaxies that light up the night sky.
Gravity has kept our feet on the ground since we started walking upright. Early theories by the Greek philosopher Aristotle (384–322 bc) were interesting but far from the truth. His Universe was built in concentric spheres with Earth at the centre, followed by water, air, fire, and enclosed by the heavens — a rock fell to the Earth because it wanted to go to its original sphere. Clearly, he was wrong.
Aristotle’s concepts were challenged during the Renaissance when the Italian Galileo Galilei (1564–1642 ad) infamously dropped different weights from the tower of Pisa. Contrary to the Greek theory which stated that the heavier an object is, the faster it falls, Galileo saw the objects all fall at the same rate. Theories need to match observations, otherwise they fail — an invaluable technique used time and again by any decent scientist including the Malta group of astrophysicists led by Dr Kris Zarb Adami.
“Space is a dynamic entity ‘moving forward in time, the two being bound by light itself”
The first person to suggest a good theory for why rocks fall was Isaac Newton (1643–1727 ad). As the story goes, watching an apple fall triggered Sir Isaac Newton to come up with his theory of bodies. He said that anything with mass had a force that attracted everything towards it — the bigger the mass, the bigger the force. Since the apple is smaller than the Earth, it falls towards it, and since the Earth is smaller than the Sun, the Earth goes around the Sun. Newton’s law was successfully used to predict the motion of planets and helped discover Neptune.
By the 20th century, holes in Newton’s ideas started to appear when scientists discovered that Mercury’s orbit differed slightly from Newtonian predictions. In 1915, along came Einstein (1879–1955 ad) who again revolutionised our understanding of gravity through the introduction of his theory of general relativity. Newton had considered time and our three-dimensional space to be independent. Einstein replaced this with the notion of spacetime, which combines space and time into one continuous surface. Space is a dynamic entity ‘moving forward’ in time, the two being bound by light itself.
Large objects like the Sun bend the fabric of spacetime (it is convenient to think of spacetime as a sheet of fabric with balls lying on top of it — bigger balls curve the fabric more). Smaller objects (such as the Earth) try to follow the shortest route around the Sun. The shortest way is curved and it is easy to see how this comes about.
Consider the shortest route from the North Pole to the South Pole, you would naturally move down a curved longitude, which forms part of a circle round the Earth. This concept also explains why the Earth traces an orbit round the Sun. The orbit is the ‘best straight line’ that Earth can trace
in the curved spacetime surrounding the Sun. As John Archibald Wheeler neatly summarises it: ‘Spacetime tells matter how to move, matter tells spacetime how to curve’.
Einstein’s biggest blunder
Einstein’s theory of general relativity describes how gravity works. Einstein wanted his equations to represent a static Universe that did not change with time. To this end, he introduced a factor called the cosmological constant that would bring the Universe to a halt. However, this idea was short-lived. Another great (though highly egotistical) physicist called Edwin Hubble discovered that the Universe was expanding; this was confirmed in the late nineties and led to a Nobel Prize in 2011. It not only means that all matter will eventually disperse throughout the Universe and future generations will see only a blank night sky, but also poses a problem in that the reason for this expansion is completely unknown and unpredicted from Einstein’s theory. And it is not a small factor at all, since this mysterious energy makes up 68% of the energy in the Universe. Nicknamed ‘dark energy’ because it is unseen, this is the biggest problem in modern astrophysics and cosmology.
“If a star’s light is being bent by a galaxy, from Earth it will appear that the star’s light has changed, when in reality it would not have changed at all”
Scientists either have to accept that dark energy is true, or that Einstein’s model has met its limits and physics needs a new way to model gravity, at least on the largest of scales. The Malta astrophysics group is trying to verify and find new models of gravity — these so-called alternative theories of gravity. The idea is to compare observations to the different gravitational theories, including Einstein’s, and see which works best.
Our focus is split two-ways: one is the effect that celestial bodies have on each other’s orbital motion and the other is the bending of light around heavenly bodies. For example, our sun bends spacetime, causing the planets to go round it in ellipses. The sun also wobbles around a very small orbit. Observations show that the orbiting objects go round a bit longer than we would expect. The extra amount is miniscule, so measurements are taken after many orbits as this magnifies the effect. We use this as a possible test to disqualify alternative theories and have already shown how an important alternative theory of gravity cannot be true.
This is how fundamental science works. If a model does not match observations it needs to be modified to arrive at something that does give all the predictions we require. The end result must be a complete theory by itself but the different components could find their birth in a wide variety of unconnected sources.
The Malta astrophysics group considered a theory called conformal Weyl gravity that is similar to general relativity in every respect except one. This theory behaves exactly like Einstein’s but imposes a further constraint — mainly that the gravitational field remains the same no matter how much it is stretched or squeezed. Simply put, as long as the mass remains the same, gravity does not change. This assumption solves many problems. It makes dark matter and dark energy unnecessary. Dark matter is needed to explain the motion of stars in galaxies. Like dark energy, it is called dark because it cannot be seen or analysed in any way. Making them irrelevant would fill a gaping hole of knowledge for astrophysics.
When the group tested the Weyl theory, it gave the same result as general relativity and a small additional term. That was not a problem, since effects of this term were so small that they could not be observed with today’s largest telescopes. The problem, as shown by the Maltese astrophysics group, is that the term grows larger with distance and contradicts observations at the largest galactic scales. This was an important nail in the coffin for the Weyl theory of gravity and Einstein’s theory still remains the best model.
Our next step is to test other alternative theories of gravity by analysing how objects orbit each other. In the same way we disproved conformal Weyl gravity, we hope that these tests will help astrophysicists to eventually come closer to a model that correctly explains the cosmos.
Gravitational Lensing is perhaps the most sensitive test of gravity on cosmological scales. To understand how it works, consider a lit candle and a wine glass. Imagine holding the wine glass and peering at the candle through the glass’ base. The flame will be distorted and changes shape. Now picture you are with a friend who stands a couple feet by your side. The flame will appear normal to them since they are seeing it from a different perspective and the light does not pass through the glass. Two people with a different point of view see different flame shapes. The wine glass’ base distorts the flame because it acts like a lens changing the direction light travels. Obviously in the Universe there are no wine glasses between the stars and the Earth but objects with huge masses like our sun or galaxies can act like a lens and bend the direction of light by the sheer force of gravity.
When there is no mass to affect it, light travels in straight lines, but insert a massive object and hey presto, the light deflects around it as if it were going through a curved glass lens. The area in which an object feels the gravitational pull of the Earth is called the Earth’s gravitational field. Each object in the Universe has a gravitational field and can therefore pull other objects towards it — like the Earth’s effect on the Moon, which keeps it in orbit.
Anything that enters an object’s gravitational field will feel a gravitational pull towards the center of the object. Imagine a ray of light traveling from a point to another with nothing in between. In this case the ray will travel in a straight line. Nevertheless, if the ray meets with an object along its way to the Earth, the object will pull the ray towards it as a consequence of the object’s gravity. Even though the ray of light will try to keep moving in a straight line, the gravity of the object is so strong that it bends the ray’s path. If a star’s light is being bent by a galaxy, from Earth it will appear that its light has changed, when in reality it would not have changed at all. This effect is called Gravitational Lensing and is currently one of the best tests for alternative theories of gravity, since one can measure the deflection of light and check whether it agrees with the theoretical predictions.
Extreme situations like the bending of light by galaxies cause problems for Einstein’s theory. When summing up the masses of the galaxies, we obtain the mass of the objects that are visible in the cluster. Comparing the predicted light deflection with the observed one, astronomers consistently find that the light is bent ‘more’ than is expected. The way to solve this issue is obvious. Introduce a completely invisible mass that increases the amount of bending until the predictions fit the observation: enter dark matter!
The idea of dark matter emerged a while ago. In 1933, Swiss astronomer Fritz Zwicky suggested it when studying how a galaxy rotation changes as one goes further away from the galaxy’s center. Zwicky observed that the speed or velocities predicted by Einstein’s theory should tear the galaxy apart. In reality, something must be keeping it whole. The idea of an invisible substance called dark matter was born.
Dark matter keeps the Universe together by opposing dark energy that pushes the Universe apart. Dark energy is related to the cosmological constant, previously discarded as Einstein’s biggest blunder, now reintroduced in astrophysicists’ equations to explain the accelerated expansion of the Universe.
The problem with dark matter is that it has never been seen. There is only indirect proof of its possible existence. Deandra Cutajar’s work focused on testing theories where no dark matter is needed. If true, this would put a small spanner into Einstein’s equations.
She tested two theories. They passed the first tests, but they have to pass many more to unseat Einstein’s general Relativity. Going back to the Swiss astronomer Zwicky, the two theories could explain why galaxies are not ripped apart by the speed with which they spin. Dark matter could be dead.
In another test, both theories failed to explain the extra gravitational effect observed in lensing. One theory failed miserably, while the other yielded less accurate results than Einstein’s general relativity. Dark matter is reborn; on the other hand, it cannot remain dark. It needs to be found and studied.
No theory of gravity has yet been found to beat Einstein’s equations. The explanation of how gravity works according to Einstein is better than Newton’s. A curved spacetime clearly explains why light is bent. Einstein’s theory of gravity still holds water and apart from the cosmological constant (his biggest blunder), he was right on most things. When his stunning prediction of how light can bend was observed, he replied, ‘I knew the theory was correct. Did you doubt it?’
What the future holds for any theory of gravity is uncertain, but what is definitely true is that the astrophysics group in Malta cannot accept the fact that we don’t understand 95% of the universe.