The circles of life

Disease and treatment 28. mar 2018 10 min Centerleder, professor Jørgen Kjems Written by Morten Busch

The circles of life: birth and childhood; adulthood and reproduction; then old age and death. By day and by season; tide and tempest. People’s cells are also propelled by this regularity. Our genes – DNA – is transcribed to RNA, which in turn is converted to proteins, the building blocks of life, before again being broken down and reused in a new cycle.

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Jørgen Kjems, the recipient of this year’s Novo Nordisk Prize, has often been accused of deviating from the research cycle. Instead of focusing on one topic throughout his career, he has constantly sought out new avenues – despite being part of discovering, early in his career, an important deviation in the life cycle of cells: more than 90% of the RNA cells produce is never converted to protein. Instead, it is a key to how our body regulates itself and presumably also why humans have been so successful as a species.

“Looking, for example, at a worm and a person, both have approximately the same number of genes and the same amount of DNA. Actually, a tomato and a carp have much more DNA than a person. It is not DNA that is so important. However, if you look at how RNA is produced, then you see the complexity of a human being, and this is why our brains are so incredibly complex.”

DNA as a fad

Curiosity not only almost cost Jørgen Kjems his career – but also his life. Already as a child he wanted to take everything apart and then reassemble the bits. Very early in childhood, he made drawings of how a car is assembled and how the mechanism makes it run. It was not just LEGO and Mechanics that he dismantled and reassembled into cars and houses, for example.

“It was a bit dangerous every once in a while. One episode I can remember was sticking my fingers into the TV and getting a high-voltage shock. So my days could well have been numbered early in my career because I always want to see how things are put together and how they work. And by understanding that, you can also build new things and create structures that can help people some day.”

Initially, Jørgen Kjems wanted to become a chemist or a physicist, but during his university studies he started to realize that body is in essence really just a large machine – comprising small components that are actually quite similar to the construction of a car.

“But it is as if nature has many more structures and large molecules, many more strings to play on. Soon, my goal was to try to understand them, so I began to study molecules in nature, and it seemed natural to take account of the hot topic in the mid-1980s – DNA and how its biological cousin, RNA, is translated into proteins.”

Living at 100°C in volcanic hot springs

At that time, Jørgen Kjems therefore focused on the key dogma process that explains how DNA is decoded and copied to RNA and how it then is then finally converted to protein.

“I began to carry out my MSc project on the structure of ribosomal RNA which at those days was considered to be the skeleton of the ribosome, the machine making the proteins in the cell

Based on his technical interest, Jørgen Kjems became interested in understanding the mechanism, but while he was investigating ribosomes, something else grabbed his attention. At that time, a whole new kingdom of organisms had been discovered.

“We studied ribosomes in the Archaea microorganisms (single-cell prokaryotes similar to bacteria) living in volcanic hot springs at 100°C. What motivated me right from the start was simply understanding how such a mechanism can function at this temperature. In the midst of my studies, it was like being struck by lightning, which often happens in research when something new crops up while investigating something completely different.”

95% waste

What Jørgen Kjems discovered was that the RNA of Archaea contains large fragments that are removed after RNA has been made in a process termed RNA splicing. At that time, this phenomenon was only known in humans and higher organisms. Kjems could now see that this also occurred in hot spring Archaea and similar organisms. This was a completely new discovery and, fittingly, the article was published in Nature, one of the world’s most prestigious journals.

“At that time, it was also thought that all RNA molecules were linear, but the spliced out RNA in these Archaea organisms were actually circular. This was a very unusual observation, and researchers had only been able to see something similar before in some special viruses, so this was also one element of a major discovery.”

The discovery kick-started Jørgen Kjems’ RNA research career. At the beginning, researchers believed that the RNA that had been cleaved out was waste that had been jettisoned while the rest had been turned into useful information for protein production in the cell. However, on further investigation, it was discovered that most of the RNA produced in the cell had no apparent function.

“This process actually removed almost 97% of the RNA. At that time, it was not really understood: why do we have so much extra RNA. Why is our genome so large if we only use 3–4% of it? It was not until the late 1980s and the early 1990s that it began to dawn on people that this RNA must have some function.”

HIV hides

In 1989, it was time for Jorgen Kjems to take the RNA a step further. After completing his PhD project, he wanted to go abroad as a postdoctoral fellow. He moved first to Harvard Medical School and later to Massachusetts Institute of Technology (MIT), working in the laboratory of Philip A. Sharp, who later received a Nobel Prize for his discovery of RNA splicing.

“It was actually an incredibly fascinating time. It was like the peak of one’s scientific career to have the opportunity to work alongside such a genius. I had worked with Archaea microorganisms but suddenly I was working on the human immunodeficiency virus (HIV), although the processes were more or less the same.”

HIV has a very simple genome comprising a small RNA that does not code for very much by itself. But then something amazing happens. The RNA is cleaved into pieces and reassembled in different ways and suddenly more than 60 proteins can be made from one small RNA, thus proving that many things can be made from one extremely small piece of information material.

“For a virus to thrive, it must not take too much RNA along, but it must still be capable of making a complex expression in the host. HIV can suddenly produce more than 60 different proteins by splicing one small RNA. Human cells therefore have difficulty finding out what the virus is doing. It is only when it starts to produce new virus that it first signals its presence to our immune system. Then it is too late because the virus has spread around the body.”

Microscopic medicine

When Jørgen Kjems returned from MIT to Denmark in 1992, he continued to study the processes surrounding the intricate RNA splicing system of HIV. However, before long, a completely new phenomenon appeared – actually a phenomenon that had been partly discovered by his former mentor at MIT, Philip A. Sharp.

“I also got a head start on this when I heard from my old laboratory that something new was about to happen. This new phenomenon is called RNA interference, which is what happens when cells produce some tiny RNA that can regulate all the other RNA. It turns out that this tiny regulator has an incredibly important function.”

Researchers called this tiny regulator microRNA, and it soon became apparent that it plays an essential role in regulating cellular metabolism and gene expression. MicroRNA can bind to other RNA molecules that the cell uses as a template when it needs to produce protein. The production of specific proteins is in this way arrested.

“We soon discovered that microRNAs have such a major effect on various diseases, so we quickly began to think about drugs, because if we could deliver these tiny microRNAs or inhibitors of microRNA into cells and thereby treat nearly any irregularity in the cells associated with a disease.”

Fish bones and origami boxes

It soon became apparent, however, that getting the bloodborne microRNA to the target location, such as cancer cells, is the challenge. As on many occasions previously, Jørgen Kjems decided to pursue this specific problem. In 2008, he therefore began studying drug-delivery methods. Since then, Jørgen Kjems’ laboratory has followed two tracks: basic studies of RNA and application-oriented research on drug delivery.

“We worked with waste from shrimp-processing factories. This was a large quantity of crushed fish bones from which we made various compounds. We used the polymeric sugar molecule, chitosan, which was previously discarded, to envelop the tiny RNAs, and we demonstrated that we could deliver them to the diseased cells – in both the lungs and other sites in the body and demonstrated that we were able to treat some diseases in mice.”

Another breakthrough came rapidly thereafter. This relates to how our hereditary material is constructed using specific building blocks that complement one other, and so predictably that they can actually be used as components to build things from the bottom up. So the question was: could they design tiny DNA capsules into which they could place some RNA medicine?

Jørgen Kjems’ postdoctoral colleague Ebbe Sloth Andersen took a chance and purchased the necessary ingredients.

“I thought ‘this cannot possibly work….but it did’. The fascinating thing is that one just needs to mix things. This is like dismantling a car and putting all the parts into a big bag and shaking it. The car reassembles itself, and then a box emerges without one having to do anything other than watch the process. So this is why, every now and again, you should take a big chance because you can make a big breakthrough. We did that.”

The DNA origami boxes from Aarhus became world famous in the article published in Nature. Today, there are even copies in various museums in Germany and elsewhere. It was a major breakthrough that both the drugs and the capsule for transporting it could be made using nature’s own components, DNA and RNA.

Kidneys, liver and maybe the heart

The potential of combining tiny RNAs and physical structures became clear as early as 2010, when Jørgen Kjems received a large grant from the Lundbeck Foundation focusing on making body implants from various types of biodegradable plastic materials.

“We did this by using stem cells inserted in plastic scaffolding using a 3D printer.. This method enables the body to form new tissue. We could make new bone, fat and also cartilage.”

The genius of the implants was that the plastic slowly decomposed so that, after a while, when the person’s own stem cells had formed new tissue it was actually impossible to see the difference between the new and existing tissue.

“We use the tiny RNAs in the scaffold to guide the stem cells to produce the desired type of tissue. In the long term, we hope to using this 3D printing technology make more complex organs such as the kidneys, liver and maybe the heart.”

A world full of circles

Just like the other times Jørgen Kjems suddenly had a new discovery on his hands, he described it as being hit by lightning. In 2011, it happened again.

“We were studying these tiny RNAs, as we had done for many years. Thomas Hansen, a PhD student in my laboratory, had obtained some curious results at that time that the usual principles could not really explain. For me it was like déjà vu from the start of my early days as a PhD student.”

The circular RNA molecules from Archaea had suddenly reappeared. Jørgen Kjems decided to try to understand these circular RNAs. How are they made in the cell? What do they do? How do they work? What regulates them? It turned out to be a whole new and interesting world.

“These circular RNAs are very stable and are highly expressed in the central nervous system and tumours in particular. They function as a kind of sponge that absorbs microRNAs so that they do not influence other processes. This is a very common phenomenon in our cells: processes are regulated by taking them and preventing them from doing what they were about to do. This is therefore a new way of being able to regulate microRNA and thus our health.”

Leave without looking back

The circle was thus unbroken. Jørgen Kjems has confirmed that occasionally wandering off into different and uncharted territories is not a problem. According to Kjems, he has just had to soak up the punches people from other fields have occasionally thrown in his direction.

“Sometimes people think that you are a dilettante because you explore several fields. Sometimes people believe that if you are not an expert , so you should stay away. But I believe that this is a totally incorrect perception, because you have to move completely ignorant into a field to understand it. And it is naturally correct to consult experts and speak with them, learn new directions.”

Throughout his career, Jørgen Kjems has taken many gambles and made some blunders in other fields. In his view, this is the only way to build bridges between fields and to determine where the boundaries are between what one knows and does not know. In any case, he has not considered stopping. The interesting horizons and advances in science usually occur between the established fields.

“If you have various tracks going in the laboratory, some of them usually to look more promising. I probably tend to move in that precise direction. So there may be other tracks that die out ever so gradually. I believe that this is an evolution of processes – similar to how nature works.”

The answer is in the borderland

The new direction Jørgen Kjems has chosen to explore is the brain, and specifically epilepsy, one way being through a major EU project discovering microRNAs that appear to trigger epilepsy. They discovered that symptoms of epilepsy can be eliminated by firing tiny antisense molecules attached firmly to the microRNAs into the brain – but currently only in mice.

“This is an example of one disease, but it sets the scene that these circular RNAs and microRNAs play a role in all other nervous system diseases. We are also looking at Alzheimer’s and amyotrophic lateral sclerosis (ALS), and the circular RNA appears to play a role – especially in diseases of the brain – presumably because this is the most complex and fascinating organ in our body.”

A new basic research centre of excellence, CellPat, headed by Jørgen Kjems and located at the Interdisciplinary Nanoscience Center (iNANO) at Aarhus University will discover how to use nature’s building blocks such as RNA as novel medicine. The centre will focus on how the immune system can distinguish between external threats and the body itself and why the mechanisms sometimes fail and trigger such autoimmune diseases as rheumatoid arthritis, multiple sclerosis and diabetes. It will also try to improve the use of the patient’s own stem cells to restore human body parts. The recipe is the same as always – interdisciplinarity.

“Today, we know that really new things only emerge in the borderland between fields. We need to ensure that people do not get too obsessed about their small projects. They need to get out and interact and discuss the major problems and then try and solve them together because this cannot be done alone. The important thing is to bring people together so that the whole is greater than the sum of its parts.”

The 2018 Novo Nordisk Prize is being awarded to Jørgen Kjems for his pioneering studies demonstrating how non-coding RNA contributes to cell maintenance and disease development. Although he has been honoured with several national and international prizes and awards, the Novo Nordisk Prize is both a surprising and long-overdue recognition of exactly this approach.

“I do not consider myself as having been too obsessed with my field. I definitely did not count on the Prize being given to someone like me who had somewhat drifted around from basic research to medical applications. So I am naturally very grateful for the recognition that interdisciplinarity and a wide-ranging vision can also be useful in medicine.”

The Novo Nordisk Prize 2018 was awarded Friday 16 to Professor Jørgen KjemsInterdisciplinary Nanoscience Center at Aarhus University.

There are three main focus areas of the lab a) The understanding of how small non-coding RNA and circular RNA contribute to cell maintenance and disea...

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