A combination of two potential drugs gives hope of a ‘super blockage’ of an over-active immune system, Leiden researchers report in Nature. The breakthrough came from the crystallisation of a membrane protein.
Over-alert immune system
Our immune system is intended to protect the body against infiltrators. But sometimes it behaves too alertly, attacking the body itself. This results in chronic inflammation, such as multiple sclerosis, rheumatism or osteoarthritis.
Inhibiting inflammatory reactions
Laura Heitman, Ad IJzerman, Henk de Vries and Natalia Ortiz Zacarias from the Leiden Academic Centre for Drug Research (LACDR) are publishing their research this week in the journal Nature, research that may lead to a more effective way of inhibiting these responses. Their research focuses on the CCR2 receptor. The Leiden researchers work closely with an American team headed by Tracy Handel and Irina Kufureva.
Keyhole at nanoscale
A receptor is a kind of keyhole at nanoscale on the outside of a cell – in the cell membrane – into which a specific key molecule fits. The immune system comprises all kinds of immune cells, each with different types of receptors. The key molecules are called chemokines, and are produced by cells in diseased tissue. Immune cells are attracted automatically towards higher concentrations of chemokine, which generally means towards parts of the body where they are needed.
But patients with rheumatism or osteoarthritis produce too much CCL2, the chemokine for the CCR2 receptor. Although there are ways of blocking the CCR2 receptor, which in turn inhibits the inflammation, the inhibitors currently available prove to be largely ineffective in humans.
In order to discover how this process works at atomic level, Heitman and her colleagues examined the CCR2 protein using X-rays. This cannot be done using whole cells or a fragment of the cell membrane, where other proteins are also present. The researchers needed to have the CCR2 protein in very pure crystal form. This had never previously been done successfully. Laura Heitman: ‘If you take this kind of protein from the cell membrane, it’s very difficult to crystallise it.’
Thanks to this advance, researchers now have a detailed understanding of the three-dimensional form of the CCR2 protein, which is a good starting point for further research on the interaction beteween CCR2 and the related CCL2 chemokine.The research had immediate results: crystallisation was only possible if two inhibitors (BMS-681 and CCR2-RA-[R]) are both added to the CCR2 protein.
Possible duo medicine
Heitman: ‘This suggests a new strategy: duo therapy. By administering these two substances at the same time, you get a kind of “super blockage” of the CCR2 receptor, which is more effective than administering the two substances separately.’ Heitman refers to these substances deliberately as ‘potential medicines’: this is just the start of a process that could lead to a new duo medicine.
Heitman’s group will first continue their work with other receptors, CCR1 and CCR3 up to and including CCR9 before considering other super inhibitors. The ultimate aim is to manipulate the immune system so effectively that it only has beneficial effects, and the detrimental effects are excluded.
Learn more: Two-pronged attack on infectious diseases
The university was founded in 1575 by William, Prince of Orange, leader of the Dutch Revolt in the Eighty Years’ War. The Dutch Royal Family and Leiden University still have a close relationship; Queens Juliana and Beatrix and King Willem-Alexander are all former students.
Leiden University has six faculties, over 50 departments and enjoys an outstanding international reputation. In 2013 Leiden was the highest ranked university in the Netherlands in the Times Higher Education World University Rankings, where it was rated as the 64th best university worldwide and 61st for international reputation. Shanghai Jiao Tong University’s 2011 Academic Ranking of World Universities ranked Leiden University as the 65th best university worldwide. The Times Higher Education World University Rankings consistently rank Leiden University as the best university in Continental Europe for Arts and Humanities.
The University is associated with ten leaders and Prime Ministers of the Netherlands including the current Prime Minister Mark Rutte, nine foreign leaders, among them the 6th President of the United States John Quincy Adams, two Secretary Generals of NATO, a President of the International Court of Justice and sixteen recipients of the Nobel Prize (including renowned physicists Albert Einstein and Enrico Fermi). The university came into particular prominence during the Dutch Golden Age, when scholars from around Europe were attracted to the Dutch Republic due to its climate of intellectual tolerance and Leiden’s international reputation. During this time Leiden was home to such figures as René Descartes, Rembrandt, Hugo Grotius, Baruch Spinoza and Baron d’Holbach. The university is a member of the Coimbra Group, the Europaeum and the League of European Research Universities.
Leiden University houses more than 40 national and international research institutes.
Leiden University research articles from Innovation Toronto
Everyone benefits when cooperation runs smoothly However, people often act obstructively. Why do they do that? Professor of Social Psychology Carsten de Dreu researches this issue using a wide variety of methods, from brain scans to the role of religion.
Inaugural lecture 7 October.
Fear of being exploited
From winning a complex war to developing a life-saving drug: there are so many things that can only be achieved if people work together in harmony. They can then achieve impressive performances that also benefit the individual. So, why do colleagues or others so often make things difficult for one another? Empirical research carried out by De Dreu has shown that greed and fear are the basic reasons underlying problems with teamwork. ‘People are afraid that their contribution will mainly benefit those people who themselves contribute nothing. That’s why people hold back and invest in self-protection rather than cooperation.’
De Dreu examined the strategies people use to maximise the benefits for themselves and to reduce the risk of being exploited. He conducts experiments where the participants can invest in self-protection or attacks on others, or they can choose to do nothing. When motivated by greed, people seem to invest mainly in self-protection and less in attacks on others. ‘Fear is almost always present as a brake on cooperation, but it’s more difficult to predict when greed will crop up.’ The paradox is that fear among rival groups tends to result in people working better together. ‘It seems to happen almost automatically, often without it even being discussed.’
What does our brain look like?
As Professor of Employment and Organisation Psychology at the University of Amsterdam, De Dreu has conducted a lot of research on cooperation within organisations. In Leiden he intends to approach the subject at a higher level of abstraction. ‘We know a lot about what makes the best kind of leaders. Now I want to examine what our brain looks like when we are working together. I’m interested in that because cooperating with one another relies on very basic systems that we also use for other tasks, such as child-rearing.’
Oxytocin, the cuddle hormone
He intends to use brain scans to look at which neurohormones play a role in cooperation, such as the ‘cuddle hormone’ oxytocin. Is more oxytocin produced when people are working together successfully? And can you influence cooperation by administering a dose of this hormone? ‘This neurobiological approach has only really been used by psychologists in the past five years, and there are a lot of important research questions that have to be answered.’
The effect of religion and rules
De Dreu draws attention to his multidisciplinary approach. He is also interested in the effect of such ‘institutions’ as religion and legislation because these have an obvious influence on our behaviour. He will be working together with fellow scientists from other disciplines: sociologists, political scientists, legal specialists, religious experts and also biologists who will be examining the behaviour of rats, for example.
Managers in the scanner
De Dreu doesn’t exclude the possibility that he will again be conducting some of his research in organisations. Until then he would welcome any managers would be willing to take part in his neurobiological research. ‘I would love it if a lot of managers were willing to have scans while making decisions about their companies. But then they’d have to come in their masses, and that’s not to easy to achieve.’
Learn more: Greed and fear hamper cooperation
For the first time researchers succeeded to place a layer of graphene on top of a stable fatty lipid monolayer. Surrounded by a protective shell of lipids graphene could enter the body and function as a versatile sensor.
The results are the first step towards such a shell, and have been published in the journal Nanoscale on 28 September 2016.
In contrast to previous work, the researchers observed a stable structure when placing graphene on a single layer of lipids. A patent has been submitted for these findings. PhD candidate Lia Lima and co-workers made this discovery under the supervision of chemist Grégory Schneider.
Graphene is a surface material that consists of a single layer of carbon atoms. It is extremely thin, strong and flexible. In addition, graphene is wanted in the technological world for its effective conduction of electricity. The applications of graphene vary widely. ‘Graphene is particularly sensitive and can respond to its environment in the body’, says Schneider. Therefore, future applications for the body are for example biosensors and systems that allocate the right spot for performing diagnosis.
Bonding with graphene
To make graphene suitable for these applications, hard inorganic materials are often used as a support. However, these hard materials are not ideal for the use of graphene in the body. For this reason scientists are looking for soft, organic molecules to bind with graphene, in this case lipids.
Lipids on graphene
Lipids are fats that can be found in the protective layer of a cell – the cell membrane. This membrane consists of a double layer of lipids. When graphene could be placed between these two layers, it could travel through the body freely. ‘A method that is already used with cancer medicines,’ explains Schneider. ‘We made a single layer of lipids in the lab and transferred graphene on top: a first step towards mimicking the cell membrane.’
In their research the scientists discovered that a layer of lipids provides good support to graphene. The researchers used infrared measurements to prove the stability of the lipid layer. They also found that the lipids improve the electrical conduction of graphene. This effect of lipids is promising for future applications. Improvements of electrical conduction make it possible to measure the electrical signals of graphene in the body. These signals tell something about the environment of graphene, like the acidity or the presence of certain proteins.
Eventually graphene could travel through the body when it is stabilised by lipids. ‘However, we still have a long way to go’, says Schneider. ‘The next step is to place a lipid layer on both sides of graphene, like a sandwich.’
Learn more: Travelling through the body with graphene