The Scientist: Marius de Leeuw

Marius de Leeuw studied math and physics at Utrecht University. Afterwards, he worked as a postdoctoral researcher at consecutively the Albert-Einstein-Institute, ETH Zurich and, currently, the University of Copenhagen.

What made you decide to go into research?

I went into research because from a young age I wanted to know how things work. I liked reading science books and I loved mathematics and physics in high school. It was therefore an easy choice for me to study math and physics in university. After that, I knew I wanted to go into research and work on open problems. It is fun and interesting to work on problems that no one knows how to solve and to try to make sense of them.

What is your area of study?

My field of study is theoretical physics. I work on theories that aim to describe nature at the smallest distances. At the moment I am working on so-called holographic models. These are quantum models (such as a model with photons, the fundamental particles of light) that have an alternative description via a model of gravity. My work is purely mathematical and theoretical. I try to find equations that describe these holographic models and use them to do computations. One of the questions I am trying to address is how to describe systems with strong interactions. Examples of such systems are superconducting materials and interactions between the building blocks of matter (quarks). Strongly interacting systems are not well understood at the moment and are relevant for experiments such as those performed at the Large Hadron Collider (LHC) at CERN, the European Organization for Nuclear Research.

What is the result that you are most proud of so far?

The work I am most proud of has led to our understanding of symmetries in certain holographic models. It turns out that you can already learn a lot about models by only looking at what symmetries they have. To visualize this, consider rotating a square by 90, 180 or 270 degrees. Each of these rotations will give you the same square back. This is a symmetry of the square. Similarly, some holographic models have lots of more general symmetries. I found that these symmetries are of a new type. This discovery helped to compute observables, like particle energies.

What is the hardest thing about being a researcher?

There are two difficult things about being a researcher. The first thing is research related and it is the fact that you get stuck a lot. This often happens when solving a problem with which you simply do not know how to proceed. You feel like nothing you are trying is working and this can be very frustrating. To make matters worse, it sometimes happens that you are trying to find solutions that don’t even exist. In these circumstances, it can be hard to stay motivated. I generally try to solve this standstill by talking with colleagues to get some fresh ideas or by temporarily  working on another problem instead.

The second difficult thing is more related to the job of being a postdoc. In physics, if you want to get a permanent position at a university, it is important to have significant research experience abroad. This means you have to do several postdocs. A postdoc contract usually lasts for two years, after which you need to try to find another postdoc. So, for a long time you only have temporary contracts and have to move between countries every two years. This can be stressful, since you don’t have any job security, and makes it hard to build a social life. Moreover, in theoretical physics there is a lot of competition, so getting a postdoc (let alone a permanent position) can be very hard.

What do you enjoy most about doing research?

What I enjoy most about doing research is working on the cutting edge of science. You’re trying to solve problems that have not been solved before and to understand more and more of the workings of the universe. It is a great feeling when you understand something new or finally crack a difficult problem. Thus, although doing research can be hard and challenging, it is also rewarding and very inspiring, which motivates me to continue doing it.

PhD life: Sinterklaas

In the Netherlands, December fifth is ‘pakjesavond’, which translates literally to ‘presents evening’. It is the evening on which Sinterklaas – not to be confused with Santa Claus, we do not believe in him – celebrates his birthday by bringing presents to all the kids. At work, we also celebrated this typical Dutch holiday. We all put our shoe in the office of our professor last Friday. In accordance with tradition, many of us added a poem, carrot or drawing for Sinterklaas or his horse. This morning, all shows were filled – we much have been very good this year.

img-20161205-wa0004-1
My professor’s desk with full with shoes
We all got a chocolate letter and a PMI USB drive.
We all got a chocolate letter and a USB drive with our group name.

PhD life: teaching

Apart from doing research and developing myself, I am expected to educate the new generation of students during my PhD. Everyone doing a PhD at a university in the Netherlands has the obligation to spend about 10% of their time teaching. In our group, that comes down to supervising several students doing their bachelor or master thesis – more on that later – and assisting one course a year.

This year, like last year, I am a teaching assistant for the first year plant biology course. The course lectures are giving by professors.  I and the eight other teaching assistants take the rest of the course upon us. We each have our own group of 30-35 students. With this group we do the practicals, the student presentations and – unfortunately with two groups merged together this year – the tutorials. It is great fun. In fact, I enjoyed it so much last year that I volunteered to assist this course again this year.

During the few weeks that I spend with the students, I get the chance to actually get to know them. They are still relatively new to the whole ‘being a student’-thing and therefore somewhat insecure, but also very enthusiastic. It is great to talk with them about plants, experiments and life in general. Another perk of assisting a course is that it makes me feel so smart. Just because I am the teaching assistant, the students seem to think that I know everything. It is also fun to notice that they are generally genuinely surprised when I crack my first joke with them – she is a person too! -, but open up more and more after that.

I think that part of the reason why I liking teaching so much, is that I am good at it. While failed experiments or a seeming lack of direction sometimes make me insecure about my abilities when doing research, I am almost never insecure when I am in front of a group of students. The students listen when I talk, they respect me as their teacher and at the same time we can have a good time together. Also, ultimately, teaching works towards the same goal as this blog: spreading excitement and enthusiasm for doing research on the workings of the world around us.

PhD life: presenting science

When doing research, it can take months or even years before a result is obtained that can be published. Both I and Silvia Proietti mentioned this as one of the major challenges of working in science. This might seem to be in contrast with the idea behind this site: doing science should not be about publishing, so getting a publication only once every few years should not be a big deal. However,  behind this challenge is a bigger problem: apart from published papers, there are not many achievements we can measure our progress with. We cannot count the number of breads we baked, patients we treated or houses we helped build. We can measure the time we spent in the lab, or think of the result that might give a hint to a mechanism. Apart from that, it is almost only the number of papers that can tell us that we are doing okay.

I say ‘almost’ on purpose: there is one more thing. Apart from our papers, we can count the number of (poster) presentations we give. Being selected to give a presentation is an achievement in itself, and giving a good one is an extra achievement on top of that. During a presentation the most promising results gathered so far are combined and presented to others. Doing that in itself is already very rewarding, since it allows you to present you work proudly, instead of critically, as you would do during lab meetings. Positive feedback afterwards is kind of like the breads, patients and houses of bakers, nurses and carpenters.

Last week, I got to give my first ‘real’ presentation so far. Real in the sense that it was not a poster pitch of three minutes – although I harbor proud and happy feelings about that one – or a longer presentation, but for my own lab, PhD students in my graduate school or companies involved in my project. No, this was an eight minute presentation in front of about 100 PhD students, postdocs and professors that work in the field of life sciences in Utrecht. In contrast to ‘normal’ presentations, I was pretty nervous beforehand and felt strangely rushed when sitting back down at the end of it.

However, when I walked out of the room for coffee time, I could start to count my ‘breads’: ‘that was excellent!’ (an American professor), ‘you were the most calm presenter of the group’ (a labmember), ‘that went very well’ (my professor), and the one I like best: ‘during you presentation I realized that your project is awesome!’ (a PhD student from a neighboring group). After this, I can handle some time again without breads to count. My project is awesome, the absence of papers is not going to change that any time soon.

Journal club: roots perceive light transmitted through a plant

Light greatly influences plant growth and development. For instance, light is needed to generate energy via photosynthesis, and light cues allow plants to respond to neighbors that might overshadow them in the near future. Roots also respond to light, by changing their response to gravity and their amount of branching. However, these effects were mostly shown in experiment conducted in laboratory settings, where plants are grown on petri dishes and the roots are exposed to light. In contrast, in natural settings light often does not reach the roots, since light only penetrates a few millimeters into the soil.

Lee and colleagues were interested in the effect of light on roots in natural settings. First, they want to check whether exposing a plant to light changes gene expression in the root. They show that both direct root exposure to light and exposure of only the aboveground part of the plant, the so-called shoot, induce changes in gene expression in the root. Thus, in roots of plants that were exposed to light either at the root or at the shoot, different parts of the genetic code were ‘read’ compared with roots of plants grown in the dark. The light-induced changes were not the same in the root versus shoot exposed plants. There is a set of genes that always changes after exposure to light, though, independent of the exposure localization. Among these genes is the gene encoding the protein HY5, which is involved in the response of plants to light. The researchers show that a plant mutated in this gene, that is, a plant without a functional HY5 gene, that is grown in soil is impaired in its root’s natural response to gravity.

A clue about the method of activation of HY5 came from plants mutated in light receptors.  Light receptors are proteins that start signaling networks after absorption of light. A plant that is mutated for the gene encoding the light receptor phytochrome B (phyB), i.e. a plant with a non-functional phyB, activates HY5 much less when the shoot is exposed to light than a wild-type plant. In consequence, the mutants have less HY5 protein in their roots. The researchers then asked themselves whether root- or shoot-localized activatin of phyB results in HY5 activation. To test this, they grafted – joined parts of two plants together to form a ‘new’ plant – both a phyB mutant root with a wild-type shoot and the other way around. They then exposed the shoots of these plants to light and monitored induction of HY5 in the root. Interestingly enough, a mutation in the light receptor in the shoot did not affect HY5 expression in the root, but a mutation in the root prevented HY5 expression. This indicates that perception of light in the root is the cause of HY5 induction.

The researchers considered two possible mechanisms for the induction of phyB and HY5 expression. First, compounds produced in response to light in the shoot might travel to the root to induce a response there. Second, light itself might be transported to the root. The researchers first show that the compounds known to travel through plants to control light-mediated responses do not induce the activation of phyB in roots of dark-grown plants. Next, they checked their light transmission hypothesis. Light was shown on plant segments consisting of both root and shoot tissue with an optic fiber. This light could be detected at the root end of the segment. Thus, light can travel through the plant and could thus be responsible for the activation of phyB in the plant root. If this is true, the search for a signal that ‘informs’ the root of the light-status of the shoot can be stopped: light is transported through plants and can thus activate any necessary responses all by itself.

Lee, H. et al. (2016) Stem-piped light activates phytochrome B to trigger light responses in Arabidopsis thaliana roots. Science Signaling 9, ra106. DOI: 10.1126/scisignal.aaf6530

Disclaimer: blog posts in the category ‘journal club’ are not intended to cover the whole paper discussed. Instead, I discuss the parts that I think are most interesting for a general public. I try my utmost to prevent any mistakes in these blogs, I apologize in advance for any mistakes that I make anyway.

The Scientist: Silvia Proietti

­Silvia Proietti got a Marie Curie fellowship to perform a post-doc at Plant-Microbe Interactions at Utrecht University in 2013. She recently returned to her home country and is now a senior post-doc and lecturer in Biochemistry and Bioinformatics at the University of Tuscia, Italy. There, she will start her own research line.

 What made you decide to go into research?

I like to answer quoting Albert Einstein: “The process of scientific discovery is, in effect, a continual flight from wonder”. Ever since I was a child, I found it exciting to be outdoors admiring the scenery, trying to learn as much as I could about the things around me. When I was in high school I was impressed when learning that the tiny cells we are all made off, have very intricate and complex machinery inside of them. This drove me to choose to study molecular biology at university. At university, I saw that new things were discovered all the time. This made me want to be part of the action, to make a contribution that would improve our world. Ever since then, I cannot think of anything else I would rather do than doing science.

What is your area of study?

I study the cross-talk between plant defense hormone signaling pathways. Like humans, plants make hormones that function in many plant processes, such as development and immunity. Cross-talk between these hormones allows different hormone signaling pathways to inhibit or activate each other, allowing a plant to flexibly tailor its adaptive response to a variety of environmental cues. As mentioned, I study this crosstalk in the context of a plant’s response to pathogen attack. The plant defense hormones salicylic acid, abscisic acid and jasmonic acid play a central role in the regulation of plant immune responses against these attacks. My current interest is to understand the effect of salicylic acid and abscisic acid on the jasmonic acid pathway and to discover the regulators that mediate this effect. I believe that my results will not only provide novel knowledge about plant immunity, but will also help to develop new resistant crops by rewiring hormonal signaling pathways.

What is the result that you are most proud of so far?

After having performed a very complex and tough bioinformatics analysis, I found new potential regulators of the hormone crosstalk that I’m studying. Later on, I was able to show that these regulators are involved in plant defense against pathogens and pests. This proved to me that it will be valuable to pursue my studies on their mechanism of action. Moreover, thinking about my previous research focus, I’m proud to have characterized a plant defense protein that has a strong activity against plant and human fungal diseases. This defense protein could open new doors for using plant proteins in the medical field.

What is the hardest thing about being a researcher?

I think one of the hardest  things in science is accepting that a lot of research takes a very long time before you make progress towards understanding how things work. It is not unusual that years and years of work have to be done before the results can be published. This can cause some frustration and demotivation! In addition, as a researcher working at a university you have to deal with the fact that in academia there are mostly temporary contracts. Unfortunately, during my career I have seen many excellent scientists who have been forced out of the field because of a lack of funding or stability. This is very sad.

What do you enjoy most about doing research?

The basics of doing research are very simple. You think outside the box about something of which we do not know how it works. Then, you can ask a simple question about this something, think of a way to answer it, and perform experiments to find out if your theory is right or wrong. Both this seemingly easy and logical basis, and everything else that comes in between or around it, is exciting and makes me love to be a researcher. The idea that my research can impact the current knowledge in a significant way, in addition to being useful for the entire society is a good motivation to continue doing this job in the best way that I can. Moreover, sharing ideas, discussing results and building collaborations with other researchers, thereby often getting in contact with other cultures, also enriches my personal life.

PhD life: becoming a better world citizen

One of the major perks of being a PhD student is, to me, the group of colleagues I got along with the job. First of all, they are all smart and interested in the world around them. We can have lengthy discussions about just about anything and have a similar sense of humor. In addition, they come from all over the world. Apart from Dutch colleagues, I have colleagues from Greece, China, France, Spain, Portugal, Italy, Brazil, Austria and the UK. Together, this makes for an interesting group of people and interesting experiences.

  • While having lunch I often hear a ‘local’s’ view on world news
  • When talking with my Chinese office mates we regularly find new differences in work and daily life ethics between China and the Netherlands.
  • When chatting in the lab I realize time and again that some things considered normal here are not normal to others – animal day, for example, sent my French student into fits of laughter.
  • During our last office outing we had Chinese dumplings, which we made ourselves, the Chinese way.

Interacting with people with different nationalities makes me feel a bit like being abroad. It opens up my mind to other perspectives and teaches me both about other countries and about myself and my country. My colleagues make my work even more fun than it already is and they ensure that I will not only become a better researcher during my PhD, but that I will also become a more open-minded and knowledgeable world citizen.

Journal club: fighting disease

Even though we are constantly surrounded by disease-inducing particles, most of us are healthy most of the time. We owe this to our immune system, which can combat most diseases that we are faced with. Fighting disease is based on our immune system’s amazing ability to distinguish ‘self’ from ‘non-self’. It is because of this ability that immune cells generally do not combat our own cells, but immediately start immune responses once non-self particles are recognized. The specific immune response that is started depends on the type of immune cell and the particle encountered. Examples of immune responses are the production of toxic compounds and the activation of other immune cells.

So how are the intruders perceived in the first place? Invading particles are recognized by the so-called B cells and T cells. These immune cells have receptors in their cell membrane, the membrane that separates the inside of the cell from the surroundings. On the outside of the cell, these receptors have structures that recognize (parts of) non-self particles. You can visualize this as a lock and key, with the receptor structure being the lock and (part of) a certain invading particle the key. When the particle fits on a receptor, the receptor is activated, leading to structural changes of the inner part of the receptor. These structural changes start a signaling process that ultimately results in an immune response.

While this system works against many disease-inducing agents, we all know that our immune system is not always successful. One example in which the immune system is not always successful in clearing away the disease-inducer is cancer. Because of this, humans have developed several therapies to treat this disease. However, these do not always work. In their recently published paper Roybal and his coworkers describe their work on harnessing properties of the T cell to develop a new treatment method.

The treatment method developed by Roybal and his colleagues is based on making synthetic T cell receptors. The part of these receptors on the outside of the cell can be designed to recognize any molecule. Upon activation, the receptor gets cut in half at the membrane, releasing the part inside the cell. This part can be designed to activate almost any gene – that is, a part of the genetic code coding for a particular protein. In theory, an engineered T cell with this receptor will result in a very specific, human-defined response upon recognition of the targeted disease-inducing particle.

The researchers tested the method by developing a receptor that recognizes a certain part of cancer cells. T cells with this receptor in their membrane were then cocultured with cancer cells. To easily test whether the synthetic receptor can drive activation of a specific gene, the inner part of the receptor was first engineered to drive activation of a gene encoding a fluorescent protein. Thus, if the receptor functioned as hoped, cells encountering cancer cells would become fluorescent. Excitingly, when exposed to the cancer particles, and only then, these T cells indeed became fluorescent.

Of course making a T cell fluorescent does not directly help curing cancer. Therefore, the researchers next wanted to see whether recognition of the cancerous cells could lead to effective immune responses. Again, the receptor performed as hoped: upon activation it could drive the secretion of proteins that shape the immune response, so-called cytokines, and the differentiation of immune cells into cells with anti-tumor fates. Moreover, cells could be engineered to induce the secretion of several therapeutics, resulting in cancer cell death. This is all the more exciting because some of these therapeutics are non-functional or toxic in the human body when delivered by injection. When delivered by the synthetic T cells, they are only delivered close to the tumor, preventing the side-effects.

While promising, the experiments described so far were all conducted on cell cultures. The immune responses of the engineered T cells might thus not be beneficial or even activated at all in organisms. Therefore, as a final experiment described in their paper, the researchers tested whether the engineered T cells also produce therapeutic agents when injected into the blood of a mouse with cancer. Not many T cells ended up in the tumor, but those that got there, and only those, did secrete the intended therapeutic agent. In a second experiment with a T cell receptor driving secretion of a different therapeutic agent, injection of the T cells resulted in clearance of the tumor.

While more research is needed before engineered T cells can be used in humans, the results published are very promising for two reasons. First of all, engineered T cells deliver their therapeutic agents locally at the site of disease. This prevents possible toxic effects of the agent when present throughout the body and ensures high doses at the right place. Second, at least in theory the receptors can be engineered to recognize any particle and lead to the activation of any gene. Since the engineered cells travel throughout the body, this means that injection with synthetic T cells has potential to treat many diseases.

Roybal, K.T. et al (2016) Engineering T Cells with Customized Therapeutic
Response Programs Using Synthetic Notch Receptors. Cell 167, 419-423.
DOI: http://dx.doi.org/10.1016/j.cell.2016.09.011

Disclaimer: blog posts in the category ‘journal club’ are not intended to cover the whole paper discussed. Instead, I discuss the parts that I think are most interesting for a general public. I try my utmost to prevent any mistakes in these blogs, I apologize in advance for any mistakes that I make anyway.

PhD life: presenting my ‘half year report’

One of the things that is deemed characteristic for our group by our professor is the system of ‘half year reports’. These reports are written by PhD students and are a description of what has been done so far and what is planned for the months to come. After being sent around to the group on Thursday, the report is presented and discussed during the regular Monday morning meeting.

Last week it was my turn. I presented my second half year report, describing the work I have done the past 1,5 years. Like last time, starting to write the report was hard. At first it seemed like I had not achieved anything in the past couple of months and whatever I had done, was hard to connect and write up in one ‘flowing’ text.

Writing the report forced me to think about the bigger picture of my work. It forced me to get an overview of the work I have done so far and the work that I want to do in the future. Once I had finished the report, I felt better about all of this already. Simply taking the time to think helped in itself. With the usual nagging fear of sending around something containing mistakes I then sent it off to the rest of the group.

The following Monday I presented my work. Like always, I liked presenting my research and enjoyed answering the questions. Afterwards, it was time to discuss my report with the staff members. During this discussion the focus is mostly on the lesser parts of the research. This makes sense, because that is where I can improve, but it also resulted in a not all too satisfied feeling afterwards.

Good thing that I had a meeting with my two supervisors the following Friday. It had been a while since we had been together, because the professor had been on sabbatical for 4 months. After more than 1.5 hours of meeting time, I left my professor’s office feeling much better. I was back on track. We had decided on what was important and what was not and thought of some new experiments in the meanwhile.

It still feels like I have not made enough headway, but I guess I will just have to believe the response everyone always gives me when I tell them that: the first year is for learning how to do research on your own, the second to get that research going, the third to get your results and the fourth to write it up. With that scheme in mind, I am still on track and ready to get those results sometime soon.

The Scientist: Eline Verbon

Eline Verbon, me!, is a PhD candidate at Utrecht University, the Netherlands.

What made you decide to go into research?

My interest for doing research was not kindled by work in the lab. Instead, I became interested when writing research proposals for two courses during the final year of my undergrad. I loved the curiosity- and creativity-driven process of writing these proposals. When I later started doing research in a laboratory, I continued enjoying the thinking behind the experiments and the process of interpreting the results. That was when I decided to try to continue doing research.

What is your area of study?

I study the interaction of plant roots with bacteria naturally present in soil. The bacteria I study induce plant growth and resistance against disease and are therefore promising agents to increase crop yield. I am interested to know what happens in the root upon colonization by a bacterium on the molecular level. I believe that knowing this is both cool in itself – we will know more about cross-kingdom communication! – and will ultimately contribute to using bacteria in agricultural settings as a replacement for pesticides and/or fertilizers.

What is the result that you are most proud of so far?

Right now, among other things, I am working on a project with people in the USA. We are trying to find out how plants change the expression of their genome – the DNA that carries the genetic instructions of all processes in a cell and thus in an organism - in response to bacteria. While we are not done with the analysis, I am already very proud of this project. We have worked really hard to gather these data and the data looks promising.

What is the hardest thing about being a researcher?

It can be tough that the relevance of my work is not always immediately clear: I am not building a house, curing a patient or helping people with their finances. Sometimes I work on a project for weeks or months and it turns out it does contribute to the bigger story. On the other hand, the freedom to do what feels right and the uncertainty of what will be found is also what makes doing research great.

What do you enjoy most about doing research?

I love discussing my results with other people, both with colleagues and with my students. These interactions very often lead to new ideas and insights and make me all the more enthusiastic about what I am doing.