Derk Amsen has been appointed professor of Molecular T-Cell Immunology effective January 1 2023. In particular, Prof. Amsen will focus on the further development of therapies using T cells. Given his appointment, we interviewed Derk. In this article he gives us a T cell 101 lecture, shares about the time he sang in the car on the U.S. highway, and describes the similarities between synthetic biology and lego structures.
The immune system is a complex network consisting of molecules, cells, tissues and organs that work together to protect the body from pathogens as well as harmful cells from the individual's own body (such as cancer cells).
The immune system consists of an innate and an adaptive system. The innate immune system responds immediately to any danger/any pathogen without previous contact. This immune system is very efficient but not very specific. The adaptive system, on the other hand, develops specific responses to a pathogen after contact with a pathogen has occurred. This immune system has the ability to “learn”; the defense response is memorized by the immune system. If you encounter the same virus a second time, you are immune, due to this learning ability of the adaptive system. The adaptive immune system has two types of cells: B cells, for making antibodies and T cells, for cellular immunity.
T cells 101
T cells have a receptor on their surface that allows them to recognize small pieces of proteins (peptides), these are presented to the T cells in so-called Major Histo Compatibility (MHC) molecules. To recognize as many peptides as possible, it is important that T cells have a diversity of receptors. Each T cell has only one receptor, with which it can recognize one peptide, but different T cells have different receptors. All T cells together can recognize a great variety of antigens.
Prof. Amsen explains, "An immune response proceeds as follows: peptides from a virus you are infected with are shown to the T-cells. At first, you have only a few T cells that recognize these peptides, but they start to multiply. As a result, you get a defense response. With the next infection, you already have these T cells in your body and therefore you do not get sick anymore”.
There are two fundamentally different types of T cells in the immune system, CD8 and CD4 cells. CD8 cells are also called the cytotoxic T cells or killer cells, as these cells are capable of destroying cells. CD8 cells are important for defense against viruses, but also for immunity to cancer. Cancer is caused by DNA mutations, which create so called “neo-antigens”, that are not normally present in your body. CD8 cells can recognize a neo-antigen and kill the cells that present it. Prof. Amsen: "This is one of the hottest fields in oncology and immunology. Engaging the immune system and CD8 cells to eliminate cancer.”
CD4 cells are the leaders in the fight against infections, they are the "conductor" that tells the immune system what to do. Prof. Amsen: "Different pathogen types (for instance: viruses or bacteria) must be fought via different immune defense mechanisms. Our CD4 T cells can see what type of organisms has invaded our body and then make messenger molecules that activate the players of the immune system that are the best suited to deal with the infection”. This function is carried out by so called “conventional T cells”. However, a second type of CD4 T cell exists with a fundamentally different function. This second type, known as the regulatory T cell, suppresses immune responses. Regulatory T cells have T cell receptors with which they recognize our body’s own peptides or peptides from commensal micro-organisms that our immune system should not attack. Regulatory T cells tell the immune system: ‘this belongs in our body, do not attack it.’
The white blood cell army
Prof. Amsen works at the blood bank Sanquin. Traditionally, Sanquin has helped patients by administering red blood cells. Prof. Amsen shares, “Sanquin has been broadening its field of work for some time. In addition to red blood cells, they are increasingly expanding to white blood cells. Here, Sanquin focuses mainly on using T cells against cancer, together with partners such as the Netherlands Cancer Institute (NKI) and the Princess Máxima Center for pediatric oncology. For instance, Sanquin participated in a trial from the Netherlands Cancer Institute (NKI) in which T cells were isolated from melanoma, multiplied in cell culture and then returned to the patient. When these T cells are returned, you see that the tumor stops growing or becomes smaller in many patients and in 1 out of 5 patients even disappears completely. This really is a wonderful result compared to those obtained with traditional therapies of high-risk melanoma. While this study shows the potency of T cells as soldiers to fight cancer, there clearly still is a lot of room for improvement to help the 80% of patients that do not experience long term benefit.”
Sanquin's goal is to better understand how T cells work in order to improve them; this is also Prof. Amsen's role at Sanquin. Prof. Amsen: “T-cell therapy in cancer presents a challenge: it looks as if T-cells that have to work too hard become exhausted over time. If you look at this at the molecular level, you see that a genetic program is involved. This is likely a tolerance mechanism of the body that causes the T cells to work less effectively. By nature, it is not the goal of our immune system to attack our own body and cancer is still made up of the body’s own cells. As a result, our T cells often cannot completely cure cancer. This is something we want to change. In my research, I aim to change the T cells so that they become more robust and do not stop working before the tumor is completely cleared”.
If you see conventional T cells as soldiers, regulatory T cells can be viewed as the military police that keeps the soldiers from attacking civilians. Regulatory T cells can be used in the treatment of patients who suffer from unwanted immune responses such as rejection of transplanted organs and autoimmune diseases including MS, Rheumatism and Lupus. Prof. Amsen: "For that, it is important to know how these regulatory T cells work. You want them to do their job effectively but not suppress other immune responses. Currently, if you undergo an organ transplant, you often have to take immunosuppressive drugs for the rest of your life. These drugs make you susceptible to infections and viruses. An approach with regulatory T cells would be more attractive, because of the specific ability of regulatory T cells to recognize specific antigens from tissues. Prof. Amsen explains: “Suppose a patient receives a new kidney and this patient receives regulatory T cells that specifically recognize the kidney. Then the kidney is protected from attacks by the immune system, but if you get a respiratory infection, you can still generate a strong immune response”.
The similarities between synthetic biology and lego structures
Prof. Amsen: “Our main goal for now is to understand how these cells work and then genetically improve them. Currently at Sanquin we are experimenting with genetically modifying T cells. However, we are still mostly at the stage where we try to understand how things work. My expectation is that therapies based on these modifications will become available in the next decade. For now, my focus is the genetic regulation of T cells, and to understand which proteins direct the functions of the regulatory T cells.” Insights can then be used to modify the behavior of the cells as wanted.
One of the approaches is to make synthetic molecules by connecting pieces of different proteins together, sort of like playing with lego. Prof. Amsen: “With this, we make previously nonexistent structures that allow us to manipulate certain pathways in T cells. This is a topic I find very interesting: synthetic biology. We use our knowledge of how proteins and genes work to make new things”.
Dreaming about curing cancer
Prof. Amsen: “During my childhood, with characteristic childlike modesty, I dreamed about curing cancer. A little later, when I was in high school, I became fascinated by the ability of precursor cells (like the ultimate precursor cell: the fertilized oocyte) to develop many different types of cells and I remember fantasizing about using this to replace faulty organs. Finally, I was interested from an early age in the immune system, although I must admit I do not precisely remember why again. Eventually, I found a way to combine these three interests in my work, even though this was not necessarily all by design.”
Prof. Amsen completed his PhD at the NKI where he focused on T cell differentiation and subsequently went to Yale University as a Postdoc. Prof. Amsen: “What a fantastic department that was! The best immunology department at the time in the world (in my opinion), led by Richard Flavell, a well-known immunologist. The work I focused on there was very fundamental.”
One thing Prof. Amsen has struggled with throughout his career is that he finds too many things interesting. Because of this, it was difficult to choose a topic that he could commit to. When he joined Sanquin in 2013, this changed. Prof. Amsen says, “At Sanquin, I was given a clear direction: working on therapies that use T cells to treat patients”, as described in detail earlier in this article.
Singing loudly, I raced across the highway
Prof. Amsen: “When working at Yale, I focused on the role of a signaling molecule in T cells. The study had developed in an upside-down type of way: I had already figured out what the molecule could do and how it did it, but I had no idea if it was important. Because of technical reasons, it was very complicated to find out if this was the case. At one point I had cracked the formula. I got the key result at 4 in the morning and was ecstatic. The molecule mattered. I vividly remember racing home on the highway, singing loudly. Good thing there were no cops on the road at that hour. In the end, the insight about this membrane receptor opened up a whole field of research. Thousands of articles have been published about it, and I like to think that my discovery had a lot to do with that”.
Inspiration
When Prof. Amsen is asked what his advice would be for young researchers who aspire to become an established scientist, he states: “This career is wonderful. If you do it well, you have a surefire way to avoid the most horrible fate in life: being bored. However, it is not an easy path. You really have to want it very much, because there certainly are easier ways to make a living and there are times when only dogged tenacity will allow you to proceed. A lot of time goes into it. I can say it can completely dominate your life. Often it is difficult to detach yourself from it.’
“Still, a job where you constantly learn new things and in which you are paid to fantasize how things could work and how you could figure that out; priceless if you like those types of things”, Prof. Amsen shares. Prof. Amsen: "If I can recommend anything to young people, it is to go to a really inspiring environment. Where everyone is really interested in the work they do. Where you are exposed to smart people, ideas and insights, you grow tremendously!”
Text: Esmée Vesseur