What have your Ph.D. studies focused on?
"Overall, the title sums it up well. My research has focused on pediatric leukemia and its mechanisms of initiation and suppression. Leukemia is characterized by the abnormal and uncontrolled expansion of malfunctioning blood cells that crowd out normal cells. Most childhood leukemias are thought to originate in the womb and occur due to a genetic error or a mutation. While survival rates of pediatric cancer have increased over the years to an 80% survival rate in most cases and 90% for some forms of leukemia, the treatments are still quite toxic.
Our goal was to understand more about the disease and to find new targets for better and more specific treatments. Specifically, we focused on understanding the disease mechanisms and studied two of the most common chromosomal translocations, or genetic mutations, that lead to pediatric leukemia. Some of these mutations, such as (mixed-lineage leukemia) MLL fusions, are highly aggressive and can generate leukemia very quickly. Despite this, the incidence of leukemia during the prenatal and neonatal stages is very low (~1% of all childhood leukemia cases), and leukemia usually develops at a later stage after birth.
Therefore, we hypothesized that there may be a protein that acts as a tumor inhibitor during these early stages of life, preventing the development of leukemia. We explored different aspects of this throughout the four papers detailed in my kappa – one of which was published earlier this spring and another which we are planning to submit soon. Since these mutations occur in utero and are very hard to study in humans, we used mouse models that express the same genetic mutations to investigate their impact on the blood or hematopoietic system.
First, we looked at LIN28B, a gene recognized as the master regulator of fetal blood cell formation. Its expression is highest during the prenatal period and decreases abruptly after birth. In paper I, we used a mouse model that generates leukemia, and we tested the effect of LIN28B expression on leukemia development. LIN28B reversed leukemia in more than 50% of the mice, and it took a long time for the disease to appear in the rest.
Further analysis revealed that LIN28B obstructs critical programs of leukemia development, and these actions are mainly driven by a different tumor inhibitory protein called MYBBP1A. Our study demonstrates that the expression of tumor-inhibitory LIN28B before birth prevents leukemia initiation - and when inhibited after birth, the protection decreases, resulting in an opportunity for leukemia to develop. We hope this informs potential new therapies for patients with leukemia at any age.
As opposed to MLL fusion leukemia, ETV6-RUNX1 (E/R) leukemia is a less aggressive but more prevalent type of leukemia in older children. The first mutation also occurs in utero, but more mutations are needed to develop E/R leukemia. It can take over 15 years from when the first mutation occurs to when the second mutation occurs. Although, the incidence of E/R leukemia in adults is low.
How these pre-malignant cells can persist in the body for all this time without being recognized and eradicated by the immune system and why its incidence decreases in adults were questions we wanted to answer. By modeling E/R leukemia in mice, we found that these pre-malignant cells expand and persist in the bone marrow by activating certain pathways to avoid immune cells. We also found that exposure to infection triggers the expansion and growth of these pre-leukemic cells derived from fetal cells (as opposed to adult origin). This sheds new light on the disease mechanisms that we hope will inspire potential immunomodulatory treatments that can target the disease before it fully develops.
These are the studies I first authored, the other two I co-authored. The first co-authored paper focused on secondary mutations in the MLL mouse model in our lab, where we studied the most common mutations found when leukemia has developed and the mutations that trigger its transformation. The second and final paper presented in my thesis was done in collaboration with Göran Karlsson's research group, where we looked at normal hematopoietic stem cells and their behavior in a steady state and how this contributes to all mature blood lineages in an unperturbed setting," explained Mohamed.
Can you tell us about the cover of your thesis?
"The thesis cover is always a thing that one has in mind throughout the Ph.D. process. The cover helps to attract attention to the thesis, and many people prefer science to be communicated visually so that it's more accessible to the public.
I thought a lot about what to do for my thesis cover, and in the end, it became a very tight period from when you fulfill the Ph.D. requirements and submit the paperwork. It is around six weeks to have everything done, all the writing and cover design, for the thesis kappa. Originally, I had a completely different plan for my thesis cover. I like drawing, and I have friends that like drawing, so we agreed to meet and draw the cover ourselves. I had a completely different idea for it.
But as time passed, I didn't have time for anything like what I had planned. So, I started googling childhood cancer and found Angus Olsen, who is an Australian cartoonist in Australia who used to work for Disney. Angus’s daughter developed cancer when she was two. As a coping mechanism, he started a website where he wrote and recorded videos of this journey, beginning from her diagnosis. He started creating illustrations for himself, but also for other families that have gone through the same experience. Luckily, she survived, and she's now seven and healthy. But he dedicated part of his career to drawing childhood cancer - I was looking at his work and I was so touched by it. I really liked this one picture, so I contacted him and asked if I could use it, and he said absolutely. Now it’s my cover, which I'm very grateful for," described Mohamed.
How did you end up doing a Ph.D. at Lund Stem Cell Center?
"I am a pharmacist by training, originally from Cairo, Egypt. I studied my bachelor's degree there. When I finished, I started working in industry, working for Glaxo Smith Kline and then Pfizer for a bit. At that time, I was working in quality control and then as a medical representative. I also worked as a pharmacist in a hospital for a bit. They were all very nice experiences, but I felt that I wanted to go towards research. I was always interested in research, especially research that focuses mainly on translational aspects or pathophysiology.
I knew then that I needed to do a master's and then continue from there, and I thought why not go and study abroad? The Northern Lights and the completely different sceneries that I would ever be able to see in Egypt sold me on Finland. That's where I did most of my master's degree program before finishing at Imperial College London. My master's thesis focused on hematopoietic stem cells and infection, and I knew that this was a research area I wanted to continue in. I was very interested in stem cells and specifically blood stem cells with the leukemic angle. Knowing the field and the topic that I wanted to study, I started thinking about what countries I might be interested in living and studying in.
I looked at the labs I might be interested in, in those three places and applied, and I got all three positions. I was very close to going to the Netherlands, but when I interviewed with my to-be-supervisor, David Bryder, I liked the way it went and how big (> 14 people) and international the lab was at the time. I came for a short test period (2 months) before starting my Ph.D. here in Lund in August 2017," noted Mohamed.
What have you found the most enjoyable during your Ph.D. studies?
"I enjoyed the thinking process and project planning most. I like that we are in many ways exploring things that nobody has before. In the end, you report things that you are probably the first to see/report. It's the whole research and discovery process that I enjoy. There are things I like more than the others of course, like discussions with colleagues, coming up with new ideas, and planning a new project, more than I like, for example, conducting in vivo experiments," expressed Mohamed.
What has been the most challenging aspect?
"The most challenging part is that in science you don't explore for the sake of exploration. In the end, you need to publish several papers within a certain timeframe. When I started my PhD, I initially had a set of projects that differed greatly from the ones I eventually defended. In fact, it was less than a year before my halfway assessment that I began developing and working on my main projects.
You start many projects, and you don't know where they will lead you, or if they will do anything at all. Hypotheses don’t always work, and a major problem in academia is that negative results are not appreciated in the same way. Journals don't want to publish negative results. They are just not interested in them. So you try many different angles and aspects until you find something that clicks then you pursue it further, but you never really know. The combination of this uncertainty and the time factors can make things stressful.
This highlights the importance of project planning. Poor planning is a significant contributing factor to the delays that many of us encounter as PhD students. It is quite important then to learn/know when to stop a project or consider it good enough for publication. Of course, this is not just up to you, as supervisors have a big role in that.
As an added layer, I also, as a non-European citizen, had very big problems with the migration process, which was very challenging, particularly recently when the Swedish government changed several of the migration laws. Since Ph.D. student contracts are not long-term, and by the time you get a new extension, your contract has already expired which makes it difficult to apply for a visa extension. This last time was easier because I'm now Swedish, but before that, it was a challenging process to go through the last few years," detailed Mohamed.
What are your plans following your Ph.D. defense?
"Right after I will go on holiday for a bit, first home to Cairo and then a trip to Nicaragua.
More long-term, in the future, I want to move back into industry. Ideally, once there, I'd like to continue with research. As I explained earlier, my interest is linked to translational and preclinical impact. So, I feel like it would be nice to take this a bit further to something that has more physical output. Usually in companies you don't do research without a product in mind at the end, and I can see that this fits with my current interests. I'm also really interested in the discussion and thinking process of everything, but as a recent Ph.D. graduate, something related to that might be hard to find, so I am happy to start by working first in the wet lab. I plan to stay here in the Oresund region. I like it here and in Copenhagen, there are a lot of companies within this field, so I hope to find something in this area and explore different roles," indicated Mohamed.
Any tips or advice for future Ph.D. students?
"I would say, be open, try more things. The important thing is to know what the outcome that you're expecting is from each experiment. Don't do experiments without thinking beforehand, just because you're in a loop or something. Try to sit down and think is this an important experiment? Can I not do it? It's a very good attitude to have. Don't do things because you can but do only what you need to do. Everything comes down to the planning in the end. Think about the relevant experiments that will answer your question and bring your project forward and do those. Don't get distracted with other stuff. Since you will not always know which experiments will work, try to approach hypotheses from different angles. That you can do in parallel so that you're not wasting time," concluded Mohamed