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Modeling normal and malignant hematopoiesis in vitro - a Ph.D. Interview with Simon Hultmark

Portrait of Simon (right) and an image of his thesis cover (left).
Simon Hultmark defended his Ph.D. thesis on 06 October 2022.

Earlier this month, Simon Hultmark defended his Ph.D. thesis. In pursuit of his long-standing fascination for stem cells, his research over the last several years has focused on blood stem cells and cancer. All in an effort to contribute to the development of improved clinical therapies for patients with a type of blood cancer known as acute myeloid leukemia.

In this interview, he tells us about his interest in stem cells, his Ph.D. journey, and how he overcame several obstacles along the way.

What have your Ph.D. studies focused on?

Stem cells, and in particular blood stem cells, also known as hematopoietic stem cells (HSC), have always been a big interest of mine, especially when it comes to understanding the stem cell state, and how they differ from other mature cells. During my studies, I also became interested in better understanding what makes neoplastic cells different from normal cells and how we can improve their treatment. So, my Ph.D. thesis addresses both normal and malignant hematopoiesis with a focus on acute myeloid leukemia (AML).

HSCs can restore normal hematopoiesis in patients that need a new blood system. One of the most common reasons that patients need a new blood system is due to blood cancers like AML. By transferring someone’s else blood system to a cancer patient, the donor’s immune cells can help eradicate the patient’s cancer cells. However, this transfer has its own risk, and successful transplantation requires large donor registries to find a suitable match for a recipient. Today, there is still a shortage of immune-compatible donors in these registries, and depending on the ethnic background, it is estimated that about 20-70% of the patients in need of a donor never find one. Those that do, do not always find a good match. One potential approach to improve the quantity and quality of these registries is to expand HSCs in umbilical cord blood units. However, robust in vitro expansion of human HSCs is not yet possible. 

Therefore, our aim with this research was to address two main objectives: to identify new differentiation therapy of AML and to identify new extrinsic regulators of HSCs. Central to our work has been a co-culture model of primary blood cells that we found to be highly adjustable to different study objectives, for example, screening for novel therapeutic agents, drug synergism, patient selection, external regulators, etc.

In the end, the thesis included four papers focusing on primary samples. First, we identified a natural product that induces differentiation in a subgroup of AML patients samples through activation of the PKC pathway. This paper shows how small molecule screening and genetic profiling are powerful tools for developing personalized treatments. 

Second, we published the small molecule screening protocol based on our co-culture model of primary AML cells. One of the advantages of this protocol is the flow cytometry readout that makes the model highly adaptable to different study objectives. In the third paper, we identified potential regulators of HSCs, by an shRNA knockdown screen in our model. While it did not identify any candidates, likely due to a sub-optimal screening methodology, the list of potential regulators may still be helpful for similar studies. The last study, where I was a co-author, showed that STAG1 and STAG2 have a synthetic lethal interaction in primary AML cells, meaning that targeting them could potentially lead to new precision medicine for molecular targeted therapy,” explained Simon.

Can you tell us more about the cover of your thesis?

“Honestly, I wanted to keep it simple, plain. The original idea was to use the same color we are painting my apartment now, but the print house made the color slightly different from the one I suggested, so this is not the original color. But I still quite like it. It looks like Lund University’s color palette and feels timeless in a way. I mean, you are less likely to get tired of a color, but a picture or image might become outdated after time,” highlighted Simon.

How did you end up doing a Ph.D. at Lund Stem Cell Center?

“I’m from Skövde, Sweden originally. That’s where I did my undergraduate and graduate degrees. After that, I was very interested in stem cell research, and I tried first to get a Ph.D. position at Karolinska Institutet by joining some of their Ph.D. courses on stem cells. But that did not work out in the end, so I started to look at other programs and came across the Lund Stem Cell Center’s Research School in Stem Cell Biology. I applied and was accepted and made the move to Lund. Originally, I wanted to work with embryonic stem cells, but there were not any projects or positions available at the time. Then I met my supervisor, Mattias Magnusson, who had a project on the external regulation of HSCs. I thought this was interesting because it is about the stem cell state, but in adult stem cells instead of embryonic stem cells,” described Simon.

What have you found the most enjoyable during your Ph.D. studies? 

“I enjoyed the freedom that you have during your Ph.D. studies. In many ways, you are on your own and get to decide your schedule and how you conduct your projects. Even with a supervisor, you still have a lot of freedom as to how you carry out your day-to-day activities. I like that because your then very much driven by personal motivation and your passion. I enjoyed that feeling of being on your own with your mission to pursue the science,” explained Simon.

What has been the most challenging aspect?

“The main challenge is coming to terms with the fact that there is a real risk that you fail, that you do not get your Ph.D. Even after you invest so much time and effort into this project, you may never reach the goal in the end. I was always hard-working, but I realized along the way that hard work doesn't always pay off, you also must produce results. My first project failed and that was a harsh realization. But I was able to come back and push on with the help of my supervisor and colleagues and finished strong in the end,” noted Simon.

What are your plans following your Ph.D. defense?

“Well, for now, I am done with research. I’ve realized that it is not necessarily something that I would like to do in the long term. If I think about what I am good at, it is related to details, standards, and quality. So right now, I am curious about quality assurance or a similar position in the industry. I also like regulation, so perhaps even something in regulatory affairs, either in industry or with a regulatory agency,” stated Simon.

Any tips or advice for future Ph.D. students? 

“This is tough since the Ph.D. process is so different for each person, each situation is different. I think one thing that applies to everyone is to make sure you advocate for yourself and surround yourself with people that are willing to help you. It can be difficult in academia because even if you think the environment is quite open, everyone tends to work within their groups. It can be isolating in a way, even if you're surrounded by many other groups. Also, your supervisor’s advice is very influential in guiding you. In the beginning, you’ll need, as Ph.D. students, guidance in the lab as to how to do the experiment, and how to plan things. Therefore, it is important to find people that are invested in helping you along the way,” concluded Simon.

Contacts:

Simon Hultmark
Ph.D. student,
Research Engineer,
Email: Simon [dot] Hultmark [at] med [dot] lu [dot] se

Profile in Lund University research portal


Mattias Magnusson
Principal Investigator
Ph.D., Researcher

Phone: +46 46 222 14 46
Email: Mattias [dot] Magnusson [at] med [dot] lu [dot] setarget="_self"   

Profile in Lund University research portal

Link to the Research Group on Stem cell and Cancer Stem Cell Regulation

Ph.D. Defence Details:

Simon Hultmark defended his Ph.D. thesis “Modeling normal and malignant hematopoiesis in vitro. To screen for extrinsic regulators and differentiation therapy” on Thursday, 06 October 2022.

The opponent was Professor Krister Wennerberg, University of Copenhagen.

The chairman of the dissertation was Assistant Researcher Valgardur Sigurdsson 

Read the full Ph.D. thesis in the LU research portal.