An Interview with Associate Professor Stavroula Kousteni (Part Two)

Author(s): Scott Douglas Jacobsen

Publication (Outlet/Website): In-Sight: Independent Interview-Based Journal

Publication Date (yyyy/mm/dd): 2016/08/15

Abstract

An interview with Associate Professor Stavroula Kousteni. She discusses: tasks and responsibilities with professorship; the Women’s Commission Committee and helping solve women’s problems; greatest emotional struggle in personal and professional life; and skeletal influences on physiological processes.

Keywords: professorship, Stavroula Kousteni, women.

An Interview with Associate Professor Stavroula Kousteni: Associate Professor, Physiology and Cellular Biophysics, Columbia University (Part Two)^{[1],[2],[3],[4]}

*Footnotes throughout the interview, and bibliography and citation style listing after the interview.*

7. You are the Associate Professor in Physiology and Cellular Biophysics at Columbia University. What tasks and responsibilities come with this position? For instance, the training and outside of research.

There is training. A big part is to train students and post-doctoral researchers that come into the lab. It is hands-on training. It is teaching them how to do research, how to recognize problems, what questions to pose, how to form hypotheses, and then what is very important is how to read the results.

People can look at the same set of results and derive different interpretations. You can look at the result. You can make the result fit the hypothesis. Or even if the experiment didn’t work, you can see is that it doesn’t fit the hypothesis. But if you look at your results, you can see hidden things. This is my favourite part. I take the raw data – everybody’s raw data. They do an assay at the spectrophotometer.

They generate numbers, numbers, numbers, numbers. I look at the numbers in groups. I can look at them for days sometimes, especially when something does not exactly fit. When you do that, you can see connections that you did not expect were there. You can see possibilities that can change your hypotheses to a greater or lesser extent, and often to more exciting directions.  I tell my trainees: keep your eyes and minds open to discover new connections. In the past, I had people in the lab say, “This is not possible.”

When that new “that” was looking at them straight in the eye, I told them that this is not the place for them. If I cannot teach you that many things are possible, then this is not the place for you. Another part of my training responsibilities is to teach in courses that are run from different programs and departments. Those are different training program supported by the different Institutes of the National Institutes of Health (NIH).

I co-direct one of those programs. An endocrinology training grant that is supported by the NIDDK. It is a grant from the NIH. It has a specific fellowship for pre-docs and post-docs. So, the program tries to place them, support them with money, train them in endocrinology – a holistic view. Then there are the institutional groups we serve. For instance, I have been part of a task force with the aim to improve quality of life, communications, and working environment at the Campus.

I sat with a group of investigators and administrators. Our task was to define what areas needed to be improved in terms of facilities, provisions like childcare, and internships for older kids. Also, I serve on the senate for the Women’s Commission Committee. It is looking into identifying and resolving women’s issues, and to promote their recognition and opportunities in the university.

8. With regards to the Women’s Commission Committee, and women’s concerns and issues in the university, what are those? How can individuals, groups such as the commission or other groups in the university and other institutions solve those problems?

That women are able to perform their work with the same provisions, opportunities, and recognition as their male colleagues at the equal level. During the last few years, the university has made big steps towards this direction. More Deans and Center Directors are women than 5 years ago. Also, there are departments such as the Department of Physiology and Cellular Biophysics, the Department of Human Genetics and Development, that by looking at their faculty and faculty positions one can see that they are very supportive of women faculty. We are on a good track.

9. What seems like the greatest emotional struggle in professional or personal life?

First, in professional life, one of my struggles comes with the nature of our work. Lab trainees eventually complete their training cycle, close their project, publish, and move on to the next stage of their career.  It is an emotional struggle to lose good people among them. Imagine, you work for years to build a team and then every few years need to rebuild it. Sometimes, it feels like a wave when people leave together. Others join at the same time. Emotionally and practically, it is demanding. It takes skill, effort, and time to re-establish relationships and re-harmonize the lab functions.

The second struggle in professional life is funding. Running a lab is similar to running a small company because we need to continuously generate funds. At these times, as an investigator, you need to be resilient with the difficulties in obtaining NIH funding. To get funded, an investigator has to submit a project proposal that is reviewed by a scientific panel with relevant expertise put together by NIH officers.

In this process, we are effectively told whether what we do or propose to do has merit or not, if it is worth or not. This is an exercise in resilience. It’s a criticism of your ideas and approach. If you don’t get it in the end, you have to be able to say, “I’ll move on and put in another application.” Since NIH funding is limited now, this laborious process can be repeated several times and it hits success.

In personal life, I would say how to bring up my kids. That is the most emotionally intense experience for me.

10. How so?

In fact, it’s a challenge. It was a struggle because I spent a lot of time working rather than seeing them growing up. However, I realized the things that I could offer and teach them by behaviour, experience, and by being satisfied and fulfilled from my work. Those made the compromise worthwhile. It is a challenge considering that my knowledge and experiences go into it.

I have so many different cultures in me – growing up in one country and moving into another one while meeting so many people with different backgrounds and religious beliefs. I am a scientist and am used to observing. I am used to abstracting my ideas to construct rational lines of thinking of hypotheses and conclusions. I use all these expertise as way of teaching them how to be decent and inspired people. All of my energy outside work goes there. This effort is full of emotional charge for me. I want to help them understand how important it is to ask for things in life, how important it is to be inspired in life, and how important it is to have many experiences.

11. You have moderate representation in the media.^{[5],[6],[7],[8]} The reports covered the research on Acute Myeloid Leukemia (AML). Your main research might be summarized as “[skeletal] functions in metabolism and hematopoiesis.”[9] It is a comprehensive research program with a distinct focus.[10] Let’s explore some of this research in-depth through some queries to you: what are the general influences of the skeleton on various physiological processes?

I was not satisfied looking at bone only as bone. For me, it was more exciting to understand how different organs interact with each other. I always wanted to enter the bone field. I was able to achieve that when I became an independent investigator. I want to know how these organ interactions maintain health. Normal every day physiological processes. This is alongside my interest in hematopoiesis and cancer. My work with Ellin and Azra made me focus to myeloid malignancies.

We started a project in the lab that was looking at simple things – to see if the skeleton and the bone-forming cells have any way of interacting or influencing leukemia. As we started doing the experiments, we realized that it did. There are signalling pathways that are triggered from osteoblasts that promote or halt the progress of leukemia. We started working on the pathways. As we were going forward, we asked whether there are any genetic differences. For example, mutations in osteoblasts that would not influence the progression of the disease alone, but could be as important as inducing it or altering its course.

That was much more far reaching because these two cell types – the leukemia cells and osteoblasts – come from different lineages. It was not thought that one could influence the fate of the other. The idea of a cell outside the hematopoietic lineage affecting myeloid malignancies was starting to surface. I decided to look extensively into it at that point. We examined a particular mouse model with a mutation on a protein that we thought could be a common link between hematopoiesis and osteoblast functions.

We found that when this mutation was present only in osteoblasts, at least in mice. It was by itself adequate to trigger the development of MDS. Then the disease quickly progresses into myeloid leukemia with all of its features of AML. If you take these bone marrow cells from these mice and transplant them into mice mouse, the healthy mice will also develop AML. With the help of Azra and Ellin, we screened a large cohort of patients with MDS and AML. To this time, we have screened 350 people, patients. We were interested to see if an AML inducing pathway like this was active in the osteoblasts of patients with MDS or AML.

We found that 30-35% of these patients had this pathway active, which suggested that it might be inducing AML in humans. We knew the signal transmitted from the osteoblast to the hematopoietic cell. It was turning this cell into a leukemic one. That meant that if we could block it, then we could block the disease. This was exciting because it could be a new means of dealing with MDS and AML. We would be targeting a leukemic signal originating from a cell (the osteoblast) that is stable, has a stable function, and does not change identity.

That is unlike leukemia cells. Those tend to accumulate different mutations or mutations develop mutations that make them resistant to chemotherapy or targeted treatments. We did this experiment in mice too. We used an antibody that blocked the pathway in osteoblasts. By doing that, it blocked the disease in mice. At this time, we are looking at other molecules and mutations in osteoblasts that may affect MDS and AML progression.

We are looking at interactive molecules. What is it that the osteoblast secretes to protect from that leukemia cell? So, we’re piercing the pathway together. We are trying to learn how these cells communicate, how you can interfere in these communication signals to take advantage of them – of one signal or the other – and make the bone a place that myeloid dysplasia can’t grow.

Appendix I: Footnotes

[1] Associate Professor, Physiology and Cellular Biophysics, Columbia University.

[2] Individual Publication Date: August 15, 2016 at www.in-sightjournal.com; Full Issue Publication Date: September 1, 2016 at https://in-sightjournal.com/insight-issues/.

[3] Ph.D., Cardiff University.

[4] Photograph courtesy of Professor Stavroula Kousteni.

[5] Columbia University Medical Center. (2014, January 22). Potential Drug Target Found for Common Blood Cancer. Retrieved from http://www.dddmag.com/news/2014/01/potential-drug-target-found-common-blood-cancer.

[6] Waknine, Y. (2014, January 27). Hit the Cancer Where It Lives: A New Approach to Treating AML. Retrieved from http://www.medscape.com/viewarticle/819764.

[7] Columbia University Medical Center. (2014, January 21). Common Blood Cancer May Be Initiated by Single Mutation in Bone Cells. Retrieved from http://newsroom.cumc.columbia.edu/blog/2014/01/21/common-blood-cancer-may-initiated-single-mutation-bone-cells/.

[8] News-Medical.Net. (2014, January 21). Mutation in bone cells may cause acute myeloid leukemia: Study. Retrieved from http://www.news-medical.net/news/20140121/Mutation-in-bone-cells-may-cause-acute-myeloid-leukemia-Study.aspx.

[9] Columbia University. (2016). Kousteni, Stavroula, Ph.D. Retrieved from http://www.physiology.columbia.edu/Stavroula.html.

[10] Kousteni, Stavroula, Ph.D. (2016) states:

Research Activities

The purpose of the research in my laboratory is to understand the influence of the skeleton on various physiological processes. The long term goal is to uncover the pathogenesis of degenerative diseases and to suggest novel and adapted therapies for them. Along these lines we are studying the function of bone as an endocrine organ regulating glucose metabolism and energy homeostasis and examining the role of osteoblasts in hematopoiesis with particular emphasis in myelodysplasia (MDS) and acute myeloid leukemia (AML).

Bone as an endocrine organ

Osteoblasts, the bone forming cells, have been shown previously to influence glucose metabolism through the secretion of a bone-specific hormone, osteocalcin. We found that the activity of osteocalcin is regulated transcriptionally by osteoblast-expressed FoxO1. These findings raised for us the question of the nature of the osteoblast as an endocrine cell, and more specifically whether it secretes other hormones regulating any aspect of energy metabolism. Using a genetic approach to this problem we identified a second osteoblast-specific hormone that affects glucose metabolism and insulin secretion. We are currently expanding this work, searching for its receptor and for other functions and mechanisms of action exerted by this hormone.

Detecting Interactions between Osteoblasts and Leukemia Blasts

In current work, our lab has discovered a function of the skeleton, as an inducer of leukemogenesis. We identified a mutation in the osteoblast that disrupts hematopoiesis leading to leukemogenic transformation of hematopoietic stem cells (HSCs) and establishment of MDS progressing to AML. The same mutation and signaling pathway were identified in more than a third of patients with MDS and AML. We have also found that osteoblasts affect engraftment of leukemia blasts. We are currently characterizing the signaling pathway that mediates these actions. This work may provide a rationale for using means to manipulate the osteoblast to make the hematopoietic niche hostile to residual leukemia cells. 

Columbia University. (2016). Kousteni, Stavroula, Ph.D. Retrieved from http://www.physiology.columbia.edu/Stavroula.html.

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