An Interview with Associate Professor Stavroula Kousteni (Part One)

Author(s): Scott Douglas Jacobsen

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

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

Abstract

An interview with Associate Professor Stavroula Kousteni. She discusses: familial geographic, cultural, and linguistic background; familial background influence on her; ancient and modern Greek texts that influenced her; reference to 1984; origination of interest in medicine; and interest in pathology and cell biology in particular.

Keywords: 1984, cell biology, medicine, pathology, Stavroula Kousteni.

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

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

1. In terms of geography, culture, and language, where does your family background reside?

I was born in Athens, Greece until I went to college. It was in a city to the South on the Peloponnese. It’s called Patras, which is a port city. You need to take a boat if you want to travel from Greece to Italy. I was born in Athens. However, my culture is influenced by the island where my mother comes from, an island in the Dodecanese (the Twelve Islands), called Karpathos.

It is located between Rhodes and Crete. It is one of the most traditional islands in Greece. Its society is to a large extent governed by women. It has extremely strong roles for women in and outside the family. It has a culture that is friendly to people and celebratory of life. For example, every important event in the life of any person, whether it is engagement, marriage, or death, is usually communicated by a type of on-the-moment song, which is sung in the tune of the local instruments.

It is a way of living an emotionally intense and authentic life. It brings communication to a different level. It makes relationships between families closer. The villages on the island are small. Everyone is a ‘relative’. Many people moved to Athens after the war, formed an association, and bought a lot in the outskirts of Athens in a suburb at the North. Also, the land was divided among families who built houses and apartment buildings on it.

We lived in Karpathos. I grew in a very close, rich, and emotional community. It had a tremendous effect in my view of life. It’s my roots. It’s the place that gives me strength, sense of value, and teaches enjoyment and appreciation of life. I left this place to do a B.Sc. in Chemistry at the University of Patras in Greece. After that, I moved to the U.K. to University of Cardiff where I did my Ph.D. and a postdoctoral fellowship.

2. With respect to the “roots,” how did this familial background influence you?

First, it strengthened me as a woman in professional activities and family life. It was natural. It was expected that I would guide and create. Second, it taught me to form strong connections with an extended group of people. In early life, those were extended family. Cousins that were cousins of my cousins. To me, they were still cousins (!). It was a strong family bond that made us treat each other as brothers and sisters. When I left Greece, I sought to create a similar group of extended family.

Not friends alone. They were family by choice with a strong and supportive relationship. Third, it implanted a sense of optimism. So, I could crawl up unwavering. Even in the blackest days, when I really don’t want to know anything about still surviving (I would laugh here), I can get up. Also, the ways to express myself and celebrate life. Can you imagine if your sister is getting married and you start singing about what happened in her life? What happened in her past? What you hope for her? Most people sing and cry. However, a celebration of the life of the person and the relationship with them.

My personality and life were influenced by high school in Greece. High school is from grade 7 to grade 12. I took an exam. I was accepted to one of the academically prestigious schools called Anavryta. I have been one of those lucky people who knew very early. I wanted to do biomedical research. I was fascinated by science.

I have always been interested in biology, chemistry, and physics. However, I did not take these subjects in school. I took a rare and in-depth training in humanities and language arts, analysis of texts, Ancient Greek, Greek, new works of Greek authors, and world history. My mind learned to function through these years in that school. My language teachers were inspiring. They inspired us to think deep, analyze what we read, what we write, and how we think about life. That has shaped the way I see everything. It has shaped my style of science. As well, my will to be open-minded to understand different perspectives.

3. You mentioned Ancient Greek texts and some modern Greek texts were of influence for you. What were some of those?

Once we start learning Ancient Greek in 6^th grade, we read a translation of The Iliad and The Odyssey. A smart way to introduce us to the Ancient Greek world since the main interest was to teach us the concepts, the notions, the intrigues, the emotional relationships, the political situations, and so on, behind these works. Also, we were taught the “Herodotus Tales.” Herodotus was born in Halicarnassus, in Asia Minor, in the fifth century B.C. and has been called the ‘Father of History’, because he wrote the first comprehensive attempt at secular narrative history, considered the starting point of Western historical writing.

We were immersed in stories about Persian Wars, Babylon, Egypt, and Thrace. Also, we read and analyzed texts from Socrates. I was stunned to find ancient Greek education in the United States. For a couple of months, we toured Columbia University for my son’s college visit. He was told that independent of the direction taken. All first year students across different courses and programs are taught The Iliad. (Laughs). Then we re-read most of them in Ancient Greek, along with Thucydides “History of the Peloponnesian War” that chronicled 30 years of war between Athens and Sparta.

Ancient Greek is a complex language. As a Greek, you can recognize several words, but the syntax in intricate and often hard put into context. In Modern Greek, we read a lot of poetry, the works of Odysseus Elytis, Konstantinos Kavafys, Giorgos Seferis. One of the favorite authors analyzed in detail was Antonis Samarakis, who in his writing put a lot of emphasis in the person as an individual. On the thinking process, the person’s thinking process can change due to events in that person’s life. We read his masterpiece “The Flaw,” which was written in 1965. It is eerily prophetic of the military dictatorship that followed in Greece

4. It’s like 1984. It’s based on events, but in a future time.

It is predictive of the future. It tells the story of a suspect detained in an unspecified police state. At an unspecified time, it examines the relationship between what seems to be a leftist, or communist perhaps captive, and his interrogator and detainer. Who is taking him to whoever he needs to go, the plan is devised by the state to make him attempt to escape, thereby proving his guilt, or confess to his anti-state crimes under interrogation. The flaw is the plan’s failure to allow for the human factor, the fellow-feeling that the interrogator develops for the suspect during their time together.

The captive and the interrogator become harmonized with each other. As the relationship develops, as they relate things more intimate to them, the hesitation and awkwardness develops because part of it is asking, “How much of this relationship is true? How much is one trying to manipulate the other?” We spent a lot of time analyzing how the protagonists express themselves in their relationships.

5. Where did interest in medicine in general originate for you?

When I was in elementary school, I wanted to be an astronaut, which is funny. However, when I finished wanting to be an astronaut, I wanted to be in medicine. I had an inspiration growing up. A great aunt, she was a dentist. For a woman in Greece to be a dentist and intellectual immediately after World War II, she was an admirably accomplished woman. I was fascinated by her dynamism. I was fascinated by the humanism of medicine. I saw that through her. However, I was  thinking, “For me, this is ot enough.”

I could see by talking with her, reading newspapers, and magazines. There were many incurable diseases. My focus shifted into understanding how it works. How do people get sick? How does disease start? How can disease be treated?  This is when my interest in cancer developed too. Cancer is such a complex multifactorial and ever-changing disease. How does it all happen? Suddenly, I remember visiting the Department of Biology in Athens in 8^th grade. When we finished going through the labs, I thought, “This is what I want to do.” I want to do research. I want to do biology-oriented research.

I was lucky. It is hard to make a decision for what you want to do for the rest of your life when you are an adolescent. Colleges in Europe do not offer the range, diversity, and combinations in courses of US colleges. In Europe, you have to choose a specialty at 18 years old. So, I was lucky. I knew in 8^th grade. Those were the years we read about major DNA discoveries, breakthroughs in molecular biology, manipulating the genome in model organisms, sheep (Dolly), and later mice. All of these discoveries seemed amazing to me. The possibilities seemed endless.

You can modify the DNA, delete parts of it, or edit it. You do this to ask questions about the function of specific genes in disease and in physiology. You can look inside the cells at molecules that communicate messages. In the early 80s, it was not possible to get trained in it in Greece. I decided to apply and was accepted in the Department of Chemistry in Patras University. It was a new Department. Then and now, it has an excellent teaching faculty. The only one with a good section in Biochemistry. Part of the section in biochemistry had a course in molecular Biology, it was a dream for me. I knew from that early 8^th grade visit to the Department of Biology. I would have to go abroad to complete my studies and to do research. I could not wait to do so.

6. You found the real interest in medicine and chemistry, and not in being an astronaut…

(Laughs)

…What about pathology and cell biology in particular?

From my point of view, research can be done in two approaches. For one, it can be focused on a particular cell type or organ, which delineates its function and rules (the intracellular, intraorgan mechanisms) that regulate its fate and activity. For another, you can look at this organ from a plane view and study its integration into the whole body, which means the inter-organ communications and the transmitting signals that mediate them. In either case, you can be strictly molecular by staying focused on DNA changes and signaling events, or take a more translational/clinically applied spin by asking, “How do those apply to disease pathogenesis and to disease treatment?”

My scientific journey started with the first approach. It is now encompassing the latest. I entered the field of bone biology in 1999. I started by asking very cell focused questions: How do bone cells function? How do they maintain health and survival? How do they function to keep making bone or to resorb bone? How is this process regulated? I was looking at the specific cellular mechanism of the 3 different types of bone cells: 1) osteoblast that make bone, 2) osteoclasts that resorb bone, and 3) osteocytes that are entombed in the mineralizing of the matrix and communicate mechanical signals.

This is the more isolated view of an organ. I looked at bone as something more than an isolated island within the body. I look at it as an organ that should interact with other organs. We are used to thinking of the skeleton as a mechanical scaffold whose role is to help us grow, move around, and withstand the mechanical forces of daily life. This is one of its most amazing functions that it impressively fulfills by achieving complete renewal every 10 years. Every 10 years we have a new skeleton. However, it is not the only one. As the largest organ in the body, it makes sense that there are other roles.

I was interested in finding those. Also, I was interested in understanding how it interacts with other organs to regulate either normal physiological processes in a healthy organism or to regulate disease. My main interest is in disease pathogenesis. Where does disease start? What is the imbalance that makes a disease manifest? In following this approach, I have come to a point where I often say that I run a ‘schizophrenic’ lab. It deals with bone, but many other directions too. One direction is an unintended one. I had not envisioned it. It was something brought on by research.

When I moved to Columbia University in 2006, my lab was looking at a protein, FoxO1, which regulates bone mass in response to oxidative stress. In basic research, if you want to ask, “How does a protein work? Is its function important for a specific tissue?” You inactivate (knockout) the gene that makes the protein in mice and in this tissue. When we knocked out FoxO1 from bone and specifically osteoblasts, we created mutant mice that had a phenotype unrelated to bone mass. They had low blood glucose levels, high insulin levels, high glucose tolerance, which means that if they ate more and high fat food they did not gain weight.

In short, inactivation of a protein expressed in bone cells led in mice led to improved glucose metabolism. We followed this line of research and have subsequently generated several other genetic mouse models that serve to examine role of hormones produces by bone cells in the regulation of different aspects of energy metabolism. Half of my lab is working on these projects. The other half of the lab follows projects related to my fascination with cancer. I wanted to do this research for many, many years. Before I became an independent investigator, I was interested in hematological cancers. Because they are born, live, and thrive in the bone marrow within the bone, where hematopoiesis occurs and goes awry in such cancers, I was a hesitant in entering this vast field.

We started, shyly and cautiously, with an M.D. Ph.D. student, who did some of our initial experiments looking at how osteoblasts affect hematopoiesis. One day, an M.D. and clinical investigator Dr. Ellin Berman, from Memorial Sloan Kettering, met with me and asked if I would be interested to look whether osteoblasts affect leukemia blasts. I was thrilled. We started working on a small focused project with limited funding. Very soon Dr. Azra Raza, the head of the MDS Center at Columbia University and an amazing investigator, joined in these studies, which flourished, expanded, and drafted my new scientific identity: the study of the role of bone cells in the development of MDS and AML.

This line of research is close to my heart. An exciting part of our work is that that we are looking at MDS and AML from a different point of view. Traditionally, investigators look at hematological diseases like myeloid leukemia, myeloid dysplasia as dysregulations, genetic modifications, and mutations. All occurring in hematopoietic cells. These dysregulated cells turn malignant. We look at the disease from the point of view of completely different cells. They are not sisters, brothers, or parents of hematopoietic cells. They belong to a parallel lineage.

They are osteoblasts. They are supposed to originate from a distinct ancestor, which is different than the hematopoietic cells. We look at how osteoblasts affect the induction of myeloid malignancies. Their engraftment or progression. It is a new way to look at pathogenesis, or even treatment of MDS and AML. In fact, we found a different source of MDS and AML pathogenesis one that originates from the osteoblast. A cell outside the hematopoietic lineage. This new mechanism might hold a new promise for treatment because the osteoblasts might be a more amenable target that an AML or MDS cell.

Those malignant cells change identity constantly by accumulating new mutations or developing new protective mechanisms to outgrow treatments. Chemotherapy and other drugs that target specific mutations can be overcome by the appearance of new clones. These new clones arise or the clones become resistant. Our idea is that if you target a cell that is important for the induction of the disease and its progression, but that cell does not change its identity. You can block the signal of the cell, and then have another means to block leukemia. This research is inspiring and consuming me at the same time, not only by the thrill of the discoveries of basic science but because of its closeness to such devastating human diseases and its potential impact.

I am further influenced to my core by the work of my MD collaborators, especially Azra and Ellin. They are the closest ones to me and to my work. Often, I talk to them. I see the sensitivity with which they take care of their patients. Also, their relentless and uncompromising daily fight to save them. Over and over again, it is an inspiring fight to witness. It puts a human and humane face to the research. I can associate our work in the lab with the desired and hoped for outcome: to discover so as to treat. This is very personal and intense. I can say this approach increases personal responsibility and inspiration at the same time.

I share this view this feeling, responsibility, and try to pass them onto and to inspire my students, post-docs, and associate researcher scientists. I tell them how extremely privileged we are as researchers and as a basic science lab to have access to and to be entrusted at the same time with patient samples for our research. That we are lucky to have collaborators that have been generous in sharing their human samples with us.

It permits us to do meaningful research. Every time, we receive them, from Azra or Ellin, I say, “You should not sleep at night. You should be thankful every night that you were able to get these people’s cells. You had better do something worthwhile with them because to them it is a matter of life or death.” They hear this at least once a month. Or, every time that we get new samples. That’s how I feel about it. I committed, serious, and grateful to the work in the lab.

Appendix I: Footnotes

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

[2] Individual Publication Date: August 8, 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.

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