Carney Institute (CI): Tell us a bit about yourself.

Nikos Tapinos (NT): I grew up in Athens, Greece where I went to medical school at the University of Athens. After I finished my M.D., I examined patients for two years and was considering residency. I enjoyed interacting with patients, but I always had this question in my mind about research. I thought that something would be missing if I didn’t at least try. 

The educational system in Greece is very different than in the U.S in that medical school is very clinically oriented and dedicated towards patients. There weren’t any M.D./Ph.D. programs at the time. Through reading papers, I had a lot of exposure to research and was always interested in how we generate knowledge, not so much how you apply knowledge. So, I decided I would like to do a Ph.D. before committing to becoming a clinician. 

I reached out to a professor at Athens Medical School who had just come to Greece from the National Institutes of Health in the U.S. to develop a Ph.D. program for immunology. During our face-to-face meeting he asked me what my research experience was. Honestly, at that time I didn’t even know what a pipette was. I had no experience at all but I was very interested and felt passionate about research. 

So, I started a Ph.D. in immunology from scratch at the University of Athens studying an autoimmune disorder called Sjogren’s syndrome and identified the proteins and viral genes associated with the syndrome by examining the biopsies from actual patients. After those five years, I decided that I wanted to dedicate myself to research.  

CI: How did you transition from immunology to neuroscience?

NT: Even though I didn’t do neuroscience during my Ph.D., I was always very interested in it through reading scientific papers and from my medical studies. For my postdoc, I went to Rockefeller University and joined the lab of Emil Gotschlich, a brilliant scientist who had developed the meningitis vaccine. I was interested in the concept of regeneration; how the peripheral nerve regenerates while the central nervous system does not. My project examined live leprosy bacteria and their infection of Schwann cells, the glial cells of the peripheral nervous system. 

Leprosy bacteria don't kill the cells, instead they have a symbiotic relationship, which is why patients with leprosy demonstrate peripheral neuropathy even after taking antibiotics to clear the bacteria. We established a model for the relationship between the bacteria and glial cells to examine how bacteria hijacks the cell cycle and prevents the cell from differentiating properly. It’s an incredible system, as this same mechanism can prevent cells from becoming oncogenic and causing a tumor. 

I stayed at Rockefeller for almost eight years and became a research associate allowing me to independently submit federal grants and prepare for faculty positions. I loved my Rockefeller experience, I absolutely loved it.

After my postdoc, I continued studying Schwann cell division and proliferation at the Geisinger Clinic. We were interested in learning if these mechanisms found in the peripheral nervous system could be applied to cancerous glial cells in the brain, also known as glioma cells. My connection to neurosurgery started here, as we collected tissue from patients to generate cancer stem cell lines. 

Following this, I had the opportunity to join Brown’s neurosurgery department in association with the neuroscience department, where we developed a bank of patient-derived glioma stem cells. I brought stem cells from eight patients from my work at Geisinger and now, after five years, we have a bank of forty–five patients with glioma stem cells in the lab which we are characterizing.

CI: Tell us about some of the research going on in your lab.

NT: I’m exclusively sticking with glial cells. We still do work with Schwann cells and identified a promoter antisense RNA sequence that works as a scaffold to bring chromatin, complexes of genetic material and proteins, together into a multiprotein complex. This RNA sequence is like a molecular glue that holds the complex together. By bringing these complexes together, this tiny antisense RNA can reorganize the whole Schwann cell genome and form new topological associating domains which regulate gene expression.

We also developed an oligonucleotide to target this antisense RNA and block demyelination, the removal of the protective myelin sheath around neurons, which occurs when a nerve is injured and leads to cellular degeneration. By encapsulating the oligonucleotide into a biodegradable hydrogel and applying it on an injured nerve, we were able to stop this nerve degeneration in a living animal. This is super exciting, now we’re trying to develop this as a therapeutic for injuries in humans.

The bulk of my research focuses on glioblastoma, tumors that arise from glial cells, using cancer stem cell models. This is the toughest tumor to treat due to the incredible plasticity of glioblastoma cells, which can adapt to their environment by completely changing their gene and protein expression. Cells can undergo different changes within the same patient and populations of cells will behave differently within the same tumor. With this knowledge, our target is cellular plasticity, not a gene or a protein. How can we take plasticity away from the cells? 

RNA is at the center of plasticity regulation. We identified an enzyme tied to RNA methylation that is expressed higher in cancer cells than in normal cells. We then designed a drug to target this enzyme to inhibit tumor growth in human glioblastoma cells that are transplanted into an animal. After treatment, as we expected, the tumor doesn’t grow back. We’re now moving to put this into clinical trials as soon as possible. 

Another project we are working on is GliaTrap. When a surgeon removes a tumor from the brain, there are lingering cancer stem cells which have already migrated to other parts of the brain and can potentially form a new tumor. Since removing the bulk of the tumor leaves behind a cavity, we are developing a biodegradable hydrogel that can be injected into the brain and attracts remaining cancerous cells back to the vicinity of the surgery. It’s easier to treat cells that are trapped, giving you tremendous opportunity. We’ve tested this in cell culture with human derived tissue and in mice, finding that the glioblastoma cells migrate towards the injected gel. We’ve even shown that it can attract cells across brain structures that glioblastoma cells typically never migrate towards, meaning this is very powerful work.

CI: What advice do you have for new incoming researchers?

NT: Firstly, what I tell almost everybody is to come visit the lab, talk to people and see the different projects. Afterwards, tell me what your passion is and what you want to work with. I want students, even inexperienced students, to be extremely passionate about their project; I want them to feel happy during every minute of it. That’s the only way to be creative and so far it has worked amazingly well.

Second, is to dive into your passion. I look to go deep into every project, from the basic biology to translation and application, the whole spectrum. This is very tough and takes a lot of time, but it’s extremely rewarding. GliaTrap looks really good now, but it took more than 10 years to develop it from a concept to something tangible. Now we’re developing drugs for it and it will be incredible if we go to clinical trials. My advice is to be patient, think very deeply, and strive for excellence in everything that you do.