Pause. Take a step back. Learn about people.
Miltenyi Biotec is a community of colleagues fascinated by science and dedicated to empowering cell research. That is our drive. But what makes many of us go the extra mile are the personal contacts we make with researchers around the world. While their work undoubtedly motivates us, their stories as human beings make us smile, reflect, admire, and at times, laugh out loud. Some of them are accomplished athletes. Others lead very different lives outside of the lab. And others yet pursue unexpected hobbies and interests. Each story is unique. Each contact is an opportunity to pause, take a step back, and learn something about people.
The interviews of our Scientific Spotlight are a glimpse into the lives of scientists like you. We hope you enjoy each conversation and find inspiration from their thoughts and experiences exploring the frontiers of the biological sciences.
Interview with Dr. Paul Fairchild, Associate Professor in Medicine at the Sir William Dunn School of Pathology, Fellow and Tutor in Medicine at Trinity College, University of Oxford (UK)
On any given morning in Oxford, you may see pensive scholars on their way to a college, private hall, or department at the University of Oxford. One of them will be Dr. Paul Fairchild. For over 20 years, Paul has walked to and from work. Deep in thought, he mulls over problems, ideas, plans, and keeps himself "intellectually engaged with what we are doing, rather than answering infinite e-mails, which is more the norm, unfortunately."
Paul’s path as an immunologist did not begin in the natural sciences. Originally, his plan was to go into linguistics and learn multiple languages. But, then what? he wondered. Having changed his mind, he encountered immunology as an undergraduate and never looked back. “It made no sense to me whatsoever! So little was known about the immune system at that time. The T-cell receptor had not yet been elucidated. The MHC was taught to us as the complex that causes the rejection of allografts but if that was all you knew about it, it made no sense. Given that we’ve only done organ transplants for the last few years, how could something evolve to cause rejection?” he chuckles. “Nobody chose immunology because it was just so nonsensical.” Intrigued, he entered a field as it transitioned into a phase of exciting discoveries. He remembers how “during my PhD, the crystal structure of MHC class I was published, showing that it actually had this substance bound in a groove, which people assumed might be a foreign peptide. That was the first that was really known about what MHC did at all, and since then things have begun to slot into place.”
It was also during his PhD work with Professor Jon Austyn that Paul was introduced to dendritic cells and his interest in them has not waned. Paul was among the first to describe the antigen-presenting role of dendritic cells during clonal deletion in the thymus and he has worked throughout his career on questions of immune tolerance in the context of autoimmune disease and allograft rejection. Today, his research lab uses knowledge about what tips the immune system toward response or tolerance to figure out how to coax it back. “Even now, 30 years after understanding the way the immune system works, we still have not really got to that point of actually inducing tolerance clinically. So, it's still quite a long way off. And that's really because trying to reestablish tolerance in a primed immune system is exceptionally difficult to do” says Paul. The same but opposite inertia holds true for immunotherapies, he argues. “All tumor antigens are effectively self proteins. Some level of tolerance has been established to them. So, we're trying to break through that barrier of tolerance to trigger an immune response against what is effectively a self component.”
Interview with Dr. Paul Klenerman, Sidney Truelove Professor of Gastroenterology at the Nuffield Department of Medicine, University of Oxford (UK)
Google Paul Klenerman and you’ll stumble upon a Wikipedia page listing past accomplishments of a young fencing champion. What he does today is splashed across numerous other websites and videos with terms like University of Oxford, viral immunology, T-cell responses, HIV, hepatitis C, host-virus interactions.
Interview with Dr. Jonas Nilsson, Inaugural Perkins Chair of Melanoma Discovery at the Harry Perkins Institute of Medical Research (AU) and Professor in Experimental Cancer Surgery at the University of Gothenburg (SE)
Conversations with some people take you on an unexpected journey of unique perspectives and tantalizing insights. That’s the case with Dr. Jonas Nilsson. Last November, he packed up the family and moved across the globe from Sweden to Western Australia on a personal and professional expedition. He isn’t trekking through the Australian bush. Instead, he is clearing a path for clinical melanoma research out of Perth. In the process, he’s seized the opportunity to leave a positive mark, regardless of where life takes him next. Taking chances runs deep in his career and has prevented stagnation on more than one occasion.
“Actually, I fell into research during basic studies,” Jonas recounts. “I got really interested in a project that a professor had at the university I attended in Umeå in the north of Sweden, trying to understand what these small molecules called polyamines do. At that time, we were cloning genes in the lab. This was a bit before the human and mouse genomes were known, so we had to do these things manually. I would screen libraries full of genes and identify those that we wanted to examine. I cloned a cDNA that encodes a protein that regulates the stability of a key enzyme in the synthesis of polyamines called ornithine decarboxylase or ODC. As it turned out, that gene is growth regulated. So, when you stimulate cells to grow, the protein encoded by this gene can activate ODC to produce polyamines needed for cancer cells to divide. That was the link to cancer.”
The clone Jonas developed was the ticket to his next adventure. It caught the attention of Dr. John Cleveland, then at St. Jude Children's Research Hospital in the US, who was working on the well-known oncogenic transcription factor Myc. “He wanted to get this cDNA that I had cloned,” says Jonas smiling. “I had just finished my PhD, so I just said: ‘you can get the clone if I can go with the clone’ and that is how I moved with the clone to do my postdoc in the US.”
Jonas and his wife Lisa Nilsson were the first to dissect the downstream connection between Myc and ODC, revealing its importance in tumorigenesis. “We showed that even though inhibiting ODC to halt a growing cancer is not feasible, if you trigger polyamine inhibition before cancer develops as a chemoprevention, then it is quite powerful because elevated polyamine synthesis is required for the transformation event,” Jonas explains. “At the time, we hypothesized about genetic mechanisms but now I think it has to do with tumor-promoting inflammation, which is probably a major function of pre-cancerous elevation of ODC.”
The work granted Jonas an assistant professorship at his alma mater in Umeå, where Jonas began thinking of doing so-called patient-derived xenograft (PDX) mouse models. However, he was struggling to gain access to patient samples. That would change through a chance encounter with Professor Peter Naredi, a surgeon. “We were talking in a room full of people and it seemed like the two of us were the only ones talking. We had a discussion basically in front of everyone watching us like we were crazy. We decided we had to work together.” Again, Jonas jumped at the opportunity and with access to samples, he and Lisa successfully transplanted colon cancer tissue into a mouse.
Urged by the surgeon to try his luck for a position in a clinical department, Jonas sought openings and noticed the newly established Sahlgrenska Center for Cancer Research (SCC) at the University of Gothenburg. Jonas and the PDX models were a perfect fit. Enthusiasm for his work at the SCC lead to a shift in focus to melanoma, with surgeons collecting patient samples for a biobank study and the establishment of novel PDX models. Jonas and Lisa teamed up with Roger Olofsson Bagge and Lars Ny to establish the Sahlgrenska Translational Melanoma Group (SATMEG). Using biopsies from metastatic uveal melanoma patients undergoing liver perfusion, they have also characterized the genetics of the disease via whole-genome sequencing. The list of his achievements goes on. In fact, Jonas contributed in different ways to 5 clinical trials, including the recently published PEMDAC study for patients with metastatic uveal melanoma. “Lisa and I had a mantra for many years that our goal in research was for Lars to start another clinical trial because that was the best thing we could do for patients.”
Interview with Dr. Ahmed Ahmed, Professor of Gynecological Oncology and Director of the Ovarian Cancer Cell Laboratory at the Weatherall Institute of Molecular Medicine (UK)
In ovarian cancer circles, he is recognized for his work on p53. Dr. Ahmed Ahmed’s groundbreaking paper in 2010 demonstrated that high-grade serous ovarian cancer is a p53 mutated tumor and marked the beginning of his systematic characterization of the origin and genetic drivers of the disease. His work has greatly improved the identification of ovarian cancer patients for treatment.
I've really always had a passion for trying to understand the how and why, and I naively thought I’d find all the answers in studying medicine. But actually, there were more questions than answers. My father is a retired surgeon. I think he was also very aware that there were questions to be answered; there were things to be made better. And that's what he encouraged me to look at from very early on. He always thought that me taking the route of discovery is more important to him than keeping me next to him in Egypt. I really owe it to him that he encouraged me to learn, think, and go wherever I need to go and stay as long as I need to stay to discover new things and try to improve things for patients.
When I started in medicine, I met my wife. Her father was a professor of biochemistry at the university where we both studied. He gave me a paper written by Professor Bob Bast where he made the discovery of CA125, which is the tumor marker that we now use for ovarian cancer. That paper was really fascinating to me as a student because it showed me how following simple, solid principles of science can lead to discoveries that make a huge impact. That really infused me to pursue a career in translational medicine – seeing how Bob had done his experiments, repeatedly looking at differences in antibody reactions between ovarian cancer and normal cell lines and finding at the 125th attempt an antibody that separates the two lines. They published these very nice observations and validated them in a large group of patients, showing that CA125 can discriminate between cancer and normal. And then it became routine! Every patient with an ovarian mass benefits from this discovery because patients where CA125 is elevated have priority for rapid surgery.
A very nice, really simple idea, but done very rigorously, lead to something that has helped a lot of people. That made the connection for me. It was clear that I needed to do research and for that I came to the UK. Then I took the opportunity to work for Bob Bast, which was a turning point in my career. Those two years were amazing for me. They helped me to develop as a scientist and gave me great exposure to science in the US, which I find fascinating and exciting.
Ovarian cancers have been notoriously difficult to classify in a way that supports better patient care. I thought, maybe the difficulties stem from trying to directly classify a highly heterogenous tumor. Instead, if we classify normal cells and then look for those subclasses in the tumor, we may be able to do a better job. So, we looked to subtype normal Fallopian tube cells using single-cell RNA sequencing, classify each cell into different molecular entities. We came up with 52 genes that could separate nicely ciliated cells and four subtypes of secretory cells. Then we thought, “if we now go and look at ovarian cancers, can we classify them into different types using the 52 genes?” And the answer was “yes, we can.” If this classification was meaningful, some of these subtypes would have an impact on how well a patient does. We called the classification system the Oxford Classic and tested it in stratifying patients with serous ovarian cancer. The Oxford Classic defined epithelial-to-mesenchymal transition-high (EMT-high) tumors that were consistently correlated with poor prognosis. In every single study that we looked at – we've now looked at nine different studies – we found that the EMT-high subtype, as classified by the Oxford Classic, indicates an up to 3-fold increase in risk of patients progressing or dying early.
The implications of using normal tissue to classify a tumor is fascinating and generalizable to other tissues. We want a phenotypic classification based on molecular background and one solid way to do this is to subclassify normal tissue and then look for those subclasses in the tumor. If you're able to find those connections, they will be solid connections because they are inherited from the normal tissue, and they stay there as the tumor develops.
The Oxford classifier of carcinoma of the ovary, or Oxford Classic for short, uses a panel of 52 genes to identify subtypes of serous ovarian cancer – the most common form of cancer of the ovary, which nevertheless has eluded classification that allows predicting prognosis. By stratifying patient populations according to the Oxford Classic, clinicians can better predict disease outcome and therapy developers gain additional insights about ways to target and eradicate cancerous cells.
Interview with Dr. Agnete Kirkeby, Associate Professor at the University of Copenhagen (DK) and Lund University (SE)
“My mom helps making new medicines.” As simple as that sounds, Dr. Agnete Kirkeby’s ten-year-old daughter describes her mother’s work perfectly. Not only what she does, but also the reason that sustains her tenacity in a field that demands patience and precision like few others.
Creating novel but also “economically and efficaciously competitive therapies”, as Agnete points out, dictates her research approach. “Few of us have the privilege to actually go and apply our research to patients in the clinic. To me, the prospect of doing that is a huge driving force. Opening my eyes to this possibility – that it’s not just something you talk about but a real possibility if you decide to go that way – has been very important in the way I run research today. Every time I plan a research project, it is with that aim in mind.”
Thus, a research program in Agnete’s group begins with a clinical need where current treatments do not solve the underlying problem and where cell replacement makes sense. “The diseases we are looking at here involve small regions of the brain where our therapy can have a more targeted impact. In Parkinson’s disease, we know that the motoric symptoms are caused mainly by a small area of dopaminergic neurons that are lost. We go in and replace exactly those neurons. Similarly for Parkinson’s disease associated with dementia, another small cluster of cholinergic neurons in the basal forebrain is lost and we are looking into replacing those to regain functionality. So, we are looking at those diseases where we know specific subtypes of neurons are being lost in a rather small region but with a huge impact on symptoms.”
Other efforts in her lab are developing protocols to generate neuron subtypes of the incredibly diverse populations that constitute the hypothalamus. “We have several projects where we are generating hypothalamic neurons. One is generating hypocretin-secreting neurons with the aim of treating narcolepsy and another is working on hypothalamic neurons involved in appetite and metabolic regulation to tackle critical questions about the recently demonstrated central involvement of hypothalamic dysregulation in obesity and diabetes.” Through experience, the teams have learned that hypothalamic cells require finesse in fine-tuning developmental steps to derive the right cell types and it is possible that the inherent versatility of hypothalamic progenitor cells limits the purity of the outcome. That requirement for precision, Agnete advises, is agnostic of cell type because “when you work with stem cells, they are never forgiving. If you make a tiny mistake, you’re immediately going to be punished for it because you are not going to get what you were aiming for.”
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