Serotonin, Gut-Brain-Microbiome Axis and an Inspired Young Scientist. How a Core Facility is Born. Q&A with Prof. Beate Niesler, Institute of Human Genetics, University of Heidelberg, Germany.
Imagine you are setting up for an interview with a prominent professor at the University of Heidelberg in Germany, in which you will focus on how a scientific interest triggered the need for new technology, and how acquiring that technology led to the creation of a new core lab within the University. Imagine that you get so captured by the stories and the scientific interests and achievements behind it that the interview becomes a friendly conversation. Such was our interview with Prof. Beate Niesler, from the Institute of Human Genetics and head of the nCounter Core Facility at the University of Heidelberg.
Beate funded the nCounter Core facility to grant her team and others within the university access to a state-of-the-art gene profiling technology. Now the NanoString® nCounter® Sprint Profiler supports scientists within the University and outside.
We met with her to talk about her scientific interests and how they drove her to undertake this endeavor. We fell in love with her. We hope our readers will do the same!
NSTG: Prof. Niesler, thank you for meeting with us for our Coffee with The Core Blog Series. We would like to know more about you: your research interests are in the genetics of complex diseases such as neuro-gastroenterological disorders and associated neuropsychiatric conditions. It is a fascinating subject. What got you interested in this?
BN: To make a long story short. As a Ph.D. student, I started in psychiatric genetics with an interest in serotonin. During my post-doc, we discovered novel serotonin receptors never described before in the human genome. It turned out that some of them are restricted to the gastrointestinal tract. Serotonin is a significant player, and at the time, I was not aware that more than 90% of serotonin is actually produced in the gut and only a minimum amount of 3% in the brain. All this was new to me, and I found it fascinating. I became more interested in gut disorders, particularly in a condition called Irritable Bowel Syndrome (IBS). In this disease, patients suffer from pain, diarrhea, or constipation, but also a series of psychiatric conditions like depression, anxiety, and pain conditions like migraine, fibromyalgia, as well as chronic fatigue syndrome. As this was a complicated field, I tried to find collaborators to build my own research group: this is basically how it all started. It was in 2002, so 18 years ago.
Everything around serotonin fascinates me. Since then, my team and I wanted to understand the role of genetic and other intrinsic factors, such as the microbiota and the gut-brain axis or brain-gut axis ─ it depends from where you look. Indeed, most of the communication goes bottom up: 90% goes from the gut to the brain via the vagus nerve: there is a direct connection between the enteric nervous system and the central nervous system; only 10% is going top-down.
The new concept is that the human being is in symbiosis with the microbiota in the gut and on all epithelial surfaces. This field is called neurogastroenterology, and it encompasses different disciplines. In this field, scientists work in large teams doing complementing research, looking from different angles because this is a complex disorder where multiple factors are involved.
The pioneering work of Michael Gershon inspired me. He was the first to claim that serotonin is a neurotransmitter in the gut and coined the term “second brain” in the 1960s, referring to our belly brain, the little brain in our guts. It took him 20 years to convince the neuroscience community that serotonin is not just a brain neurotransmitter. I even spent some time at Columbia University in his lab to learn from him and to master the techniques involved in studying the nervous system in animal models.
Another inspiration for me was Emeran Mayer, from the UCLA in Los Angeles, who already in the 1970s established the concept of the brain-gut axis.
It took these scientists a long time to convince people, and I admire them for this. Interestingly, thanks to the microbiota, a lot of people are now getting interested in the gut-brain axis and think this is a new concept, but this is not true. It’s been there for quite a while!
NSTG: You are the head of the Genetics of Neurogastroenterological Disorder Research Group, and you also lead the nCounter Core Facility at the Institute of Human Genetics. How do you reconcile these many responsibilities and passions?
BN: It is not only me; my team makes that possible. Without them, I would not be able to cover all: the research team and the nCounter team. We work closely together on our research and to run the facility.
NSTG: Why did you choose the nCounter, and what is the best part of using it?
BN: In our research, we are trying to understand genetic variation, gene control, and expression regulation in our samples. I became interested in the nCounter technology because I was working with human tissue, which is very precious and hard to get. Even with my colleagues’ support in the clinic, to whom I am very grateful, human samples are often a limited commodity. NanoString was the perfect fit for me. That’s why I tried so hard to get it to Heidelberg. After my third attempt, we succeeded.
Then I realized: we cannot just put that machine in our department and let everyone use it. Of course, it’s easy to use and has little hands-on, but it’s a precious machine that needs maintenance, and if someone untrained breaks it, it would be a catastrophe. That’s when I realized, “Okay, it must be best to start a core facility and to offer the technology as a service in a standardized way”. With the support of the head of our Department Prof. Gudrun Rappold we could establish the nCounter team and the facility in labs of our Institute. I had no idea how to start, how much work it would be. Setting up a core facility was demanding as we were starting from scratch. We had no idea how to do this. If you offer a service, you have to establish adequate QC and standards, something we learned through earlier scientific projects when we collaborated with the industry: we worked according to Good Laboratory Practices (GLP).
From the beginning of this endeavor, one of my team’s members Ralph Röth and I set standard operating procedures and protocols as the foundation of the core. Then we had to establish the billing system for different users’ categories: in-house, campus, academia extern, and industry partners. We had to have a pricing system, an invoicing system, a contract system. Overall it took one year to set up everything. But already in the first few months, we had the first customers coming in: we learned and improved a lot on the way with our customers!
NSTG: Let’s talk about the core lab. How is the facility organized?
BN: We are located at the Institute of Human Genetics, which belongs to the University Hospital, Heidelberg. The team consists of two technicians: Ralph Röth and Heike Kuzan as well as Marion Schneider who supports in accounting and billing, and me. Cell Networks have funded the equipment within the University of Heidelberg; indeed, we are the Cell Networks, University Hospital of Heidelberg Core Facility.
The facility includes three labs and adequate space and equipment to store ours and our customers’ samples safely. We work according to Good Laboratory Practices (GLP), which means our QC practices are highly standardized. Each sample coming into the facility is analyzed for quantity and quality ─ on a Qubit and Bioanalyzer system, after passing QC, we run the nCounter experiment─ and we perform QC on the generated nCounter data.
On top of this, because at Heidelberg University the Core Facilities offer complementing services ─ something quite unique in Germany ─ we stay connected among ourselves and with our customers thank to the lab management system iLab: now customers that register can access all lab services in campus and track QC and data output results just by logging in. We also offer training and consultations.
NSTG: Who are your typical NanoString users? Do they tend to use more curated gene expression panels or Custom CodeSets?
BN: We have 36% external customers; the remainder are from Heidelberg Campus. We set up an appointment to discuss the project so that I can have an idea of what they want to achieve. Depending on what they decide to do, either go for the custom approach, design their CodeSet, or order a pre-made panel.
From the pre-built ones, a big favorite is the micro RNA panel, but also the nCounter PanCancer Pathway Panels and the nCounter Immunology Panels are extensively used. Since the nCounter Neuropathology Panel came on the market, we now have three projects running on it. Two projects focus on Parkinson’s and the third one on a neurodevelopmental disorder in which the enteric nervous system does not develop properly, causing lifelong gastrointestinal complaints. My team actively collaborates on these projects. I must add that in the two Parkinson’s studies, the focus is on the enteric nervous system and not on the central nervous system.
NSTG: How did you see the nCounter empowering scientists?
BN: Once a year the Heidelberg Core Facility Day takes place; with other core facilities on campus, we promote ourselves, our labs, and capabilities ─ including the NanoString technology ─ and we inform participants on what is new on the market. We teach practical labs and in seminars, introduce students and other PIs to NanoString. We also hosted last year’s NanoString’s European Summit here in Heidelberg, which was very successful.
In 2016 NanoString was involved in an extensive training class on molecular methods employed in research on Irritable Bowel Syndrome within the frame of the international network GENIEUR. We had more than 60 trainees and 20 trainers from all over the world. Lately, the core facility, in partnership with NanoString, has been involved in a research consortium on IBS and comorbid conditions. This novel consortium called DISCOvERIE and the NanoString partnership kicked off in February this year, and it’s within a broader European Commission framework program for research Horizon 2020. We are looking forward to continuing this project since everything is now delayed due to the pandemic. But the big goal is to identify biomarkers to define IBS subgroups, as this is a heterogeneous disorder. My vision is one day to have 3D Biology panels to diagnose these patient entities. Yes. I’m very, very grateful that NanoString has committed to that. It means a lot to me.
NSTG: You said that you were very interested in 3D Biology. You know that NanoString last year in 2019 launched the GeoMx® DSP. It is a groundbreaking platform that is already revolutionizing how scientists are looking at the relationships between different tissue, cells, and biomarkers in two dimensions. Do you think you will include the DSP in your facility?
BN: Definitely. This system is a must-have. I have been working to obtain it since last year. I’m applying for it through the “University of Excellence” Field of Focus 1/HMLS Research Council competition at the University of Heidelberg. I’m currently writing the proposal. Fingers crossed; if this is successful, we will implement it at our core facility.
Before GeoMx, if we wanted to have, let’s say, region-wise resolution, or cell-type-wise, we had to work with cell sorting or microdissection, which is time-consuming, takes ages to dissect everything, and then we have to extract the RNA. And still, this is not spatial resolution: at best, you can tell, “Well, this is this region in the tissue,” but yet you don’t know where precisely the genes are expressed. When I first learned about the DSP system, I was immediately fascinated by it. We have to have it. If this is not working out in this call, we will try again. We will have it one day. I’m sure. Keep your fingers crossed that we can convince the University to buy it for us.
NSTG: Fingers crossed then! Now the last question, we always like to know something fun and light about the lab and the people that work in the lab. Can you tell us something that makes your team unique, something fun, uplifting, not necessarily science related?
BN: As I said earlier, without my team I would be nothing because we have a great team spirit, something that is really important in science since often things get frustrating. You may know this: sometimes, a good chunk of what we do is for the trash bin [chuckles!!]. Therefore, it is critical always to keep a positive spirit. We like to have a good laugh. If we face any kind of issues or challenges, we usually find a way to succeed. To bring it down to or related to the facility, if there is something that we cannot help our customers with, we find a way by asking NanoString to support us. It always somehow worked out in the end. My motto is, “Never give up.” It is why we are still here. I feel that’s what best describes our team.
With her sparkling spirit, her optimism, professionalism, and a great team to always count on, we at NanoString do not doubt that Dr. B Niesler will succeed not just in obtaining the GeoMx DSP, but also in deciphering the genetics of neurogastroenterological disorders. Good Luck, BN!
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