30th September 2022

Melanie Schirmer: Bioinformatician of the Microbiome

My goal is to use the results of my research to diagnose, treat and prevent diseases.
German version/Deutsche Version
Numbers attract her. They reflect the order of the world. Their logical structure provides support and sense to all natural sciences. Studying them does not force you to commit yourself too early. This is how Melanie Schirmer came to mathematics. This is how she practised the art of abstraction and maintained the freedom to wait until after she had submitted her diploma thesis, before choosing where she wanted to apply her knowledge. In said thesis, she dealt with problems of algebraic topology, a field of intertwining formulae and spaces. But after that, Schirmer, who had studied computer science as a minor subject, felt the strong desire to put all that theory into practice. That was in the years after the completion of the Human Genome Project, when the procedures for sequencing DNA were making ever faster progress, and biologists could no longer cope with the resulting flood of data on their own. “I was fascinated by how detailed the biological information of organisms could be examined.”

Finding and fighting sequencing errors

After receiving a first-class mathematical education at University of Bonn, the Palatinate native moved to Scotland in 2010, to write her doctoral thesis at University of Glasgow. She started working with different sequencing techniques to study the function of bacteria in wastewater treatment. Illumina’s next-generation technology had only recently reached the market. Thanks to its high throughput, it made genome sequencing affordable for smaller labs, and began to displace Roche’s 454 technique. However, the new high-performance technique came with specific sequencing errors, which differed from those of the earlier techniques and were not yet sufficiently understood. “Our focus was to analyse these errors and gain insight into their patterns,” says Schirmer. “This allowed us to develop algorithms that factored in or corrected possible errors, which, in many cases, prevented them from being misinterpreted as biological signals.” Back then, the basis of her analyses mostly consisted in model communities of a few dozen known microorganisms. But Schirmer became more and more dedicated to areas of metagenomics that would truly lead her to previously uncharted territory.

Studying the genomes of entire biological communities

The term microbiota covers all bacteria, protists, fungi, archaea and viruses that, together, form a symbiotic community in a particular environment. The entire genetic information of this respective population is referred to as the microbiome. Metagenomics then denominates a field of research that attempts to decipher this microbiome and thereby venture ever deeper into the almost infinite cosmos of microbial communities. In the past, microbiome research depended on the cultivation of microorganisms, which was problematic, since a large proportion of bacteria still cannot be cultivated. Schirmer says that “sequencing techniques make the cultivation step unnecessary. They have brought a massive leap in microbiome research. Many insights into how important the microbiome is for our health would not have been possible without them.” Naturally, if you want to study the microbiome, you have to sequence a wild mix of entire communities and use the obtained data to extract both genetic identity markers and distinguishing characteristics. One such feature is the 16S part of bacterial ribosomes. All bacteria have it, but each species encodes a very specific sequence. After amplifying the 16S rRNA gene, these variable sequences can be assigned to different bacterial species, which enables researchers to determine the composition of the microbiome. “This technique was very important at the beginning of microbiome research,” Melanie Schirmer explains. “Today, sequencing is so affordable that we can decipher the complete genomes of a microbial community.”

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An excellent researcher

After defending her dissertation in Glasgow in 2014, she ventured from environmental research into medicine. “I found it tempting to apply the knowledge I had acquired to the context of human health, and many of the methods and approaches we developed were relevant to this.” The demand for her technical profile was so high, and her personality so convincing, that a proactive application was enough for her to land a post-doctoral position at one of the most prestigious research institutions in biomedicine, the Broad Institute in Cambridge, USA, which is dedicated to harnessing the full power of genomics to better treat diseases. In 2015, Schirmer went to Cambridge to join Ramnik J. Xavier and Curtis Huttenhower, two luminaries in microbiome research. “The dynamic exchange between their labs was exciting, with many different fields of expertise coming together. One worked closer to the patient, the other focused more on the development of bioinformatic methods.” In this stimulating environment, Schirmer could shine her qualities as a researcher and project manager. “Melanie was the lead in my group on four large collaborative multi-institution projects spanning many years ,” Xavier praises. “Her contributions were pivotal to make them come to fruition.” One of these projects was the 500 Functional Genomics (500FG) Project, in which she made first contact with the experimental validation of interactions between the immune system and the microbiome.

Intestinal microbes influence the release of inflammatory mediators

Every human being carries about as many microorganisms in and on them as they have cells in their body. The large intestine alone is home to about ten trillion microbes that belong to up to a thousand different species. They are absolutely vital for many important body functions such as the metabolism and the immune defense. An imbalance in their composition can make you fall sick. To determine such disease-related changes, DNA is extracted from a stool sample and sequenced. This produces several million short DNA fragments per sample – so-called reads – which are rarely longer than 300 base pairs. Then researchers filter out those sequences that originate from human cells. Then there are two ways to make sense of the millions of microbial DNA shards: Either you compare each fragment to the entries in a reference database to look for matches with microorganisms already recorded there. Or you look for overlaps and assemble the fragments into ever larger fragments, until you can examine which genes they encode, and whether they resemble known organisms or describe new ones.

Melanie Schirmer and her colleagues in the 500 FG Project carried out exactly such a metagenome analysis on stool samples taken from 500 healthy people. Simultaneously, they used blood samples from these people to determine their cytokine levels in response to inflammatory stimuli. Schirmer elaborates: “We then integrated microbiome data with immune profiles to better understand the interplay between intestinal bacteria and inflammation. As a bioinformatician, I used this to derive hypotheses about the presence and behaviour of certain microorganisms, and the expression of messenger substances such as interferon-γ. Several of these hypotheses were subsequently validated experimentally.”[i]

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Focusing on chronic inflammatory bowel diseases

However, knowing which microorganisms are present in the intestine is not enough to find a potential link between the microbiome and inflammatory bowel disease (IBD), which Schirmer became increasingly specialised in. “We also need to know what these organisms do and how they interact with humans.” Some bacteria hardly matter in terms of numbers, while their genes are very frequently transcribed. Other bacteria respond to changes in their environment, such as bowel inflammation, by adjusting their own metabolism. Therefore, Schirmer analysed not only the metagenomes but also the metatranscriptomes of 78 IBD patients, as part of the Integrative Human Microbiome Project. For certain metabolic pathways, she was indeed able to identify “dominant transcribing organisms”, and to hypothesise about their pathogenic influence.[ii] “Her analysis was transformative,” Xavier found. With bioinformatic approaches and analyses, she accelerated the transition in microbiome research from a quantitatively descriptive to a functionally understanding discipline.

What are oral bacteria doing in the intestine?

In April 2020, Schirmer transitioned to Technical University of Munich (TUM) to become the head of an Emmy Noether junior research group. There at TUM, she has been designing her own research programmes to continue investigating the functional relationship between the microbiome and human diseases. For one of these programmes, she conducts prospective studies to investigate why the intestines and other organs of IBD patients are colonised by a relatively high concentration of microorganisms typically found in the oral cavity. This is rarely seen in healthy people. To do this, she compares the genetic identity and activity of microbes from saliva and stool samples. “In our research group, we combine bioinformatics and microbiology to identify possible causes of disease. Then we isolate and further investigate suspicious bacterial strains.”

Why are women more often affected by autoimmune diseases?

For her second major project, which recently earned her an ERC Starting Grant, she focuses on a widely neglected question about women’s health: Could it be that women are much more often affected by autoimmune diseases than men, because there is a previously unnoticed crosstalk between their microbiome and their hormonal balance? “There are cycle-related fluctuations in the microbial diversity of healthy women that don’t occur in men, and these fluctuations are different in women using hormonal contraceptives.” This gender difference is not adequately accounted for in clinical trials and microbiome research, as Schirmer points out. The systematic multi-omics analysis of microbial-hormonal interactions can shed new light onto the causes of disease, and one day it may even lead to the development of new microbiome-based treatments.

Finding a balance between the microbiome and the immune system

The development of chronic inflammatory bowel diseases is also partly genetically determined, says Schirmer. But not all people with a genetic predisposition to the disease end up actually developing it. Many findings point to an involvement of the microbiome. Contrary to the human genome, the microbiome can be changed relatively easily. “My goal is to use the results of my research to diagnose, treat and prevent diseases in which the balance between the microbiome and the human immune system is disturbed.” Munich is a great location for pursuing this goal. The city’s Technical University is home to the collaborative research centre Microbiome Signatures, where Melanie Schirmer learns from others while bringing in some fresh expertise from Boston. For now, her position in Munich is limited until May 2027. With its Life Sciences Bridge Award, the Aventis Foundation wants to support her on her way to a permanent professorship.

Please also listen to the podcast with Melanie Schirmer on “Reassessment of Research Evaluation” brought to you by Elsevier in partnership with Science Business: https://sciencebusiness.net/research-revalution-episode-2

Author: Joachim Pietzsch, Wissenswort
Photos: © Astrid Eckert

[i] Schirmer et al., 2016 Linking the Human Gut Microbiome to Inflammatory Cytokine Production Capacity. Cell 167, 1125–1136 November 3, 2016

[ii] Schirmer et al., 2016 Dynamics of metatranscription in the inflammatory bowel disease gut microbiome.

Nature Microbiologyht https://doi.org/10.1038/s41564-017-0089-ztps://doi.org/10.1038/s41564-017-0089-z