The human blood system is a marvel of constant regeneration, with millions of new cells replacing old blood and immune cells every second. These cells originate from hematopoietic (or blood-forming) stem cells in the bone marrow, maturing through several different developmental stages into the red and white blood cells, platelets, and B and T cells that keep us alive. While clinical blood tests can easily count these cells, determining the specific contribution of thousands of individual stem cells to overall blood production remains a significant challenge.
By observing natural mutations in human DNA, researchers can gain fundamental insights into how stem cells maintain healthy blood formation or how they behave when disease strikes. However, hunting for a single mutation within a genome of three billion base pairs is expensive, time-consuming and prone to error, even with today’s most advanced technology.
Cellular power plants reveal the origin of blood cells
To bypass these hurdles, Leif S. Ludwig focuses on natural mutations within the mitochondrial genome – a much smaller, more manageable DNA molecule found within cellular power plants known as mitochondria. By pairing this approach with sophisticated single-cell sequencing technologies, his team can analyze tens of thousands of blood and bone marrow cells simultaneously, effectively mapping the activity of blood-forming stem cells. This single-cell analysis of natural genetic variation does more than track lineage; it provides vital information on the health of individual cells. In a clinical setting, this could eventually help doctors to predict the success of stem cell transplants or fine-tune cell and gene therapies with unprecedented precision.
Beyond this work on hematopoietic stem cells, Ludwig is tackling the challenge of inherited mitochondrial mutations. These defects are among the most common genetic disorders and can trigger a wide range of metabolic diseases affecting multiple organ systems. Despite their prevalence, the molecular causes of these conditions remain poorly understood. By investigating how mitochondrial gene variants influence different cellular and metabolic phenotypes, Ludwig aims to lay the groundwork for new therapeutic approaches. This pioneering research has earned him the prestigious, DFG-funded Heisenberg Professorship for Stem Cell Dynamics and Mitochondrial Genomics at the BIH.
“The Heisenberg program supports outstanding scientists, so it was no surprise to us that Ludwig was selected for this honor,” says Prof. Christopher Baum, Chair of the BIH Board of Directors and Chief Translational Research Officer of Charité. “His exceptional work combines basic research and application-oriented studies. Ludwig and his team are thus strengthening the translational network that brings together the BIH, Charité, and the MDC for the benefit of patients.”
About Leif Ludwig
Leif Si-Hun Ludwig studied biochemistry at Freie Universität Berlin and then human medicine at Charité – Universitätsmedizin Berlin. As a doctoral candidate and postdoc, he conducted research at the Whitehead Institute of Biomedical Research and the Broad Institute of MIT and Harvard, both in in Cambridge, Massachusetts, in the United States. Since November 2020, he has been an Emmy Noether Group Leader in the joint focus area “Single-Cell Approaches for Personalized Medicine” of the BIH, the Berlin Institute for Medical Systems Biology of the Max Delbrück Center for Molecular Medicine (MDC-BIMSB), and Charité. His laboratory is based at MDC-BIMSB. Ludwig has received multiple awards for his research, including the Hector Research Career Development Award in 2021 and the Paul Ehrlich and Ludwig Darmstaedter Prize for Young Researchers and the Heinz Maier-Leibnitz Prize in 2023. In 2024, he became a member of the EMBO Young Investigator Network.
A light switch for genes
For decades, the development of specialized body cells from pluripotent stem cells was viewed as a one-way street. However, groundbreaking research has since proven that mature cells can indeed be “reprogrammed” back into stem cells by introducing specific genes. The resulting induced pluripotent stem (iPS) cells hold immense promise for regenerative medicine, offering the potential to repair or even replace damaged organs. Crucially, because these therapies can be derived from a patient’s own cells, they pave the way for truly personalized medical treatment.
This cutting-edge field is the focus of Daniel Ortmann’s research at the BIH. The stem cell biologist plans to investigate the precursor cells of the mesoderm and endoderm – the embryonic tissues responsible for forming not only bones, muscles, the circulatory system and the kidneys (mesoderm) but also the liver, thyroid gland, pancreas and parts of the digestive tract (endoderm). He is particularly interested in deciphering the mechanisms that dictate how the early mesoderm and endoderm differentiate into certain cell types in the body.
In a major leap forward, Ortmann and his colleagues developed a method that precisely controls how genes are toggled on and off, much like a light switch. One of these high-precision “switches,” patented under the name OPTi-OX, allows researchers to program cells into specific target types with greater efficiency and higher quality than ever before. This breakthrough was so pivotal that it served as the foundation for the biotechnology company bit.bio.
Despite these advances, the field of cell therapy still faces a significant hurdle: purity. If even a few unprogrammed stem cells remain in a treatment, they carry the risk of forming tumors. To solve this, Ortmann recently co-founded Plurify, a biotech start-up that uses RNA-based technology to eliminate these unwanted cells. By ensuring the purity of the final product, the goal is to make cell-based therapies safer, more effective, and ultimately more affordable for the general public.
As he takes up the BIH Professorship for Cellular Programming, Ortmann is concentrating on moving these innovations from the lab to the clinic. “My goal is to perfect cellular programming so we can produce therapeutic cells of the highest quality at scale,” he says. “We don’t just want to understand cellular biology; we want to reprogram it in order to cure diseases. The clinical excellence of Charité and the translational ecosystem of the BIH provide the ideal environment for this work.”
About Daniel Ortmann
Daniel Ortmann studied molecular medicine at the University of Ulm from 2003 to 2008. He then did his PhD work at the University of Cambridge from 2009 to 2014, remaining there as a postdoctoral researcher until 2019. Ortmann worked at bit.bio from 2019 to 2023, where he held several leadership positions, including Senior Scientist, Head of Discovery and Principal Scientist. After briefly serving as a Founder in Residence at Deep Science Ventures from 2023 to 2024, he co-founded Plurify in 2024.
