Interpreter of signals
An egg holds the potential of life, says Dr. Annette Hammes. Out of single cell, an entire organism with all of its unique characteristics, including an unfathomably complex brain, can develop. But an egg also carries the risk of developmental disorders. A single mistimed signal or gene activation in this precisely orchestrated process can lead to rare and sometimes severe disabilities.
One such condition is spina bifida, in which the spine fails to close properly. It affects up to five in 10,000 children in Europe. Another is holoprosencephaly, a defect in which the forebrain fails to divide into two hemispheres. Severe forms are often fatal before birth; milder cases may cause significant neurological and cognitive impairments. “Each developmental disorder is rare on its own – but together, they are the leading cause of infant mortality,” says Hammes, who leads the Molecular Signaling Pathways in Cortical Development lab at the Max Delbrück Center.
Driven by a deep sense of curiosity, Hammes is investigating the molecular missteps behind these conditions. She studies how signaling pathways shape the development of the brain, central nervous system, and heart.
A finely tuned network of signals
In humans, brain development begins in the third week of pregnancy with a process called neurulation. One of the embryo’s three germ layers – the ectoderm – forms the neural plate, which bulges at the edges and closes to form the neural tube, the precursor structure of the brain and spinal cord.
This process is governed by a multitude of signaling molecules called morphogens. These molecules bind to the surface of neural stem cells and trigger a cascade of effects: instructions tell cells when to activate or deactivate specific genes. These cells in turn, carry out their specific roles in the developing embryo. While researchers have mapped many of the major signaling pathways, mechanical signals from surrounding tissue – which also influence cell behavior – remain poorly understood.
To study these signals during brain development, Hammes compares mouse brains with human cell cultures. Thanks to induced pluripotent stem cells, she can replicate aspects of embryonic brain development in the lab. Advanced microscopy and omics technologies provide deeper insight: proteomics reveals which proteins are active, while transcriptomics identifies RNA molecules.
This allows Hammes to pinpoint what proteins and genes are involved at various developmental stages. “Even for pathways we think we understand well, new methods show us we’re only scratching the surface,” she says. “Depending on the tissue, organ, cell type, or stage of development, the complexity of these pathways is only just beginning to be revealed.”
Tiny errors, serious consequences
In holoprosencephaly, for example, the Sonic Hedgehog (SHH) pathway is often disrupted by mutations. If, for example, the SHH co-receptor LRP2 on the surface of stem cells is not functional, the neural tube may not form properly. Surviving children can have severe facial deformities, such as fused eyes. Milder forms may result in cleft lip and palate.
Hammes discovered that two genes – ULK4 and PTTG1 – can compensate for defects in the LRP2 receptor. When these genes are highly active, they bolster the SHH pathway and either reduce the severity of malformations or prevent them altogether. “If we can figure out exactly how PTTG1 and ULK4 are regulated, we could specifically stimulate them to restore the signaling pathway,” she says.
For Hammes, decoding these developmental mechanisms in detail is a prerequisite for future targeted therapies. “Basic research is where my heart is,” she says. “But every now and then, I take the long view and think of clinical applications.” One can learn a lot by comparing healthy and disrupted brain development. “When and why does the system break down – and when should we intervene?”
In collaboration with colleagues at Charité – Universitätsmedizin Berlin, Hammes is also exploring the role of folate – vitamin B9 – during pregnancy. Supplementation is widely recommended to prevent neural tube defects such as spina bifida. “In cell culture, we’re looking at folate’s exact effects during neurulation – beyond its known role in promoting cell division – and whether it might sometimes have negative consequences.”
A sensory signal for healthy hearts
Hammes also investigates embryonal heart development – and how it is linked with the brain. The two are more tightly connected than one would think, she says. During neurulation, a special population of precursor cells begins a long migration through the embryo. “Neural crest cells form facial bone and cartilage, sensory neurons in the skin, and structures in the eye, inner ear, and heart,” says Hammes. “When the brain develops abnormally, this is why other organs are often affected as well.”
With her team, she discovered that PIEZO2 – a mechanosensitive ion channel in neurons –does more than relay the sense of touch from skin to the brain. It also plays a crucial role in heart development. “If PIEZO2 is missing or overly active, coronary vessels don’t form properly,” she explains. The result: thickened heart muscle and a high risk of hypertension, heart attack, and aneurysms.
To explore PIEZO2’s role, Hammes’ team developed complex cell culture models. But she has also kept the “long view” of clinical application in her sights. If researchers could reactivate a dormant PIEZO2 channel, it might help repair damaged vessels after a heart attack.
With heart and mind
Hammes’ interest in the health of the heart goes back decades. After studying biology at the University of Bonn, she completed her doctorate at the University of Würzburg, researching calcium pumps that regulate calcium ion flow in heart muscle cells. She discovered that a specific pump controls the growth and maturation of heart cells.
Around 1993, she arrived at the Max Delbrück Center. What began as a three-year stay has turned into more than 30. As a postdoc, she investigated a gene critical for kidney function. Just after submitting her findings to the journal “Cell,” she reached a major personal milestone: “That was on a Saturday – on Sunday, my first daughter was born,” she recalls. At the Max Delbrück Center, she had met researcher Gary Lewin, with whom she now shares three children. Family was an important reason for her to stay in Berlin.
In Professor Thomas Willnow’s lab, Hammes studied the receptor LRP2’s role in kidney function – only to notice many mice developed holoprosencephaly. This observation launched her into a new research direction. She eventually unraveled the mechanisms behind the disorder. In 2006, she was awarded a Delbrück Helmholtz Fellowship to study brain and heart development, organ crosstalk, and the origins of congenital defects. She launched her own research group in 2017.
Always new questions
Hammes is motivated by a passion for the unknown. “I tend to be incredibly enthusiastic,” she says. With her children now grown, she’s throwing herself into her work. Her dog Mali, a herding breed, often joins her at the office. When she takes a break, she trains Mali how to track.
She encourages her PhD students to embrace the same curiosity that drives her: “There’s so much left to discover! We’re not even seeing the tip of the iceberg.” If anything, the iceberg continues to grow. How environmental factors shape the developing brain is still unclear, she says, and researchers continue to identify potentially new threats. “We don’t yet know how microplastic particles accumulating in neurons affect embryonic brain development, for example.”
New technologies are also revealing previously invisible brain structures – such as delicate connections between neurons during early development. Their function remains unknown. “We need to go back to basics first,” says Hammes. The egg – with all its pathways and missteps – still holds many mysteries.
Text: Mirco Lomoth
