From first families to first trials
Julie van der Zee on biobanking, trust, and the long road from discovery to intervention
How a decades-long conversation with families turned early gene discovery into trial readiness
“We still get emails…”
Every few months, an email lands in Julie van der Zee’s inbox from a family whose history with the Antwerp neurogenetics teams goes way back, sometimes for 30 years or more. A parent or aunt once participated in the early studies that mapped one of the genetic causes of familial Alzheimer’s; now an adult child writes with new questions: Should I consider carrier testing? What about preimplantation genetic diagnosis? Are there clinical studies we could join?
For Julie, who leads the biobank efforts at the VIB-UAntwerp Center for Molecular Neurology, those messages are the living proof that long-horizon science only delivers if relationships, records, and ethics are cared for as diligently as the data.
“Discoveries don’t end at publication,” she says. “Families don’t stop needing information. Closing the loop is part of the job.”
Back then: mapping families
In the 1980s and 1990s, Antwerp research teams led by Christine Van Broeckhoven identified and followed large multigenerational families with early-onset Alzheimer’s disease, including presenilin (PSEN1) kindreds. The work was painstaking: clinical histories, pedigrees, consent documents and linked biomaterials that allowed molecular follow-up as methods evolved.
It was also a different era for genetics. Before next-generation sequencing, discovery relied on linkage maps, positional cloning, Sanger reads... All expensive, low-throughput approaches, she says.
“A single locus could take years to pin down. Large, well-phenotyped families were often the only hope of finding a gene.”
Julie stepped into that tradition in 2003, just after MAPT (tau) had been identified as the first gene for inherited frontotemporal dementia (FTD), and as teams were realizing that many FTD families were MAPT-negative despite mapping to the same 17q21 region.
“That paradox is where I entered the field,” she recalls. As a young PhD student inspired by Christine Van Broeckhoven’s work, Julie and her colleagues went back to the drawing board. They re-contacted and expanded two Flemish FTD families, which meant more home visits, additional clinical documentation, and extensive biosampling.
Early genetic profiling delivered a surprise: the two families (who didn’t know one another) were genetically related, pointing to a shared ancestor. With that insight, additional patients and smaller kindreds could be linked into a growing pedigree, finally giving the statistical power to narrow the signal to GRN (progranulin), about 1.7 Mb centromeric to MAPT, in 2006.
“That was the turning point,” Julie says. “It explained a large slice of tau-negative FTD and set the stage for progranulin-based therapies.”
The discovery didn’t close the book, but signaled the start of decades of follow-up research into disease mechanisms and how to reverse them.
“Nevertheless, that early discipline of pairing biosamples with solid phenotyping and contactable consent still underpins what we can do today,” Julie says. “It’s why the next generation can find us when they need to.”
Long road from mutation to trial
But progress toward therapies wasn’t linear. Years passed with more questions than answers. As research continued in many labs across the globe, the team in Antwerp kept the thread intact by maintaining contact points with families, curating legacy records into modern systems when relevant, and updating consent and ethics as the regulatory landscape changed.
“It’s perhaps not the most glamorous work,” Julie smiles. “But keeping histories straight and documents usable meant those collections wouldn’t become stranded assets.”
That continuity now pays off. Belgium’s progranulin (GRN) families have begun to see tangible movement: recent Leuven-led trials reported increased granulin levels, with clinical effects still under evaluation. Through Rik Vandenberghe’s team (UZ Leuven/KU Leuven), Leuven is one of the clinical trial sites of a GRN gene therapy (Prevail Therapeutics), while Rose Bruffaerts’ group (UZA/UAntwerp) in Antwerp represents a clinical trial site for a GRN protein replacement therapy (Denali Therapeutics & Takeda).
“For our GRN families, being able to say ‘there’s a trial and the biomarker moves in the right direction’ is definitely meaningful,” Julie notes. “It doesn’t promise outcomes, but it shows we are building an arc from discovery to intervention, slowly but surely.”
GRN in context
Then / In 2006, haploinsufficient loss-of-function mutations in GRN were identified as a major genetic cause of FTD, typically with TDP-43 pathology. Carriers have ~50% lower circulating progranulin. These discoveries were made by teams led by Christine Van Broeckhoven, former Director of the VIB-UAntwerp Center for Molecular Neurology, side by side with Rosa Rademakers at the Mayo Clinic, who heads the VIB-UAntwerp Center for Molecular Neurology today.
Impact / GRN transformed diagnostics worldwide (low plasma/serum granulin became a practical biochemical flag for carriers) and reframed FTD biology around lysosomal and inflammatory pathways.
Now / Therapeutic concepts aim to restore progranulin, e.g. through AAV-mediated gene transfer, recombinant protein, or small-molecule enhancers. Early trials have shown target engagement, but determining clinical benefit will take longer and larger studies.
Meanwhile, gene-targeted strategies for PSEN1 mutations are moving onto the horizon (in addition to the anti-amyloid drugs that are reaching the market). Julie is hopeful that, in the near future, she will also be able to reach out to those families they worked with all those years ago to offer them a chance at participating in a clinical study.
Close contact with clinical partners closes the loop on both ends, she says:
“Through the clinical sites of our partners, patients and carriers are included in the research collections. At the other end of the 'circle', many clinics are also trial sites for studies targeting genes we and others have identified, like PSEN1, GRN, C9orf72.”
PSEN1 in context
Then / The Antwerp team led by Christine Van Broeckhoven mapped multigenerational families with early-onset Alzheimer’s and identified missense mutations in PSEN1, which encodes the catalytic core of the γ-secretase complex. Many variants shift APP processing and raise the Aβ42/Aβ40 ratio, a hallmark of early amyloid pathology.
Impact / The work enabled molecular diagnosis and counselling for affected families, created well-annotated cohorts for longitudinal study, and seeded cell/animal models that underpin therapeutic development.
Now / International efforts now explore gene-specific or pathway-targeted approaches (e.g., allele-selective strategies, γ-secretase modulation, downstream amyloid-targeting), with trial pipelines where well-documented families are crucial for design and recruitment.
Biobanking 2.0
Between those early studies and today’s trials lies a lot of careful, often invisible work. Many of the emails Julie receives are about choices: carrier testing, reproductive decisions, and whether to take part in research.
“To support those choices, consent has to ‘travel’—across time, across institutions, and across use-cases,” Julie explains. “We’ve reworked templates so samples and data can be responsibly reused in academic and non-academic collaborations, nationally and internationally.”
Since 2018, Belgium’s biobank law has set a high bar for traceability and oversight. CMN now operates as a decentralized hub within Biobank Antwerp (UZA–UAntwerp): samples can be stored and processed locally at CMN, while legal/ethical compliance is centralized and consistent. Pre-approved consent language and agreement templates allow collaborations to move quickly, without cutting corners.
“Families don’t see the bureaucratic procedures, and they shouldn’t have to,” Julie says. “But reducing friction for researchers is part of honoring participants’ contribution and their wish to move the field forward. It’s important because it gets the science done.”
The same ethos now informs Banking the Brain, a Flemish effort led by VIB-CMN (Kristel Sleegers) and Biobank Antwerp to make well-consented, shareable collections the norm, so families’ contributions keep powering new studies.
Learn more about biobanking
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People first
CMN’s biobank today is bigger than any single disease. Longitudinal healthy-elderly cohorts sit alongside disease-focused collections in Alzheimer’s, FTD, ALS, Parkinson’s, epilepsy, and peripheral neuropathies.
Low-burden sampling opens doors for early biomarker work, variant-aware selection feeds iPSC and CRISPR models, while deep annotation supports both discovery and validation.
But the center of gravity hasn’t changed: people.
“Biobanking is science, regulation, and logistics,” Julie says. “But at heart, it’s a relationship between researchers and participants, across generations. Keep that relationship healthy, and the science will follow.”
Liesbeth Aerts
