An ETH spin-off aims to bring gene scissors to the clinic

She is basically more the introverted type, as Lilly van de Venn relates, and she was one of the shy ones during her schooldays. This was after her classmates at Rychenberg High School in Winterthur had suggested that she wasn't intelligent enough to study at ETH Zurich. "The decision to study biochemistry at exactly this particular university was also a reaction out of defiance," says van de Venn. "I wanted to prove them wrong."

So, in 2012, she embarked on her basic studies in biochemistry at ETH Zurich along with 160 students. After a week, there were only 60 left, and by the time she graduated with her bachelor's degree, the class was down to 20 students. "The studies were difficult and there was little time for anything else," she recalls. "But when something really interests me, I have no problem immersing myself in a topic."

In the spotlight for her own business idea

Thirteen years later, Lilly van de Venn is the CEO of a spin-off that does not yet have a name but is already raising high hopes. There is certainly no trace of her former shyness during our conversation at the Institute of Molecular Health Sciences on the H?nggerberg campus. Today, the 32-year old speaks enthusiastically and convincingly about her research, whether in English or German.By now she finds it easy to give presentations and pitches when talking about her business idea at start-up competitions, research conferences or addressing potential investors: a precise and efficient method for reliably detecting unwanted cuts in the genome that are known as off-target effects. This is a crucial issue for therapies based on genetic engineering.

Thanks to CRISPR/Cas molecular biology technology, scientists are able to cut DNA in a targeted manner to remove, switch off or insert genes. This offers great hope for curing sickle cell  anaemia, for example, a hereditary disease of the red blood cells. Today, patients often have to take medication for the rest of their lives with no prospect of a cure. CRISPR/Cas can be used in clinics as follows: blood stem cells are taken from patients. In the laboratory, researchers remove and replace the inherited and disease-causing sequence in the cell's genome. The modified cell is subsequently inserted into the bone marrow, where it divides and multiplies independently ¨C together with the repaired gene. "One of the major challenges is ensuring that CRISPR/Cas only cuts at the intended locations in the genome," explains van de Venn. "Unintended cuts might cause cancer, for example."

Keeping a keen eye on the cutting edges

When the biochemist first heard about off-target effects in cells during her master's degree, she was concerned. "But the more I thought about it, the more interesting I found the question of how to find these unintended interfaces." Given that a typical human cell contains around six billion DNA building blocks, or base pairs, it is extremely difficult to keep track of changes made with CRISPR/Cas. Researchers have therefore been searching for years for methods to identify and describe unintended interactions. Jacob Corn, Professor of Genome Biology at the Institute for Molecular Health Sciences at ETH Zurich is one of the leading experts in this field. He is co-author of an article published in the journal Science in 2019 that presented a protocol dubbed "DISCOVER Seq", a kind of instruction manual for detecting off-target effects.

DISCOVER Seq exploits the principle that all cuts, whether intentional or unintentional, must be repaired in a cell in order for it to remain healthy. Certain proteins are involved in this repair process. The authors' idea is that if these proteins can be found, then it should be possible for all the sites where repair is taking place to also be located, allowing us to deduce where the DNA was previously cut. In order to accomplish this, the researchers fixed millions of cells by "gluing" the DNA and the specific proteins (MRE11) involved in DNA repair together with formaldehyde. With the help of a suitable antibody that binds to MRE11 and certain reagents, they were then able to extract the proteins with cut sites from the previously fragmented DNA in the solution and detect them.

While still studying to obtain her master's degree, van de Venn contacted Corn, who was then working at the University of California, Berkeley. She suggested that she could further develop DISCOVER Seq as part of her doctoral thesis and optimise the protocol for medical applications. "Originally, a large number of cells were needed to detect off-target effects. However, this is neither practical nor feasible in a hospital setting." In addition, processing a sample was a lengthy and complex process.

van de Venn therefore wanted to achieve better analysis results with less starting material. What she didn't know at the time was that Corn was in the process of moving his research group to ETH Zurich. A few months later, the master's graduate began her doctoral thesis in the Corn Lab, right next to the laboratory where she had already worked with CRISP/Cas for her master's thesis.

After months of experimentation, the researcher achieved a breakthrough. She opted for a drug from cancer research for the first time to fix the MRE 11 protein. This is crucial because the further the protein moves away from the interface, the weaker the measurement signal becomes and the more difficult it is to detect off-target effects. "Jacob was skeptical at first, but he thought I should just give it a try." And indeed, the active ingredient molecule proved a perfect fit. It blocks the site where the protein normally moves on the DNA. Today, van de Venn only needs a few cells from a biopsy to detect off-target effects. "This fits into the regular workflow at the clinic when clarifications are being made for patients."

Assessing risks

At the beginning of 2025, the biochemist founded a spin-off company together with her doctoral colleague Charles D Yeh. Their first product is called AutoDISCO/HT-DISCOVER, a standardised procedure for the routine analysis of off-target effects in the development of gene therapies. "We can tell our partners where unwanted cuts in the genome are visible and carry out an initial risk assessment."

van de Venn is convinced that her business idea has come together at just the right time: several clinical trials in patients with blood disorders had to be discontinued due to side effects caused by off-target effects. The European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) have subsequently tightened their regulations for the approval of gene therapies. They now require off-target effects to be routinely monitored. In 2023, the first therapy based on CRISPR/Cas-edited stem cells (Casgevy) was approved in the US and the UK, followed by the EU one year later.

Such therapies still cost between two and three million US dollars and are only accessible to a few patients in wealthy countries. They necessitate highly specialised laboratory and hospital infrastructure and continue to entail biological risks. van de Venn hopes that costs will fall sharply in the future and that therapies will become more widely available, similar to the situation with chemotherapy for cancer today.  Market research companies predict that gene editing will be a 40 billion US dollar market by 2033. Researchers believe that gene therapies could also be used in the future to treat muscle degenerative diseases or genetic kidney or liver damage.