Linnarsson has long been fascinated by the brain’s complexity. As a Wallenberg Scholar, he has previously created a detailed map of human brain cells, and also of brain development during the fetal stage.

Development of the brain, like that of the body’s other organs, starts with a fertilized egg cell. It divides into more cells, which change form and characteristics to eventually generate the thousands of different cell types found in an adult brain.

“The human brain forms from a single cell, and builds itself.”

Linnarsson is a pioneer in the field of single-cell analysis. In 2011 he showed that it is possible to measure gene activity in hundreds of individual cells simultaneously, which has enabled deeper analyses of the brain’s cell types. Thanks to rapid technological developments it is now possible to study millions of cells in a single experiment.

Focusing on brain cancer

Linnarsson is now directing his research toward clinical applications.

“I’ve always known that if I were going to study diseases of the brain, cancer would be the natural choice. It is biologically fascinating and enormously challenging,” he says.

His own experience has also affected him. His father died suddenly of a glioblastoma at the age of only 49.

Glioblastoma is one of the most aggressive and hard-to-treat forms of brain cancer. Despite intensive use of surgery, radiotherapy and chemotherapy, the average survival time is only slightly more than a year after diagnosis. There is therefore a need for new strategies.

Linnarsson and his colleagues have discovered that glioblastoma cells resemble stem cells from the fetal stage, and are therefore not normally found in the adult brain.

“We see that the tumor cells try to ‘build a brain,’ but the process is chaotic and fails, driving tumor growth instead,” he explains.

This insight led to the discovery of hundreds of tumor-specific enhancers – regulating DNA sequences that are only active in tumor cells. During normal fetal development these enhancers control key processes in brain development. In glioblastoma, however, they are reactivated in an abnormal way.

The idea is to use these cancer-specific enhancers to develop drugs that target only tumor cells.

“This means we can design synthetic DNA molecules that are activated only in tumor cells, allowing therapies that leave healthy cells unharmed.”

Mapping the identity of cancer cells

In order to succeed, the researchers have to produce a detailed map of all cell types in the tumors. They are using advanced methods to analyze the gene activity and DNA structure of individual cells. So far they have analyzed over half a million cells from 52 tumors, which gives some idea of the diversity of tumors both within and between patients.

This mapping is essential since effective treatment must attack all types of cancer cells in the tumor. Otherwise there is a risk that some cells will survive, enabling the tumor to grow back.

When I was younger and started researching, I wasn’t much interested in diseases, but now the opposite applies: I think it’s highly gratifying to be able to find a therapy that might work. We have access to powerful tools, and it’s easier to go from fundamental discoveries to clinical studies.

The next step is to use the information to create vectors, minute DNA packages that can deliver a fatal load to the cancer cells. When these vectors enter a tumor cell a gene is activated that kills the cell. If they enter a healthy cell, however, nothing happens, since the regulating DNA sequence is only active in cancer cells.

Activating the body’s defenses

Reaching the glioblastoma cells poses a major challenge, since they spread deep into the brain tissue. The researchers are examining different lines of attack, including injection directly into the tumor, and vectors capable of crossing the blood-brain barrier.

As an alternative, they are exploring the possibility of using the immune system itself to fight the tumor. Instead of trying to kill all tumor cells in a direct attack, they are hoping to be able to program a small proportion of them so they can start to display a tumor-specific antigens to the immune system.

“The unique feature of this strategy is that we only need to get to a small proportion of the tumor cells. When those cells activate the immune system, the immune cells can search for and destroy the rest of the tumor on their own,” explains Linnarsson.

This approach has yielded promising results in mouse models for other forms of cancer, such as melanoma. The researchers are planning to test their vectors on laboratory-cultured tumors (organoids), created from patients’ cells, and in mouse models containing transplanted human tumors.

On the threshold

Although there is a long way ahead to future therapies, Linnarsson is cautiously optimistic:

“I think that we’re about to cross a threshold, in that we now have the tools to make a real difference.”

Rapid developments in single-cell analysis, synthetic biology and AI make it possible to design new molecules and drugs with a precision that used to be inconceivable. Linnarsson sees his research as part of a major transformation in the field of biomedicine.

Close collaboration with the health care sector is also crucial. The project involves not only molecular biologists, but also immunologists and doctors working in direct contact with patients.

“It’s essential to have doctors who are engaged both in clinical work and in scientific research. They provide us with insights into practical aspects of the disease, and help us to design therapies that are clinically relevant,” Linnarsson says.

Text Nils Johan Tjärnlund
Translation Maxwell Arding
Photo Magnus Bergström