Drugs from hamster cells

On a dark December night in 1948, the American researcher Robert Briggs Watson set out on a perilous 11-hour drive to Shanghai Airport to escape Mao’s communist regime. Despite relentless rain beating down on the windows and mudslides threatening to block the roads, Watson made it aboard the last Pan Am flight out of China.

With him he brought a negligible transport box that would later prove to contain the key to modern-day drug production: 20 Chinese hamsters.

Modifying genes to produce anti-cancer drugs

Carrying his live luggage on board the aircraft, Watson could hardly have foreseen that modern-day biotechnologists would go on to isolate cells from the ovaries of female hamsters, culture the cells, modify their genes—and use them to produce medicinal drugs.

Today, we know that the cells are relatively easy to grow, and that their genes can be modified to produce anti-cancer drugs, haemophiliac medicine, psoriasis medicines, and hormones.
In a laboratory at DTU Biosustain, a so-called bioreactor is hard at work. The machine runs silently. Only a computer screen reveals how the so-called CHO cells—Chinese Hamster Ovary—are performing. A network of interweaving plastic tubes supplies the cells with the right nutrients.

The cells in this experiment are producing the drug Rituximab—a monoclonal antibody that destroys the immune system’s B cells. For healthy people, the substance would be dangerous, but for leukaemia patients whose B cells are hyperactive, not working properly, or are being produced in too large numbers, for example, Rituximab is vital.

“It looks very promising,” says Senior Researcher Helene Faustrup Kildegaard, pointing at the graph on the screen.

The cell is a factory

DTU Biosustain is an international research centre with sections in both Sweden and the USA. In recent years, the centre has worked hard to establish a large unit devoted to CHO cell production. One of the research goals is to force more nutrients to transform from ‘uninteresting’ proteins into anti-cancer drugs within the cell, for example.

“We view the cell as a factory, where our task is to remove all of the machinery not involved in producing the desired drug. We only keep the machinery essential to production,” says Bjørn Voldborg, Director of CHO Cell Line Development.

One of the things that has enabled researchers to make specific changes to the CHO cell metabolism is the mapping of the entire CHO cell genome.

Bioreactor with an experiment in which hamster cells are in the process of producing the drug Rituximab used to treat leukaemia patients. Photo: Ulrik Jantzen.

Sugar is the key

CHO cells usually produce drugs which are large complex proteins. The challenge is that the cell’s proteins do not always completely match human proteins. The reason for this is that the cell ‘embellishes’ the protein with several antenna-like sugar groups—and hamster cell antennae do not resemble human cell antennae. Patients therefore risk suffering an allergic reaction, as their immune system identifies the protein as originating from a foreign organism.

However, now the researchers can control the process to a far greater extent than before:

“We’ve found a way to force the cell to primarily build the right sugars so it only has the correct ‘antennae’. We are thus able to produce the correct product more often and far cleaner than before,” says Bjørn Voldborg.

Highly skilled manpower in demand

Global annual sales of CHO-manufactured drugs run into a two-digit billion-dollar figure and over half of the best selling cancer antibodies are derived from CHO cells. CHO cell research is therefore essential—also for the industry.

“CHO cells are a well-known and recognized system in which to express proteins. Previously, you might have had a concentration of the desired product of 0.1 to 1 gram per litre—now we are up to 2 to 5 grams per litre. So productivity has been improved thanks to research and development,” says Torben P. Frandsen, Vice President of biotech company CMC, which, among other areas, is involved in CHO cell production. He continues:

“We are also finding it difficult to attract highly qualified manpower, which is why it is essential for us that more skilled CHO researchers are trained.”

DNA scissors open black box

Until as recently as four years ago, designing a CHO cell factory was a bit like throwing some screws and nuts into a black box, shaking the box, and hoping that a radio would come out the other end. The problem for the researchers was that they could not choose where to insert the genes. Chance dictated whether the gene was inserted in the hereditary material in an area where the cell could make proper use of it. Destroying gene function also proved costly and difficult—as much as DKK 35,000 (EUR 5,000) per gene modification.

About three or four years ago, a new technology—CRISPR-Cas9—saw the light of day, and with it, the researchers were able to cut the DNA precisely where they wanted it. And equally important: The fragment of genetic code required for cutting—the so-called gRNA—costs as little as a few hundred kroner. In recent years, researchers from DTU Biosustain have worked tirelessly to optimize CHO cell technology.

“CRISPR has enabled us to see inside the black box and more rapidly determine which genes control what. We can systematically turn off genes and insert new ones. The method has revolutionized research,” says Helene Faustrup Kildegaard.

Watch the film about DTU’s work with cell factories.