Ulrich Rothbauer: Alpaca antibodies for the pharmaceutical industry

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Ulrich Rothbauer has developed mini antibodies that can be used as a detection tool in living cells. Source: Rothbauer

20.02.2008  - 

Time permitting, alongside his main work on enzymes that play a key role in gene regulation, Rothbauer also conducted research on a certain kind of small antibody found in alpacas, a South American camelid. Somewhat unexpectedly, the doctoral biologist from the Ludwig Maximilians University of Munich (LMU) succeeded in making a scientific breakthrough with this other work, which was ultimately little more than a side project. Building on the alpaca antibodies, he found a way of using the immune molecules as a detection tool in living cells, a task for which normal antibodies are simply too large. "That was a laboratory highlight for me, especially when you consider the frustration that’s often involved in this line of work," recalls the 37-year-old. "It’s really something special, to be breaking new ground, seeing something that nobody has seen before." Now, the researcher wants to start a company, which will sell the new analysis methods and biomarkers to the pharmaceutical industry. With this idea, he was also able to convince the jury of the GO-Bio Competition from the German Federal Ministry of Education and Research (BMBF). In autumn 2007, it was announced that Rothbauer was one of the nine winners.

At first glance, Rothbauers CV doesn’t look especially varied: His working life has been spent exclusively at the LMU in Munich. Rothbauer began his studies and his researcher career there, and has participated in various working groups as well as written his doctoral thesis at the university. "I have always thought that I should get round to moving on. But there are so many good groups here. Munich is a cluster for researchers, and there really is a lot happening here," says Roth, justifying his lack of itchy feet. Thus, after his doctoral studies, he once again chose a position at the LMU. Professor Heinrich Leonhardt was starting out in Munich and was looking for a post-doc with whom he would set up a biochemistry laboratory. "I found that particularly attractive: Not to start work in an up-and-running laboratory, but to create something new.”

In the lab, it was all about DNA methyltransferase, Professor Leonhardt’s “favourite enzyme”. This is a substance that brings about molecular changes known as methylation on the genetic material, thereby playing an important role in gene regulation. This research on the "favourite enzyme" and the creation of the laboratory involved much work; nevertheless, Rothbauer remained devoted to his side project. "When time remained in the evening, I would get busy with my camelid-antibody research," recalls Rothbauer three years later. These camel-like animals are also known as camelids, a group that, alongside camels, also includes alpacas. For immunologists, the camelids exhibit a unique feature in mammals: They have two different chemical classes of antibodies.

Alpacas are camelids that have particularly small antibodies. Pictured here are Anna, Annabell and Ferdel, who have all provided antibodies for Rothbauer’s research.Source: Rothbauer

Normal antibodies do not function in living cells

Antibodies are the key molecules in the immune system. These proteins can be found in every vertebrate, and their task is to recognise foreign material in the organism, such as pathogens or cancer cells, after which they are destroyed by the immune system. Just as a correct key must exist for every lock, the immune system attempts to construct a suitable antibody all every foreign material. For researchers, antibodies are an indispensable tool. A scientist needs only to inject a rabbit or a goat with the substance of interest, and then extract the specific antibodies that bind to this substance from the animal’s blood. Using antibodies, for example, doctors can prove whether a patient is HIV-positive, or whether a bird is carrying bird flu.

However, antibodies do come with one disadvantage: They are comparatively large molecules, consisting of four long amino acid chains. Antibodies cannot be used in living cells because they are too big and accumulate in the insides of the cells. To date, nobody has succeeded in shrinking the antibodies. This is where the alpacas come in: In addition to regular antibodies, these creatures also possess "heavy chain antibodies”, also known as camelid-antibodies. Unlike the usual four chains, these are made up of only two identical amino acid chains.

"This is a gimmick of nature, which only camels and no other mammals possess," believes Rothbauer. Only a few types of shark and bony fish have similarly constructed antibodies. "Professor Leonhardt had long thought that camelid antibodies could be used inside living cells," recalls Rothbauer. Researcher friends who were also working on this molecule, however, suspected that the camelid antibodies would behave exactly like normal antibodies, meaning that they would never work within the cell. "But we were stubborn. We believed that it would work, so we gave it a go.”

Fusing a jellyfish gene and an alpaca gene

Rothbauer tried many different things in the lab. He succeeded in drastically shrinking camelid antibodies without undermining their ability to bind to foreign particles. The small fragments were fused with the so-called "Green Fluorescent Protein". This is a fluorescent green dye that is naturally produced by jellyfish. Rothbauer has christened the resulting hybrid substance made of an alpaca gene and a jellyfish gene “Chromobody”. As a result of the fluorescence, researchers can track exactly where the substance is heading, and where it eventually accumulates. "To say the least, we were surprised when it actually worked extremely straightforwardly in the cells. We’ve carried out many tests to see whether it really is true.” The checks confirmed that Rothbauer and his team had done it on their first attempt – a means of detection using camelid antibodies within living cells.

Rothbauer has big plans for his Chromobodies: He wants to set up a company to sell the advanced analytical methods and biomarkers to the pharmaceutical industry. His approach has already won him third prize in a Bavarian business plan competition; it was also one of the winners of the Go-Bio competition from the German Federal Ministry for Education and Research (BMBF). The competition was set up to facilitate the application of commercially interesting scientific ideas (more...) "This is the first time that I have come into contact with such things as business plans or patent applications," says Rothbauer. But the scientist is not afraid of the challenge: "The commercialisation of my research is a new and interesting area in my life.”

Author: Ragnar Vogt