A First-Hand Look at Evolution

Joachim Wittbrodt rules over 3,500 aquariums and close to 50,000 fish. As a boy, the biologist liked to catch them, now they have “caught” him — Wittbrodt examines the eyes of vertebrates, especially of fish.

“Fish are ideal: you can keep large numbers of them and their eyes have basically the same structure as human eyes”, says the zoologist, who conducts research within the CellNetworks Cluster of Excellence at Heidelberg University. The main difference is that fish eyes grow and regenerate continuously. However, according to Wittbrodt, even human eyes have a cell type with the capacity to regenerate. “Right now, we’re testing this repair work on fish eyes. Maybe the results can someday be applied in ophthalmology, to help heal retinal injuries, for instance.”

Prof. Dr. Joachim Wittbrodt

“Have you ever noticed that young fish are not cute?” Joachim Wittbrodt asks the question almost casually. But this observation is a precondition of his research. Unlike in small children, fish eyes are not disproportionately large at birth. That is why small fish are just that: small fish. And because their organs, too, grow throughout their life, we can observe developmental processes in fish that are long completed by the time a human baby is born.

Joachim Wittbrodt has revolutionised the way in which we watch animals during their development. “This is life”, he exclaims while the flat screen on his office wall shows the first day in the life of a zebrafish embryo. The film begins with the first cells, shows how they divide and begin to migrate and ends when the head and tail are clearly discernible. Wittbrodt and his team have marked individual cells with a fluorescent gene. Now they observe what becomes of each cell. Sometimes they rewind, e.g. to find out where a cell that ends up in the eye originally came from. That is how they refuted the dogma that cells march to their destination in close formation like an army. In the past, Wittbrodt was fascinated by molecular biology, because hypotheses could only be tested by means of sophisticated experiments. “Today, it’s just a tool. We can observe and analyse processes directly.”

The key to these new possibilities is located in a room adjoining Wittbrodt’s lab: the Digital Scan Laser Light Sheet Microscope (DSLM). It stimulates fluorescence in individual cell layers of the organism — by means of a plane of light similar to that produced by a narrow gap between two curtains. The DSLM was developed by Heidelberg physicist Ernst Stelzer of the European Molecular Biology Laboratory (EMBL) and his team at Wittbrodt’s initiative — the idea was born during a coffee break. “We finally wanted to look inside living animals”, says Wittbrodt. Now he gets 500 images per minute, and makes them into a film. The DSLM needs about 10,000 times less light than standard micro - scopes. Where embryos were bleached to death in the past, researchers can now watch them grow live and in colour — for up to 24 hours. This ground-breaking discovery won Wittbrodt and Stelzer the 2009 HMLS Investigator Award of the “Heidelberg Molecular Life Sciences” (HMLS).

Wittbrodt’s office has a view of Heidelberg Castle. “It looks like tradition and stagnation”, he says, “but everything here is in a constant state of flux.” Short ways, flexible decisions — these characteristics of Heidelberg University came as a positive surprise. When they were in danger of losing a good colleague who was offered a sequencing lab elsewhere, several scientists and the “Cellular Networks” Cluster of Excellence chipped in to purchase devices for 800,000 EUR. “That kind of thing is only possible if no one takes himself too seriously”, says Wittbrodt. It was the same with the founding of the Centre for Organismal Studies (COS) that combines botany and zoology — also an idea that originated in the cafeteria. “The botanists know pretty much everything there is to know about metabolites, and we are experts in development and imaging”, he explains. “It’s the perfect match. Together, we can look into cells while they grow and move, and adapt them to the respective conditions. That’s really unique.”

The lab next to Wittbrodt’s office is a beehive of activity. The biologist’s research group includes 22 doctoral candidates, postdoctoral researchers, and technical and administrative staff. Seven of his former doctoral candidates and nine of his postdoctoral researchers are now professors — not least because of Wittbrodt’s leadership skills. “I don’t constantly look into my co-worker’s lab journals. Otherwise pretty soon I’ll be the only one thinking.” One of Wittbrodt’s doctoral candidates created fish in which the gene for green fluorescent protein (GFP) is always active in all cells. He christened the fish “Wimbledon” after the perennially green “holy lawn” of tennis. When the researchers transplanted these cells into the area of the fish eye that permanently creates new retinal cells from stem cells, they made an astonishing discovery: The stem cells did not just develop into certain cell types of the retina, like retinal ganglion cells or amacrinal cells, they actually formed all of the cell types that together make up the retina.

There are many indicators that in the human eye, which does not have such a stem cell region, the structure-forming Müller glia assume this multipotent function. “Maybe one day, we’ll just have to stimulate these cells and they’ll repair eye damage on their own”, says Wittbrodt, thinking of possible future scenarios. He wants to publish a paper on this subject this year. It wouldn’t be his first coup.