Project Wonder - The art of science at the Medical College of Wisconsin

See-Through Skin Science

What happens when fish skin is as easy to see through as a fishbowl? Scientists at MCW are working on new ways to enable a fish with see-through skin to act as a front-row seat for viewing, studying and better understanding normal growth and development as well as how diseases progress over time. Danionella cerebrum is the name of the tiny, transparent fish of interest in these studies. These fish are typically about half the size of the smallest sardine or herring and are found in the wild within streams that line the slopes of the Bago Mountains in Myanmar.

Danionella cerebrum are unique due to having see-through skin as larvae and adults, unlike zebrafish that have transparent skin as larvae but not as adults, which has proved challenging for longer-term studies that would compare images of a fish’s inner workings taken throughout its life cycle. Adult Danionella cerebrum also are far smaller than adult zebrafish, which makes it easier to capture images of tissues and cells deep beneath the skin.

As promising as Danionella cerebrum have been, scientists also have encountered new challenges when using a microscope to safely capture images of live fish. While techniques developed for larval zebrafish work well for larval Danionella cerebrum, methods for imaging adult zebrafish have required modifications. An approach was reported in 2018 that successfully used low doses of anesthesia and partial submersion in a gel to calm and immobilize the adult fish for a short time while images were taken. Adult Danionella cerebrum can only safely tolerate anesthesia for a brief period of time, however, and the anesthesia itself has side effects that would interfere with some experiments.

Pui Ying (Penny) Lam, PhD, assistant professor of cell biology, neurobiology and anatomy, published findings in Disease Models and Mechanisms in December 2022 regarding a new method for imaging live adult Danionella cerebrum. After inserting an intubation tube that enables the fish to breathe safely, she fully submerged the fish in a gel and placed it in a 3D-printed imaging chamber designed to fit upright or inverted microscopes. Dr. Lam demonstrated that adult fish can be imaged for several hours without anesthesia and emerge unharmed. The experimental results show that this process can be repeated over periods of days, weeks or even months, enabling a wide variety of potential long-term studies.

Dr. Lam’s manuscript suggests a number of potential experiments that are now possible because of this innovative way of imaging the fish with the see-through skin, including investigating interactions between the immune system, nervous system and the gut microbiome. While they are more miniscule than a minnow, Danionella cerebrum are poised to provide scientists with an oversized opportunity to make new discoveries about health and disease.

Animation and soundtrack:
Alex Boyes

Bonnie Freudinger, ME, and Alexander Sherman for assistance in designing and fabricating of the imaging chamber (MCW engineering core)
Suresh Kumar, PhD, Christopher Olsen, PhD, and Garrett Sauber for help with laser calibration and alignment for proof of principle experiment (MCW microscopy core)
Adam Douglass, PhD, and Ariadne Penalva, PhD, for providing wild-type D. cerebrum and guidance on husbandry and animal handling (University of Utah)
Adam Douglass, PhD, University of Utah, and Steve Mangos, PhD, Rush University Medical Center, for feedback on the manuscript and on MCW’s aquatic facility core for the husbandry of D. cerebrum.