Scientists are a step closer to unraveling one of the greatest mysteries of the biological world: how stem cells morph into different organs and tissues to create a living creature.
Thanks to a remarkable little fish, and some very cleaver engineering at Lawrence Berkeley National Laboratory, they now can watch in real time as an undistinguishable blob of cells gradually change into an embryonic zebra fish, one cell at a time.
Until now, scientists could only observe this process by harvesting a living animal and examining each step as it moves through the embryonic stage.
It would be far more constructive if they could actually see those changes from the very beginning in a live subject and follow the process through to the end. And that's exactly what researchers in Carolyn Bertozzi's lab have accomplished.
The star of their show, however, is a tiny transparent fish that has become a lab darling. Scientists can literally see inside a zebra fish without having to kill it and cut it up.
Bertozzi's team wasn't interested in just looking inside the fish. They wanted to examine it on the cellular level with an atomic force microscope. The researchers invented a way to zero in on sugar molecules, called glycans, on the surface of individual cells inside a zebra fish within seven hours after her eggs were fertilized.
"We wanted to look at how the sugars change in a live embryo all the way from the point of conception to when the organism is fully developed with all its organs and systems, so we did that with the zebra fish," Bertozzi said in a telephone interview.
Initially, the embryo "just looks like a ball of cells and there's no obvious formation of organs yet," Bertozzi said. "So a lot of these cells have not yet made a decision about what they are going to be when they grow up. We want to look at the sugars as they make those decisions."
What role could sugar possibly play in this complex process? A huge role, according to Bertozzi, who started studying glycans a couple of decades ago because nobody knew much about them. As she put it, the field was "uncharted territory."
After many years of research in her lab and other labs around the world, sugars are earning a lot of respect.
Bertozzi believes they might be the on-scene commander, and the traffic cop, and the communications director in the complex process of assembling a living animal. Do they play a major role in the process by which stem cells morph into different cells?
"I'd be shocked if they didn't," she said.
Glycans, or sugar molecules, are found primarily on the outer surface of all cells.
"The description I use for my students [at U.C. Berkeley] is it's like a peanut M&M: It's got a sugar coating, but the sugars look like they encode a language," Bertozzi said. "So when two cells get together, they kind of peck on each other's sugars to get information."
So sugars probably act as architects and traffic cops, directing some stem cells to become neurons, and others to become blood cells, and so on throughout the formation of the embryo.
But not only do the stem cells morph, so do the sugars on their surface. The sugars are chemically and biologically different on a stem than on an adult cell. It's not clear why that should be the case, but it may turn out to be very helpful a few years, or possibly decades, down the road.
It may help, for example, locate stem cells in a mature organism and reprogram them to fix a broken spinal cord.
"We now know that early embryos have mostly stem cells," Bertozzi said. "But even adults, you and I, still have a few stem cells in our bodies and we rely on those stem cells to help regenerate damaged tissues and damaged cells. If we could just harvest our own stem cells and use them to regenerate organs, we would have an incredible opportunity to treat degenerative diseases, many of which are associated with aging.
"But adult stem cells are hard to find and hard to isolate because they are few and far between," she said.
It may be, however, that those adult stem cells have a unique signature in their sugar coating, and thus they may not be as hard to find, and as hard to reprogram, as it seems.
Bertozzi's colleagues published their findings in the Proceedings of the National Academy of Science. The lead author is Jeremy Baskin, who is now doing post-doctoral research at Yale University.
The researchers are excited about their work because it adds to our understanding of how nature works.
"Obviously, that's a major driving force," Bertozzi said.
But if they can figure out this complex puzzle, the possible list of applications is endless.
For example, some scientists contend that despite the wonderful role stem cells provide in creating the organs and tissues that make life possible, there may be a few bad apples in the crowd. Some believe some stem cells actually cause cancer, or at least allow it to spread, but that's a very contentious arena.
If it's true, and if the code in the sugar coating can be deciphered, it may be possible to target those cancer-causing stem cells and wipe them out before they do all that damage. But that's a long shot. No one really knows at this point.
But if Bertozzi's team is right, there is no doubt that sugars are major players in changing a clump of cells into a distinct living organism. And a small fish is allowing them to do "transformative research" because it is, well, so transparent.
"Zebra fish are a far distance from human beings, on the one hand," she said. "But on the other hand, they are vertebrates and when you get right down to it we share a lot of the same bits and pieces. Our parts list is not too different from theirs."