Weizmann Institute of Science scientists revealed the source of the crystalline richness of the animal world and showed how from two simple molecules a dizzying variety of complex biological properties can be produced
What do fish, chameleons, crabs and Walter White, the chemist from the series "Breaking Bad" have in common? The answer is that everyone knows how to make crystals! But while the infamous White Master produces methamphetamine crystals subconsciously for criminal purposes, living beings produce natural crystals for mostly positive and very useful purposes: from vision and camouflage to thermoregulation and communication.
Although many of the molecular crystals produced by living things in their cells are made up of only two molecules - guanine and hypoxanthine - when you examine the various products obtained in this way, your head spins from the abundance of shapes, uses and optical properties. The ability to produce such a large variety using two simple building blocks has intrigued many researchers, but so far no explanation has been found for the crystalline richness of the animal world. Now, in research published in the scientific journal Nature Chemical Biology The scientists of the Weizmann Institute of Science solved the mystery and provided a comprehensive and detailed description of the "biological recipes" used by the cells to prepare an extremely diverse and versatile menu of crystals.
The hero of the story is the zebra fish - a small fish with a spectacular colorful appearance, whose body is studded with many colored crystals. In close-up photos you can see that the tissues of the fish containing crystals are different from each other: while the gill covers are decorated with silver colors, the eyes reflect bluish light, and the skin cells shine in a shimmering yellow or blue.
"In order to understand the source of the differences between the crystals, we decided to isolate them from the tissues, and we discovered crystals that are very different from each other in their shape, composition and arrangement in the cell" says Dr. Dvir Gur, who heads the research group. Using an electron microscope, the research team noticed that the crystalline gill caps are long and narrow, in the eyes they are rather short, and in the skin - almost square. "We realized that the zebrafish crystals are actually a perfect research opportunity to understand how the structure and properties of crystals are determined in the living world, without having to compare crystals formed in different animals that differ in their genetic load," explains Dr. Gore.
When the researchers examined the different crystals of the zebrafish, they noticed that their shape was affected by the ratio between the guanine and hypoxanthine molecules. This finding reminds, for example, the work of the confectioner, who has to choose the right ratio between ingredients to install different flavors: for example, a high ratio of cream to chocolate will produce an airy mousse, while a balanced or low ratio will produce a chocolate ganache suitable for filling or coating. Similarly, when the crystal contains different ratios of guanine and hypoxanthine, its shape changes and with it its optical properties, and accordingly also the way it will be used by animals. After measuring the ratio between the building blocks of the different fish crystals, the researchers were able to imitate the three crystal forms of the fish artificially in test tubes that contained varying ratios of the two building blocks.
The proteins that return the light to the gills
But guanine and hypoxanthine are not only building blocks of crystals, but also essential molecules used by all living things and necessary for the construction of DNA and the normal functioning of the cell. To understand the mechanism behind the balance between them in the crystal, and how the very creation of the crystals in the cell does not harm other biological processes, Rachel Dice, the doctoral student who led the research, isolated the cells that produce crystals - called iridophores - and together with an interdisciplinary research team, deciphered the mechanisms The biologicals that allow them to produce "custom" crystals.
"This is the first time that we were able to isolate the iridophores, identify the proteins found in them, and compare them to cells that do not produce crystals," says Dice, "When we looked at the list of proteins of the iridophores, we were surprised to discover two seemingly contradictory trends: on the one hand, the iridophores seemed to contain an extremely high amount of enzymes responsible for breaking down and assembling the building blocks of the crystal, and on the other hand, there was a lower than normal amount of other enzymes with a similar structure that belong to the same family."
These findings made the researchers suspect that each group of iridophores has a unique enzyme balance - and that it is the unique balance in the cell that determines the ratio between the building blocks of each crystal and, as a result, the structure and function of the crystals in the various tissues. "Humans have only one enzyme that is responsible for the final step in the preparation of guanine, while in fish we have identified five different enzymes," says Dr. Gore. The abundance of these enzymes in the fish allows it to produce different ratios of the building blocks guanine and hypoxanthine used to create the crystals, without disrupting the various cell functions.
Finally, the researchers put the mechanism to the test: they created a fish that is unable to express one of the enzymes needed to create crystalline guanine - the pnp4a enzyme. In normal zebrafish, the enzyme appears in high amounts in the iridophores of the eye, and in lower amounts in the iridophores of the skin. When the researchers created a fish that could not produce the enzyme, the crystals in its eyes shrank and turned from elongated to square crystals, similar to those observed in the fish's skin. The experiment confirmed that each group of cells has a unique enzyme balance, and when the balance is disrupted, changes occur in the building blocks of the cell and, as a result, in the structure of the crystals in it.
"One of the beautiful things about the research is that we were able to decipher the story from beginning to end: from the genes that allow the fish to produce a large variety of enzymes with similar but different functions, through the unique level of expression of each enzyme in the cell, to the way in which the presence of the enzymes determines the relationship between the building blocks of the crystals - and thus their features", concludes Dr. Gore. The researchers attribute the ability to reveal the mechanism in its entirety to the interdisciplinary nature of the research team, which included biologists alongside experts in optics and materials. The findings not only improve our ability to understand nature and imitate its materials, but also highlight the beauty and simplicity of nature: how two simple molecular structures produce a wealth of complex biological functions.
Ola Bayko, Dolev Brenman-Begin, Dr. Tali Lerer Goldstein, Dr. Zohar Eyal and Dr. Tzvia Olander from the Department of Molecular Genetics also participated in the study; Dr. Moshe Goldsmith from the Department of Biomolecular Sciences; Yonghai Dong, Dr. Ziv Porat and Dr. Huey Heinig from the Department of Life Science Research Infrastructures; Dr. Sophia Luchkina from the Department of Neuroscience; Dr. Smeder Levin-Zeidman, Dr. Ido Pinks and Dr. Neta Varsano from the Department of Chemical Research Infrastructures; Dr. Mittal Koperverser from the Israeli National Center for Personalized Medicine for Nancy and Steven Grand, and Sylvia Kaufman and Dr. Rita Mateus from the Max Planck Institute.
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