[MUSIC] So in this presentation I'd like to tell you about the field of chemical biology. Give you a little bit of history and tell you why we think that chemical biology is a very powerful approach to study biology. But first, let me tell you a little bit about biology. Biology and all the things that happen in biology follow the laws of Physics. Physics governs the forces involved in the motion, in the mechanics, in the enzymatic reactions, etc of life and live cells are made of chemicals. These chemicals are interconverted between each other there assembled into macromolecules. For example the hereditary material, DNA and can be assembled into other complex structures. For example, membranes which lead to production of a cell which is a building block of organs, an organisms. So life is just the combination of physics, chemistry and biology and if we re going to understand biology, we need to understand the molecular basis of life. And for this we need to understand the physics, chemistry and the biology altogether. And when these fields of physics and chemistry and biology get together, we can increase our understanding of life. So the biological chemistry came about when chemists decided to be interested in biology and what they did was to observe nature, an isolate the molecules of nature and characterize them. And some examples are shown here. Urea, quinine and vancomycin. These molecules were isolated from biological materials. Also, you have the examples that I mentioned before, for example, DNA which was isolated from biological material and turned out to be the hereditary material. Now the chemists were inspired by nature but they also tried to mimic nature. But only later on, after they had isolated these molecules from their biological sources, where they able to actually synthesize them in the test tube by themselves. Now the biological chemists isolated the materials and described what they were, but we still didn't know how these molecules fit together. And to do this, a new field was created, which is called biochemistry. And what the biochemists did was to take everything apart and try to reconstitute it together to learn how it worked. And one of the big questions they asked was how do all these chemical processes fit together in the cell? And here we have an example of one of those complex pathways which was discovered and delineated by biochemistry. And that's a pathway of glycolysis. It starts with a sugar usually coming from starch or glycogen an you get glucose. This glucose is phosphorylated and goes through the glycolytic pathway which you see here to give you pyruvate. This pathway produces ATP, a form of energy and also reducing power, which is also a form of energy which is converted to ATP in the mitochondria. Now, the biochemists isolated enzymes which catalyzed these reactions, and they characterize these enzymes in a test tube and could understand how well they worked. And they were able to show, for example, here with the enzyme triosephosphate isomerase that nature has an awesome power to do better than actually than the chemists can do. So if you look at the triosephosphate isomerase and when they studied the in vitro, they found that its rate constant was over 100 million molecules per second. And this is actually almost the fastest rate possible, meaning that this is probably diffusion limited in the cell. And it's a 1 billion fold increase in the rate over the background. Now the biochemists and the enzymologists could take all this apart, they could even reconstitute, some pathways, simple pathways, such as glycolysis. But how do we know that the same pathways are regulated and work as they do inside the cell? And this is where came up the field of chemical biology. The goal of the field of chemical biology is to control chemical processes inside the cell. Here we have the test tube, which was the field of the biochemists. And now we're taking a cell culture, which is where the chemical biologists will work. And what they try to do is to control and visualize these processes in the cells or in an organism, for example here a zebrafish embryo. So the zebrafish embryo is fertilized and then the cells divide. There's a number of symmetric and asymmetric divisions that give you eventually an embryo and a fish, and this takes about three months. Now there are ways to intervene with this developmental process. And when we do that, you can see that these errors can be lethal and are easily seen. So for example, this kind of aberrant development could be seen through a genetic intervention using tools of genetics, or through a chemical biological intervention using a small compound. Now chemical biologists were inspired by nature, and as the chemists, they isolated molecules from nature, and we have an example here which is staurosporin. So staurosporin is a kinase inhibitor, and it inhibits kinases inside the cell, but it didn't work so well, for example, in the clinic. It was modified by medicinal chemistry to form midostaurin. Midostaurin is now derived from staurosporin and is approved drug to treat cancer. Another prime example of naturally inspired inhibitor design is penicillin. Penicillin was isolated by Fleming from a fungus, because it killed bacteria, and penicillin was used as an antibiotic for years. However, it's been improved by medicinal chemists who made carbenicillin, which is a more effective inhibitor of bacterial growth and a more effective antibiotic. So the chemical biologist is inspired from nature and can intervene inside the organism or inside the cell. So we want to control the chemical biological processes in the cell, but we need to visualize them. We need to be able to see them, so that we can follow them. And in order to do this, we can introduce molecules inside the cells or inside an organism that allows us to see the molecules in motion. And one of the frequent tools that is used to do this is the green fluorescent protein. What one does is to fuse the coding region for this protein with the coding region of the protein of interest to make a fusion protein. And this makes your protein visualizable inside the cell. And the example that I'd like to show you here is of a protein called a EB3 GFP. This protein binds to the end of microtubules, and then it allows you to visualize these microtubules in action, where they grow, because its binding only to the end. Now we're going to treat these cells with the EB3 GFP with an inhibitor. And this is a very special inhibitor, designed by chemical biologists, that responds to light. So when this is irradiated with a certain wavelength of light, it is activated. When it's shined with another type of light, a different wavelength, it's inactivated. So we can reversibly control the activity of this inhibitor. And now I'm going to show you what you can see when you use this system in a cell. So here, before the movie starts, you see the EB3 bound to the ends of the microtubules. Now when the movie starts, you're going to see that this EB3 moves out. The periphery of the cell because this is the direction in which the microtubules are growing. And then you'll see that we'll flash the inhibitor and we'll activate the inhibitor. Microtubules will disassemble and the EB3 signal will become diffuse. When we shine another wavelength of light, we'll reverse this process and it will become active again and the microtubules will grow. So here you see the process, the microtubules are growing. Shine the light, they disassemble. Another light, they reassemble. So this illustrates one of the best examples of chemical biology. We can control and visualize processes inside the cell with a reverse ability, with a temporal control that is just amazing and unable to do with any other techniques, for example genetics. [MUSIC]
