That part, I ran through very, very quickly because I want to save time to discuss a little bit about interventions. [FOREIGN]. We know only this much about the disease. We have more genes to clone. We have, more cellular responses to study. However, we can't wait. Whenever we're going to send something we right away, put it to action. And one of our goals in biomedical research is simply to help patients. People started very early on. Here, I want to mention three things. Two of them are quite successful. The third one is being done now. The stem cell approach, I will not dig too much because it's really in the middle. You can have embryo generated stem cells, and put it into human brain that has been done in several countries. And in fact, it's pretty good. But, now we want to have IPS cells. And induce that into and put it back to the patient's brain, with a great advancement in stem cell biology, now it becomes possible. This week, [FOREIGN] published yet another cell paper and it's on the cover of cell. It's a wonderful, wonderful thing. I recommend everybody to read it. Maybe someday we can really induce all these cells to the specific cell type we want and somehow put it in. Two difficulties exist. The first one is when you induce these kind of things, in the population you many times have tumor cells because remember these are stem cells. They have a full capability of growing. The bad side is, what if one percent of these guys turned out to be tumor? Then you're injecting that into a brain. Yes, you risk your part of PD but three years later you have brain tumor. That's a bad thing. That's one. Second one, is even more daunting, more difficult. That is, remember the projection we showed. These are very long range projections. We have developed that, because in development of neurons, start from here then they migrate and grow, when we finish development, all the routes are closed. Now, if you put stem cells into a place, how do you let them grow those axons and dendrites? >> [COUGH] >> How do you do that? There's no space anymore. They cannot go all the way from substation Niagara all the way to striatum. That's a very big difference, at long distance. How do you do that? That remains one of the question, we cannot answer today. When people succeeded in putting the cells, embryonic cells into the brain, that is simply serve as a reservoir of dopamine. But they are not integrated in the surgical. This is something we cannot answer today. It's for you to think about it. Let's go back to the old, old but effective way of making drug which is chemical compound. This one I showed at the beginning of our class. Here is the metabolism, metabolic paths of dopamine. Now, with that knowledge, my question to you is, can you propose some strategy that can, we can develop drugs? What do you do? If you are given $10 billion dollars, what do you do? What are the points you can imagine you can make a drug? It's easy, guys. Think about it. One, yeah, please. >> [INAUDIBLE] >> Blocks your MT. What she's [FOREIGN] says, blocks your MT, so you have less metabolism out of dopamine. Effectively, you increase dopamine concentration. Very good. And? What are others, please? >> Transfers to L dopa. >> L dopa. [APPLAUSE] Thank you very much, that's the first line of medicine, you hit the jackpot, good. That's not a very difficult question. [APPLAUSE] [FOREIGN] >> [INAUDIBLE] >> Activation of AADC. Theoretically, you can do that. In reality, it's very hard. Remember. We have an enzyme which evolved through millions of years of evolution to make the more active. It's pretty difficult. Unlike receptors, receptor you have a mimic [INAUDIBLE]. You can activate what we call agonists. Enzymes are in general. It can be done, but it is difficult. To make it work better is difficult. Anything else? >> [INAUDIBLE] >> You can block COMT, you can block MAO. Make those two less efficient, you increase the dopamine concentration. Very good. Those are the major ones. If you look at this [APPLAUSE], what else can you do? How about forget about dopamine cells? Let's get on to the next neuron directly. Can we do that? Can we do that? Take a pill, somehow it bypasses dopaminergic neurons, and gets to the postsynaptic membrane. Get on those receptors directly, can we do that? >> [INAUDIBLE] >> Exactly. Those somehow you partially agonist can do that. Just go to the receptor directly. And congratulations, you guys are great [APPLAUSE]. This is exactly what pharmaceutical companies had been doing for the past, the 30 years. L dopa, Levodopa is still the mainstream, by far the biggest drug MPD, and it's quite effective. And they are dopamine agonists, they are MAO inhibitors, COMT inhibitors, and so on and so forth. A combination of these drugs contributed largely to the control of PD in a first maybe seven to ten years. People's response to them are different. Some people responded very, very well. Other ones are not so well. And the time that they can last is different. Some people after only five to seven years, they given up resistance to L dopa. Other people, fortunate people, they can be 15 years or longer they are still responding to L dopa very positively. It depends. Now, what we want to use is a combination of these guys to alleviate the patient's pain. However, none of these stop neurodegeneration. In the patient's brain, the room allergic cells are still dying. You can see that. I want to tell you another very effective treatment that has been developed in the recent years. That's a surgical procedure. [SOUND]. Called deep brain stimulus, DBS, just one more small thing. Remember, we have indirect pathway. [SOUND]. We have the direct pathway. We know the direct pathway. We know the indirect pathway. And the PD and HD there are coming from the imbalance of the two. One side is bad. Can you just block the other one a little bit so that the net output [APPLAUSE] is actually pretty good? Simple way of thinking. What we do, is that we plant those really, really small microelectrodes into the brain. It's difficult, because these structures are deep in the brain. You have to pass through all the tissues to get there. In terms of procedure, it's never our first choice. Because with that, always you have bleeding and all that problems. We use that only when L dopa no longer works and agonists that doesn't work. It's the last measure. That one shows an imaging guided surgery procedure to put that into the brain. Now, this is what the electrodes look like. There are a few electrodes combined at the tip, because you want to make sure if one of them is broken or no longer works, you have a four. Spare ones. And it's planted in and then it has its own battery. Now outside you have this remote control thing. It's very much like our TV remote control. You can adjust when the electricity should go on and off because if I'm sleeping, I don't want this one to be active. It saves energy, it fits my needs. Also, frequency, duration, amplitude, these are the parameters that you can adjust for each individual, it's actually very different. After that, the function of this DBS device is installed and patients can benefit from that. Therefore, I want to show you another movie that. This is a patient that, after many years of L dopa treatment Is no longer able to respond. For example, we asked her to just make a turn. It's very hard for her to initiate an action, very hard. You can see the posture and stability. Out of desperation, we don't have any other treatment methods anymore. We went through the surgical, this one's done in the hospital. Here's what we have. This is after the. [SOUND]
