"Hear directly from the team that developed the groundbreaking ability to make new, healthy neurons that can replace those lost in Parkinson’s disease and their vision to turn their discovery into a life-changing therapy"
Researchers from the University of California at San Diego believe that they have found a way to reverse PD by creating new neurons from astrocytes.
Bad news is that it will take over a decade to bring this to those who need it.
I'm having a problem with the link to youtube, so I can only post this title for a search at that site:
"Creating New Neurons: The Potential to Reverse Parkinson’s Disease"
It's from the University of California Television (UCTV)
Written by
Zardoz
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This is brilliant work and very promising. If it does succeed it will be many years to get into the clinic. That said, this is the most promising treatment involving new neurons I have seen.
Transcript below. Most important paragraphs starred for emphasis.
With that, let's talk about our speakers today. Today, we are delighted to have three amazing speakers talking about the creation of new neurons in the brain, really, a new approach that's never been seen in neurosciences, and they're going to talk to you about it today. The first up is Xiang-Dong Fu, who's Distinguished Professor of Cellular and Molecular Medicine. Doctor Fu has long studied the basic biology of RNA and the proteins that bind to it. He's also dedicated his career to studying a protein called PTB, which you're going to hear about today, which is capable of turning genes on and off. His life's work has brought him the most significant discovery yet; the ability to convert astrocytes, a type of cell in the brain, into healthy neurons by inhibiting one gene, PTB. His lab took this discovery one step further to show in a mouse model, the new neurons were capable of replacing those lost to Parkinson's disease. We're going to be delighted to hear about Xiang-Dong Fu's research.
We're also delighted to have Don Cleveland, the Chair of the Department of Cellular and Molecular Medicine, and Distinguished Professor of Cellular and Molecular Medicine and Neurosciences. Dr. Cleveland is a pioneer of designer DNA drugs that are currently in clinical trials to treat a range of neurodegenerative diseases, including Parkinson's. For this work, he received the Breakthrough Prize in Life Sciences in 2018, which is a true honor, very rarely given. It's actually a larger prize financially than the Nobel Prize. It's basically Facebook and Google coming together to show scientists that they have such importance, similar to what you would see in the Academy Awards. They highlight the top scientists who have made major breakthroughs. Dr. Cleveland was awarded this in 2018 for his amazing work in RNA therapies. Hopefully, he will talk to you a little bit about that.
Then finally, we have Dr. William Mobley, Distinguished Professor, Associate Dean of Neurosciences Initiatives, who is a fantastic partner to us. His research focuses on neurotrophic factor signaling, especially in the context of neurodegenerative disorders. These include Alzheimer's disease, Down's syndrome, and Huntington's disease. His goal is to learn about the causes of dysfunction in neural circuits, which can then lead to developing treatments. His numerous contributions to neurosciences have garnered him many awards and honors, including both the Zenith and Temple Awards for research in Alzheimer's disease from the Alzheimer's Association, the Cotzias Award from the American Academy of Neurology, and several other. He's truly an esteemed member of the Department of Neurosciences, and has been a tremendous force to bringing groups together to advance translation of discoveries to the bedside. With that, I'm going to first invite back our Director of the Center for Parkinson's Disease and Other Movement Disorders, Dr. Irene Litvan, to say a few words before we start the presentation. Hi, good morning. It is our pleasure to have the incredible team of investigators talking to all of you. Many of you have asked about this, and now you have the opportunity to listen.
But before I say that, let me tell you a little bit about me. I am the professor of neurology. I'm directing the Parkinson's and Movement Disorders Center. I'm interested in early and accurately diagnosed patients so they can be part of studies that can actually treat patients that have a specific disease. Obviously, I'm very interested in treating Parkinson's disease and all the Parkinsonian disorders, and my focus on diagnosing them well is to be able to slow the progression or stop or even cure now all Parkinson's disease and other Parkinsonian disorders. As you know, there are no treatments that can slow or stop the progression of Parkinson's disease. However, as I show you on Monday, we do have several studies using different approaches to try to do so. There are many experimental trials at present, but none of them are with the idea of trying to reverse the disease. That's for sure. Dr. Fu made an incredible discovery; he found a code to be able to transform astrocytes into neurons.
What are the astrocytes? The astrocytes are cells in the brain that basically they function to regulate the brain functions. They are implicated in the development of neurons and the connections between neurons called synapses. They control, as well, the permeability of the blood brain barrier, that is what sustains basically the environment that is around the cells. They also limit, for example, or help the entrance of certain molecules and limits the ones that are very big. There are difficulties in getting them inside the brain and that's why the possibilities that this group has found are extremely important. What do the astrocytes when they are mature do? They expressed some of the genes that are enriched in the cell that actually created them, suggesting that they can also retain the proliferations of new cells. What I think is remarkable is to be able to find a code to regulate, turn on or off those astrocytes to make neurons again. These could ideally replace neurons that are damaged or at least those that are about to be damaged. These obviously revolutionized the treatment of Parkinson's and perhaps other neuro-degenerative diseases as well. You will have the last read of this week with this team of excellent investigators. Probably if this moves forward they're going to be Nobel Prize winners obviously. We're really looking forward to the development of all these therapies.
Before I let them talk, I wanted to share one slide that I had shown you the first day. You need to understand that this is what we call the early drug delivery. They have identified a drug and they are trying it in animal models, but there is much more to do. There are studies that are required to show it in animals that are bigger than mice and there are many steps that go before that, that they will explain. Before all that shows that it's safe and is able to really do what it is attempted, then we go into the clinical development of the drug that is the different phases that I explained last Monday. That would be to try to see if in healthy volunteers and then in patient, the drug is safe and we can find the right dose to be able to expand it and then we do the phase 2 in which we do the evaluation of the drug versus the placebo. The other phases that come along like the expanding this in a bigger population, eventually get the FDA review and if all goes well, then the drug goes into the market. This is not something that you're going to have tomorrow. I just wanted to bring that up to clarify some doubts and some questions that I have already received when seeing patients in clinic. Now Doctor Brewer, take it away.
Thank you so much, Irene. That's a great and very helpful slide to tell us about the process of bringing this all the way to the bedside and I'm just delighted that we're at the beginning phase and where so much of the innovation and creativity is taking place. This team of folks that we brought together for you is going to talk about it. Thanks very much and with that, I will turn it over to Dr. Fu, Mobley, and Cleveland.
Good afternoon. I'm so delighted to participate in this lovely event and share with you our excitement of discoveries made in the lab by this group of team and colleagues all at UCSD. As we can see from this slide, Parkinson's disease is caused by the loss of dopaminergic neurons. As you can see here in the anatomy of the human brain, if you take a PET scan, you can see there is a normal brain, you can see there is dopamine neurons and are regulated actually in the brain region called the substantia nigra and then send their axons to this second brain region called striatum, where they release dopamine active neuron to control motor, as well as allow motor functions. As you can see here, normal brains have this lovely dopamine release and retake activities which can be captured by PET scan. But on the right, as you can see in Parkinson's disease brain, this function is damaged, featured by the loss of dopaminergic neurons in their brain and then another cause of problems. Currently, because of intensive studies, multiple treatment strategy have been developed which helps the patient tremendously, particularly by intake of L-Dopa supplement or conduct a brain stimulation to improve or stimulating the motor neuron functions. However, it is important that this management is for management of symptoms rather than have any potential to either slow down, hold the disease progress or even reverse the disease. Last problem we are facing and we tried to find a way to address this challenge problems in the labs, this is related to actually big picture problems as featured here and when the neurons no longer function or die, the question is, can one actually make new neurons to replace them? Unfortunately, the dogma in the field of neuroscience is that as put by the founder, considered founder of modern neuroscience, Ramon Cajal. This is his famous quote that, "In adult centers, the nerve paths are something fixed, ended, immutable. Everything may die, nothing may be regenerated. It is for the science of future to change, if possible, this harsh decree."
Fortunately and excitingly at the UCSD, we just overcome this harsh decree by showing it is possible actually to generate new neurons. Therefore, once was thought to be lost permanently, now we can make them appear again, regenerate neurons. Actually, this remind one of my colleague, Will Mobley, a Greece song, called a Christian songs, "Once I was lost, but now I'm found; was blind, but now I can see." I don't know what's the tune of this sounds. Maybe Will can sing some to you someday when we have a chance to meet in person. Come back to science, and then this regeneration things actually has been observed, has been a discipline, in fact. Further, lower animals like featured here with the hydro, that once they lost their body part of it, they can really grow. Then they regrow by converting some of those so-called somatic cells back into a stem-like cells and then they generate the rest of the body in quite efficient way. In fact, that this has been seen in many different form of amphibians, as I can show illustrated here. We're going to have a look at the way in which an amputated limb grows over the course of about 90 days in a salamander. That's a time-lapse movie, watching that thing grow. Now we're going to see what's really going on. Here is the salamander, and it's got a completely new limb. It looks perfect. It has inside bone. It has nerves and muscle, and it can even wiggle. Now we're watching what this newt can do that we cannot do. Cells are streaming out of the surrounding tissues into the area of the wound and forming what we call a blastema, which is a group of undifferentiated cells that are in fact really just like stem cells. They're multi-colored because they come from skin, from muscle, and even from cartilage. These have a miraculous memory of what they used to be [NOISE] and are able to form a perfectly functional limb. Therefore, if amphibian can do that, many other lower vertebrate can do that. What about a mouse, monkey, or even our own brain? That's the question that has been fascinating the scientific world for many decades. This bring up to the central nervous systems.
Now that we know our brain started with human stem cells and then turned into the neural progenitors, and then those neural progenitors give rise to neurons as well as the astrocyte. Therefore, this astrocyte and the neurons actually are brother and sisters. Can the identity of this, a brother and a sister, derived from common parents are being switched? That's the question we're asking. Now we've found indeed, it is possible to do so. We identify a PTB. Jim mentioned our RNA-binding protein, now they function as a master regulator of cell identity in the development. We found this particular molecules is actually progressively decreased when one cell become neurons, indicating that it serve as an important gatekeeper for neurogenesis, this important process. This brings us to a general concept that we're highlighting here, the cell identity or identity theft. Can we experimentally, either enhance or stimulate this process? To supply our brain, new neurons are lost to degeneration.
At a molecular level, we've spend a long time and figure out how this work and revealing true general are regulatory loop. Without laboring you with details, we just want to highlight some of the key feature in this regulatory circuitries. As you can see here, between neuron and the astrocyte, this portion of the regulatory events, you can see here every components and looks identical. The still size represented their level of expression, but the only difference is the front one. The first loop that operating differently in neuron was astrocyte with the PTB protein, high the expressed in astrocyte but very low in neurons. To illustrate this point further, I made a cartoon to illustrate this one. As if in order to change the identity of an astrocyte to neuron, we have to go through two bridges. Interestingly, most of the cells, both bridges are not lower yet so that you have incredible barrier to get through this process. But however, in astrocytes, it's quite different. The second bridge is already lower, it's there for traffic to flow. What we need to do is to make the first bridge connected for the traffic to go. Now we can generate new neurons. This is the concept and this is how the molecular pathway told us to do, and we demonstrated this may indeed the case, as shown in the next slides. The next slides, we isolate the astrocyte from mouse brain. In fact, we also isolated astrocyte from a human brain. I know when this slides were treated with our reagents, ie by molecularly suppressing this protein called a PTB, now we tend all those cells into a neuron and they show the markers for neurons like this one. This red ones is all the neurons here, these markers. Then there's a green ones, these only mature neurons here expressed as markers.
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Together, this slide shows that we can not only generate neurons, but also functional ones that show all characteristics of a mature neuron can do. This is a new neuron we can generate in vitro. Then more interestingly, now we apply this approach to a mouse brain directory without going through all those tedious aspect of in vitro manipulation of cells. Indeed, we can see here, as you can see on the right side, that if you stain the mouse brain with this tyrosine hydroxylase which is the mark of a dopaminergic neuron, in the two hemisphere, both left and right, you can see this dopaminergic neuron originated in nigra and then projected into this broad region called striatums. Then in the diseased brains, we can recreate, recapitulate this disease conditions in mouse brain by induced the damage of loss of dopaminergic neuron. As you can see here, this side of the brain, we injected molecules that basically wipe out the whole population of dopaminergic neurons. This is what I showed you in the PET scan in human brain, in Parkinson's brain as well. Now remarkably, after reprogramming by injecting our reagent via a virus, and then we can restore this population of dopaminergic neurons by staining. Most importantly, what you can show as featured in the left-hand side, that this healthy brain generate a high level of a striatum dopamine. Then this dopamine is reduced to a basal level because the loss of dopaminergic neuron. Now after reprogramming, I believe, we can restore their functions, this dopamine level in the brain.
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Now with this demonstration of a chemical and a morphological restoration, most importantly that we show, this also completely reflect at the behavioral level. We call this remarkable process of disease reversal. As you can see here in normal mice and we measured their motor symptoms, which we generally categorize them as parkinsonian phenotype, which actually measured one directional or rotation phenotype in the mouse brain. As you can see here, there's bias in rotating, either counterclockwise. That's why the baseline is zero here with normal mice. You can see here with the dopamine-deficient mice, all mice actually rotating in one direction. This is a feature of the disease and the incredibly after the reprogramming, every single one going down in the time-caused manner. In two months or three months, most of the mouse we tend, their normal level of behavior indicating that we have achieved a disease reversal. We have monitored at least one group of this mice for their lifetime, and the reversal is a lifetime achievement. They are completely normal like the rest of the mice. This is demonstrating that it is possible to make a new neuron and make them to replace the lost ones and them restore the functionalities.
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At this point, we are now at a point to translate our basic science discovery to a novel what we called cell replacement therapy. For this purpose, when we actually do better than just using virus which is designed for a provided experimental evidence, the better approach would be to use the so-called designer DNA drug that has been pioneered by my colleague, Don Cleveland, as introduced earlier by James. Now, we can use this to designer drug to convert astrocytes to neurons. In fact, we can even do better. We can not only make a new neurons, but in the meantime, combine with a different DNA designer drug to inactivate disease genes. Thus, we are able to make not only new neurons, but to make a new healthier new neurons. At this point, I would like to let Dr. Cleveland to bring you the reason highlight in the development of laser designer DNA drug in fighting against Parkinson's disease as well as many other neurodegenerative disease.
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What I'd like to describe very briefly today was the process of discovery and then development of using designer DNA drugs to change gene expression within the nervous system as therapy for neurodegenerative disease and then how we're going to now exploit that to make replacement neurons in Parkinson's disease. The discovery, which began in about 15 years ago, was that we could use little pieces, snippets of DNA, the substance that genes are made up of. You can synthesize them. If you can get them inside the target cell, neuron, astrocyte, whatever, then the little piece of DNA can pair with the information intermediate from any selected target gene and it forms a hybrid with that target gene and makes the information intermediate in RNA look like a viral product. We have an antiviral mechanism that then destroys that information in intermediate. If we can do that for any selected target gene, like PTB, the protein that Dr. Fu just discussed, then we could turn off PTB. What the investigators, the team that I lead here at UC San Diego, what we did was to demonstrate that with these designer DNA drugs that we can deliver them very broadly throughout the nervous system and effectively. Indeed, we determined that when you take an aspirin, you get three or four hours worth of relief. But we discovered that after modifying these DNA, these little designer DNA drugs, to modifying them appropriately, we don't get three or four hours of relief. We don't get three or four days of relief, not three or four weeks either. It is actually 3-4 months worth of efficacy. Now we're going to dose animals or patients three or four times a year. Over the years, why do we call a designer DNA? Well, this is the DNA backbone that you see in the structures on the right-hand side of the slide. That backbone, you can modify the DNA and we have, the chemists have now done that and produced DNAs that bind to the target intermediate with 10 times the affinity of authentic DNA and give this very long lasting efficacy.
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Here's one such example of how these designer DNA drugs can be used and it was the discovery of the gene that is the most frequent cause of the motor neuron disease, ALS, frequently called Lou Gehrig's disease. It's also happens to be the cause of the second most frequent, dementia, and that discovery, as you can see here, was on September 21st, 2011. Using this designer DNA drugs, we designed the therapy the day after the therapy approach, we achieve proof of principle that we could change the expression of this disease-causing gene to silence it. We achieved the proof of principle in 2015, and we dosed the first patient at UC San Diego in September of 2018, almost exactly seven years from the discovery of the gene target. Additionally, in this Lou Gehrig's disease, a gene was discovered by a pair of teams, mine and a team at Harvard. As you see here in early January of 2019, we think it's the best target for therapy for almost all instances of ALS. Our timescale now, even with COVID last summer, we achieved proof of principle using a designer DNA drug that we could restore, that we could change the synthesis of the gene that is implicated in broadly in ALS and we now propose, working with a San Diego company Ionis that we can get to clinical trial in 2023, about four years from the discovery of the original gene, and even more so for Parkinson's.
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Those of you who participated yesterday will have heard much about LRRK2. It's a gene whose mutation is the most frequent cause of inherited Parkinson's disease. The gene becomes hyper activated in that disease, and as Dr. Breuer mentioned in the introductions before, I was fortunate in 2018 to receive the breakthrough prize in life sciences. I received it from Sergey Brin, the founder of Google. Brin is quite public about it. He's probably the most famous individual who carries LRRK2 mutation. Indeed I chatted with him to say that we were going to have an on-target therapy for Parkinson's disease from LRRK2 and indeed, well, we're going to use our designer DNA drug to turn down this hyperactive LRRK2 gene. Indeed, that trial initiated very late in 2019, just before the COVID explosion, the UC San Diego's strategy, partnered with Ionis and their large pharma partner Biogen.
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In summary, over the last 15 years from efforts at UC San Diego, there have been now, as we count them here, seven approaches to treat degenerative disease of the human nervous system. One in kids, in children a disease called spinal muscular atrophy, and that is the first approved approach for using this designer DNA drug therapy in the human nervous system. It takes the fatal childhood disease and turns it in the kids who are now five and six years old walking. We're hopeful that this will be a very long-term efficacy. There were ongoing trials in ALS, one for mutation in one gene, the SOD1 gene. That's now in a large Phase 3 trial where we're hopeful that we're going to see next year how effective that we've been. We have an additional trial to target a gene product that accumulates apparently in Alzheimer's disease. At the top of this slide, a fourth one in the top-left for the most frequent cause of ALS that I mentioned earlier that went to trial patient dosed at UCSD in 2018.
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In Parkinson's disease in the red box, I indicated we have LRRK2 as a target and we have a second target for a gene whose product misaccumulates in almost every Parkinson's patient, that too initiated about a year ago. Now why am I mentioning that? Well back to this example that Dr. Fu introduced where you use chemically killing the substantia nigra neurons on one side of a mouse. Here, again, you see that image where the neurons on one side, these tyrosine hydroxylase positive green neurons. In this image, there's the normal ones on the left-hand side and killed most of them on the right-hand side and their innervation into the higher regions of the brain where their job is to deliver dopamine. As Dr. Fu indicated what we're going to try to do now is to use a designer DNA drug single-dose injection to now determine, can we make replacement neurons that will grow up and replace the missing ones on this right-hand side of the mouse brain? If you look at normal mice and do behavioral assays, they always behave normally, no surprise there. But now if you take these mice in which we've induced Parkinson's like disease and measure them right after that, what do you see? You see, there's Parkinson's like disease in 1, 2, 3, 4, 5, 6 mice.
Now we ask, if we dose them with a designer DNA drug to suppress PTB, what happens? The answer is, the most affected mouse gets better over a three month period, so does the next one. In fact, six of these seven of our mice that we've treated with this designer DNA drug have generated replacement neurons that have restored dopamine synthesis in those mice, reversed the disease course, and all but one, the one in red, where we almost certainly failed to correctly inject the drug. As excitingly, you can do this in normal animals. Just suppressing PTB in the portion of the brain most affected in Alzheimer's disease, you can generate new neurons. We've looked at the band of green and neurons in this region of the mouse brain. Now you see some yellow neurons. Those are ones that we carefully marked to show that they're the new ones and they make these beautiful red processes that receive signal inputs. They integrate into the normal circuitry and we can do this in aged mouse. We argue that, yes, a designer DNA drug to suppress PTB can generate new neurons in the real mouse. How are we going to now develop a therapy in Parkinson's disease? Well, we know that converting these astrocytes into replacement neurons is a strategy that has succeeded in this example of the Parkinson's like disease in mice. We think it's going to be useful broadly in many different neurodegenerative diseases and that even more so if you make a new neuron, but it's susceptible to the disease mechanism that was killing the original neurons, we can use additional designer DNA drugs to suppress the intrinsic disease mechanism as well. We can slow disease advance and generate new replacements. That's exactly what we're proposing to do. To discuss that with you, I'd like to invite my colleague, Dr. Will Mobley to discuss how would you take the work from where it is today into real therapy. Will.
Thanks, Don, and thanks Fu, and thanks to everyone who's listening in this afternoon. What you're listening to is really a revolutionary story. It's a case of lost and found, if you will. It's a case in which neurons that are lost, whose loss is quite devastating, have actually been found again, through conversion of astrocytes to those missing neurons. That is remarkable. Who would have thought five years ago that we would be having this discussion? I don't think I would have. I knew Fu and I knew what he was up to. But at that point, it was pretty basic science. Whereas we could have cheered it on, there was no guarantee that that would ultimately translate from a tissue culture dish to a mouse and to a mouse model of Parkinson's disease. But here we are. What was lost has now been found. It's our job now at UCSD to build upon this body of evidence so that we can make this really remarkable finding available and bring hope to those people who have lost something, but who now may be able to be rescued from their disease. Not just Parkinson's disease, but surely Parkinson's is a great first case. But we've got work to do.
We're at that first early stage, that Irene show, those first two chevrons. Early discovery and early pre-clinical. We have to really understand whether our approach is going to work in other models of Parkinson's disease. It's very important for us to create, as much as possible, a disease-relevant context going forward. We have to learn how to do this in old astrocytes. Old astrocytes may be less easily converted than young ones, but we think we have strategies that will allow us to address that. Clearly, if one's going to treat people who are elderly, one is going to have to be able to convert their astrocytes to new neurons. We have to show this is safe. We have to show that by down-regulating, by pushing PTB levels down, that we don't cause adverse effects. As mentioned earlier, we have to protect those new neurons from harm. We have to make sure that they survive indefinitely. That in some ways, well most ways, they're not susceptible to the same underlying mechanisms that caused their now dead partners to die. We have to show that our approaches work not just in mice, but in non-human primates. The primate brain is much more like the human brain than the mouse brain and it's much bigger. We need to know that both the mechanisms are working and that those new neurons can grow their axons effectively to striatum. We need to revise and enhance the compounds we're using. We need to be quite clever about the reagents we're developing, and we need to be thoughtful about how to deliver these reagents to the brain. I'm very excited about the ASL Project. Couldn't be more excited. But we still need to develop and enhance our thinking about those reagents and others so that we can bring them to the well-being of those people that suffer from Parkinson's disease.
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As a neurologist, I've never really ever before conceived of the idea that we could reverse disease in severely affected people. We rally around preventing disease, and of course we should do that, and we deliver symptomatic therapy and that's helpful. We always hope that we can make the disease manifestations less severe. But the concept of finding new neurons is revolutionary and it happened here at UCSD. It happened because of basic science idea convened at a discussion among colleagues that ultimately, I think, provides great promise. There is a realistic hope for people who suffer and it comes from UCSD. It's scientists as clinicians. Thanks for listening. Fantastic. I mean, truly inspiring in many ways. I invite Irene Litvan to come back to the fore as we start the question and answer period.
Thank you, Doctors Fu, Cleveland, and Mobley. We look forward to hearing your thoughts on some of these questions that are coming through. There's a lot of folks very inspired by the work that you're doing. One of the questions which is great, or a comment, "Watching this presentation fills me with hope and joy. I know there's work needed to get this from breakthrough to actual therapy, but I imagine many of us will mark today on our calendar signifying one of the most important days of our lives." I hope that fills you with inspiration as you move forward toward bringing this to the bedside. A question that a person has for Dr. Fu and the whole team, so we'll present this to Dr. Fu, "How does it feel to see this technique showing so much promise?" Wow, okay. I've been devoting most of my career in a path of 40 years in studying basic research. Many of us do. But even those working in the medical school the question is, how frequently one would arrive to do discovery that actually can be useful and
Worth hanging on for, so I'm going to do so and when it comes out I will let you know because I'll be one of the first. Meanwhile, my attitude is mentally I will be on vacation pending same, no matter how bad things get. I recommend others do with a can to make it through to the same. Meantime, no matter what we encounter and how we deal with it, it is what it is until then.
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