为什么基因治疗能成为消灭HIV的合理工具 - David Baltimore P2
本视频由科普中国和生物医学大讲堂出品
David Baltimore (Caltech) Part 2: Why Gene Therapy Might be a Reasonable Tool for Attacking HIV
Lecture Overview:
In this set of lectures, I describe the threat facing the world from the human immunodeficiency virus (HIV) and a bold proposal on how we might meet the challenge of eliminating this disease by engineering the immune system.
In part 1, I provide a broad introduction to viruses, describing their basic properties and my own history of studying the replication of RNA viruses which led to the discovery of reverse transcriptase. I also illustrate the distinguishing features of equilibrium viruses (e.g. the common cold) that have adapted to co-exist with their host and non-equilibrium viruses (e.g. HIV) that have recently jumped from another species, are not adapted to the new host, and which can lead to disastrous outcomes (e.g. loss of immune function with potential lethality in the case of HIV).
In part 2, I describe the growing health problem that is facing the world with the spread of HIV and the limitations of current drug therapies and vaccine strategies. We need new ideas for tackling this problem. Here and in the next segment, I describe bold strategies of using gene therapy to conquer HIV, The approach that I describe in this segment involves gene therapy to produce short hairpin RNAs (siRNA) that target the destruction of a critical co-receptor of HIV, which the viruses that needs to infect cells. I discuss initial proof-of-principle experiments that suggest this approach might be feasible and the next steps needed to develop this idea into a real therapy.
In this last segment, I describe another gene therapy strategy for HIV in which we propose to develop antibody-like proteins that can be expressed by a patient's B cells and will target the HIV virus for destruction. To achieve this objective, hematopoietic (blood) stem cells must to be targeted with the gene, which will ultimately develop into B cells that express the therapeutic molecule. The ultimate goal is to produce a life-long supply of anti-HIV neutralizing antibodies. In this lecture, I describe the molecular methods underlying this strategy and a development path from proof-of-principle studies in mouse to safe trials in humans. This project receives funding from the Bill and Melinda Gates Foundation.
Speaker Bio:
After serving as President of the California Institute of Technology for nine years, in 2006 David Baltimore was appointed President Emeritus and the Robert Andrews Millikan Professor of Biology. Born in New York City, he received his B.A. in Chemistry from Swarthmore College in 1960 and a Ph.D. in 1964 from Rockefeller University, where he returned to serve as President from 1990-91 and faculty member until 1994.
For almost 30 years, Baltimore was a faculty member at Massachusetts Institute of Technology. While his early work was on poliovirus, in 1970 he identified the enzyme reverse transcriptase in tumor virus particles, thus providing strong evidence for a process of RNA to DNA conversion, the existence of which had been hypothesized some years earlier. Baltimore and Howard Temin (with Renato Dulbecco, for related research) shared the 1975 Nobel Prize in Physiology or Medicine for their discovery, which provided the key to understanding the life-cycle of HIV. In the following years, he has contributed widely to the understanding of cancer, AIDS and the molecular basis of the immune response. His present research focuses on control of inflammatory and immune responses as well as on the use of gene therapy methods to treat HIV and cancer in a program called "Engineering Immunity".
Baltimore played an important role in creating a consensus on national science policy regarding recombinant DNA research. He served as founding director of the Whitehead Institute for Biomedical Research at MIT from 1982 until 1990. He co-chaired the 1986 National Academy of Sciences committee on a National Strategy for AIDS and was appointed in 1996 to head the National Institutes of Health AIDS Vaccine Research Committee.
In addition to receiving the Nobel Prize, Baltimore's numerous honors include the 1999 National Medal of Science, election to the National Academy of Sciences in 1974, the Royal Society of London, and the French Academy of Sciences. For 2007/8, he is President of the AAAS. He has published more than 600 peer-reviewed articles.
声乐学习与特定的轴突导向基因的表达有关 - Erich Jarvis P3
本视频由科普中国和生物医学大讲堂出品
Erich Jarvis (Duke/HHMI) Part 3: Genes specialized in vocal learning circuits
In Part 1, Jarvis explains that vocal learning is the ability to hear a sound and repeat it. Only 5 groups of mammals (including humans) and 3 groups of birds (parrots, hummingbirds and songbirds) are capable of vocal learning. Jarvis and his lab members imaged changes in gene expression in bird's brains after singing. They found that hummingbirds, songbirds and parrots each have pathways in specific areas of the brain that are not found in non-vocal learning birds. Interestingly, analogous networks exist in the human brain but not in non-vocal learning monkeys.
In Part 2, Jarvis proposes a mechanism by which vocal learning may have evolved. He suggests that the brain areas that control vocal learning are the result of a duplication of a pre-existing neural circuit that controls motor movement. A similar duplication event may have occurred during the evolution of humans with the result that both humans and Snowball, a cockatoo, can sing and dance to a beat!
In Jarvis' third talk, he demonstrates that the brain pathways necessary for vocal learning are associated with the expression of particular axonal guidance genes. He also proposes that the evolutionary events responsible for the development of vocal learning may be a general mechanism for the development of other complex behavioral traits.
控制老化的基因 - Cynthia Kenyon P1
本视频由科普中国和生物医学大讲堂出品
Cynthia Kenyon (UCSF) Part 1: Genes that Control Aging
Once it was thought that aging was just a random and haphazard process. Instead, the rate of aging turns out to be subject to regulation by transcription factors that respond to hormones and other signals. In the nematode C. elegans, in which many key discoveries about aging were first made, the aging process is subject to regulation by food intake, sensory perception, and signals from the reproductive system. Changing genes and cells that affect aging can lengthen lifespan by six fold, and can also delay age-related disease, such as the growth of tumors.
基因分裂和RNA剪接 - Melissa Moore P1
本视频由科普中国和生物医学大讲堂出品
Melissa Moore (U. Mass/HHMI) Part 1: Split Genes and RNA Splicing
In the first part of her talk, Dr. Moore explains that eukaryotic pre-mRNA contains long stretches of non-protein coding sequences interspersed with protein coding regions. By recognizing specific sequences, cellular machinery splices out the non-coding introns leaving just the protein-coding exons in mRNA. Although at first glance this may seem like a wasteful process, it is splicing that facilitates the evolution of new genes, and alternative splicing that allows a limited number of genes to produce a large number of proteins.
Tagrisso的伴随诊断 - 陈巍学基因(31)
欢迎来到【陈巍学基因】。我们这个节目，主要是介绍基因组学，和临床分子诊断的最新技术进展。
今天，会和大家谈一谈阿斯利康在开发Tagrisso这个新药过程中对4种伴随诊断方法的研究结果。
Tagrisso是阿斯利康公司开发的一个针对EGFR基因有耐药突变的晚期非小细胞肺癌者的药物，是酪氨酸激酶抑制剂类的靶向抗癌药物。
Tagrisso可以选择性地抑制突变型的EGFR，对发生耐药的肿瘤有强抑制作用；而对野生型的EGFR的抑制作用较弱，即对身体正常表皮细胞的生长抑制作用较弱。
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小鼠的基因分型
尽管人类基因组在10年前就已经被绘制图谱，科学家们仍然远远没有理解每个人类基因的功能！评估基因功能的一种方法是破坏其编码的序列，然后评估这种变化（表现型）对动物的生物学影响。这种方法通常用在小鼠（小家鼠）中，因为它与人类的遗传学高度相似。要想跟踪好几代携带遗传改变的动物，有必要筛选每只小鼠的DNA，这种方法被称为基因分型。
本短片概述了小鼠基因分型的理论和实际应用。首先介绍了小鼠遗传学的基本原理，包括回顾了纯合子，杂合子，野生型，突变体和转基因的名词。接下来，逐步介绍了从小鼠组织中提取和纯化基因组DNA的方法。我们还提供例子演示了如何分析基因分型结果，以及如何追踪具有所需基因型的小鼠。最后，我们呈现了一些有代表性的基因分型方法的应用以证明为什么这种常用的技术是小鼠研究必不可少的。
用CRISPR寻找新肿瘤药 - 陈巍学基因（32）
欢迎来到【陈巍学基因】，我们这个节目，主要是给大家介绍基因组学，和临床分子诊断的最新技术进展。
今天要和大家谈的，是用CRISPR方法，来寻找新的、可能的肿瘤药物。
提出这个方法的，是加拿大Donnelly Centre的Traver Hart。Traver Hart把他的这项研究成果，发表在《Cell》杂志2015年12月3日这一期上。论文的题目是《High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities》。我们这期节目，就主要围绕这篇文章来进行讲解。
文章的核心内容，就是：
1.用CRISPR方法，把几种肿瘤细胞系的几乎所有的基因都做一遍敲除，也就是“Knock out”。
2.然后用高通量测序，来看哪些基因被敲除之后，细胞的生长会受到抑制。
3.接下来，在几种肿瘤细胞系之间进行比较，看哪个基因，是对一个特定细胞系的生长，是必需的，而在别的细胞系当中，这个基因是非必需的。那么，这个基因就可能是治疗这种肿瘤的，潜在的、新的治疗靶点
本视频详细介绍了这种全新的方法，和用这个方法找到的一系列潜在的新药化合物的实例。
用血小板RNA-seq测肿瘤 - 陈巍学基因（33）
Myron G. Best 等人发现，可以用血小板RNA-seq测序结合生物信息学分析，很好地判断： 1、一个人是否患有肿瘤； 2、是患的哪种肿瘤； 3、肿瘤中有哪些突变。 本视频介绍了这项发现的成果、实验方法、分析思路。
控制衰老的基因电路
In the early 1990s, most scientists did not think that aging was subject to active regulation by the genes. Exciting results from Dr. Kenyon's lab, however, showed that a single mutation in the daf-2 gene caused the tiny roundworm C. elegans to live twice as long as normal. This gene encodes a hormone receptor that regulates lifespan not only in worms, but in flies, mammals and possibly humans as well.
寻找控制生长发育的基因
Eric Wieschaus and Christiane Nusslein-Volhard wanted to understand which genes regulated embryonic development in Drosophila. It took them 2 years to design their experiment and only a few months to execute. A combination of good design and good luck allowed them to start with 40,000 flies and identify just 139 genes necessary for embryonic development.