Ep. 40: “Gene Editing Mistakes” Featuring Dr. Frederick Alt
Mar 17, 2015
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Dr. Frederick Alt, a leading geneticist from Harvard Medical School, reveals fascinating insights into gene editing. He discusses a novel method for detecting off-target effects, crucial for CRISPR's precision. The conversation also touches on groundbreaking studies linking autism genes to cognitive performance, and how memory manipulation in mice offers tantalizing possibilities. Alt emphasizes the importance of specificity in gene editing technologies and their implications for future biomedical research. A must-listen for anyone interested in genetic advancements!
Gene editing technologies like CRISPR face significant challenges due to off-target effects, raising concerns about safety in therapeutic applications.
The HTGTS method enhances accuracy in detecting off-target effects by providing a comprehensive analysis of DNA alterations during gene editing.
Advancements in gene editing are pivotal for precision medicine, particularly in correcting genetic defects and improving treatments for immunodeficiencies.
Deep dives
The Advancements in Gene Editing Technologies
Gene editing technologies, particularly CRISPR, have revolutionized the ability to make precise modifications to DNA. This technology allows scientists to introduce cleavage at specific points in the genome using engineered enzymes like Cas9, guided by RNA to match target sequences. However, with this advancement comes the challenge of off-target effects, which are unintended modifications elsewhere in the genome that can lead to potential complications in gene therapy applications. The podcast highlights the importance of ensuring the specificity of these edits to avoid negative consequences, particularly in sensitive applications like stem cell therapy.
Understanding Off-Target Effects
Off-target effects represent a significant concern in gene editing, as unintended cuts in the genome can potentially lead to detrimental outcomes, including oncogenesis. These effects are particularly problematic when editing somatic cells, where introducing undesired changes could lead to harmful mutations. The podcast discusses how existing methods for detecting off-target effects were often inadequate, causing worries about their prevalence and impact. The accuracy of identifying these off-targets is crucial, particularly when conducting gene therapy on human patients, to prevent unforeseen complications.
The Impact of HTGTS Technology
The HTGTS (High ThruPoet Genome-Wide Translocation Sequencing) technology provides a novel approach to detecting both on-target and off-target effects of gene editing. This method allows researchers to identify where breaks in DNA occur and what downstream effects those breaks might have across the genome. Unlike traditional techniques that might only catch a fraction of off-target sites, HTGTS can reveal a far more comprehensive picture of the alterations resulting from gene editing. This advancement serves as a powerful tool for scientists, helping to guide safer and more effective gene therapy approaches.
Applications in Stem Cell Research
Gene editing technologies, coupled with the insights provided by HTGTS, hold immense potential for stem cell research, particularly in correcting genetic defects. Researchers are exploring ways to utilize these technologies for precision medicine, especially regarding immunodeficiencies and other hereditary conditions. The podcast further illustrates a collaboration where gene editing was applied to RAG1, a gene associated with immune function, highlighting the collaborative nature of modern scientific research. Such applications emphasize the need for careful assessment of gene editing tools to ensure they are safe and effective for therapeutic use.
Navigating the Future of Gene Therapy
The future of gene therapy hinges on both the advancements in editing technologies and the rigorous assessment of their impacts. The conversations in the podcast reflect a shared commitment within the scientific community to refining these techniques, ensuring they can be applied confidently in clinical settings. As researchers gain more understanding and tools like HTGTS become mainstream, the goal is to minimize risks associated with gene therapy while maximizing its therapeutic potential. This forward momentum underscores the significance of continuous improvement in safety and efficacy as the field evolves.
Guest:
Our guest, world-renowned geneticist, Dr. Fred Alt from Harvard Medical School talks about his latest paper in Nature Biotechnology where he describes a novel method to detect off target effects of gene editing technology.
Resources and Links
False Memories Implanted into the Brains of Sleeping Mice – By directly manipulating the brains of sleeping mice, researchers tricked the animals into thinking they had received a reward at a specific place when they wake up.
Autism Genes Linked to Higher Intelligence: Treading a Fine Line between Intellectual Disability and Superiority – A comprehensive study conducted shows that genetic variation, which increases risk for autism, is associated with better cognitive ability in non-autistic individuals.
Left or Right? The Brain Knows Before You Move – Scientists at Janelia Research Campus have identified a neural circuit that connects motor planning to movement.
Mutation May Cause Early Loss of Sperm Supply – Brown University biologists have determined how the loss of a gene in male mice results in the premature exhaustion of their fertility.
Sobering Effect of the Love Hormone – Oxytocin, sometimes referred to as the 'love' or 'cuddle' hormone, prevents alcohol from accessing specific sites in the brain that cause alcohol's intoxicating effects, sites known as delta-subunit GABA-A receptors.
Tapping into Beer's Therapeutic Potential – This article describes the study conducted by Chinese researchers on xanthohumol, a compound found in hops that prevented the brain cells from dying and also increased cell production of several antioxidants that counteracted oxidative damage.
Severe Depression Linked with Inflammation in the Brain – This article shows that there was a significant inflammation in the brains of the people with depression, and the inflammation was most severe among the participants with the most severe depression.
Ghrelin Hormone Supplement Increases Sex Drive – New studies have found that a supplement of ghrelin - the "appetite hormone" - increased the sexual activity of mice.
Diabetes in Rats Treated with Engineered Probiotic – Cornell researchers have engineered human lactobacilli, a common gut bacteria, to secrete a protein called Glucagon-like peptide 1 which may help people control diabetes.
Do You Have the 'Smart Gene' that also Helps You Live Longer? – Researchers have discovered that a KL-VS variant of the Klotho gene associated with longevity has some added benefits: improved learning and a better memory.
Largest-ever Autism Genome Study Finds Most Siblings Have Different Autism-risk Genes – This article reveals that the disorder’s genetic underpinnings are even more complex than previously thought: Most siblings who have autism spectrum disorder have different autism-linked genes.
Wide House Passage of Embryonic Stem Cell Research Ban in Oklahoma Despite Concerns – This article reports that the House overwhelmingly passed legislation Monday designed to prevent embryonic stem cell research in Oklahoma.
Limited Self-Renewal of Stem Cells in the Brain – This article describes that the self-renewal rate of the stem cells is however limited, explaining why their number drops over the course of a lifetime.
New Test Uses Human Stem Cells to Identify Drug Side Effects – Scientists have developed a test that uses cells from a single donor's blood to predict whether a new drug will cause a severe reaction in humans.
Lung Cancer Stem Cell Therapy to be Trialed in UK – This article reports that trial will involve 56 patients in UK with metastatic lung cancer who will undergo treatment using genetically modified bone marrow stem cells.
Some Breast Cancers Are Like 'Stem Cells Gone Bad' – Testing breast cancer cells for how closely they resemble stem cells could identify the most aggressive cases of the disease.
Stem Cells Reduce MS Brain Damage – This article describes in what could herald a major advance in treating multiple sclerosis,
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