Intellia Therapeutics said Friday the first six patients to receive its CRISPR-based treatment for a genetic swelling disorder have safely had small, corrective changes made to dysfunctional DNA inside their liver cells.
Preliminary results from the study — just the second to show that CRISPR-based gene editing can be delivered systemically and performed in vivo, or inside the body — found that the treatment, NTLA-2002, reduced levels of the disease-causing protein, kallikrein, by 65% and 92% in the low-and high-dose cohort, respectively. In the low-dose group, the one-time infusion also reduced by 91% the painful swelling “attacks” commonly experienced by patients with a rare condition called hereditary angioedema, or HAE. Participants in the high-dose group have not yet completed the 16-week observation period.
Adult bone marrow (BM) houses a tiny pool of hematopoietic stem cells (HSCs) that have the ability to maintain not only themselves but also all the rest of highly turning over blood lineages throughout the mammalian life (1, 2). Hence, the ability to sustain HSC in tissue culture would allow serial introduction of gain or loss of function mutations efficiently in hematopoietic system. However, our failure to expand HSC in culture has hampered the use of this approach. In fact, BM suspension cultures lose rapidly their HSC content despite vigorous growth of progenitors and more differentiated cells at least for 3 weeks even in optimal cytokine milieu (3, 4). Therefore, the phenomenon of stem cell exhaustion or senescence may set the limits that make it impossible even in principle to expand HSC in culture for longer periods (5–7).
Mouse HSC do expand in vivo (8, 9), at least up to 8000-fold, as shown by Iscove and Nawa (9) through serial transplantation experiments that assessed carefully the input and output contents of HSC in each transfer generation. Recently also in vitro approaches have been improved and refined culture conditions with new growth factors can now support up to 30-fold expansion of mouse HSC ex vivo (10). However, since it is not clear to what extent external culture conditions can be improved, alternative but not mutually exclusive efforts to change the intrinsic properties of HSC have been taken. Seminal experiments in this respect by Humphries, Savageau and their colleagues have shown that ectopic expression of HOXB4 transcription factor in BM cells support the survival and expansion of HSC in vivo and importantly also in vitro (11–13). By rigorously monitoring the HSC content in their cultures of HOXB4-transduced BM cells, they found that HSC could be expanded up to 41-fold in the 2-week liquid cultures (13). HOXB4 belongs to a large family of HOX transcription factors that are crucial for the basic developmental processes in addition to their role in maintenance of different stem cell compartments.
Capitalizing on the findings of Humphries, Savageau and their colleagues, we have established long-term murine BM cultures of HOXB4-transduced cells (HOX cells) and monitored their stem cell content to find out how extensively genetically modified HSC and their multipotent primitive progenitors (MPPs) can be expanded in culture for experimental purposes. In addition and for comparison, we established BM cultures transduced with constructs encoding for Nucleoporin 98 (NUP)–HOXB4 (NUP cells) fusion protein again following the lead of Humphries et al. (14) who showed that ectopic expression of similar fusions promoted in vivo even more robust expansion and survival of HSC.
Chardan hosted its 4th Annual Chardan Genetic Medicines Conference in October 2020, featuring over 80 public and private companies representing in vivo gene therapy, ex vivo gene therapy, gene editing, RNA medicines, and other subsegments of the genetic medicines space. Among our various panels with preeminent thought leaders, we spoke with newly-minted Nobel laureate, President of the Innovative Genomics Institute, and Professor of Molecular and Cell Biology and Chemistry at UC Berkeley, Jennifer Doudna.
PhD about open questions and areas of innovation in the CRISPR gene editing space.
Both science fiction and actual science have demonstrated the malleability of memory, from implanting artificial memories to suppressing bad ones. MIT researchers recently added to the body of memory work with their recent publication in Nature about swapping positive and negative memories in lab mice.
Memories are complicated. For one thing, as soon as we experience something, our brains go to work, associating the memory with context, whether it’s emotional or geographical or involving the people surrounding the event. Because memories aren’t exact recordings of what has actually happened (which is what makes eyewitnesses notoriously unreliable), psychologists and scientists have long been toying with it, seeing how they can manipulate people to either create new associations surrounding an event, remember things that had been long buried, or even implant new memories. MIT’s recent study sought to identify the neurological basis for such ideas.
The subjects in the study were mice that had been genetically engineered to express a protein sensitive to light—a handy move, given that the scientists can use a laser to activate different neurons. They created positive memories in half of the mice by allowing them to hang out with a female mouse, and they created negative experience in the other half of the mice by subjective them to mild electric shocks. Thus, the experiences activated the neurons in the hippocampus that give structure to memories, as well as the neurons in the amygdala that associate memories with emotions.
With billions of dollars flooding into longevity, what role will epigenetic clocks play in measuring and intervening in aging?
When Horvath first described epigenetic clocks, scientists began to speculate that altering them could reverse aging. After all, if certain patterns of DNA methylation at certain sites in cells in certain tissues of your body are hallmarks of aging, could shifting them somehow reverse aging?
Optimizing Human-System Performance — Dr. Greg Lieberman, Ph.D., Neuroscientist / Lead, U.S. Army Combat Capabilities Development Command Army Research Laboratory, U.S. Army Futures Command
Dr. Greg Lieberman, Ph.D. (https://www.arl.army.mil/arl25/meet-arl.php?gregory_lieberman) is a Neuroscientist, and Lead, Optimizing Human-System Performance, at the U.S. Army Combat Capabilities Development Command, Army Research Laboratory (DEVCOM ARL).
DEVCOM ARL, as an integral part of the Army Futures Command, is the Army’s foundational research laboratory focused on operationalizing science to ensure overmatch in any future conflict. DEVCOM ARL shapes future concepts with scientific research and knowledge and delivers technology for modernization solutions to win in the future operating environment.
With a Ph.D. from the University of Vermont in Neuroscience, a Postdoctoral Fellowship in Cognitive Neuroscience from University of New Mexico, and a BA from University of Massachusetts Amherst in Psychology, Dr. Lieberman’s research and research leadership experience ranges from genetics to learning theory, animal behavior to artificial intelligence, and human variability to team dynamics; with additional expertise in S&T strategy and the opportunities afforded by the Future of Work.
Specific areas of Dr. Lieberman’s technical expertise include maximizing human potential, human-autonomy teaming; neuroanatomical organization and connectivity; brain structure-function coupling; learning-driven neuroplasticity; non-invasive neurostimulation and cognitive enhancement; neuroimaging; mind-body medicine and mindfulness meditation; and the mechanisms of neurodegenerative disease, neuropathology, and brain injury.
In nature, evolutionary chromosomal changes may take a million years, but scientists have recently reported a novel technique for programmable chromosome fusion that has successfully created mice with genetic changes that occur on a million-year evolutionary scale in the laboratory. The findings might shed light on how chromosomal rearrangements – the neat bundles of structured genes provided in equal numbers by each parent, which align and trade or mix characteristics to produce offspring – impact evolution.
In a study published in the journal Science, the researchers show that chromosome level engineering is possible in mammals. They successfully created a laboratory house mouse with a novel and sustainable karyotype, offering crucial insight into how chromosome rearrangements may influence evolution.
“The laboratory house mouse has maintained a standard 40-chromosome karyotype — or the full picture of an organism’s chromosomes — after more than 100 years of artificial breeding,” said co-first author Li Zhikun, researcher in the Chinese Academy of Sciences (CAS) Institute of Zoology and the State Key Laboratory of Stem Cell and Reproductive Biology. “Over longer time scales, however, karyotype changes caused by chromosome rearrangements are common. Rodents have 3.2 to 3.5 rearrangements per million years, whereas primates have 1.6.”
Biotech start-up Pretzel Therapeutics launched Monday with $72.5 million in Series A financing to develop novel, mitochondria-based therapies for rare genetic disorders and diseases of aging.
Pretzel plans to target mitochondrial diseases, a highly heterogenous group of conditions caused by DNA mutations in the mitochondria or the nucleus. These disorders are very rare, afflicting around one in 5,000 people.
Pretzel CEO Jay Parrish told BioSpace the funding “should enable us to get close to the clinic if not into the clinic with one or more programs.”
You won’t be able to blame it on your genetics anymore: with CRISPR, it’s so easy to hacn into your DNA. CRISPR technology is our future, and experiments with DNA hacking are booming. CRISPR biotechnology is not science fiction anymore, it is our very near future. Would you hack and reprogram your own DNA with CRISPR? Breaking the code of life, hacking DNA at home.
Welcome to the world of a new nature. We can now literally cut and paste DNA with the new CRISPR technology. There is a revolutionary development going on that will have major consequences for humans, plants and animals. The new biotechnology is here.
‘Bio is the New Digital’. We are able to accurately reprogram the genetic code of our body cells, embryos, bacteria, viruses and plants. With the CRISPR technology we can adjust the characteristics of each organism to our needs. This allows us to permanently ban diseases, improve our body conditions and adapt plants to our food needs.
The special feature of CRISPR technology is that it is relatively simple. In the past year, the number of experiments and applications has exploded. Around the world, people have been tinkering with CRISPR: experimenting at home with the ‘Do it Yourself CRISPR kits’.
Scientists call for new ethical frameworks. The demand for the (un)desirable so-called designer babies is imminent. Although this is not yet the case, we can put an end to hereditary diseases in the short term. We may also want to make bacteria that can eat oil or plastic, pigs in which human organs can grow or bring extinct animals back to life. It looks like science fiction but it is now closer to our reality than ever. With: Emmanuelle Charpentier (geneticist), John van der Oost (microbiologist), Andrew Hessel (biotechnologist), Niels Geijsen (cell biologist), Josiah Zayner (biohacker) and Ivan van der Meij (FSHD patient).
