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The Vibrant Philly Biotech Scene: Proteovant Therapeutics Using Artificial Intelligence and Machine Learning to Develop PROTACs
Reporter:Stephen J. Williams, Ph.D.
It has been a while since I have added to this series but there have been a plethora of exciting biotech startups in the Philadelphia area, and many new startups combining technology, biotech, and machine learning. One such exciting biotech is Proteovant Therapeutics, which is combining the new PROTAC (Proteolysis-Targeting Chimera) technology with their in house ability to utilize machine learning and artificial intelligence to design these types of compounds to multiple intracellular targets.
PROTACs (which actually is under a trademark name of Arvinus Operations, but is also refered to as Protein Degraders. These PROTACs take advantage of the cell protein homeostatic mechanism of ubiquitin-mediated protein degradation, which is a very specific targeted process which regulates protein levels of various transcription factors, protooncogenes, and receptors. In essence this regulated proteolyic process is needed for normal cellular function, and alterations in this process may lead to oncogenesis, or a proteotoxic crisis leading to mitophagy, autophagy and cellular death. The key to this technology is using chemical linkers to associate an E3 ligase with a protein target of interest. E3 ligases are the rate limiting step in marking the proteins bound for degradation by the proteosome with ubiquitin chains.
A review of this process as well as PROTACs can be found elsewhere in articles (and future articles) on this Open Access Journal.
Protevant have made two important collaborations:
Oncopia Therapeutics: came out of University of Michigan Innovation Hub and lab of Shaomeng Wang, who developed a library of BET and MDM2 based protein degraders. In 2020 was aquired by Riovant Sciences.
Riovant Sciences: uses computer aided design of protein degraders
Proteovant Company Description:
Proteovant is a newly launched development-stage biotech company focusing on discovery and development of disease-modifying therapies by harnessing natural protein homeostasis processes. We have recently acquired numerous assets at discovery and development stages from Oncopia, a protein degradation company. Our lead program is on track to enter IND in 2021. Proteovant is building a strong drug discovery engine by combining deep drugging expertise with innovative platforms including Roivant’s AI capabilities to accelerate discovery and development of protein degraders to address unmet needs across all therapeutic areas. The company has recently secured $200M funding from SK Holdings in addition to investment from Roivant Sciences. Our current therapeutic focus includes but is not limited to oncology, immunology and neurology. We remain agnostic to therapeutic area and will expand therapeutic focus based on opportunity. Proteovant is expanding its discovery and development teams and has multiple positions in biology, chemistry, biochemistry, DMPK, bioinformatics and CMC at many levels. Our R&D organization is located close to major pharmaceutical companies in Eastern Pennsylvania with a second site close to biotech companies in Boston area.
The ubiquitin proteasome system (UPS) is responsible for maintaining protein homeostasis. Targeted protein degradation by the UPS is a cellular process that involves marking proteins and guiding them to the proteasome for destruction. We leverage this physiological cellular machinery to target and destroy disease-causing proteins.
Unlike traditional small molecule inhibitors, our approach is not limited by the classic “active site” requirements. For example, we can target transcription factors and scaffold proteins that lack a catalytic pocket. These classes of proteins, historically, have been very difficult to drug. Further, we selectively degrade target proteins, rather than isozymes or paralogous proteins with high homology. Because of the catalytic nature of the interactions, it is possible to achieve efficacy at lower doses with prolonged duration while decreasing dose-limiting toxicities.
Biological targets once deemed “undruggable” are now within reach.
Roivant develops transformative medicines faster by building technologies and developing talent in creative ways, leveraging the Roivant platform to launch “Vants” – nimble and focused biopharmaceutical and health technology companies. These Vants include Proteovant but also Dermovant, ImmunoVant,as well as others.
Roivant’s drug discovery capabilities include the leading computational physics-based platform for in silico drug design and optimization as well as machine learning-based models for protein degradation.
The integration of our computational and experimental engines enables the rapid design of molecules with high precision and fidelity to address challenging targets for diseases with high unmet need.
Our current modalities include small molecules, heterobifunctionals and molecular glues.
Roivant Unveils Targeted Protein Degradation Platform
– First therapeutic candidate on track to enter clinical studies in 2021
– Computationally-designed degraders for six targets currently in preclinical development
– Acquisition of Oncopia Therapeutics and research collaboration with lab of Dr. Shaomeng Wang at the University of Michigan to add diverse pipeline of current and future compounds
– Clinical-stage degraders will provide foundation for multiple new Vants in distinct disease areas
– Platform supported by $200 million strategic investment from SK Holdings
Other articles in this Vibrant Philly Biotech Scene on this Online Open Access Journal include:
The Map of human proteins drawn by artificial intelligence and PROTAC (proteolysis targeting chimeras) Technology for Drug Discovery
Curators: Dr. Stephen J. Williams and Aviva Lev-Ari, PhD, RN
UPDATED on 11/5/2021
Introducing Isomorphic Labs
I believe we are on the cusp of an incredible new era of biological and medical research. Last year DeepMind’s breakthrough AI system AlphaFold2 was recognised as a solution to the 50-year-old grand challenge of protein folding, capable of predicting the 3D structure of a protein directly from its amino acid sequence to atomic-level accuracy. This has been a watershed moment for computational and AI methods for biology. Building on this advance, today, I’m thrilled to announce the creation of a new Alphabet company – Isomorphic Labs – a commercial venture with the mission to reimagine the entire drug discovery process from the ground up with an AI-first approach and, ultimately, to model and understand some of the fundamental mechanisms of life.
For over a decade DeepMind has been in the vanguard of advancing the state-of-the-art in AI, often using games as a proving ground for developing general purpose learning systems, like AlphaGo, our program that beat the world champion at the complex game of Go. We are at an exciting moment in history now where these techniques and methods are becoming powerful and sophisticated enough to be applied to real-world problems including scientific discovery itself. One of the most important applications of AI that I can think of is in the field of biological and medical research, and it is an area I have been passionate about addressing for many years. Now the time is right to push this forward at pace, and with the dedicated focus and resources that Isomorphic Labs will bring.
An AI-first approach to drug discovery and biology The pandemic has brought to the fore the vital work that brilliant scientists and clinicians do every day to understand and combat disease. We believe that the foundational use of cutting edge computational and AI methods can help scientists take their work to the next level, and massively accelerate the drug discovery process. AI methods will increasingly be used not just for analysing data, but to also build powerful predictive and generative models of complex biological phenomena. AlphaFold2 is an important first proof point of this, but there is so much more to come. At its most fundamental level, I think biology can be thought of as an information processing system, albeit an extraordinarily complex and dynamic one. Taking this perspective implies there may be a common underlying structure between biology and information science – an isomorphic mapping between the two – hence the name of the company. Biology is likely far too complex and messy to ever be encapsulated as a simple set of neat mathematical equations. But just as mathematics turned out to be the right description language for physics, biology may turn out to be the perfect type of regime for the application of AI. What’s next for Isomorphic Labs This is just the beginning of what we hope will become a radical new approach to drug discovery, and I’m incredibly excited to get this ambitious new commercial venture off the ground and to partner with pharmaceutical and biomedical companies. I will serve as CEO for Isomorphic’s initial phase, while remaining as DeepMind CEO, partially to help facilitate collaboration between the two companies where relevant, and to set out the strategy, vision and culture of the new company. This will of course include the building of a world-class multidisciplinary team, with deep expertise in areas such as AI, biology, medicinal chemistry, biophysics, and engineering, brought together in a highly collaborative and innovative environment. (We are hiring!) As pioneers in the emerging field of ‘digital biology’, we look forward to helping usher in an amazingly productive new age of biomedical breakthroughs. Isomorphic’s mission could not be a more important one: to use AI to accelerate drug discovery, and ultimately, find cures for some of humanity’s most devastating diseases.
AI research lab DeepMind has created the most comprehensive map of human proteins to date using artificial intelligence. The company, a subsidiary of Google-parent Alphabet, is releasing the data for free, with some scientists comparing the potential impact of the work to that of the Human Genome Project, an international effort to map every human gene.
Proteins are long, complex molecules that perform numerous tasks in the body, from building tissue to fighting disease. Their purpose is dictated by their structure, which folds like origami into complex and irregular shapes. Understanding how a protein folds helps explain its function, which in turn helps scientists with a range of tasks — from pursuing fundamental research on how the body works, to designing new medicines and treatments. “the culmination of the entire 10-year-plus lifetime of DeepMind” Previously, determining the structure of a protein relied on expensive and time-consuming experiments. But last year DeepMind showed it can produce accurate predictions of a protein’s structure using AI software called AlphaFold. Now, the company is releasing hundreds of thousands of predictions made by the program to the public. “I see this as the culmination of the entire 10-year-plus lifetime of DeepMind,” company CEO and co-founder Demis Hassabis told The Verge. “From the beginning, this is what we set out to do: to make breakthroughs in AI, test that on games like Go and Atari, [and] apply that to real-world problems, to see if we can accelerate scientific breakthroughs and use those to benefit humanity.”
Two examples of protein structures predicted by AlphaFold (in blue) compared with experimental results (in green). Image: DeepMind
There are currently around 180,000 protein structures available in the public domain, each produced by experimental methods and accessible through the Protein Data Bank. DeepMind is releasing predictions for the structure of some 350,000 proteins across 20 different organisms, including animals like mice and fruit flies, and bacteria like E. coli. (There is some overlap between DeepMind’s data and pre-existing protein structures, but exactly how much is difficult to quantify because of the nature of the models.) Most significantly, the release includes predictions for 98 percent of all human proteins, around 20,000 different structures, which are collectively known as the human proteome. It isn’t the first public dataset of human proteins, but it is the most comprehensive and accurate.
If they want, scientists can download the entire human proteome for themselves, says AlphaFold’s technical lead John Jumper. “There is a HumanProteome.zip effectively, I think it’s about 50 gigabytes in size,” Jumper tells The Verge. “You can put it on a flash drive if you want, though it wouldn’t do you much good without a computer for analysis!” “anyone can use it for anything” After launching this first tranche of data, DeepMind plans to keep adding to the store of proteins, which will be maintained by Europe’s flagship life sciences lab, the European Molecular Biology Laboratory (EMBL). By the end of the year, DeepMind hopes to release predictions for 100 million protein structures, a dataset that will be “transformative for our understanding of how life works,” according to Edith Heard, director general of the EMBL. The data will be free in perpetuity for both scientific and commercial researchers, says Hassabis. “Anyone can use it for anything,” the DeepMind CEO noted at a press briefing. “They just need to credit the people involved in the citation.” The benefits of protein folding
Understanding a protein’s structure is useful for scientists across a range of fields. The information can help design new medicines, synthesize novel enzymes that break down waste materials, and create crops that are resistant to viruses or extreme weather. Already, DeepMind’s protein predictions are being used for medical research, including studying the workings of SARS-CoV-2, the virus that causes COVID-19. “it will definitely have a huge impact for the scientific community” New data will speed these efforts, but scientists note it will still take a lot of time to turn this information into real-world results. “I don’t think it’s going to be something that changes the way patients are treated within the year, but it will definitely have a huge impact for the scientific community,” Marcelo C. Sousa, a professor at the University of Colorado’s biochemistry department, told The Verge. Scientists will have to get used to having such information at their fingertips, says DeepMind senior research scientist Kathryn Tunyasuvunakool. “As a biologist, I can confirm we have no playbook for looking at even 20,000 structures, so this [amount of data] is hugely unexpected,” Tunyasuvunakool told The Verge. “To be analyzing hundreds of thousands of structures — it’s crazy.”
Notably, though, DeepMind’s software produces predictions of protein structures rather than experimentally determined models, which means that in some cases further work will be needed to verify the structure. DeepMind says it spent a lot of time building accuracy metrics into its AlphaFold software, which ranks how confident it is for each prediction.
Example protein structures predicted by AlphaFold. Image: DeepMind Predictions of protein structures are still hugely useful, though. Determining a protein’s structure through experimental methods is expensive, time-consuming, and relies on a lot of trial and error. That means even a low-confidence prediction can save scientists years of work by pointing them in the right direction for research. Helen Walden, a professor of structural biology at the University of Glasgow, tells The Verge that DeepMind’s data will “significantly ease” research bottlenecks, but that “the laborious, resource-draining work of doing the biochemistry and biological evaluation of, for example, drug functions” will remain. Sousa, who has previously used data from AlphaFold in his work, says for scientists the impact will be felt immediately. “In our collaboration we had with DeepMind, we had a dataset with a protein sample we’d had for 10 years, and we’d never got to the point of developing a model that fit,” he says. “DeepMind agreed to provide us with a structure, and they were able to solve the problem in 15 minutes after we’d been sitting on it for 10 years.”
Why protein folding is so difficult
Proteins are constructed from chains of amino acids, which come in 20 different varieties in the human body. As any individual protein can be comprised of hundreds of individual amino acids, each of which can fold and twist in different directions, it means a molecule’s final structure has an incredibly large number of possible configurations. One estimate is that the typical protein can be folded in 10^300 ways — that’s a 1 followed by 300 zeroes.
Protein folding has been a “grand challenge” of biology for decades
Because proteins are too small to examine with microscopes, scientists have had to indirectly determine their structure using expensive and complicated methods like nuclear magnetic resonance and X-ray crystallography. The idea of determining the structure of a protein simply by reading a list of its constituent amino acids has been long theorized but difficult to achieve, leading many to describe it as a “grand challenge” of biology. In recent years, though, computational methods — particularly those using artificial intelligence — have suggested such analysis is possible. With these techniques, AI systems are trained on datasets of known protein structures and use this information to create their own predictions.
DeepMind’s AlphaFold software has significantly increased the accuracy of computational protein-folding, as shown by its performance in the CASP competition. Image: DeepMind Many groups have been working on this problem for years, but DeepMind’s deep bench of AI talent and access to computing resources allowed it to accelerate progress dramatically. Last year, the company competed in an international protein-folding competition known as CASP and blew away the competition. Its results were so accurate that computational biologist John Moult, one of CASP’s co-founders, said that “in some sense the problem [of protein folding] is solved.”
DeepMind’s AlphaFold program has been upgraded since last year’s CASP competition and is now 16 times faster. “We can fold an average protein in a matter of minutes, most cases seconds,” says Hassabis.
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The company also released the underlying code for AlphaFold last week as open-source, allowing others to build on its work in the future.
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Liam McGuffin, a professor at Reading University who developed some of the UK’s leading protein-folding software, praised the technical brilliance of AlphaFold, but also noted that the program’s success relied on decades of prior research and public data. “DeepMind has vast resources to keep this database up to date and they are better placed to do this than any single academic group,” McGuffin told The Verge. “I think academics would have got there in the end, but it would have been slower because we’re not as well resourced.”
Why does DeepMind care?
Many scientists The Verge spoke to noted the generosity of DeepMind in releasing this data for free. After all, the lab is owned by Google-parent Alphabet, which has been pouring huge amounts of resources into commercial healthcare projects. DeepMind itself loses a lot of money each year, and there have been numerousreportsof tensions between the company and its parent firm over issues like research autonomy and commercial viability.
Hassabis, though, tells The Verge that the company always planned to make this information freely available, and that doing so is a fulfillment of DeepMind’s founding ethos. He stresses that DeepMind’s work is used in lots of places at Google — “almost anything you use, there’s some of our technology that’s part of that under the hood” — but that the company’s primary goal has always been fundamental research. “There’s many ways value can be attained.”
“The agreement when we got acquired is that we are here primarily to advance the state of AGI and AI technologies and then use that to accelerate scientific breakthroughs,” says Hassabis. “[Alphabet] has plenty of divisions focused on making money,” he adds, noting that DeepMind’s focus on research “brings all sorts of benefits, in terms of prestige and goodwill for the scientific community. There’s many ways value can be attained.” Hassabis predicts that AlphaFold is a sign of things to come — a project that shows the huge potential of artificial intelligence to handle messy problems like human biology.
“I think we’re at a really exciting moment,” he says. “In the next decade, we, and others in the AI field, are hoping to produce amazing breakthroughs that will genuinely accelerate solutions to the really big problems we have here on Earth.”
Abstract PROTACs-induced targeted protein degradation has emerged as a novel therapeutic strategy in drug development and attracted the favor of academic institutions, large pharmaceutical enterprises (e.g., AstraZeneca, Bayer, Novartis, Amgen, Pfizer, GlaxoSmithKline, Merck, and Boehringer Ingelheim, etc.), and biotechnology companies. PROTACs opened a new chapter for novel drug development. However, any new technology will face many new problems and challenges. Perspectives on the potential opportunities and challenges of PROTACs will contribute to the research and development of new protein degradation drugs and degrader tools.
Although PROTAC technology has a bright future in drug development, it also has many challenges as follows: (1) Until now, there is only one example of PROTAC reported for an “undruggable” target; (18) more cases are needed to prove the advantages of PROTAC in “undruggable” targets in the future. (2) “Molecular glue”, existing in nature, represents the mechanism of stabilized protein–protein interactions through small molecule modulators of E3 ligases. For instance, auxin, the plant hormone, binds to the ligase SCF-TIR1 to drive recruitment of Aux/IAA proteins and subsequently triggers its degradation. In addition, some small molecules that induce targeted protein degradation through “molecular glue” mode of action have been reported. (21,22) Furthermore, it has been recently reported that some PROTACs may actually achieve target protein degradation via a mechanism that includes “molecular glue” or via “molecular glue” alone. (23) How to distinguish between these two mechanisms and how to combine them to work together is one of the challenges for future research. (3) Since PROTAC acts in a catalytic mode, traditional methods cannot accurately evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) properties of PROTACs. Thus, more studies are urgently needed to establish PK and PD evaluation systems for PROTACs. (4) How to quickly and effectively screen for target protein ligands that can be used in PROTACs, especially those targeting protein–protein interactions, is another challenge. (5) How to understand the degradation activity, selectivity, and possible off-target effects (based on different targets, different cell lines, and different animal models) and how to rationally design PROTACs etc. are still unclear. (6) The human genome encodes more than 600 E3 ubiquitin ligases. However, there are only very few E3 ligases (VHL, CRBN, cIAPs, and MDM2) used in the design of PROTACs. How to expand E3 ubiquitin ligase scope is another challenge faced in this area.
PROTAC technology is rapidly developing, and with the joint efforts of the vast number of scientists in both academia and industry, these problems shall be solved in the near future.
PROTACs have opened a new chapter for the development of new drugs and novel chemical knockdown tools and brought unprecedented opportunities to the industry and academia, which are mainly reflected in the following aspects: (1) Overcoming drug resistance of cancer. In addition to traditional chemotherapy, kinase inhibitors have been developing rapidly in the past 20 years. (12) Although kinase inhibitors are very effective in cancer therapy, patients often develop drug resistance and disease recurrence, consequently. PROTACs showed greater advantages in drug resistant cancers through degrading the whole target protein. For example, ARCC-4 targeting androgen receptor could overcome enzalutamide-resistant prostate cancer (13) and L18I targeting BTK could overcome C481S mutation. (14) (2) Eliminating both the enzymatic and nonenzymatic functions of kinase. Traditional small molecule inhibitors usually inhibit the enzymatic activity of the target, while PROTACs affect not only the enzymatic activity of the protein but also nonenzymatic activity by degrading the entire protein. For example, FAK possesses the kinase dependent enzymatic functions and kinase independent scaffold functions, but regulating the kinase activity does not successfully inhibit all FAK function. In 2018, a highly effective and selective FAK PROTAC reported by Craig M. Crews’ group showed a far superior activity to clinical candidate drug in cell migration and invasion. (15) Therefore, PROTAC can expand the druggable space of the existing targets and regulate proteins that are difficult to control by traditional small molecule inhibitors. (3) Degrade the “undruggable” protein target. At present, only 20–25% of the known protein targets (include kinases, G protein-coupled receptors (GPCRs), nuclear hormone receptors, and iron channels) can be targeted by using conventional drug discovery technologies. (16,17) The proteins that lack catalytic activity and/or have catalytic independent functions are still regarded as “undruggable” targets. The involvement of Signal Transducer and Activator of Transcription 3 (STAT3) in the multiple signaling pathway makes it an attractive therapeutic target; however, the lack of an obviously druggable site on the surface of STAT3 limited the development of STAT3 inhibitors. Thus, there are still no effective drugs directly targeting STAT3 approved by the Food and Drug Administration (FDA). In November 2019, Shaomeng Wang’s group first reported a potent PROTAC targeting STAT3 with potent biological activities in vitro and in vivo. (18) This successful case confirms the key potential of PROTAC technology, especially in the field of “undruggable” targets, such as K-Ras, a tricky tumor target activated by multiple mutations as G12A, G12C, G12D, G12S, G12 V, G13C, and G13D in the clinic. (19) (4) Fast and reversible chemical knockdown strategy in vivo. Traditional genetic protein knockout technologies, zinc-finger nuclease (ZFN), transcription activator-like effector nuclease (TALEN), or CRISPR-Cas9, usually have a long cycle, irreversible mode of action, and high cost, which brings a lot of inconvenience for research, especially in nonhuman primates. In addition, these genetic animal models sometimes produce phenotypic misunderstanding due to potential gene compensation or gene mutation. More importantly, the traditional genetic method cannot be used to study the function of embryonic-lethal genes in vivo. Unlike DNA-based protein knockout technology, PROTACs knock down target proteins directly, rather than acting at the genome level, and are suitable for the functional study of embryonic-lethal proteins in adult organisms. In addition, PROTACs provide exquisite temporal control, allowing the knockdown of a target protein at specific time points and enabling the recovery of the target protein after withdrawal of drug treatment. As a new, rapid and reversible chemical knockdown method, PROTAC can be used as an effective supplement to the existing genetic tools. (20)
Peroxisome proliferator-activated receptor (PPAR-gamma) Receptors Activation: PPARγ transrepression for Angiogenesis in Cardiovascular Disease and PPARγ transactivation for Treatment of Diabetes
In our chat, he summarized the key advances in transcatheter aortic valve replacements (TAVR) therapy and explained a key TAVR trend that came out of TVT for “lifetime patient management.”
It was clear at the meeting that the standard-of-care thinking on TAVR replacements has shifted from just getting a valve implanted and managing immediate complications to looking decades down the road and considering next steps with that same patient. TAVR now makes up about 70% or more of the procedure volume for aortic valve replacements. Latib said the focus of many sessions at TVT was on the longer-term management of valve patients since it is clear TAVR is becoming the standard of care. If a patient gets surgical or TAVR valve today, they will likely need a replacement in 10-20 years. More times than not, Latib explained, this replacement will come in the form of another TAVR valve deployed inside the first valve.
Latib said several sessions discussed what strategy is best, with many experts favoring surgical valve replacement first and two TAVR procedures later in life to eliminate the need for open heart surgery when the patient is much older and more frail. However, many experts admitted this might not be the strategy that gets adopted as a practical standard of care because most patients want the less invasive option versus surgery.
“I think all the companies have realized that they need to move their technologies in that direction,” Latib explained. “The bar has been set really high and so we are going to see a lot of new technologies or iterations of technology.”
The Edwards Lifesciences Sapien X4, the forth generation of the Sapien valve, is about to start the ALLIANCE pivotal trial. It is designed specifically for lower-risk patients with a lower frame height for better coronary access and it is the first balloon-expandable valve that allows the operator to turn the valve to align the commissures, which also will aid further coronary access. The valve is also designed to reduce the need to use oversized valves to ensure a good fit in the anatomy
“What this means is when you do the next valve you are not going to have issues with coronary access and having a more physiologically aligned valve on the commissures made help the valve last longer,” Latib said.
He said the Abbott Portico and Boston Scientific Acurate Neo2 TAVR systems are also undergoing revisions to make them more user friendly and compatible with the shifting needs of TAVR.
Tiberio Frisoli, M.D., interventional structural cardiologist, senior staff physician, Henry Ford Hospital, explains how his center performs transcaval transcatheter aortic valve replacement (TAVR) access for patients who have suboptimal abdominal aortic and femoral vascular anatomy. Transcaval access was pioneered at Henry Ford Hospital and involves using femoral vein access and then using a surgical radio frequency cutter to bore a hole from the interior venacava into the aorta to allow the TAVR delivery catheter to path through.
This procedure was developed to enable more patients to receive TAVR via the preferred femoral access route. Some patients are not candidates for femoral artery access because of calcified lesions and heart atherosclerotic plaque, which narrows the vessel lumen, and makes it difficult to thread catheters through. The transcaval access technique can bypass the restricted arteries or heavy calcified plaques to still enable a minimally invasive procedure without the need for surgery.
Comparative Study: Four SARS-CoV-2 vaccines induce quantitatively different antibody responses against SARS-CoV-2 variants
Reporter: Aviva Lev- Ari, PhD, RN
Marit J. van Gils, A. H. Ayesha Lavell, Karlijn van der Straten, Brent Appelman, Ilja Bontjer, Meliawati Poniman, Judith A. Burger, Melissa Oomen, Joey H. Bouhuijs, Lonneke A. van Vught, Marleen A. Slim, Michiel Schinkel, Elke Wynberg, Hugo D.G. van Willigen, Marloes Grobben, Khadija Tejjani, Jonne Snitselaar, Tom G. Caniels, Amsterdam UMC COVID-19 S3/HCW study group, Alexander P. J. Vlaar, Maria Prins, Menno D. de Jong, Godelieve J. de Bree, Jonne J. Sikkens, Marije K. Bomers, Rogier W. Sanders doi:https://doi.org/10.1101/2021.09.27.21264163
Abstract
Emerging and future SARS-CoV-2 variants may jeopardize the effectiveness of vaccination campaigns. We performed a head-to-head comparison of the ability of sera from individuals vaccinated with either one of four vaccines (BNT162b2, mRNA-1273, AZD1222 or Ad26.COV2.S) to recognize and neutralize the four SARS-CoV-2 variants of concern (VOCs; Alpha, Beta, Gamma and Delta). Four weeks after completing the vaccination series, SARS-CoV-2 wild-type neutralizing antibody titers were highest in recipients of BNT162b2 and mRNA-1273 (median titers of 1891 and 3061, respectively), and substantially lower in those vaccinated with the adenovirus vector-based vaccines AZD1222 and Ad26.COV2.S (median titers of 241 and 119, respectively). VOCs neutralization was reduced in all vaccine groups, with the largest (5.8-fold) reduction in neutralization being observed against the Beta variant. Overall, the mRNA vaccines appear superior to adenovirus vector-based vaccines in inducing neutralizing antibodies against VOCs four weeks after the final vaccination.
Figure 2:Binding and neutralization titers post-vaccination against VOCs.
(A) Median with interquartile range of binding titers to wild-type and VOCs S proteins represented as mean fluorescence intensity (MFI) of 1:100,000 diluted sera collected four-five weeks after full vaccination for the four vaccination groups. The lower cutoff for binding was set at an MFI of 10 (grey shading). Vaccine groups are indicated by colors with BNT162b2 in green, mRNA-1273 in purple, AZD1222 in orange and Ad26.COV2.S in blue. (B) Median with interquartile range of half-maximal neutralization (ID50) titers of D614G and VOCs pseudoviruses for sera collected after full vaccination for the four vaccination groups. The lower cutoff for neutralization was set at an ID50 of 100 (grey shading). Vaccine groups are indicated by colors with BNT162b2 in green, mRNA-1273 in purple, AZD1222 in orange and Ad26.COV2.S in blue. (C) Median ID50 neutralization of D614G and VOCs plotted against the reported vaccine efficacy against symptomatic infection2–5,12–17. Vaccine groups are indicated by colors with BNT162b2 in green, mRNA-1273 in purple, AZD1222 in orange and Ad26.COV2.S in blue. Circles represent WT data, squares for Alpha, diamond for Beta, nabla triangle for Gamma and delta triangle for Delta. Spearman’s rank correlation coefficient with p value are indicated. The result of the AZD1222 phase 3 trial conducted in South Africa, demonstrating poor (10%) efficacy against Beta variant, is not shown.
A laboratory for the use of AI for drug development has been launched in collaboration with Pfizer, Teva, AstraZeneca, Mark and Amazon
Reporter: Aviva Lev-Ari, PhD, RN
AION Labs unites pharma, technology and funds companies including IBF to invest in startups to integrate developments in cloud computing and artificial intelligence to improve drug development capabilities. An alliance of four leading pharmaceutical companies – AION Labs , the first innovation lab of its kind in the world and a pioneer in the process of adopting cloud technologies, artificial intelligence and computer science to solve the R&D challenges of the pharma industry, today announces its launch. AstraZeneca , Mark , Pfizer and Teva – and two leading companies in the field of high-tech and biotech investments, respectively – AWS ( Amazon Web Services Inc ) and the Israeli investment fund IBF ( Israel Biotech Fund ) – which joined together to establish groundbreaking ventures Through artificial intelligence and computer science to change the way new therapies are discovered and developed. “We are excited to launch the new innovation lab in favor of discoveries of drugs and medical devices using groundbreaking computational tools,” said Matti Gil, CEO of AION Labs. We are prepared and ready to make a difference in the process of therapeutic discoveries and their development. With a strong pool of talent from Israel and the world, cloud technology and artificial intelligence at the heart of our activities and a significant commitment by the State of Israel, we are ready to contribute to the health and well-being of the human race and promote industry in Israel. I thank the partners for the trust, and it is an honor for me to lead such a significant initiative. ” In addition, AION Labs has announced a strategic partnership with X BioMed , an independent biomedical research institute operating in Heidelberg, Germany. BioMed X has a proven track record in advancing research innovations in the field of biomedicine at the interface between academic research and the pharmaceutical industry. BioMed X’s innovation model, based on global mass sourcing and incubators to cultivate the most brilliant talent and ideas, will serve as the R & D engine to drive AION Labs’ enterprise model.
Greylock Partners has raised $500 million to invest exclusively in seed-stage startups. The announcement comes a year after the firm raised $1 billion for its 16th flagship fund to invest in early- and growth-stage tech startups.
Guo and general partner Saam Motamedi said in an interview the fund is part of an expansion of a $1.1 billion fund, which we reported last year, to $1.6 billion, The Information reported. The funding is among the industry’s largest devoted to seed investments, which often represent a startup’s first outside capital.
The pool of funds will give the 56-year-old venture capital firm the ability to write large checks at “lean-in valuations” and emphasize its commitment to early-stage investing, said general partner Sarah Guo. In a thread post on Twitter, Greylock said, “We at @GreylockVC are excited to announce we’ve raised $500M dedicated to seed investing. This is the industry’s largest pool of venture capital dedicated to backing founders at day one.”
This study aims to assess whether information derived from the raw 12-lead electrocardiogram (ECG) combined with clinical information is predictive of atrial fibrillation (AF) development.Methods and results
We use a subset of the Telehealth Network of Minas Gerais (TNMG) database consisting of patients that had repeated 12-lead ECG measurements between 2010 and 2017 that is 1 130 404 recordings from 415 389 unique patients. Median and interquartile of age for the recordings were 58 (46–69) and 38% of the patients were males. Recordings were assigned to train-validation and test sets in an 80:20% split which was stratified by class, age and gender. A random forest classifier was trained to predict, for a given recording, the risk of AF development within 5 years. We use features obtained from different modalities, namely demographics, clinical information, engineered features, and features from deep representation learning. The best model performance on the test set was obtained for the model combining features from all modalities with an area under the receiver operating characteristic curve (AUROC) = 0.909 against the best single modality model which had an AUROC = 0.839.Conclusion
Our study has important clinical implications for AF management. It is the first study integrating feature engineering, deep learning, and Electronic medical record system (EMR) metadata to create a risk prediction tool for the management of patients at risk of AF. The best model that includes features from all modalities demonstrates that human knowledge in electrophysiology combined with deep learning outperforms any single modality approach. The high performance obtained suggest that structural changes in the 12-lead ECG are associated with existing or impending AF.
Graphical Abstract
A look at the experimental environment: digital markers (HRV and MOR), deep learning features (DNN), and clinical data (EMR) are combined in a model training to predict atrial fibrillation
The students trained a deep learning system (layered neural network) using more than a million ECG records of more than 400,000 patients, thus creating a mechanism to predict human chances of developing atrial fibrillation over a five-year period. They then combined the deep neural network with information. Clinical on the patient.This model was able to correctly predict the risk of developing atrial fibrillation in 60% of cases, while maintaining a high specificity rate of 95% (i.e. only 5% of the people identified as people at risk did not develop the disease
Tweets and Re-Tweets of Tweets by @pharma_BI@AVIVA1950 at 2021 Virtual World Medical Innovation Forum, Mass General Brigham, Gene and Cell Therapy, VIRTUAL May 19–21, 2021
REAL TIME EVENT COVERAGE as PRESS by invitation from 2021 Virtual World Medical Innovation Forumat #WMIF2021 @MGBInnovation:
for sharing this screen capture of the impressive lineup of #GCT “Disruptive Dozen” panelists at #WMIF2021
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Aviva Lev-Ari
@AVIVA1950
· May 21
@MGBInnovation #WMIF Best Global event on Gene Cell Therapy covered in real time @AVIVA1950 @pharma_BI Disruptive Dozen technologies four are based on Gene Editing, AAV and non viral vector for drug delivery are included
PART 1: ALL THE TWEETS PRODUCED by @AVIVA1950 on May 21, 2021
Bob Carter, MD, PhD Chairman, Department of Neurosurgery, MGH William and Elizabeth Sweet, Professor of Neurosurgery, HMS Neurogeneration REVERSAL or slowing down?
Penelope Hallett, PhD NRL, McLean Assistant Professor Psychiatry, HMS efficacy Autologous cell therapy transplantation approach program T cells into dopamine genetating cells greater than Allogeneic cell transplantation
Roger Kitterman VP, Venture, Mass General Brigham Saturation reached or more investment is coming in CGT Multi OMICS and academia originated innovations are the most attractive areas
Peter Kolchinsky, PhD Founder and Managing Partner, RA Capital Management Future proof for new comers disruptors Ex Vivo gene therapy to improve funding products what tool kit belongs to
Chairman, Department of Neurosurgery, MGH, Professor of Neurosurgery, HMS Cell therapy for Parkinson to replace dopamine producing cells lost ability to produce dopamine skin cell to become autologous cells reprogramed
Kapil Bharti, PhD Senior Investigator, Ocular and Stem Cell Translational Research Section, NIH Off-th-shelf one time treatment becoming cure Intact tissue in a dish is fragile to maintain metabolism to become like semiconductors
Ole Isacson, MD, PhD Director, Neuroregeneration Research Institute, McLean Professor, Neurology and Neuroscience, MGH, HMS Opportunities in the next generation of the tactical level Welcome the oprimism and energy level of all
Erin Kimbrel, PhD Executive Director, Regenerative Medicine, Astellas In the ocular space immunogenecity regulatory communication use gene editing for immunogenecity Cas1 and Cas2 autologous cells
Nabiha Saklayen, PhD CEO and Co-Founder, Cellino scale production of autologous cells foundry using semiconductor process in building cassettes by optic physicists
Joe Burns, PhD VP, Head of Biology, Decibel Therapeutics Ear inside the scall compartments and receptors responsible for hearing highly differentiated tall ask to identify cell for anticipated differentiation control by genomics
Kapil Bharti, PhD Senior Investigator, Ocular and Stem Cell Translational Research Section, NIH first drug required to establish the process for that innovations design of animal studies not done before
Robert Nelsen Managing Director, Co-founder, ARCH Venture Partners Manufacturing change is not a new clinical trial FDA need to be presented with new rethinking for big innovations Drug pricing cheaper requires systematization
David Berry, MD, PhD CEO, Valo Health GP, Flagship Pioneering Bring disruptive frontier platform reliable delivery CGT double knockout disease cure all change efficiency scope human centric vs mice centered right scale acceleration
Kush Parmar, MD, PhD Managing Partner, 5AM Ventures build it yourself, benefit for patients FIrst Look at MGB shows MEE innovation on inner ear worthy investment
Robert Nelsen Managing Director, Co-founder, ARCH Venture Partners Frustration with supply chain during the Pandemic, GMC anticipation in advance CGT rapidly prototype rethink and invest proactive investor .edu and Pharma
The # of US patients with Parkinson’s Disease is expected to double over next 30 years. Penelope Hallett PhD, Co-Director of the Neuroregeneration Research Inst
Marcela Maus, MD PhD, are working to expand the reach of this transformative technology. #WMIF2021
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Mass General Brigham Innovation
@MGBInnovation
· 3h
Disruptive Dozen: 12 Technologies that Will Reinvent GCT #9. Building the Next Wave of CAR-T-cell Therapies #WMIF2021 #GCT #GeneAndCellTherapy #CellTherapy #CarT #DisruptiveDozen
and global colleagues at #WMIF2021. On Thursday, May 20, my colleagues and I will discuss the advantages of RNA-targeted medicines and how they might shape the future of medicine for patients.
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Mass General Brigham Innovation
@MGBInnovation
· May 10
Are you part of the @MassGenBrigham network and interested in #GeneAndCellTherapy? Join us at the World Medical Innovation Forum on 5/19-5/21. Register today! https://worldmedicalinnovation.org/register/ #WMIF2021
Incredible opportunity to get up to speed with the most innovative technologies in medicine ! Gene and cell therapy are revolutionizing healthcare ! #WMIF2021#MedTwitter
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Mass General Brigham Innovation
@MGBInnovation
· May 11
#WMIF2021 is an opportunity for innovators from around the globe to meet, explore, challenge, and reflect on the issues influencing the adoption of novel technologies in #healthcare. Register now to join the conversation: https://worldmedicalinnovation.org/register/
Currently, the only cure for some common blood disorders is a bone marrow transplant, which can be risky. Now, gene therapies are also in the works, including a CRISPR-based #genetherapy being tested in clinical trials with encouraging early results. #WMIF2021
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Mass General Brigham Innovation
@MGBInnovation
· 3h
Disruptive Dozen: 12 Technologies that Will Reinvent GCT #2. A Genetic Fix for Two Common Blood Disorders #WMIF2021 #GCT #GeneAndCellTherapy #BloodDisorders #DisruptiveDozen
Researchers have pinpointed key genes involved in cholesterol and lipid metabolism that represent promising targets for new cholesterol-lowering treatments. #WMIF2021
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Mass General Brigham Innovation
@MGBInnovation
· 3h
Disruptive Dozen: 12 Technologies that Will Reinvent GCT #1. A New Generation of Cholesterol-Loweing Therapies #WMIF2021 #GCT #GeneAndCellTherapy #DisruptiveDozen
I really enjoyed this remarkable panel #WMIF2021. Thank you Meredith Fisher for moderating and thank you David, Bob and Kush for openly sharing your big picture view
Variability, delays, manufacturing as an afterthought make #GCT challenging from an investment POV — need to rethink the ecosystem and drive efficiency, invest in tech innovation says Bob Nelson ARCH Venture Partners
We need to change the scale and scope of how #GCT is advancing from discovery to development — systematization critical. Can’t have thousands of one-off therapies say early-stage investors. Major mis-match between where things are now and what could be.
Today I moderated a panel on Gene and Cell Therapy Delivery, Perfecting the Technology. We highlighted non-viral delivery technologies as key enablers of gene therapy and editing. Learn more: https://lnkd.in/d-Xqzqh#WMIF2021
Congratulations to the 2021 Innovation Discovery Grants winners: @lynchielydia, Peter Sage, @GrishchukL, Benjamin Kleinstiver, Petr Baranov, announced at the #WMIF2021. It’s exciting to see the range of breakthrough research in #geneticdisease at @MassGenBrigham…
for sharing this screen capture of the impressive lineup of #GCT “Disruptive Dozen” panelists at #WMIF2021
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Aviva Lev-Ari
@AVIVA1950
· May 21
@MGBInnovation #WMIF Best Global event on Gene Cell Therapy covered in real time @AVIVA1950 @pharma_BI Disruptive Dozen technologies four are based on Gene Editing, AAV and non viral vector for drug delivery are included
PART 1: ALL THE TWEETS PRODUCED by @AVIVA1950 on May 20, 2021
Bob Brown, PhD CSO, EVP of R&D, Dicerna small molecule vs capacity of nanoparticles to deliver therapeutics quantity for more molecule is much larger CNS delivery most difficult
Jeannie Lee, MD, PhD Molecular Biologist, MGH Prof Genetics, HMS 200 disease X chromosome unlock for neurological genetic diseases: Rett Syndrome, autism spectrum disorders female model vs male mice model restore own protein
Suneet Varma Global President of Rare Disease, Pfizer review of protocols and CGT for Hemophilia Pfizer: You can’t buy Time With MIT Pfizer is developing a model for Hemophilia CGT treatment
Gallia Levy, MD, PhD CMO, Spark Therapeutics Hemophilia CGT is the highest potential for Global access logistics in underdev countries working with NGOs practicality of the Tx Roche reached 120 Counties great to be part of the Roche
Theresa Heggie CEO, Freeline Therapeutics Safety concerns, high burden of treatment CGT has record of safety and risk/benefit adoption of Tx functional cure CGT is potent Tx relative small quantity of protein needs be delivered
Suneet Varma Global President of Rare Disease, Pfizer Gene therapy at Pfizer small, large molecule and CGT – spectrum of choice allowing Hemophilia patients to marry 1/3 internal 1/3 partnership 1/3 acquisitions review of protocols
Ron Renaud CEO, Translate Bio What strain of Flu vaccine will come back in the future when people do not use masks. AAV vectors small transcript size fit reach cytoplasm more development coming
Melissa Moore Chief Scientific Officer, Moderna Many years of mRNA pivoting for new diseases, DARPA, nucleic Acids global deployment of a manufacturing unit on site where the need arise Elan Musk funds new directions at Moderna
Lindsey Baden, MD Director, Clinical Research, Division of Infectious Diseases, BWH Associate Professor, HMS In vivo delivery process regulatory for new opportunities for same platform new indication using multi valence vaccines
Melissa Moore Chief Scientific Officer, Moderna Many years of mRNA pivoting for new diseases, DARPA, nucleic Acids global deployment of a manufacturing unit on site where the need arise Elan Musk funds new directions at Moderna
Ron Renaud CEO, Translate Bio 1.6 Billion doses produced rare disease monogenic correct mRNA like CF multiple mutation infection disease and oncology applications
Melissa Moore CSO, Moderna mRNA vaccine 98% efficacy for Pfizer and Moderna more then 10 years 2015 mRNA was ready (ZIKA, RSV), as the proteine is identify manufacturing temp less of downside in the future ability to store at Ref
Richard Wang, PhD CEO, Fosun Kite Biotechnology Co. Ltd Possibilities to be creative and capitalize the new technologies for new drug Support of the ecosystem by funding new companies Autologous in patients differences cost challenge
Tian Xu, PhD Vice President, Westlake University ICH Chinese FDA -r regulation similar to the US Difference is the population recruitment, in China patients are active participants Dev of transposome non-viral methods, price
Alvin Luk, PhD CEO, Neuropath Therapeutics Monogenic rare disease with clear genomic target Increase of 30% in patient enrollment Regulatory reform approval is 60 days no delay
We’re excited to attend this week’s #WMIF2021 to talk all things cell and genetic therapies. Join our Chief of VCGT Bastiano Sanna tomorrow at 9:50am EDT for a discussion on the promise of cell therapies for type 1 diabetes. Register now! https://bit.ly/3otngYd
John Fish, Board Chair, Brigham Health, Chairman & CEO, Suffolk on the Novartis Main Stage to introduce the “Collaboration is Key: GCT R&D of the Future” fireside chat with Jay Bradner, MD, President, NIBR
Thomas VanCott, PhD, Chief Technology & Strategy Officer, Catalent Cell & Gene Therapy, says that time, improvements and scaling up in manufacturing will lead to allogeneic cell therapies. He recognizes that upfront costs are high, but will decrease in the long term #WMIF2021
Today Lisa Michaels, Editas CMO, will participate in the panel “Gene Editing – Achieving Therapeutic Mainstream” at the World Medical Innovation Forum #WMIF2021 in Boston. For those attending, be sure to tune in!
, views GCT as the ultimate precision medicine. AI, machine learning, and data science comprise one of the big disruptive forces that will address misdiagnosis, smooth out workflow, reduce cost and enhance recovery. #WMIF2021
CSO Laura Sepp-Lorenzino, PhD, in our “GCT Delivery | Perfecting the Technology” panel this afternoon! #WMIF2021
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Intellia Therapeutics
@intelliatweets
· 6h
Today, Intellia CSO, @LauraSeppLore will be participating in the World Medical Innovation Forum’s panel on Gene and Cell Therapy Delivery, Perfecting the Technology. #WMIF2021 @MGBInnovation. Click here to learn more: https://worldmedicalinnovation.org
is back with us this afternoon sharing a First Look at “Versatile Polymer-Based Nanocarriers for Targeted Therapy and Immunomodulation.” #WMIF2021#GCT#geneandcelltherapy
VP of Clinical Development, Manasi Jaiman, during the “Diabetes | Grand Challenge” panel today. #WMIF2021
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ViaCyte
@ViaCyte
· 8h
Join us at #WMIF2021 today! Our own Manasi Jaiman, VP, Clinical Development, will participate in the Diabetes: Grand Challenge panel to discuss regenerative medicine approaches for T1D utilizing stem-cell derived islet cell replacement therapy.
, discusses how GCT is in the embryonic phase. Bayer is ready to treat its first Parkinson’s patient, and is exploring therapeutic technologies to treat diseases with single gene defects #WMIF2021
Today Lisa Michaels, Editas CMO, will participate in the panel “Gene Editing – Achieving Therapeutic Mainstream” at the World Medical Innovation Forum #WMIF2021 in Boston. For those attending, be sure to tune in! @MassGenBrigham https://bit.ly/3hx1XTV #geneediting #biotechnology
to discuss the current state of CAR-T and its future prospects. These conversations are important for the development of potential #CART therapies. #WMIF2021
‘s #WMIF2021 — Thanks to the MGB team for facilitating a great discussion!
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Mass General Brigham Innovation
@MGBInnovation
· 7h
Overview of our #mRNA Vaccines panel today, highlighting improved manufacturing capabilities & potential for #personalizedmedicine. Thank you to Lindsey Baden @bwh_id & panelists Kate Bingham, SV Health Investors, Melissa Moore @moderna_tx and Ron Renaud @TranslateBio #WMIF2021
investigators are ready to give you an early preview of their #GCT research in the First Look sessions at #WMIF2021. Exciting opportunities to dramatically change how disease is treated!
Our “Rare and Ultra Rare Diseases | GCT Breaks Through” panelists on the role of family organizations & patient advocacy groups in moving us forward on the regulatory side – “It’s absolutely essential” #WMIF2021
Congratulations! Lydia Lynch PhD, Brigham and Women’s Hospital receives an Innovation Discovery Grant for “Generating Superior ‘Killers’ for Adoptive Cell Therapy in Cancer” at #WMIF2021.
Looking forward to the Diabetes Grand Challenge and how #GCT could help millions of people. Read about what facing this disease and how cell therapies could lessen the burden from Manasi Jaiman, MD, VP, Clinical Development
Today is Day 2 of the World Medical Innovation Forum. Which panel you are most excited to see today? Reply and let us know! #WMIF2021 https://worldmedicalinnovation.org/agenda/
Cell and gene therapies hold promising potential for rare disease, blood cancers, and viral diseases. Register for #WMIF21 to hear about our work to pioneer cutting-edge science across our pipeline to advance breakthroughs that change patients’ lives: https://on.pfizer.com/3f3CGzj
Congratulations! Peter Sage PhD, Brigham and Women’s Hospital receives an Innovation Discovery Grant for “Novel Strategies to Enhance Tfr Treatment of Autoimmunity” at #WMIF2021
Congratulations! Yulia Grishchuk PhD, Massachusetts General Hospital, receives an Innovation Discovery Grant for “AAV-Based Gene Replacement Therapy Improves Targeting and Clinical Outcomes in a Childhood CNS Disorder” at #WMIF2021
Congratulations! Jinjun Shi, PhD, Brigham and Women’s Hospital, receives an Innovation Discovery Grant for “Long-Lasting mRNA Therapy for Genetic Disorders” at #WMIF2021
Final thoughts from “Benign Blood Disorders” panelists on academic/industry collaboration — the pace of #innovation is incredibly exciting, and I think it will be even faster together. #WMIF2021
Congratulations! Benjamin Kleinstiver PhD, Massachusetts General Hospital, receives an Innovation Discovery Grant for “Towards a Permanent Genetic Cure for Spinal Muscular Atrophy” at #WMIF2021
FDA’s Peter Marks, at #WMIF2021, notes # of INDs for gene therapies was flat in 2020 vs. 2019. But the fact IND submissions didn’t decline, he said, is a sign of how strong the gene therapy field is, given pandemic’s disruption.
Melissa Moore/Moderna- one advantage of mRNA is ability to do multivalent vaccines she said. She said they are already testing multivalent covid vaccines in clinical trials & testing flu vaccines. #wmif2021
Kate Bingham/SV Health & former head of UK Vaccine Taskforce: they haven’t seen escape variants in UK yet she said. mRNA is quickest platform to address escape variants probably. Needle delivery w/ supply cold chain has been the challenge. Deploying 3 vaccines in UK #WMIF2021
, notes that the science behind gene cell therapies is converging with technological development. How therapies are brought to market is still the question, as there is no roadmap when reimagining medicine #WMIF2021
Melissa Moore/Moderna: clear advantage of mRNA vaccine is how quickly we can manufacture the vaccines. Downsides- need 2store at low temperatures & limited shelflife 4storage in refrigerator. I know that both companies [Moderna, Pfizer/BioNTech] r working 2change this #wmif2021
We’re committed to addressing the unmet needs of people living with rare genetic diseases. Our SVP, External Innovation and Strategic Alliances, Leah Bloom, discusses the promise #genetherapy holds for communities impacted by rare diseases during #WMIF2021.
Speed of vaccination is critical to prevent escape variants says Kate Bingham, SV Health Investors, UK, at #WMIF2021, exploring what’s next for the technology w panel led by Lindsey Baden MD,
for sharing this screen capture of the impressive lineup of #GCT “Disruptive Dozen” panelists at #WMIF2021
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Aviva Lev-Ari
@AVIVA1950
· May 21
@MGBInnovation #WMIF Best Global event on Gene Cell Therapy covered in real time @AVIVA1950 @pharma_BI Disruptive Dozen technologies four are based on Gene Editing, AAV and non viral vector for drug delivery are included
PART 1: ALL THE TWEETS PRODUCED by @AVIVA1950 on May 19, 2021
Thomas VanCott, PhD Global Head of Product Dev, Gene & Cell Therapy, Catalent 2/3 autologous 1/3 allogeneic CAR-T high doses scale up is not done today logistics issues centralized vs decentralized allogeneic are health donors
Ropa Pike, Director, Enterprise Science & Partnerships, Thermo FIsher Scientific Centralized biopharma industry is moving to decentralized models site specific license
Rahul Singhvi, ScD CEO and Co-Founder, National Resilience, Inc. Investment company in platforms to be shared by start ups in CGT. Production cost of allogeneic: cost of quality 30% reagents 30% cell 30% Test is very expensive
Oladapo Yeku, MD, PhD Clinical Assistant in Medicine, MGH Outstanding moderator and most gifted panel on solid tumor success window of opportunities studies
Knut Niss, PhD CTO, Mustang Bio tumor hot start in 12 month clinical trial solid tumors Combination therapy will be an experimental treatment long journey checkpoint inhibitors to be used in combination maintenance
Barbra Sasu, PhD CSO, Allogene T cell response at prostate cancer tumor specific cytokine tumor specific signals move from solid to metastatic cell type for easier infiltration
Jennifer Brogdon Executive Director, Head of Cell Therapy Research, Exploratory Immuno-Oncology, NIBR 2017 CAR-T first approval M&A and research collaborations TCR tumor specific antigens avoid tissue toxicity
Jay Short, PhD Chairman, CEO, Cofounder, BioAlta, Inc. Tumor type is not enough for R&D therapeutics other organs are involved in periphery difficult to penetrate solid tumors biologics activated in the tumor only, positive changes
Stefan Hendriks Global Head, Cell & Gene, Novartis Confirmation the effectiveness of CAR-T therapies, 1 year response to 5 years 26 months Patient not responding a lot to learn Patient after 8 months of chemo can be helped by CAR-T
Jeffrey Infante, MD , Oncology, Janssen R&D Direct effect with intra-tumor single injection with right payload Platform approach Prime with 1 and Boost with 2 – not yet experimented with Do not have the data at trial
Nino Chiocca, MD, PhD Neurosurgeon-in-Chief BWH, HMS Oncolytic therapy DID NOT WORK Pancreatic Cancer and Glioblastoma Intra-tumoral heterogeniety hinders success Oncolytic VIRUSES – “coldness” GADD-34 20,000 GBM 40,000 pancreatic
Loic Vincent, PhD Head of Oncology Drug Discovery Unit, Takeda Classification of Patients by prospective response type id UNKNOWN yet, population of patients require stratification
Loic Vincent, PhD Head of Oncology Drug Discovery Unit, Takeda R&D in collaboration with Academic Vaccine platform to explore different payload IV administration may not bring sufficient concentration to the tumor is administer IV
Nino Chiocca, MD, PhD Neurosurgeon-in-Chief and Chairman, Neurosurgery, BWH Harvey W. Cushing Professor of Neurosurgery, HMS Challenges of manufacturing at Amgen what are they?
David Reese, MD Executive Vice President, R&D , Amgen Inter lesion injection of agent vs systemic therapeutics cold tumors immune resistant render them immune susptible Oncolytic virus is a Mono therapy addressing the unknown
David Reese, MD Executive Vice President, Research and Development, Amgen Inter lesion injection of agent vs systemic therapeutics cold tumors immune resistant render them immune suseptible Oncolytic virus is a Mono therapy
Robert Coffin, PhD Chief R&D Officer, Replimune 2002 in UK promise in oncolytic therapy GNCSF Phase III melanoma 2015 M&A with Amgen oncolytic therapy remains non effecting on immune response data is key for commercialization
Ann Silk, MD Physician, Dana Farber-Brigham and Women’s Cancer Center, HMS Which person gets oncolytics virus if patient has immune supression due to other indications Safety of oncolytic virus greater than Systemic treatment
Marianne De Backer/Bayer on post M&A & company culture: They acquired AskBio & thought about how to preserve their freedom so they could continue to operate. Bayer decided to keep them independent & so they can operate at arm’s length. #wmif2021
Merit Cudkowicz, MD Chief of Neurology, MGH ALS – Man 1in 300, Women 1 in 400, next decade increase 7% 10% ALS is heredity 160 pharma in ALS space diagnosis is late 1/3 of people are not diagnosed active community for clinical trials @pharma_BI@AVIVA1950
Adam Koppel, MD, PhD Managing Director, Bain Capital Life Sciences What acquirers are looking for?? What is the next generation vs what is real where is the industry going?
Debby Baron, Worldwide Business Development, Pfizer Scalability and manufacturing regulatory conversations, clinical programs safety in parallel to planning getting drug to patients
Marianne De Backer, PhD Head of Strategy, BD & Licensing, Bayer Absolute Leadership: Gene editing, gene therapy, via acquisition and alliances Operating model of the acquired company discussed acquired continue independence
Sean Nolan Board Chairman, Encoded Therapeutics & Affinia Executive Chairman Jaguar Gene Therapy Istari Oncology As acquiree multiple M&A acquirer looks at integration and cultures companies Traditional integration vs acquisition
Debby Baron, Worldwide Business Development, Pfizer CGT is an important area Pfizer is active looking for innovators, advancing forward programs of innovation with the experience Pfizer has internally
Marianne De Backer, PhD Head of Strategy, Business Development & Licensing, and Member of the Executive Committee, Bayer Absolute Leadership in Gene editing, gene therapy, via acquisition and strategic alliance
Manny Simons, PhD CEO, Akouos Biology across species nerve ending in the cochlea engineer out of the caspid, lowest dose possible, get desired effect by vector use, 2022 new milestones
Mathew Pletcher, PhD SVP, Head of Gene Therapy Research and Technical Operations, Astellas Continue to explore large animal guinea pig not the mice, not primates (ethical issues) for understanding immunogenicity and immune response
Mathew Pletcher, PhD SVP, Head of Gene Therapy Research and Technical Operations, Astellas Work with diseases poorly understood, collaborations needs example of existing: DMD is a great example explain dystrophin share placedo data
Rick Modi CEO, Affinia Therapeutics Speed R&D Speed better gene construct get to clinic with better design vs ASAP Data sharing clinical experience patients selection, vector selection, mitigation, patient type specific
Dave Lennon, PhD President, Novartis Gene Therapies big pharma therapeutics not one drug across Tx areas: cell, gene iodine therapy collective learning infrastructure development Acquisitions growth # applications for scaling
Rick Modi CEO, Affinia Therapeutics Copy, paste EDIT from product A to B novel vectors variant of vector coder optimization choice of indication is critical exploration on larger populations Speed to R&D to better gene construct get
Louise Rodino-Klapac, PhD EVP, Chief Scientific Officer, Sarepta Therapeutics AV based platform 15 years in development 1 disease indication vs more than one indication stereotype, analytics as hurdle 1st was 10 years 2nd was 3 years
Katherine High, MD President, Therapeutics, AskBio Three drugs approved in Europe in the CGT Regulatory Infrastructure CGT drug approval – as new class of therapeutics Participants investigators, regulators, patients i.e., MDM
Peter Marks, MD, PhD Director, Center for Biologics Evaluation and Research, FDA Immune modulators Immunotherapy Genome editing can make use of viral vectors future technologies nanoparticles and liposome encapsulation 50% more staff
Peter Marks, MD, PhD Director, Center for Biologics Evaluation and Research, FDA Recover Work load for the pandemic Gene Therapies IND application remained flat Rare diseases urgency remains Guidance T-Cell therapy vs Regulation
Peter Marks, MD, PhD Director, Center for Biologics Evaluation and Research, FDA June 2020 belief that vaccine challenge manufacture scaling up FDA did not predicted the efficacy of mRNA vaccine vs other approaches expected to work
Jim Holland CEO, http://Backcountry.com Parkinson patient Constraints by regulatory on participation in clinical trial wish to take Information dissemination is critical
Patricia Musolino, MD, PhD Co-Director Pediatric Stroke and Cerebrovascular Program What is the Power of One – the impact that a patient can have on their own destiny connecting with other participants in same trial can be beneficial
Barbara Lavery Chief Program Officer, ACGT Foundation Patient has the knowledge of the symptoms and recording all input needed for diagnosis by multiple clinicians Early application for CGT
Jack Hogan Patient, MEE Constraints by regulatory on participation in #clinicaltrials advance stage is approved participation Patients to determine the level of #risk they wish to take
Barbara Lavery Chief Program Officer, ACGT Foundation Advocacy agency beginning of work Global Genes educational content and out reach to access the information
Dave Lennon, PhD President, Novartis Gene Therapies Modality one time intervention, long duration of impart, reimbursement, ecosystem FDA works by indications and risks involved, Standards manufacturing payments over time payers
Dave Lennon, PhD President, Novartis Gene Therapies Promise of CGT realized, what part? #FDA role and interaction in CGT #Manufacturing aspects which is critical
Julian Harris, MD Partner, Deerfield Hope that CGT emerging, how therapies work, #neuro, #muscular, #ocular, #genetic diseases of #liver and of #heart revolution for the industry 900 #IND application 25 approvals #Economic driver
Luk Vandenberghe, PhD Grousbeck Family Chair, Gene Therapy, MEE Associate Professor, Ophthalmology, HMS #Pharmacology#Gene-Drug, Interface academic centers and industry many CGT drugs emerged in Academic center
Ravi Thadhani, MD CAO, Mass General Brigham Professor, Medicine and Faculty Dean, HMS Role of #academia special to spear head the #Polygenic#therapy – multiple #genes involved, #plug-play #delivery
The field of #genetherapy is growing. New therapies will come to market for rare and chronic diseases, and new therapies will drive scientific innovation and economic growth. #WMIF2021 (2/6)
In our First Look sessions clinicians/researchers from Harvard-affiliated hospitals highlight the potential of their research & new technologies. Next we’ll hear from Khalid Shah PhD, Vice Chair of Research
Tomorrow is Day 1 of #WMIF2021! Hear from the world-renowned CEOs, investors, clinicians and scientists bringing game-changing discoveries and insights to #GCT. Register to attend today: https://worldmedicalinnovation.org/register/
‘s World Medical Innovation Forum this week, discussing the future of #genetherapy. Here are our five predictions for where the industry is headed. #WMIF2021 (1/6)
explains at #WMIF2021 why the first FDA-approved gene therapy for inherited disease was for an inherited retinal degeneration, and what lessons have been learned from the success of that treatment.
Together with @BayerPharma, we are pleased to be part of #WMIF2021, organized by @MassGenBrigham. This year’s event focuses on the transformative potential of #cellandgene therapy (#GCT).
“We are more committed to our mission than ever before – laser-focused on realizing the transformative potential of #genetherapy for patients.” – Dave Lennon, President, during #WMIF2021
Patricia Musolino, MD PhD, Co-Director Pediatric Stroke and Cerebrovascular Program at MGH, discusses her work developing #genetherapy treatments for cerebral genetic vasculopathies #GCT #geneandcelltherapy #WMIF2021
chair Dr. Joan Miller moderates a panel on AAV gene therapy featuring director of Inherited Retinal Disorders Service and Ocular Genomics Institute, Dr. Eric Pierce.
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Mass General Brigham Innovation
@MGBInnovation
· 23h
Our “AAV Success Studies | Retinal Dystrophy | Spinal Muscular Atrophy” panelists have taken the stage. #WMIF2021 @MassEyeAndEar @REGENXBIO @spark_tx @NovartisGene
We are proud sponsors of the Virtual World Medical Innovation Forum (#WMIF2021). This year’s program will focus on the impact of gene and cell therapy as a way to potentially advance quality patient care, reduce cost and improve outcomes. Learn more:
Jonathan Kraft introducing #wmif2021 session with Pfizer CSO & president of R&D Mikael Dolsten and MGH oncologist & chair of MGH Cancer Center Daniel Haber.
president Dave Lennon & Deerfield partner Julian Harris having a “fireside chat.” Dave/Novartis: sees gene therapy as driver for economy generating need for highly skilled workers Incl manufacturing
Kite Pharma CEO (Gilead subsidiary) Christi Shaw said there are 120 biopharma companies working on CAR-T cell therapy & they are continuing to look for new partnerships. She also mentioned logistical challenges currently getting to Israel & helping patients there. #WMIF2021
FDA’s Dir of Center for Biologics Evaluation & Research Peter Marks interviewed by Vicki Sato- chairwoman of Vir Biotechnology, ex Vertex president & ex Biogen VP Research. Around June ’20, started 2c progress in covid vaccines w/ enough candidates moving forward #WMIF2021 1/n
“Once you work on cell and gene therapy, its really hard to go back and work on anything else” says moderator Marcela Maus, MD PhD in our “CAR-T | Lessons Learned | What’s Next” panel #WMIF2021#GCT#geneandcelltherapy
Ex Merck president R&D Roger Perlmutter is now Eikon Therapeutics CEO & is on #WMIF2021 oncolytic virus in cancer panel w/Amgen EVP R&D David Reese, ex BioVex CTO (T-VEC inventor
, join our leaders for panels and presentations discussing what’s next for #genetherapy and the key trends shaping the industry as it evolves. #WMIF2021https://bit.ly/3eYYls4
Dolsten/Pfizer discussed covid vaccines and real world evidence study in Israel. Was sole provider of vaccines in Israel. 95%-98% efficacy replicated in real world. Well above 90% efficacy in asymptomatic disease. #wmif2021
ICYMI: An illustration depicting the “AAV Delivery” panel discussion about advances in the area of #AAVGeneTherapy delivery. Thank you to the panelists from
Casey Maguire PhD, Associate Professor of Neurology, at the podium to present his work developing improved #genetherapy vectors. #WMIF2021 “First Look: Enhanced Gene Delivery and Immunoevasion of AAV Vectors without Capsid Modification”
Casey Maguire PhD, Associate Professor of Neurology, at the podium to present his work developing improved #genetherapy vectors. #WMIF2021 “First Look: Enhanced Gene Delivery and Immunoevasion of AAV Vectors without Capsid Modification”
Mikael Dolsten, MD PhD, CSO & President, Worldwide Research, Development and Medical @pfizer takes the stage for a Fireside Chat, moderated by @MGHCancerCenter Daniel Haber, MD, PhD. “Pfizer’s Future in Cell and Gene Therapy” #WMIF2021
Dave Lennon/Novartis: manufacturing has been a roadblock for many cell & gene therapy companies. Expects to see more investments earlier. Engineering advances will unlock scale & address bigger & bigger patient populations. Oppty to ID patients early #WMIF2021
Marianne De Backer/Bayer on post M&A & company culture: They acquired AskBio & thought about how to preserve their freedom so they could continue to operate. Bayer decided to keep them independent & so they can operate at arm’s length. #wmif2021
Ken Custer/Eli Lilly-said they’re relatively new in cell & gene therapy. They invested in 1 of Sean Nolan’s (ex AveXis CEO) new companies,Jaguar Gene Therapy. Lilly’s legacy in neuroscience is noted & bought Prevail last yr. Clinical trial w/ Parkinson’s w/GBA1 mutation #wmif2021
, was the first in the U.S. to be approved for FDA gene therapy surgery. In 2018 he underwent therapy to treat retinitis pigmentosa by having a synthetic gene inserted into his retina. With improved eyesight he can now play sports #WMIF2021
The acquisition market in #GCT: looking for breakthroughs for patients, technologies for intractable diseases, manufacturing expertise, pioneering companies with deep experience — all for “the modality of the future”. M&A panel at #WMIF2021
Christi Shaw/Kite Pharma: Only 4 out of 10 patients eligible for CAR-T are being referred for CAR-T cell therapy by oncologists. The other 6 out of 10, referred to palliative care only. Consistency of manufacturing is also very important. #wmif2021 1/n
Marianne De Backer/Bayer on post M&A & company culture: They acquired AskBio & thought about how to preserve their freedom so they could continue to operate. Bayer decided to keep them independent & so they can operate at arm’s length. #wmif2021
Benjamin List Max-Planck-Institut für Kohlenforschung, Mülheim an der Ruhr, Germany
David W.C. MacMillan Princeton University, USA
“for the development of asymmetric organocatalysis”
Meet UC’s 2021 Nobelists
Three UC-affiliated scientists have won Nobel Prizes this year: UCSF professor David Julius, UCLA alum Ardem Patapoutian and UC Irvine alum David W.C. MacMillan.
Three UC-affiliated scientists were awarded Nobel Prizes this week. UC San Francisco professor David Julius shared the Nobel Prize in physiology or medicine with UCLA alum Ardem Patapoutian. UC Irvine alum David W.C. MacMillan won in chemistry.
From: University of California <webeditor@ucop.edu> Reply-To: University of California <webeditor@ucop.edu> Date: Friday, October 8, 2021 at 1:02 PM To: Aviva Lev-Ari <avivalev-ari@alum.berkeley.edu> Subject: 3 UC Nobel Prize winners!
Building molecules is a difficult art. Benjamin List and David MacMillan are awarded the Nobel Prize in Chemistry 2021 for their development of a precise new tool for molecular construction: organocatalysis. This has had a great impact on pharmaceutical research, and has made chemistry greener.
Many research areas and industries are dependent on chemists’ ability to construct molecules that can form elastic and durable materials, store energy in batteries or inhibit the progression of diseases. This work requires catalysts, which are substances that control and accelerate chemical reactions, without becoming part of the final product. For example, catalysts in cars transform toxic substances in exhaust fumes to harmless molecules. Our bodies also contain thousands of catalysts in the form of enzymes, which chisel out the molecules necessary for life.
Catalysts are thus fundamental tools for chemists, but researchers long believed that there were, in principle, just two types of catalysts available: metals and enzymes. Benjamin List and David MacMillan are awarded the Nobel Prize in Chemistry 2021 because in 2000 they, independent of each other, developed a third type of catalysis. It is called asymmetric organocatalysis and builds upon small organic molecules.
“This concept for catalysis is as simple as it is ingenious, and the fact is that many people have wondered why we didn’t think of it earlier,” says Johan Åqvist, who is chair of the Nobel Committee for Chemistry.
Organic catalysts have a stable framework of carbon atoms, to which more active chemical groups can attach. These often contain common elements such as oxygen, nitrogen, sulphur or phosphorus. This means that these catalysts are both environmentally friendly and cheap to produce.
The rapid expansion in the use of organic catalysts is primarily due to their ability to drive asymmetric catalysis. When molecules are being built, situations often occur where two different molecules can form, which – just like our hands – are each other’s mirror image. Chemists will often only want one of these, particularly when producing pharmaceuticals.
Organocatalysis has developed at an astounding speed since 2000. Benjamin List and David MacMillan remain leaders in the field, and have shown that organic catalysts can be used to drive multitudes of chemical reactions. Using these reactions, researchers can now more efficiently construct anything from new pharmaceuticals to molecules that can capture light in solar cells. In this way, organocatalysts are bringing the greatest benefit to humankind.
Benjamin List, born 1968 in Frankfurt, Germany. Ph.D. 1997 from Goethe University Frankfurt, Germany. Director of the Max-Planck-Institut für Kohlenforschung, Mülheim an der Ruhr, Germany.
David W.C. MacMillan, born 1968 in Bellshill, UK. Ph.D. 1996 from University of California, Irvine, USA. Professor at Princeton University, USA.
The Nobel Prize in Physiology or Medicine 2021 was awarded jointly to David Julius and Ardem Patapoutian “for their discoveries of receptors for temperature and touch.”
Reporter: Aviva Lev-Ari, PhD, RN
Article ID #291: The Nobel Prize in Physiology or Medicine 2021 was awarded jointly to David Julius and Ardem Patapoutian “for their discoveries of receptors for temperature and touch.”. Published on 10/4/2021
WordCloud Image Produced by Adam Tubman
UPDATED on 12/18/2021
Nobel Prize Lecture in Stockholm, Sweden, 12/7/2021
UPDATED on 10/14/2021
49th (2019) – Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Research
for their remarkable contributions to our understanding of the sensations of temperature, pain and touch
David Julius – 49th (2019) – Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Research
for their remarkable contributions to our understanding of the sensations of temperature, pain and touch
(2021 Nobel Prize) Morris Herzstein Chair in Molecular Biology and Medicine Professor and Chair, Department of Physiology School of Medicine The University of California, San Francisco San Francisco, CA USA
Ardem Patapoutian – 49th (2019) – Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Research for their remarkable contributions to our understanding of the sensations of temperature, pain and touch
(2021 Nobel Prize) Investigator, Howard Hughes Medical Institute Professor, Department of Neuroscience The Scripps Research Institute La Jolla, CA USA
David Julius was born in 1955 in New York, USA. He received a Ph.D. in 1984 from University of California, Berkeley and was a postdoctoral fellow at Columbia University, in New York. David Julius was recruited to the University of California, San Francisco in 1989 where he is now Professor.
Ardem Patapoutian was born in 1967 in Beirut, Lebanon. In his youth, he moved from a war-torn Beirut to Los Angeles, USA and received a Ph.D. in 1996 from California Institute of Technology, Pasadena, USA. He was a postdoctoral fellow at the University of California, San Francisco. Since 2000, he is a scientist at Scripps Research, La Jolla, California where he is now Professor. He is a Howard Hughes Medical Institute Investigator since 2014.
Meet UC’s 2021 Nobelists
Three UC-affiliated scientists have won Nobel Prizes this year: UCSF professor David Julius, UCLA alum Ardem Patapoutian and UC Irvine alum David W.C. MacMillan.
Three UC-affiliated scientists were awarded Nobel Prizes this week. UC San Francisco professor David Julius shared the Nobel Prize in physiology or medicine with UCLA alum Ardem Patapoutian. UC Irvine alum David W.C. MacMillan won in chemistry.
From: University of California <webeditor@ucop.edu> Reply-To: University of California <webeditor@ucop.edu> Date: Friday, October 8, 2021 at 1:02 PM To: Aviva Lev-Ari <avivalev-ari@alum.berkeley.edu> Subject: 3 UC Nobel Prize winners!
Key publications
Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997:389:816-824.
Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H, Skinner K, Raumann BE, Basbaum AI, Julius D. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 1998:21:531-543.
Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 2000:288:306-313
McKemy DD, Neuhausser WM, Julius D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 2002:416:52-58
Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, Earley TJ, Dragoni I, McIntyre P, Bevan S, Patapoutian A. A TRP channel that senses cold stimuli and menthol. Cell 2002:108:705-715
Coste B, Mathur J, Schmidt M, Earley TJ, Ranade S, Petrus MJ, Dubin AE, Patapoutian A. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science 2010:330: 55-60
Ranade SS, Woo SH, Dubin AE, Moshourab RA, Wetzel C, Petrus M, Mathur J, Bégay V, Coste B, Mainquist J, Wilson AJ, Francisco AG, Reddy K, Qiu Z, Wood JN, Lewin GR, Patapoutian A. Piezo2 is the major transducer of mechanical forces for touch sensation in mice. Nature 2014:516:121-125
Figure 4 The seminal discoveries by this year’s Nobel Prize laureates have explained how heat, cold and touch can initiate signals in our nervous system. The identified ion channels are important for many physiological processes and disease conditions.
In the latter part of the 1990’s, David Julius at the University of California, San Francisco, USA, saw the possibility for major advances by analyzing how the chemical compound capsaicin causes the burning sensation we feel when we come into contact with chili peppers. Capsaicin was already known to activate nerve cells causing pain sensations, but how this chemical actually exerted this function was an unsolved riddle. Julius and his co-workers created a library of millions of DNA fragments corresponding to genes that are expressed in the sensory neurons which can react to pain, heat, and touch. Julius and colleagues hypothesized that the library would include a DNA fragment encoding the protein capable of reacting to capsaicin. They expressed individual genes from this collection in cultured cells that normally do not react to capsaicin. After a laborious search, a single gene was identified that was able to make cells capsaicin sensitive (Figure 2). The gene for capsaicin sensing had been found! Further experiments revealed that the identified gene encoded a novel ion channel protein and this newly discovered capsaicin receptor was later named TRPV1. When Julius investigated the protein’s ability to respond to heat, he realized that he had discovered a heat-sensing receptor that is activated at temperatures perceived as painful (Figure 2).
Figure 2 David Julius used capsaicin from chili peppers to identify TRPV1, an ion channel activated by painful heat. Additional related ion channels were identified and we now understand how different temperatures can induce electrical signals in the nervous system.
The discovery of TRPV1 was a major breakthrough leading the way to the unravelling of additional temperature-sensing receptors. Independently of one another, both David Julius and Ardem Patapoutian used the chemical substance menthol to identify TRPM8, a receptor that was shown to be activated by cold. Additional ion channels related to TRPV1 and TRPM8 were identified and found to be activated by a range of different temperatures. Many laboratories pursued research programs to investigate the roles of these channels in thermal sensation by using genetically manipulated mice that lacked these newly discovered genes. David Julius’ discovery of TRPV1 was the breakthrough that allowed us to understand how differences in temperature can induce electrical signals in the nervous system.
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