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Nobel Prize in Chemistry 2024 to David Baker, Demis Hassabis and John M. Jumper
Reporter: Aviva Lev-Ari, PhD, RN
UPDATED on 10/22/2024
ProteinMPNN, which is now available free on the open-source software repository GitHub, will give researchers the tools to make unlimited new designs. “The challenge, of course … is what are you going to design?” Baker says.
In a second Nobel win for AI, the Royal Swedish Academy of Sciences has awarded half the 2024 prize in chemistry to Demis Hassabis, the cofounder and CEO of Google DeepMind, and John M. Jumper, a director at the same company, for their work on using artificial intelligence to predict the structures of proteins. The other half goes to David Baker, a professor of biochemistry at the University of Washington, for his work on computational protein design. The winners will share a prize pot of 11 million Swedish kronor ($1 million).
The potential impact of this research is enormous. Proteins are fundamental to life, but understanding what they do involves figuring out their structure—a very hard puzzle that once took months or years to crack for each type of protein. By cutting down the time it takes to predict a protein’s structure, computational tools such as those developed by this year’s award winners are helping scientists gain a greater understanding of how proteins work and opening up new avenues of research and drug development. The technology could unlock more efficient vaccines, speed up research on cures for cancer, or lead to completely new materials.
Hassabis and Jumper created AlphaFold, which in 2020 solved a problem scientists have been wrestling with for decades: predicting the three-dimensional structure of a protein from a sequence of amino acids. The AI tool has since been used to predict the shapes of all proteins known to science.
“I’ve dedicated my career to advancing AI because of its unparalleled potential to improve the lives of billions of people,” said Demis Hassabis. “AlphaFold has already been used by more than two million researchers to advance critical work, from enzyme design to drug discovery. I hope we’ll look back on AlphaFold as the first proof point of AI’s incredible potential to accelerate scientific discovery,” he added.
Baker has created several AI tools for designing and predicting the structure of proteins, such as a family of programs called Rosetta. In 2022, his lab created an open-source AI tool called ProteinMPNN that could help researchers discover previously unknown proteins and design entirely new ones. It helps researchers who have an exact protein structure in mind find amino acid sequences that fold into that shape.
Most recently, in late September, Baker’s lab announced it had developed custom molecules that allow scientists to precisely target and eliminate proteins associated with diseases in living cells.
“[Proteins] evolved over the course of evolution to solve the problems that organisms faced during evolution. But we face new problems today, like covid. If we could design proteins that were as good at solving new problems as the ones that evolved during evolution are at solving old problems, it would be really, really powerful,” Baker told MIT Technology Review in 2022.
born 1962 in Seattle, WA, USA. PhD 1989 from University of California, Berkeley, CA, USA. Professor at University of Washington, Seattle, WA, USA and Investigator, Howard Hughes Medical Institute, USA.
University of Washington, Seattle, WA, USA
Howard Hughes Medical Institute, USA
Demis Hassabis “for protein structure prediction”
born 1976 in London, UK. PhD 2009 from University College London, UK. CEO of Google DeepMind, London, UK.
Google DeepMind, London, UK
John M. Jumper “for protein structure prediction”
born 1985 in Little Rock, AR, USA. PhD 2017 from University of Chicago, IL, USA. Senior Research Scientist at Google DeepMind, London, UK.
Google DeepMind, London, UK
The Nobel Prize in Chemistry 2024 is about proteins, life’s ingenious chemical tools. David Baker has succeeded with the almost impossible feat of building entirely new kinds of proteins. Demis Hassabis and John Jumper have developed an AI model to solve a 50-year-old problem: predicting proteins’ complex structures. These discoveries hold enormous potential.
“One of the discoveries being recognised this year concerns the construction of spectacular proteins. The other is about fulfilling a 50-year-old dream: predicting protein structures from their amino acid sequences. Both of these discoveries open up vast possibilities,” says Heiner Linke, Chair of the Nobel Committee for Chemistry.
Proteins generally consist of 20 different amino acids, which can be described as life’s building blocks. In 2003, David Baker succeeded in using these blocks to design a new protein that was unlike any other protein. Since then, his research group has produced one imaginative protein creation after another, including proteins that can be used as pharmaceuticals, vaccines, nanomaterials and tiny sensors.
The second discovery concerns the prediction of protein structures. In proteins, amino acids are linked together in long strings that fold up to make a three-dimensional structure, which is decisive for the protein’s function. Since the 1970s, researchers had tried to predict protein structures from amino acid sequences, but this was notoriously difficult. However, four years ago, there was a stunning breakthrough.
In 2020, Demis Hassabis and John Jumper presented an AI model called AlphaFold2. With its help, they have been able to predict the structure of virtually all the 200 million proteins that researchers have identified. Since their breakthrough, AlphaFold2 has been used by more than two million people from 190 countries. Among a myriad of scientific applications, researchers can now better understand antibiotic resistance and create images of enzymes that can decompose plastic.
Life could not exist without proteins. That we can now predict protein structures and design our own proteins confers the greatest benefit to humankind.
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This year’s Nobel Prize laureates in chemistry Demis Hassabis and John Jumper have developed an AI model to solve a 50-year-old problem: predicting proteins’ complex structures.
In 2020, Hassabis and Jumper presented an AI model called AlphaFold2. With its help, they have been able to predict the structure of virtually all the 200 million proteins that researchers have identified. Since their breakthrough, AlphaFold2 has been used by more than two million people from 190 countries. Among a myriad of scientific applications, researchers can now better understand antibiotic resistance and create images of enzymes that can decompose plastic.
2024 Nobel Prize in Physiology or Medicine jointly to Victor Ambros and Gary Ruvkun for the discovery of microRNA and its role in post-transcriptional gene regulation
Reporter: Aviva Lev-Ari, PhD, RN
Updated 10/22/2024
The revolution in our understanding of transcriptional regulation and dark regions of the genome
The genome of higher eukaryotes are comprised of multiple exonic and intronic regions, with coding and noncoding DNA respectively. Much of the DNA sequence between exonic regions of genes, the sequences encoding the amino acids of a polypeptide, was considered either promoter regions regulating an exonic sequence or ‘junk DNA’, which had merely separated exons and their regulatory elements. It was not considered that this dark DNA or junk DNA was important in regulating transcription of genes. It was felt that most gene regulation occurred in promoter regions by response element factors which bound to specific sequences within these regions.
MicroRNA (miRNA), originally discovered in Caenorhabditis elegans, is found in most eukaryotes, including humans [1–3]. It is predicted that miRNA account for 1-5% of the human genome and regulate at least 30% of protein-coding genes [4–8]. To date, 940 distinct miRNAs molecules have been identified within the human genome [9–12] (http://microrna.sanger.ac.uk accessed July 20, 2010). Although little is currently known about the specific targets and biological functions of miRNA molecules thus far, it is evident that miRNA plays a crucial role in the regulation of gene expression controlling diverse cellular and metabolic pathways.
MiRNA are small, evolutionary conserved, single-stranded, non-coding RNA molecules that bind target mRNA to prevent protein production by one of two distinct mechanisms. Mature miRNA is generated through two-step cleavage of primary miRNA (pri-miRNA), which incorporates into the effector complex RNA-induced silencing complex (RISC). The miRNA functions as a guide by base-pairing with target mRNA to negatively regulate its expression. The level of complementarity between the guide and mRNA target determines which silencing mechanism will be employed; cleavage of target messenger RNA (mRNA) with subsequent degradation or translation inhibition
Fig. (1). MicroRNA maturation and function.
Figure. miRNA maturation and function. Source: Macfarlane LA, Murphy PR. MicroRNA: Biogenesis, Function and Role in Cancer. Curr Genomics. 2010 Nov;11(7):537-61. doi: 10.2174/138920210793175895.
The following is an interview in the journal Journal of Cellular Biology with Dr, Victor Ambros on his discovery of miRNA.
Source: Ambros V. Victor Ambros: the broad scope of microRNAs. Interview by Caitlin Sedwick. J Cell Biol. 2013 May 13;201(4):492-3. doi: 10.1083/jcb.2014pi. PMID: 23671307; PMCID: PMC3653358.
Once, we thought we understood all there was to know about how gene expression is regulated: A cell can tinker with the expression level of a given protein’s messenger RNA by modifying the activity, abundance, and type of transcription factors in the nucleus or with the RNA’s stability once it is made. But then came a surprising story about a short RNA in C. elegans called lin-4, which didn’t encode a protein but prevented expression of the protein encoded by another gene, lin-14, through antisense binding to lin-14 mRNA (1, 2). Today, we know that lin-4 was just the first example of a large number of small RNAs, called microRNAs, which regulate the expression of various other proteins in a similar way.
Victor Ambros, whose lab published that first story about lin-4, has been studying microRNAs (3, 4) and their regulation (5, 6) ever since, pushing forward our understanding of this powerful mechanism. We called him at his office at the University of Massachusetts Medical School to get some perspective on microRNAs and his career and to learn about some of the latest developments in his lab.
“That shared discovery is one of the most precious moments in my career.”
FROM FARM TO LAB TABLE
How did you end up doing a PhD with David Baltimore?
I was the first scientist in my family. My dad was an immigrant from Poland. He came to the States just after World War II and met my mom. They got married, moved to a farm in Vermont, and started farming. My siblings and I grew up amongst the cows and pigs and helped with the haying and cutting corn, stuff like that.
When I was about nine, I got interested in science, and after that I always wanted to be a scientist. I was an amateur astronomer; I built a telescope and started to imagine that I could actually do astronomy or physics as an occupation. But I quickly changed my mind when I reached college, in part because I realized that my math skills weren’t really up to the task of being a physicist and also because I discovered molecular biology and genetics and just fell in love with both subjects. David taught one of the advanced biology classes I took as an undergraduate at MIT, and that probably had some influence on my decision to work with him. After college, I worked as a technician in David’s lab for a year. I liked it a lot and stayed on in his lab when I entered graduate school at MIT. I was lucky because I had gotten a little bit of traction on a project and continued on that as a grad student, so I ended up finishing grad school fairly efficiently.
Had you any idea at the time what the nature of the lin-4 mutant was?
The assumption was that it was a protein product. I mean, nobody ever thought that there would be any other kind of regulator. There really wasn’t any reason to imagine that there were any other kinds of molecules necessary, other than proteins, to carry out everything that’s done in a cell—especially with regard to the regulation of gene expression. The complexity of gene regulation by proteins alone was so enormous that I never imagined—and nobody I knew imagined—that we needed to look for new kinds of regulatory molecules. The realization that lin-4 was antisense to the 3′-untranslated region of lin-14 was totally the result of communication between Gary and me. That shared discovery is one of the most precious moments in my career. But at the time I didn’t realize that this might be the first example of a general mechanism for regulating gene expression because I was prone to thinking that whatever I was studying in the worm was not generally applicable. It wasn’t until genome sequences were made available that the prevalence of this mechanism became clear.
THE RIGHT CONTEXT
You’ve moved to studying processes that modulate microRNA function…
One protein we’ve studied is called Nhl-2. It’s an example of an emerging class of proteins that can modulate, positively or negatively, the RNA-induced silencing complex (RISC) that inhibits mRNAs targeted by microRNAs. This class of genes may have either general effects on RISC activity or, in some cases, more specific effects. One area of interest in the lab right now is trying to understand the specific outcomes for the regulation of particular microRNAs. Do they always interact with all their targets, or is their activity on some targets promoted or inhibited at the expense of other targets? Can their interaction with certain targets be modified depending on context? We’re using genetic and genomic approaches to identify new modulatory cofactors.
Watch Video
Victor Ambros was born in 1953 in Hanover, New Hampshire, USA. He received his PhD from Massachusetts Institute of Technology (MIT), Cambridge, MA, in 1979 where he also did postdoctoral research 1979-1985. He became a Principal Investigator at Harvard University, Cambridge, MA in 1985. He was Professor at Dartmouth Medical School from 1992-2007 and he is now Silverman Professor of Natural Science at the University of Massachusetts Medical School, Worcester, MA.
Gary Ruvkun was born in Berkeley, California, USA in 1952. He received his PhD from Harvard University in 1982. He was a postdoctoral fellow at Massachusetts Institute of Technology (MIT), Cambridge, MA, 1982-1985. He became a Principal Investigator at Massachusetts General Hospital and Harvard Medical School in 1985, where he is now Professor of Genetics.
This year’s Nobel Prize honors two scientists for their discovery of a fundamental principle governing how gene activity is regulated.
The information stored within our chromosomes can be likened to an instruction manual for all cells in our body. Every cell contains the same chromosomes, so every cell contains exactly the same set of genes and exactly the same set of instructions. Yet, different cell types, such as muscle and nerve cells, have very distinct characteristics. How do these differences arise? The answer lies in gene regulation, which allows each cell to select only the relevant instructions. This ensures that only the correct set of genes is active in each cell type.
Victor Ambros and Gary Ruvkun were interested in how different cell types develop. They discovered microRNA, a new class of tiny RNA molecules that play a crucial role in gene regulation. Their groundbreaking discovery revealed a completely new principle of gene regulation that turned out to be essential for multicellular organisms, including humans. It is now known that the human genome codes for over one thousand microRNAs. Their surprising discovery revealed an entirely new dimension to gene regulation. MicroRNAs are proving to be fundamentally important for how organisms develop and function.
Ambros and Ruvkun were interested in genes that control the timing of activation of different genetic programs, ensuring that various cell types develop at the right time. They studied two mutant strains of worms, lin-4 and lin-14, that displayed defects in the timing of activation of genetic programs during development. The laureates wanted to identify the mutated genes and understand their function. Ambros had previously shown that the lin-4 gene appeared to be a negative regulator of the lin-14 gene. However, how the lin-14 activity was blocked was unknown. Ambros and Ruvkun were intrigued by these mutants and their potential relationship and set out to resolve these mysteries.
Ambros and Ruvkun performed further experiments showing that the lin-4 microRNA turns off lin-14 by binding to the complementary sequences in its mRNA, blocking the production of lin-14 protein. A new principle of gene regulation, mediated by a previously unknown type of RNA, microRNA, had been discovered! The results were published in 1993 in two articles in the journal Cell.
Ruvkun cloned let-7, a second gene encoding a microRNA. The gene is conserved in evolution, and it is now known that microRNA regulation is universal among multicellular organisms.
Andrew Z. Fire and Craig C. Mello, awarded the Nobel Prize in 2006, described RNA interference, where specific mRNA-molecules are inactivated by adding double-stranded RNA to cells.
Mutations in one of the proteins required for microRNA production result in the DICER1 syndrome, a rare but severe syndrome linked to cancer in various organs and tissues.
Matthew S. Smith is a Contributing Editor for IEEE Spectrum and the former Lead Reviews Editor at Digital Trends.
The Nobel Prize Committee for Physics caught the academic community off-guard by handing the 2024 award to John J. Hopfield and Geoffrey E. Hinton for their foundational work in neural networks.
The pair won the prize for their seminal papers, both published in the 1980s, that described rudimentary neural networks. Though much simpler than the networks used for modern generative AI like ChatGPT or Stable Diffusion, their ideas laid the foundations on which later research built.
Even Hopfield and Hinton didn’t believe they’d win, with the latter telling The Associated Press he was “flabbergasted.” After all, AI isn’t what comes to mind when most people think of physics. However, the committee took a broader view, in part because the researchers based their neural networks on “fundamental concepts and methods from physics.”
“Initially, I was surprised, given it’s the Nobel Prize in Physics, and their work was in AI and machine learning,” says Padhraic Smyth, a distinguished professor at the University of California, Irvine. “But thinking about it a bit more, it was clearer to me why [the Nobel Prize Committee] did this.” He added that physicists in statistical mechanics have “long thought” about systems that display emergent behavior.
Hopfield first explored these ideas in a 1982 paper on neural networks. He described a type of neural network, later called a Hopfield network, formed by a single layer of interconnected neurons. The paper, which was originally categorized under biophysics, said a neural network could retain “memories” from “any reasonably sized subpart.”
Hinton expanded on that work to conceptualize the Boltzmann machine, a more complex neural network described in a 1985 paper Hinton co-authored with David H. Ackley and Terrence J. Sejnowski. They introduced the concept of “hidden units,” additional layers of neurons which exist between the input and output layers of a neural network but don’t directly interact with either. This makes it possible to handle tasks that require a more generalized understanding, like classifying images.
So, what’s the connection to physics?
Hopfield’s paper references the concept of a “spin glass,” a material in which disordered magnetic particles lead to complex interactions. Hinton and his co-authors drew on statistical mechanics, a field of physics that uses statistics to describe the behavior of particles in a system. They even named their network in honor of Ludwig Boltzmann, the physicist whose work formed the foundation of statistical mechanics.
And the connection between neural networks and physics isn’t a one-way street. Machine learning was crucial to the discovery of the Higgs boson, where it sorted the data generated by billions of proton collisions. This year’s Nobel Prize for Chemistry further underscored machine learning’s importance in research, as the award went to a trio of scientists who built an AI model to predict the structures of proteins.
Smyth saw Hopfield’s efforts first-hand as a student at the California Institute of Technology. “Hopfield was able to bring together mathematicians, engineers, computer scientists, and physicists. He got them in the same room, got them excited about modeling the brain, doing pattern recognition and machine learning, unified by mathematical theories he brought in from physics.”
In 2012, Hinton co-founded a company called DNNResearch with two of his students; Ilya Sutskever, who later co-founded OpenAI, and Alex Krizhevsky. Together, the trio collaborated on AlexNet, a hugely influential neural network for computer vision. Hinton also taught at the University of Toronto, where he continued to champion machine learning.
Navdeep Jaitly, now a deep learning researcher at Apple, said Hinton inspired new generations of engineers and researchers. In Jaitly’s case, the influence was direct; Jaitly studied under Hinton at the University of Toronto.
“I came in with experience in statistical modeling,” says Jaitly, “but Hinton still managed to entirely change how I think about problem solving. In terms of his contributions to machine learning, his methods are central to almost everything we do.”
Born 1933 in Chicago, IL, USA. PhD 1958 from Cornell University, Ithaca, NY, USA. Professor at Princeton University, NJ, USA.
Geoffrey E. Hinton University of Toronto, Canada
Born 1947 in London, UK. PhD 1978 from The University of Edinburgh, UK. Professor at University of Toronto, Canada.
was announced on 10/8/2024 in Stockholm, Sweden.
“for foundational discoveries and inventions that enable machine learning with artificial neural networks”
They trained artificial neural networks using physics
This year’s two Nobel Laureates in Physics have used tools from physics to develop methods that are the foundation of today’s powerful machine learning. John Hopfield created an associative memory that can store and reconstruct images and other types of patterns in data. Geoffrey Hinton invented a method that can autonomously find properties in data, and so perform tasks such as identifying specific elements in pictures.
John Hopfield invented a network that uses a method for saving and recreating patterns. We can imagine the nodes as pixels. The Hopfield network utilises physics that describes a material’s characteristics due to its atomic spin – a property that makes each atom a tiny magnet. The network as a whole is described in a manner equivalent to the energy in the spin system found in physics, and is trained by finding values for the connections between the nodes so that the saved images have low energy. When the Hopfield network is fed a distorted or incomplete image, it methodically works through the nodes and updates their values so the network’s energy falls. The network thus works stepwise to find the saved image that is most like the imperfect one it was fed with.
Geoffrey Hinton used the Hopfield network as the foundation for a new network that uses a different method: the Boltzmann machine. This can learn to recognise characteristic elements in a given type of data. Hinton used tools from statistical physics, the science of systems built from many similar components. The machine is trained by feeding it examples that are very likely to arise when the machine is run. The Boltzmann machine can be used to classify images or create new examples of the type of pattern on which it was trained. Hinton has built upon this work, helping initiate the current explosive development of machine learning.
AACR 2023 Meeting Highlights: Reports from Plenary Sessions and Major Symposium Talks
Reporter: Stephen J. Williams, Ph.D.
Highlights from Sunday April 16,2023
Nobel Laureate will discuss her work investigating the glycobiology of cancer
Carolyn R. Bertozzi, PhD, shared the Nobel Prize in Chemistry in 2022 for her invention of bioorthogonal chemistry, which is a class of chemical reactions that are compatible with living systems. These chemistries allow researchers to explore molecular imaging and drug targeting without interfering with natural biological processes. Bertozzi’s AACR Award for Outstanding Achievement in Chemistry in Cancer Research, and her lecture, focus on the glycobiology of cancer.
Carolyn R. Bertozzi, PhD
“There is a family of receptors on immune cells that bind carbohydrates,” said Bertozzi, Baker Family Director of the Sarafan ChEM-H Institute and Anne T. and Robert M. Bass Professor of Chemistry at Stanford University. “Called the ‘sialic acid-binding immunoglobulin-like lectins’ — abbreviated Siglecs — these receptors bind carbohydrates that possess the sugar sialic acid. There are 14 Siglec family members in humans and they are found in various combinations on every type of immune cell — T cells, macrophages, neutrophils, NK cells, all of the immune cell types that are important in anti-cancer immunity. As tumors progress, they often overexpress sialoglycan ligands for Siglecs, which allows them to engage these receptors and suppress immune-cell reactivity. We have focused on developing immune therapies that disrupt Siglec-ligand interactions.”
Bertozzi will discuss this area of her research during her award lecture, Targeting the Glycocalyx for Cancer Immune Therapy, at 4:30 p.m. ET Sunday in Tangerine Ballroom 3-4 (WF3-4) at the convention center.
“The signaling biochemistry of the Siglec family of checkpoint receptors is similar to the signaling biochemistry that PD-1 participates in,” Bertozzi explained. “They are like PD-1 except that they bind sugars rather than proteins, and they are present on every type of immune cell, including activated T cells, but also myeloid-derived cell types.”
“Glycobiology is an important area to become more familiar with if you want to truly be able to move the needle,” she said. “The science we have uncovered has led to the identification of exciting new targets, which has enabled us to invent new therapeutic modalities.”
Familiar small molecules and antibodies are of marginal use in targeting sugars, Bertozzi explained. Because carbohydrates are different types of molecules than traditional cancer targets, they need nontraditional mechanisms of action.A new class of targeted enzymes can edit the cell surface glycocalyx (or sugar coating) and deprive cancers of their ability to engage Siglec receptors. Without the broad inhibitory activity of Siglecs, the immune system remains free to engage and, hopefully, destroy tumors. At least one investigative agent is in phase I human trials and is poised to move into phase II.
“Glycobiology might explain why so many patients don’t respond to anti-PD-1 and anti-PD-L1 antibodies,” Bertozzi said. “We think a large fraction of tumors suppress the immune response through Siglec engagement.”
Other Articles on Real Time Coverage of AACR Meetings on this Open Access Scientific Journal Include:
The Nobel Prize in Physiology or Medicine 2023, jointly to Katalin Karikó and Drew Weissman for their discoveries concerning nucleoside base modifications that enabled the development of effective mRNA vaccines against COVID-19
Reporter: Aviva Lev-Ari, PhD, RN
The breakthrough
Karikó and Weissman noticed that dendritic cells recognize in vitro transcribed mRNA as a foreign substance, which leads to their activation and the release of inflammatory signaling molecules. They wondered why the in vitro transcribed mRNA was recognized as foreign while mRNA from mammalian cells did not give rise to the same reaction. Karikó and Weissman realized that some critical properties must distinguish the different types of mRNA.
RNA contains four bases, abbreviated A, U, G, and C, corresponding to A, T, G, and C in DNA, the letters of the genetic code. Karikó and Weissman knew that bases in RNA from mammalian cells are frequently chemically modified, while in vitro transcribed mRNA is not. They wondered if the absence of altered bases in the in vitro transcribed RNA could explain the unwanted inflammatory reaction. To investigate this, they produced different variants of mRNA, each with unique chemical alterations in their bases, which they delivered to dendritic cells. The results were striking: The inflammatory response was almost abolished when base modifications were included in the mRNA. This was a paradigm change in our understanding of how cells recognize and respond to different forms of mRNA. Karikó and Weissman immediately understood that their discovery had profound significance for using mRNA as therapy. These seminal results were published in 2005, fifteen years before the COVID-19 pandemic.
Eight Subcellular Pathologies driving Chronic Metabolic Diseases – Methods for Mapping Bioelectronic Adjustable Measurements as potential new Therapeutics: Impact on Pharmaceuticals in Use
In this curation we wish to present two breaking through goals:
Goal 1:
Exposition of a new direction of research leading to a more comprehensive understanding of Metabolic Dysfunctional Diseases that are implicated in effecting the emergence of the two leading causes of human mortality in the World in 2023: (a) Cardiovascular Diseases, and (b) Cancer
Goal 2:
Development of Methods for Mapping Bioelectronic Adjustable Measurements as potential new Therapeutics for these eight subcellular causes of chronic metabolic diseases. It is anticipated that it will have a potential impact on the future of Pharmaceuticals to be used, a change from the present time current treatment protocols for Metabolic Dysfunctional Diseases.
According to Dr. Robert Lustig, M.D, an American pediatric endocrinologist. He is Professor emeritus of Pediatrics in the Division of Endocrinology at the University of California, San Francisco, where he specialized in neuroendocrinology and childhood obesity, there are eight subcellular pathologies that drive chronic metabolic diseases.
These eight subcellular pathologies can’t be measured at present time.
In this curation we will attempt to explore methods of measurement for each of these eight pathologies by harnessing the promise of the emerging field known as Bioelectronics.
Unmeasurable eight subcellular pathologies that drive chronic metabolic diseases
Glycation
Oxidative Stress
Mitochondrial dysfunction [beta-oxidation Ac CoA malonyl fatty acid]
Insulin resistance/sensitive [more important than BMI], known as a driver to cancer development
Membrane instability
Inflammation in the gut [mucin layer and tight junctions]
Epigenetics/Methylation
Autophagy [AMPKbeta1 improvement in health span]
Diseases that are not Diseases: no drugs for them, only diet modification will help
Image source
Robert Lustig, M.D. on the Subcellular Processes That Belie Chronic Disease
These eight Subcellular Pathologies driving Chronic Metabolic Diseases are becoming our focus for exploration of the promise of Bioelectronics for two pursuits:
Will Bioelectronics be deemed helpful in measurement of each of the eight pathological processes that underlie and that drive the chronic metabolic syndrome(s) and disease(s)?
IF we will be able to suggest new measurements to currently unmeasurable health harming processes THEN we will attempt to conceptualize new therapeutic targets and new modalities for therapeutics delivery – WE ARE HOPEFUL
In the Bioelecronics domain we are inspired by the work of the following three research sources:
Michael Levin is an American developmental and synthetic biologist at Tufts University, where he is the Vannevar Bush Distinguished Professor. Levin is a director of the Allen Discovery Center at Tufts University and Tufts Center for Regenerative and Developmental Biology. Wikipedia
THE VOICE of Dr. Justin D. Pearlman, MD, PhD, FACC
PENDING
THE VOICE of Stephen J. Williams, PhD
Ten TakeAway Points of Dr. Lustig’s talk on role of diet on the incidence of Type II Diabetes
25% of US children have fatty liver
Type II diabetes can be manifested from fatty live with 151 million people worldwide affected moving up to 568 million in 7 years
A common myth is diabetes due to overweight condition driving the metabolic disease
There is a trend of ‘lean’ diabetes or diabetes in lean people, therefore body mass index not a reliable biomarker for risk for diabetes
Thirty percent of ‘obese’ people just have high subcutaneous fat. the visceral fat is more problematic
there are people who are ‘fat’ but insulin sensitive while have growth hormone receptor defects. Points to other issues related to metabolic state other than insulin and potentially the insulin like growth factors
At any BMI some patients are insulin sensitive while some resistant
Visceral fat accumulation may be more due to chronic stress condition
Fructose can decrease liver mitochondrial function
A methionine and choline deficient diet can lead to rapid NASH development
Health Care Policy Analysis derived from the Farewell remarks from AMA President Jack Resneck Jr., MD | AMA 2023 Annual Meeting
Curators: Aviva Lev-Ari, PhD, RN, Stephen J. Williams, PhD and Prof. Marcus W. Feldman
Article ID #301: Health Care Policy Analysis derived from the Farewell remarks from AMA President Jack Resneck Jr., MD | AMA 2023 Annual Meeting. Published on 6/10/23
WordCloud Image Produced by Adam Tubman
Bot Name: ChatGPT, GPT-4
Date of Update: 07/03/2023 Programmer’s Name: Frason K. Human Verifier: Aviva Lev-Ari & Dr. Stephen J. Williams
On June 10, 2023, I watched the video, below which represents the delivery of the Farewell remarks from AMA by the AMA President, Jack Resneck Jr., MD at the AMA 2023 Annual Meeting on 6/10/2023.
Upon completion of watching this video, I concluded that I should include it as an embedded video in this article as a new Audio Podcast in our Library of 300 “Interviews with Scientific Leaders” same title of a research category in the ontology of LPBI Group’s PharmaceuticalIntelligence.com Journal.
The context for the decision made in favor of embedding the video of AMA President, Jack Resneck Jr., MD, Farewell remarks from AMA at the AMA 2023 Annual Meeting on 6/10/2023 is one of Policy Analysis of the Health Care system in the US in 2023.
Aligned with this decision was to qualify Dr. Resneck Jr, MD speech to be an equivalent to an “Interview with a Scientific Leader in the domain of Health Policy” to be included in LPBI Group’s Library of 300 audio podcast Interviews planned to be published in July 2023.
Key points made by Dr. Resneck Jr, MD in the video
growing number of states and courts forcing themselves into the most intimate and difficult conversations patients and physicians
The challenges facing the medical profession and delivery of care by Providers:
A dysfunctional health care environment, and
The climate of anti-science aggression
In his own words: Dr. Resneck Jr, MD
We need to fix what’s broken in health care, and it’s NOT the doctor.
The Wisconsin Supreme Court agreed with us that patients and judges can’t force physicians to administer substandard care.
Courts have invalidated parts of No Surprises Act rules that plainly ignored Congressional intent and put a thumb on the scale to favor insurance companies… thank you Texas Medical Association and AMA!
The 5th Circuit Court is staying- for now – an egregious ruling that would have stripped patients of the right to access preventive care service with no out-of-pocket costs, a key piece of the Affordable Care Act.
The U.S. Supreme Court is delaying attempts by a single district judge with no scientific or medical training to take mifepristone off the market nationally and upend our entire FDA drug regulatory process.
We’ve helped shift the national conversation about protecting patient data and making sure digital health and AI tools are proven BEFORE being deployed.
We’ve broadened and intensified our work to embed equity and racial justice, and to push upstream to affect structural and social drivers of health inequities.
The AMA doesn’t win every battle. But we are more resolute in our work because of the threats to our profession and our patients.
I’m still appalled by the Medicare cuts. What on earth was Congress thinking? Practices are on the brink. Our workforce is at risk. Access to care stands in the balance
Physician burnout
One in five physicians plans to leave their practice within two years, while one in three is reducing hours.
Only 57 percent of doctors today would choose medicine again if they were just starting their careers.
two in five physicians go beyond mere daydreams of another career to wishing they had never chosen this path in the first place
And shame on political leaders, fueling fear and sowing division by making enemies of public health officials, of transgender adolescents, of physicians doing anti-racism work, and of women making personal decisions about their pregnancies.
The burnout and the moral injury are real … I’ve felt it myself. I hear this concern in the voices of medical students, residents, and even young physicians when they ask me … “Am I going to be okay?” “Have I made the right career choice?”
Medicare payment reform for “a dilapidated Medicare payment system”
fighting for long overdue fixes to a broken Medicare payment system, and obnoxious prior auth abuses, even when policymakers have neglected the problems for decades.
We absolutely must tie future Medicare payments to inflation, and we’re readying a major national campaign to finally achieve Congressional action.
Linking physician payment to inflation is an absolute top priority, an existential must to keep practices afloat, and pillar #1 of our plan. An important step on that path was the recent introduction of a bipartisan bill to finally align the Medicare fee schedule with MEI.
key role in legislation to extend Medicare Telehealth coverage.
State after state is making progress to constrain prior authorization, and CMS issued rules to do the same in Medicare Advantage plans.
Medicaid work requirements that conflict with AMA policy were kept out of the debt ceiling bill.
Scope of practice expansions
In partnership with states and specialties, our advocacy has helped protect patients from outrageous and broad scope expansions more than 50 times so far this year.
defending against broad scope expansions that put patients at risk, even when it requires gearing up again and again, in state after state.
When politicians force their way into our exam rooms Interfering with the sacred patient-doctor relationship is about CONTROL. : battling in state legislatures and courthouses for the very soul of our nation and our profession – to protect patients from those outside influences wanting to dictate the terms of their care … …telling them what medical treatments their physicians can provide … …what FDA-approved medicines we can prescribe…. …even what words we can use …
I loved traveling to Mississippi and witnessing their progress from startling COVID inequities to achieving one of the nation’s top vaccination rates among Black residents.
And we have been instrumental in helping create confidential wellness programs for physicians and removing outdated questions from past impairment from licensing and credentialing forms.
Gun Violence Victims – Preventable and needless homicides and suicides continue, and the political inaction is atrocious.
But solid majorities of Americans believe in commonsense gun reforms in line with our AMA recommendations.
You wouldn’t know it from 20 state legislatures racing to criminalize abortion and rob women of access to reproductive health care… But most people in this country support our policies and the fundamental rights of patients to make their own decisions about their health.
>> Insurance impact on delivery of care by providers
m health insurers still bullying us with prior auth delays and denying care …
We’ve joined others in suing Cigna for shortchanging doctors and patients.
The Voice of Dr. Stephen J. Williams
The outgoing president of the AMA, Dr. Jack Resneck, gives an impassioned speech about his concerns for the present and future of medicine, his profession, and the issues which will face future physicians, and all involved in healthcare. These issues have been building up for decades now in the U.S. and his remarks hopefully will be taken more to heart by those who can enact change, instead of wafting in the ongoing partisan debates in Washington. He eventually outlines the actions which could be taken but ultimately laments the inaction of many parties involved, including business, the political class, and his own physician profession. Dr. Resneck rightly states that the AMA must carry the burden of equitable and sustainable healthcare into the future and must continue the fight in this regard. He likens this fight for equitable and sustainable medicine like a marathon, where there is no defined end, no finish tape for medical professionals except to persevere in their task.
However, there are more extraneous issues to the profession where the physician has to
get back up, shake the dust off, and keep running
He notes some of the problems occurring not in direct control of the profession are
the constant onslaught and tiresome battle against disinformation
large insurers
a political class that has jeapardized the physician/patient relationship with either their action and inaction
the financial burdens placed on the small physician practice of rising third party “inflators” like higher rents, increased drug prices, higher operating costs
These laments have been felt by many parallel professions where the standards and practice to the profession have been subjugated and hijacked by other outside interests (middle men). And when the ultimate decisions of conduct are not governed by the constituents or stakeholders of the profession but by a cadre of business people, profiteers or social engineers problems like this result. As such, Dr. Resneck sees the draconian Medicare cuts as such an onslaught. This has been voiced in an earlier posting describing how these problems have crept in the biomedicine and biotech field as well as in medical care in Can the Public Benefit Company Structure Save US Healthcare?
One must consider then, as Dr. Resneck had, is it time to reinvent the healthcare structure in this country to allow more equitable, sustainable delivery of healthcare and to stave off a potential crisis in the number of physicians staying in the profession? As such he had suggested the AMA move forward with their “revival plan” in order to force legislation to reform Medicare as well as individual regulatory reform. To date there has been some success by the AMA to this effect, but as he eluded to, these efforts have been rather piecemeal instead of an overall reform.
The Voice of Aviva Lev-Ari, PhD, RN
Gun Violence, all should not have to happen and burden the care delivery system designed to deal with chronic and acute diagnoses.
As Supervisor of a Long Term Acute Hospital in Waltham, MA in 2010:
I became familiar with care plans of patients victims of gun violence and the life long disabilities cause by ONE gun shot to the brain or to the spine. Accidents that are preventable and needless.
I found Dr. Resneck’s address to be a call for continuation of a long term fight the AMA is involved in, with all the constituents of the Medical profession. They are very many and very powerful:
Big Pharma,
FDA,
State and Federal legislators,
HMOs,
Health Insurers,
For-profit, and
not-for-profit institutions
all having interests that are private and public and often conflicting ones, chiefly are the following:
Gun reforms made impossible by The National Rifle Association (NRA)’s supporters linking the defense to bear arms with the Constitution
20 state legislatures racing to criminalize abortion and rob women of access to reproductive health care…
Drug pricing and Insurance denying coverage
Need for redesign of the Curriculum of in Medical School to include the rapid change in technology, medical devices, knowledge base in life sciences and more
Dr Resneck’s talk has three components: two are rather pessimistic and concern Medicine as a profession and Health-care as a goal of medicine. The positive part, which was quite brief, concerned the continuing work of the AMA in its advocacy for better conditions for physicians and for a more equitable distribution of health care.
Medicine as a part of science continues to be assailed by anti-science political groups. 57% of doctors surveyed said they would not choose Medicine as a profession if given the chance to relive their lives. Part of this is the failure of Medicare and other insurance mechanisms to properly compensate physicians. Part is due to attacks on the profession by anti-science anti education social media and state legislatures. Whereas Medicine was once the profession of choice for the best students, universities are seeing the premed majors overtaken by computer-related fields. Dr. Resneck also referred to the importance of maintaining high standards of medical ethics, which is increasingly difficult in today’s political and economic climate.
With respect to the specifics of health care, Dr. Resneck stressed the attack on the medical professions by laws and regulations that outlaw people rights to their own bodies, manifest in anti-abortion and anti-gender affirming procedures, anti-education book banning, political opposition to measures, supported by the majority of Americans, that would reduce gun violence, and the difficulty of achieving improvements in government procedures for reimbursement of health care services. The AMA is involved in trying to elicit medically sound decisions on these.
Dr Resneck was positive, if not very optimistic about the AMA’s important role in advocacy for reform of Medicare and the Health-Care system, reform that is essential for the sustainability of Medicine as a profession.
We recommend AMA to add to their Library resources from LPBI Group:
W. Gerald “Jerry” Austen, MD influential in the design and creation of a cardiopulmonary (heart-lung) bypass machine and the intra-aortic balloon pump at MGH as renowned cardiac surgeon
Curator and reporter: Aviva Lev-Ari, PhD, RN
This article is classified in the ontology of LPBI Group’s Journal PharmaceuticalIntelligence.com under the Category of Research
Interviews with Scientific Leaders
This category includes 300 articles. LPBI Group’s will publish in July 2023 its Library of Audio Podcasts on “Interviews with Scientific Leaders.”
The presentations in the video below, about W. Gerald “Jerry” Austen, MD contributions to cardiac surgery are considered to be testimonials as well as qualify as “Interviews with a Scientific Leader” in the domains of cardiac surgery and cardiac repair medical devices with a special focus on:
cardiopulmonary (heart-lung) bypass machine, and
the intra-aortic balloon pump
On these two domains, LPBI Group had published extensively as the sources cited, below: Articles, e-Books in English and Spanish and Chapters in these book on the very specialty of Dr. Austen as included in the title of this article.
Recently, Mass General celebrated the life and legacy of W. Gerald “Jerry” Austen, MD — a renowned cardiac surgeon, beloved family man and visionary leader.
SOURCE
In Memoriam: W. Gerald Austen, MD – Mass General Giving
For 70 years, Dr. Austen was part of the Mass General community, having completed his residency at the hospital and continuing to become one of the most distinguished and well-regarded physicians in the hospital’s more than 200-year history. At 39 years old, he was named Mass General’s chief of surgical services — a position he held for nearly 29 years. Under his leadership, the Department of Surgery became one of the greatest academic departments of surgery in the country. Among his many contributions, he was influential in the design and creation of a cardiopulmonary (heart-lung) bypass machine and the intra-aortic balloon pump.
Hundreds of Dr. Austen’s closest friends, colleagues and family members gathered at Boston Symphony Hall to commemorate his legacy. A variety of speakers — from current Mass General President David F. M. Brown, MD, to former hospital President Peter Slavin, MD, and retired Chairman, President and CEO of Abiomed Mike Minogue — shared fond memories of Dr. Austen, further illustrating his unmatched and lasting impact on others.
The Mass General community will continue to mourn the loss of such a giant in the medical world and will carry on Dr. Austen’s legacy through compassionate care and an unparalleled commitment to all patients.
Susan Hockfield, ex-President of MIT delivered a speech about mechanical engineering and biomedicine, medical devices and cardiac repair devices. How proud Dr. Austen was about his MIT education and functions he fulfilled for this institutions and others.
Other related contributions on the specialty of Dr.W. Gerald “Jerry” Austen, MD – cardiac surgery are covered in e-books and articles on this Open Access Online Scientific Journal, include the following:
Articles
319 articles in the Cardiac and Cardiovascular Surgical Procedures Category
98 articles in the Aortic Valve Category
Among patients with aortic stenosis who were at intermediate surgical risk, there was no significant difference in the incidence of death or disabling stroke at 5 years after TAVR as compared with surgical aortic-valve replacement
Chapter 13: Valve Replacement, Valve Implantation and Valve Repair
13.2 Aortic Valve
13.2.1 New method for performing Aortic Valve Replacement: Transmural catheter procedure developed at NIH, Minimally-invasive tissue-crossing – Transcaval access, abdominal aorta and the inferior vena cava
13.2.4 Surgical Aortic Valve Replacement (SAVR) vs Transcatheter Aortic Valve Implantation (TAVI): Results Comparison for Prosthesis-Patient Mismatch (PPM) – adjusted outcomes, including mortality, heart failure (HF) rehospitalization, stroke, and quality of life, at 1 year
13.2.6 Off-Label TAVR Procedures: 1 in 10 associated with higher in-hospital 30-day mortality, 1-year mortality was similar in the Off-Label and the On-Label groups
13.2.11 One year Post-Intervention Mortality Rate: TAVR and AVR – Aortic Valve Procedures 6.7% in AVR, 11.0% in AVR with CABG, 20.7 in Transvascular (TV-TAVR) and 28.0% in Transapical (TA-TAVR) Patients
13.2.16 The Centers for Medicare & Medicaid Services (CMS) covers transcatheter aortic valve replacement (TAVR) under Coverage with Evidence Development (CED)
Chapter 7: Ventricular Failure: Assist Devices, Surgical and Non-Surgical
7.1 Trends in the Industry
The Voice of Series A Content Consultant: Justin D. Pearlman, MD, PhD, FACC
In addition to minimally invasive treatments for coronary disease and valve disease, there are minimally invasive alternatives to heart transplant for the dangerously weak heart (extreme heart failure) which can otherwise result in Cardiogenic Shock. These involve various means to augment or complement the pumping function of the heart, such as a Ventricular Assist Device (VAD) .
With respect to the performance of Mitral Valve Replacement, the current practice favors bioprosthetic valves over mechanical valve replacement for most patients, initially just used for elderly to avoid need for coumadin, but now used at younger ages due to improvements in longevity of the bioprosthetic valves, plus less damage to red cells.
7.1.2 Percutaneous Endocardial Ablation of Scar-Related Ventricular Tachycardia
7.2.4 Experimental Therapy (Left inter-atrial shunt implant device) for Heart Failure: Expert Opinion on a Preliminary Study on Heart Failure with preserved Ejection Fraction
7.3.1 Dilated Cardiomyopathy: Decisions on implantable cardioverter-defibrillators (ICDs) using left ventricular ejection fraction (LVEF) and Midwall Fibrosis: Decisions on Replacement using late gadolinium enhancement cardiovascular MR (LGE-CMR)
Chapter 11: Comparison of Coronary Artery Bypass Graft (CABG) and Percutaneous Coronary Intervention (PCI) / Coronary Angioplasty
11.1 Hybrid Cath Lab/OR Suite
The Voice of Series A Content Consultant: Justin D. Pearlman, MD, PhD, FACC
In an uncommon reversal of opinion, the combined forces of the American Heart Association (AHA) and the American College of Cardiology (ACC) reviewed compelling data and reversed a prior assessment on the need for an on-site cardiovascular surgery support for sites offering interventional cardiac catheterization. The data show that sites offering the intervention without a surgeon achieve better results that sites that ship patients out for the interventions, and that the risk without on-site thoracic surgery backup is negligible.
AHA, ACC Change in requirement for surgical support: Class IIb -> Class IIa Level of Evidence A: Supports Nonemergent PCI without Surgical Backup (Change of class IIb, level of Evidence B).
Larry H Bernstein, MD, FCAP and Justin D Pearlman, MD, PhD, FACC
11.1.2 Coronary Reperfusion Therapies: CABG vs PCI – Mayo Clinic preprocedure Risk Score (MCRS) for Prediction of in-Hospital Mortality after CABG or PCI
Author and Curator: Larry H. Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN
11.1.6 Patients with Heart Failure & Left Ventricular Dysfunction: Life Expectancy Increased by coronary artery bypass graft (CABG) surgery: Medical Therapy alone and had Poor Outcomes
11.2.8 CABG: a Superior Revascularization Modality to PCI in Patients with poor LVF, Multivessel disease and Diabetes, Similar Risk of Stroke between 31 days and 5 years, post intervention
Named for ACGT co-founder, Edward Netter, the award recognizes a researcher who has made unparalleled and groundbreaking contributions to the field of cell and gene therapy for cancer. Dr. Mackall is a leader in advancing cell and gene therapies for the treatment of solid tumors, with a major focus on children’s cancers.
In addition to being an ACGT research fellow and a member of ACGT’s Scientific Advisory Council, Dr. Mackall is the Ernest and Amelia Gallo Family professor of Pediatrics and Medicine at Stanford University, the founding director of the Stanford Center for Cancer Cell Therapy, associate director of the Stanford Cancer Institute, leader of the Cancer Immunotherapy Program and director of the Parker Institute for Cancer Immunotherapy. She has led numerous groundbreaking clinical trials to treat children with sarcomas and brain cancers.
“There is exciting progress happening in the field of cancer cell and gene therapy,” said Kevin Honeycutt, CEO and president of ACGT. “We continue to see the FDA approve cell and gene therapy treatments for blood cancers, while research for solid tumors is now progressing to clinical trials. These successes are linked to the funding of ACGT, and Dr. Crystal Mackall is one of the best examples of a researcher who refused to accept the status-quo of standard cancer treatment and committed to developing novel cell and gene therapies for children with difficult-to-treat tumors. ACGT is proud that Dr. Mackall is an ACGT Research Fellow, a member of ACGT’s Scientific Advisory Council, and the newest recipient of the Edward Netter Leadership Award.”
The ACGT Awards Luncheon will celebrate the non-profit organization’s 20th anniversary and usher in a new decade as the only nonprofit dedicated exclusively to funding cancer cell and gene therapy research. ACGT funds innovative scientists and biotechnology companies working to harness the power of cell and gene therapy to transform how cancer is treated and to drive momentum toward a cure.
The Edward Netter Leadership Award will be presented to Dr. Mackall by Carl June, MD, of the University of Pennsylvania, who received the honor at ACGT’s 2019 Awards Gala. ACGT grant funding enabled Dr. June to research and develop cell and gene therapies that led to the first FDA approvals of CAR T-cell therapies for cancer.
For more than 20 years, Alliance for Cancer Gene Therapy has funded research that is bringing innovative treatment options to people living with deadly cancers – treatments that save lives and offer new hope to all cancer patients. Alliance for Cancer Gene Therapy funds researchers who are pioneering the potential of cancer cell and gene therapy – talented visionaries whose scientific advancements are driving the development of groundbreaking treatments for ovarian, prostate, sarcoma, glioblastoma, melanoma and pancreatic cancers. One hundred percent of all public funds raised by Alliance for Cancer Gene Therapy directly support research and programs. For more information, visit acgtfoundation.org, call (203) 358-5055, or join the Alliance for Cancer Gene Therapy community on Facebook, Twitter, LinkedIn, Instagram and YouTube @acgtfoundation.
# # #
Other Related Articles in this Open Access Scientific Journal Include
Chemistry Nobelist Carolyn Bertozzi’s years at UC Berkeley
Reporter: Aviva Lev-Ari, PhD, RN
Article ID #298: Chemistry Nobelist Carolyn Bertozzi’s years at UC Berkeley. Published on 10/24/2022
WordCloud Image Produced by Adam Tubman
UPDATED on 12/8/2022
Watch the Nobel Prize lectures in chemistry
Watch now!
Carolyn R. Bertozzi: The Bioorthogonal Chemistry Journey, from Laboratory to Life Morten Meldal: Molecular Click Adventures, a Leap from Shoulders of Giants K. Barry Sharpless: Click Chemistry: the Certainty of Chance
K. Barry Sharpless Scripps Research, La Jolla, CA, USA
“for the development of click chemistry and bioorthogonal chemistry”
It just says click – and the molecules are coupled together
The Nobel Prize in Chemistry 2022 is about making difficult processes easier. Barry Sharpless and Morten Meldal have laid the foundation for a functional form of chemistry – click chemistry – in which molecular building blocks snap together quickly and efficiently. Carolyn Bertozzi has taken click chemistry to a new dimension and started utilising it in living organisms.
Chemists have long been driven by the desire to build increasingly complicated molecules. In pharmaceutical research, this has often involved artificially recreating natural molecules with medicinal properties. This has led to many admirable molecular constructions, but these are generally time consuming and very expensive to produce.
“This year’s Prize in Chemistry deals with not overcomplicating matters, instead working with what is easy and simple. Functional molecules can be built even by taking a straightforward route,” says Johan Åqvist, Chair of the Nobel Committee for Chemistry.
Barry Sharpless – who is now being awarded his second Nobel Prize in Chemistry – started the ball rolling. Around the year 2000, he coined the concept of click chemistry, which is a form of simple and reliable chemistry, where reactions occur quickly and unwanted by-products are avoided.
Shortly afterwards, Morten Meldal and Barry Sharpless – independently of each other – presented what is now the crown jewel of click chemistry: the copper catalysed azide-alkyne cycloaddition. This is an elegant and efficient chemical reaction that is now in widespread use. Among many other uses, it is utilised in the development of pharmaceuticals, for mapping DNA and creating materials that are more fit for purpose.
Carolyn Bertozzi took click chemistry to a new level. To map important but elusive biomolecules on the surface of cells – glycans – she developed click reactions that work inside living organisms. Her bioorthogonal reactions take place without disrupting the normal chemistry of the cell.
These reactions are now used globally to explore cells and track biological processes. Using bioorthogonal reactions, researchers have improved the targeting of cancer pharmaceuticals, which are now being tested in clinical trials.
Click chemistry and bioorthogonal reactions have taken chemistry into the era of functionalism. This is bringing the greatest benefit to humankind.
Carolyn Bertozzi as a young professor at UC Berkeley. (Photo courtesy of College of Chemistry)
Carolyn Bertozzi, a professor at Stanford University who today shared the 2022 Nobel Prize in Chemistry, spent her formative and most creative years at UC Berkeley.
After graduating from Harvard University in 1988, she earned her Ph.D. in chemistry from Berkeley in 1993 and, following postdoctoral and faculty positions elsewhere, returned to join the chemistry faculty and Berkeley Lab in 1996.
For 19 years, until 2015 — the year she left to help lead Stanford’s Sarafan ChEM-H institute — she developed at Berkeley the chemical biology techniques for which she received the Nobel Prize. She calls these techniques bioorthogonal chemistry, building off the “click chemistry” developed by her Nobel Prize co-winners, K. Barry Sharpless of Scripps Research in La Jolla, California, and Morten Meldal of the University of Copenhagen in Denmark.
“Carolyn Bertozzi is a true trailblazer in chemical biology,” said Doug Clark, dean of the College of Chemistry. “Her lab is among the most prolific in the field, consistently producing innovative and enabling chemical approaches, inspired by organic synthesis, for the study of complex biomolecules in living cells. Carolyn’s work and spirit embody what is best about the scientific tradition and history of the College of Chemistry and of UC Berkeley.”
Carolyn Bertozzi, now the Anne T. and Robert M. Bass Professor in the School of Humanities and Sciences and a professor of chemistry at Stanford University. (Photo courtesy of Stanford University)
During a video press conference this morning from Stanford, Bertozzi, 55, described bioorthogonal chemistry as chemical reactions “not interacting with or interfering with biology.”
“What that means in practice is that we basically develop pairs of chemical groups, and those pairs of groups are perfectly suited for each other,” she said. “And when they encounter each other, they want to react and form a bond, and they love each other so much that you can surround those chemical groups with thousands of other chemicals — that’s what you have in biological systems, in your cells, in your body, there’s thousands of chemicals — but these two chemicals that are bioorthogonal will ignore all of that. And they’ll find each other and form a bond with each other, do chemistry with each other.”
Bertozzi’s rationale for developing these reactions was to study the sugars that coat the outside of cells — a field called glycobiology — that has been a passion of hers since her graduate student days at Berkeley. At Berkeley, she worked in the lab of Mark Bednarski, a young assistant professor and a rising star in the field of chemical biology, at the time a relatively new field in which the biochemical processes inside cells are manipulated and studied using techniques of organic chemistry.
In a 2011 interview, Bertozzi discussed the role Berkeley played in her career.
“I credit the UC Berkeley environment for catalyzing my interests in chemical biology and glycobiology from the outset, as I first learned about the opportunities in these fields as a graduate student in this very department,” she said. “I was encouraged to join the lab of a new professor, Mark Bednarski, and he introduced me to the chemistry and biology of sugars. I have been enraptured by this still-burgeoning area of science ever since, in light of the critical roles that sugars play in cell signaling, organ development, immunobiology and in numerous diseases.”
A friend and former colleague of Bertozzi’s at Berkeley, Matt Francis, now chair of the Department of Chemistry, was one of the first to congratulate Bertozzi today after the streamed announcement from Stockholm at 2:45 a.m. PDT, which he was watching. He immediately texted her congratulations.
Carolyn Bertozzi in 2001. (Photo credit: Peg Skorpinski)
“As soon as I heard her name in Swedish, I sent it, and I got an emoji back immediately — the shocked face emoji,” he said. “She’s a total rock star, and this is well deserved.”
Francis came to Berkeley in 2001, when Bertozzi was already well known for her research, and she was a critical academic mentor, he said.
“She did more than just do great science. She really mentored a lot of us who are on the faculty now and helped us get our groups off the ground and was always there to talk to us,” he said. “She was just a great colleague.”
She is equally known for mentoring students at both Berkeley and Stanford. She and Berkeley chemistry colleague Judith Klinman also were instrumental in establishing a chemical biology major within the chemistry department, which currently enrolls half the 480 undergraduates majoring in chemistry in the department.
During the Stanford press conference, Bertozzi explained what led to her Nobel Prize-winning work.
“Bioorthogonal chemistry was a tool that my lab created originally to study cell surface sugars — in fact, to image cell surface sugars using microscopes,” she said. “But then, it turned out to be so useful just as a platform for studying biology that lots of other labs picked up on it and started using those same chemistries to study other molecules, like proteins DNA and RNA. And they, and it turns out you, can study these molecules in live cells and in laboratory animals. And the most exciting development is now there’s a pharmaceutical company doing these chemistries inside the body of human cancer patients as a means to deliver drugs to cancers. So, the field has really progressed a long way in the last 25 years, and it’s very exciting for me to see this.”
She emphasized that her work built on that of co-winners Sharpless and Meldal.
“Before the advent of bioorthogonal chemistry and the related chemistry that professors Sharpless and Meldal developed, which they call click chemistry, there was really no way to study certain biological processes. They were just invisible to the scientists,” she said. “But these chemistries make those processes visible, and we have benefited from that — specifically, to study cell surface sugars.”
A photo of Carolyn Bertozzi taken the morning of Oct. 5, 2022, shortly after she heard that she had won the 2022 Nobel Prize in Chemistry. (Image credit: Andrew Brodhead)
The click chemistry reactions Sharpless and Meldal developed involved copper, however, which is often toxic to living cells. According to Francis, Bertozzi found a novel way around using copper.
“Carolyn’s lab came up with a way around it where they built strain into one of the molecules. In other words, they spring-loaded that molecule so it made it much more readily reactive without the copper,” he said. “And that is now what most people use to label live cell surfaces. It’s called strain promoted click chemistry. She really changed the way people think about the chemistry that we could do in a living organism.”
Francis said that copper-based click chemistry is arguably still faster and is used today in situations without living cells, but Bertozzi’s copperless click chemistry — as well as her previous work on the Bertozzi-Staudinger ligation — is the only technique that works in living cells.
Much of her research while at Berkeley was done in collaboration with scientists at Berkeley Lab. She was one of six Berkeley Lab scientists who led the establishment of the Molecular Foundry, a nanoscience research facility that provides scientists from around the world with access to cutting-edge expertise and instrumentation, and she served as its director from 2006 until 2010.
“It was a privilege to watch how the success of her (Bertozzi’s) discoveries unfolded here on the Berkeley campus and beyond,” said Clark, who also is a faculty scientist at Berkeley Lab. “On behalf of the College of Chemistry community, we extend our heartiest congratulations to Carolyn for her spectacular work and this well-deserved honor.”
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This year’s Nobel Prize laureates in chemistry Demis Hassabis and John Jumper have developed an AI model to solve a 50-year-old problem: predicting proteins’ complex structures.
In 2020, Hassabis and Jumper presented an AI model called AlphaFold2. With its help, they have been able to predict the structure of virtually all the 200 million proteins that researchers have identified. Since their breakthrough, AlphaFold2 has been used by more than two million people from 190 countries. Among a myriad of scientific applications, researchers can now better understand antibiotic resistance and create images of enzymes that can decompose plastic.
Read more about their story: https://bit.ly/4diKiJ2