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The global stem cell therapy market was valued at $10–12 billion in 2022 and is projected to grow at a compound annual growth rate (CAGR) of 10–15%, potentially surpassing $31.41 billion by 2030. The application prospects for stem cell therapies can be categorized into three main areas: off-the-shelf cell therapies, regenerative medicine, and gene therapy vehicles. Among the 25 approved stem cell therapies worldwide, mesenchymal stem cell (MSC) therapies and hematopoietic stem cell (HSC) therapies constitute 76% of the total, reflecting their advanced technological maturity. Global Transactions of Stem Cell Therapy in Patsnap SynapseMechanisms of Stem Cell TherapyThe mechanisms of stem cell therapy revolve around their core properties of self-renewal and multi-lineage differentiation, which grant them significant value in regenerative medicine and tissue repair. Self-renewal refers to the ability of stem cells to proliferate indefinitely without differentiation, maintaining their undifferentiated state. Through mitosis, stem cells produce progeny that preserve stem cell quantity and functionality. This process is regulated by multiple signaling pathways, including the transcription factors Oct4, Sox2, and Nanog in embryonic stem cells, while adult stem cells rely primarily on the p16-Rb and p19-p53 signaling pathways. Clinical Trials for Cell Therapies Using PSCs1Multi-lineage differentiation allows stem cells to transform into various cell types, such as neurons, cardiomyocytes, and osteocytes, under specific conditions. This differentiation process is influenced by microenvironmental factors and signaling pathways like Wnt, Notch, BMP, and Hedgehog. By introducing specific growth factors and chemical agents, scientists can precisely guide stem cell differentiation into desired cell types for treating diseases such as osteoarthritis, spinal cord injuries, myocardial infarction, and neurological disorders. Main Targets of Stem Cell Therapy Applications in Patsnap SynapseStem cells also exhibit remarkable immunomodulatory and anti-inflammatory effects, helping to suppress abnormal immune responses and restore immune system balance. MSCs, in particular, have been widely studied and proven effective in these areas. MSCs regulate immune cell function through direct cell-to-cell contact and secretion of effector molecules such as growth factors, cytokines, and chemokines. For instance, MSCs can inhibit T-cell activation and proliferation while promoting the activity of regulatory T cells (Tregs), thereby alleviating inflammation. Additionally, MSCs secrete anti-inflammatory factors like transforming growth factor-beta (TGF-β) and interleukin-10 (IL-10), which reduce inflammatory mediators, alleviate symptoms, and protect tissues from further damage. The stem cell hierarchy2The paracrine effects of stem cells involve the secretion of various bioactive molecules such as cytokines, growth factors, chemokines, microRNAs, and extracellular vesicles, which participate in intercellular communication, tissue repair, and regeneration. These molecules play crucial roles in diverse physiological and pathological processes. For example, growth factors secreted by stem cells, including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF), promote angiogenesis, accelerate wound healing, and facilitate tissue repair. Anti-inflammatory cytokines such as interleukin-6 (IL-6), IL-10, and TGF-β help regulate immune cell function, suppress inflammation, and support tissue repair. For instance, IL-10 reduces the production of inflammatory mediators, mitigating inflammation and protecting tissues from further damage. Layers of complexity in stem cell systems2Stem cells possess homing ability, a critical biological characteristic that enables them to migrate toward injured or inflamed sites in the body. Damaged tissues release bioactive factors that bind to receptors on the surface of stem cells, directing them to the injury site. For example, damaged tissues secrete stromal cell-derived factor-1 (SDF-1), which interacts with the CXCR4 receptor on stem cells, guiding their migration. Additionally, growth factors, adhesion molecules, and inflammatory factors released at the injury site further enhance stem cell migration and homing. The homing process encompasses not only migration but also the differentiation of stem cells into necessary cell types within the specific microenvironment of the injury, contributing to tissue repair and regeneration. Stem cell therapy design2Stem cells can differentiate into various types of tissue cells, aiding the regeneration and repair of damaged or dysfunctional tissues. Whether addressing skin wounds, myocardial injury, or neurodegenerative diseases, stem cell therapy provides new cellular sources for damaged tissues, promoting recovery and functional reconstruction. For instance, mesenchymal stem cells (MSCs) can differentiate into bone, cartilage, and adipose cells, making them suitable for treating conditions like osteoarthritis and spinal cord injuries. Their multi-lineage differentiation potential allows stem cells to transform into cell types needed by injured tissues under specific conditions, replacing damaged or dead cells and restoring tissue function. For example, following myocardial infarction, MSCs can differentiate into cardiomyocytes, replacing damaged myocardial cells and improving cardiac function. This cell replacement capability not only offers a new source of cells but also facilitates structural and functional recovery of damaged tissues. Another critical mechanism is microenvironment regulation. Stem cells secrete various growth factors and cytokines to modulate the microenvironment of injured tissues, promoting cell proliferation and tissue repair. For example, hepatocyte growth factor (HGF) secreted by stem cells supports liver cell regeneration and improves liver function. Additionally, vascular endothelial growth factor (VEGF) promotes angiogenesis, improving blood supply to damaged tissues and accelerating the repair process. Development of the induced pluripotent stem cell (iPSC) technology3Stem cells can also secrete anti-apoptotic factors that prevent cell death, which is crucial for protecting damaged tissues and maintaining tissue homeostasis. By inhibiting apoptosis, stem cell therapy enhances tissue survival and repair, improving therapeutic outcomes. Anti-apoptotic factors such as Bcl-2 and Bcl-xL inhibit apoptotic signaling pathways, protecting cells from damage. For instance, Bcl-2 prevents apoptosis by inhibiting the release of cytochrome c from mitochondria, thereby protecting cells in damaged tissues. This anti-apoptotic effect helps maintain tissue integrity and functionality, reducing cell loss. Additionally, stem cells secrete antioxidants and anti-inflammatory factors, shielding cells from oxidative stress and inflammatory damage, and preserving cell survival and function. Major Diseases Targeted by Stem Cell Therapy in Patsnap SynapseRegional R&D Characteristics of Stem Cell TherapyAs a regenerative medicine technique, stem cell therapy uses stem cells or their derivatives to stimulate the body's healing processes and repair damaged, diseased, or injured tissues, representing a promising frontier in transplantation. Key Development Regions for Stem Cell Research in Patsnap SynapseThe United States leads stem cell research and application, supported by a robust scientific foundation and a comprehensive regulatory framework. Hematopoietic stem cell transplantation for hematologic diseases was among the earliest stem cell technologies adopted clinically and remains the only globally recognized stem cell therapy. U.S. research institutions and companies, such as the Mayo Clinic, have made significant advances, exploring stem cell treatments for neurodegenerative diseases, cardiac conditions, and diabetes. Europe is also at the forefront, with countries like Germany, the UK, and France making notable contributions through institutions and companies like BioTime and STEMCELL Technologies. Germany's Max Planck Institute and the University of Cambridge in the UK have achieved significant breakthroughs in both fundamental and clinical applications of stem cells. European firms like TiGenix and Promethera Biosciences have conducted extensive clinical trials on stem cell therapies for liver and cardiovascular diseases. Clinical Research Directions and Targets of Stem Cell Research in Patsnap SynapseChina has made remarkable progress in stem cell research and applications, fostered by governmental support and favorable policies. Institutions like Peking University and companies affiliated with East Hospital have achieved notable outcomes. Japan, led by Kyoto University and the University of Tokyo, has also made significant advances, with Shinya Yamanaka receiving a Nobel Prize for discovering induced pluripotent stem cells (iPSCs). South Korean firms such as Celltrion and GC Pharma have conducted extensive trials on stem cell therapies for autoimmune and neurodegenerative diseases. Indian companies, like Stempeutics Research, have also made strides in treating osteoarthritis and spinal cord injuries using stem cell therapies. Main R&D Institutions for iPSC Drugs in Patsnap SynapseGlobal Competitive Landscape of Stem Cell TherapyFate Therapeutics is a leading biopharmaceutical company specializing in regenerative medicine and immunotherapy, focusing on developing immune cell therapies based on induced pluripotent stem cells (iPSCs). Utilizing its proprietary iPSC technology platform, the company generates and expands NK and T cells with specific biological properties for treating cancer and other immune-related diseases. Key products include iPSC-derived NK cells (such as FT500, FT516, FT538, and FT596) and T cells (such as FT819), which have demonstrated good safety profiles and preliminary efficacy in various clinical trials. For example, in a Phase 1 clinical trial for relapsed/refractory B-cell lymphoma, FT516 achieved complete remission in six out of eight patients. Fate Therapeutics has a strong foundation in iPSC technology, a broad patent portfolio, and collaborations with major pharmaceutical companies, accelerating its product development and commercialization. Its robust manufacturing capabilities and extensive clinical data position it as a leader in stem cell drug research. Mesoblast Limited is a biopharmaceutical company dedicated to developing allogeneic mesenchymal precursor cell (MPC)-based therapeutic products, focusing on cardiovascular, orthopedic, and immune diseases. Its flagship product, Remestemcel-L, has been approved in Japan for treating steroid-refractory acute graft-versus-host disease (SR-aGVHD) and has shown promising results in clinical trials for chronic heart failure and acute respiratory distress syndrome (ARDS). Another key product, Rexlemestrocel-L, has exhibited significant efficacy in Phase 3 trials for chronic heart failure and chronic low back pain. With its proprietary MPC technology platform and extensive clinical experience, Mesoblast has amassed substantial clinical data in the cardiovascular and orthopedic fields, showcasing its strong competitive edge. The company’s partnerships with global pharmaceutical firms have further accelerated its product development and commercialization. Product Pipeline of Mesoblast Limited in Patsnap SynapseAthersys, Inc. is a biotechnology company focused on regenerative medicine, primarily developing MultiStem® cell therapy based on multipotent adult progenitor cells (MAPCs). This therapy has shown broad therapeutic potential and positive clinical results for diseases such as stroke, traumatic brain injury, and ARDS. MultiStem® has received FDA Fast Track and RMAT designations, expediting its development and approval processes. Leveraging its proprietary technology platform and rich clinical experience, Athersys collaborates with international partners to advance the clinical research and commercialization of its products, offering new treatment options for patients with various diseases. BlueRock Therapeutics focuses on cell therapies using iPSC technology, targeting neurodegenerative and cardiovascular diseases. Its core product, bemdaneprocel (BRT-DA01), an iPSC-derived dopaminergic neuron therapy for Parkinson’s disease, has received FDA Fast Track designation and demonstrated good safety and cell survival in Phase 1 clinical trials. BlueRock benefits from its close collaboration with Bayer, which provides strong R&D and financial support, positioning it as a leader in the cell therapy field. TiGenix NV (acquired by Takeda) focuses on gastrointestinal and cardiovascular diseases, with its primary product, Cx601 (allogeneic adipose-derived stem cells), approved in the EU as the first stem cell therapy for complex perianal fistulas. Promethera Biosciences specializes in liver diseases, with its main product, HepaStem® (allogeneic liver stem cells), targeting acute liver failure and supported by unique technology and multiple clinical trials. Cellular Biomedicine Group (CBMG) focuses on cancer immunotherapy and autoimmune diseases, leveraging its experience with CAR-T and mesenchymal stem cell therapies, with several products in clinical trial stages. In China, significant progress has been made in the stem cell drug field. EdiGene focuses on gene editing and stem cell therapy, with its edited hematopoietic stem cell product ET-01 approved for clinical trials, showcasing deep expertise in gene editing technology. BGI Shenzhen excels in genomics and stem cell research, offering personalized and precision medicine solutions widely applied in genetic disease diagnosis and cancer screening. Vcanbio dominates China’s cell storage market, providing high-quality cell storage services and stem cell therapy products, with several stem cell products, such as dental pulp stem cell injections and Inaticabtagene Autoleucel cell injections, entering clinical trials. Guanhao Biotech has extensive experience in regenerative medicine and cell therapy, offering various biomaterials and cell therapy products, with several advancing to clinical trials. These companies highlight China’s progress and innovation in the stem cell drug field. With technological advancements and policy support, China is expected to achieve more breakthroughs, offering global patients expanded treatment options. SummaryThe global stem cell therapy market is projected to grow steadily, potentially exceeding $31.41 billion by 2030. The application of stem cell therapy continues to expand from hematologic diseases to neurological, cardiovascular, and metabolic disorders. With improved policies, continuous innovation, and deeper clinical applications, China's stem cell medical industry is set for broader growth prospects, offering new hope for treating refractory diseases. Personalized therapy, based on individual patient characteristics, is becoming a key trend in the industry, with customized treatment plans likely to dominate future stem cell therapies. Technological innovation and breakthroughs will further drive industry growth, providing new strategies for severe chronic diseases. How to obtain the latest research advancements in the field of biopharmaceuticals? In the Synapse database, you can keep abreast of the latest research and development advances in drugs, targets, indications, organizations, etc., anywhere and anytime, on a daily or weekly basis. Click on the image below to embark on a brand new journey of drug discovery! Refrence  1.Yamanaka S. Pluripotent Stem Cell-Based Cell Therapy-Promise and Challenges. Cell Stem Cell. 2020 Oct 1;27(4):523-531. doi: 10.1016/j.stem.2020.09.014. PMID: 33007237.2.Tewary M, Shakiba N, Zandstra PW. Stem cell bioengineering: building from stem cell biology. Nat Rev Genet. 2018 Oct;19(10):595-614. doi: 10.1038/s41576-018-0040-z. PMID: 30089805.3.Induced pluripotent stem cells (iPSCs): molecular mechanisms of induction and applications.

ROCKVILLE, Md. and SUZHOU, China, Nov. 17, 2024 /PRNewswire/ -- Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in discovering, developing and commercializing therapies to address global unmet medical needs primarily for malignancies, today announced that a New Drug Application (NDA) for its inhouse developed investigational novel Bcl-2 selective inhibitor, lisaftoclax (APG-2575), for the treatment of patients with relapsed or refractory (r/r) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has been accepted and recommended the Priority Review designation by the Center for Drug Evaluation (CDE) of China's National Medical Products Administration (NMPA). This NDA, the first for a domestically developed Bcl-2 inhibitor in China, could potentially lead lisaftoclax to become the second Bcl-2 inhibitor approved anywhere in the world. This NDA is based on results from a pivotal registrational Phase II study in China (APG2575CC201) that evaluated the efficacy and safety of lisaftoclax in patients with r/r CLL/SLL. The primary endpoint of the study is the overall response rate (ORR). CLL/SLL is a hematologic malignancy caused by mature B-cell neoplasms. It primarily affects older populations and is among the most common leukemia subtypes in the Western World, with over 100,000 new diagnoses reported globally each year1. In China, where the incidence rate of CLL/SLL is lower than that of the western countries, the disease is occurring at a rapidly rising rate, with a younger age of onset and higher aggressiveness2. SLL and CLL are two different manifestations of the same disease and approximately 20% of all SLL cases would progress to CLL3. Treatments such as immunotherapies and Bruton's tyrosine kinase inhibitors (BTKis) have significantly improved patients' responses to initial treatment. However, due to the limitations of existing treatment options, the poor prognosis of patients, severe impact on patients' quality of life and high complexity of the disease, patients with r/r CLL/SLL are in desperate need for new treatment options that are safe and effective. The introduction of Bcl-2 inhibitors has further revolutionized the treatment of CLL/SLL. Bcl-2 is an apoptosis suppressor factor that regulates cell survival by controlling mitochondrial membrane permeability. It suppresses apoptosis by inhibiting the release of cytochrome C from mitochondria or by binding to apoptotic activators to inhibit the activity of caspase. The overexpression of Bcl-2, found in a variety of hematologic malignancies, particularly CLL/SLL, is a key mechanism by which tumor cells evade apoptosis. However, the development of Bcl-2 as a therapeutic target is challenging mainly because its mechanism of action is based on the protein-protein interaction (PPI). The binding interface of Bcl-2 is relatively large, making it difficult for small-molecule inhibitors to exert blocking effects. Additionally, the Bcl-2 protein is located on the mitochondrial membrane, and mitochondria, with its double-membrane structure, is among the most complex and challenging cellular components. Drugs must first penetrate the cell membrane before they can further act on the mitochondrial membrane. In nearly 40 years since the discovery of this target, only one Bcl-2 inhibitor has been approved globally, a reality highlighting the immense difficulty and challenges in this field of research and development. In western countries, the treatment of CLL/SLL has entered a new era of chemotherapy-free and fixed-duration regimens, while no Bcl-2 inhibitor has been approved in China in this therapeutic area. Therefore, patients in China have an urgent unmet need for such novel therapies that can offer both efficacy and safety. Lisaftoclax is a novel, investigational orally administered small-molecule Bcl-2 selective inhibitor being developed by Ascentage Pharma to treat patients with malignancies by selectively blocking the antiapoptotic protein Bcl-2 and hence restoring the normal apoptosis process in cancer cells. Lisaftoclax is the first Bcl-2 inhibitor in China and the second anywhere globally that has demonstrated compelling clinical benefit and entered a pivotal registrational study. Lisaftoclax has broad therapeutic potential for a variety of hematologic malignancies and solid tumors, particularly as a single agent and in combinations in CLL/SLL. Lisaftoclax is a potential drug that may offer patients a safe, effective, and easy to use treatment option. Lisaftoclax is being evaluated in multiple registrational Phase III studies, including a global registrational Phase III study of lisaftoclax in combination with a BTKi in previously treated patients with CLL/SLL (cleared by the US FDA); a global registrational Phase III study of lisaftoclax in combination with acalabrutinib for the first-line treatment of treatment-naïve patients with CLL/SLL; a global registrational Phase III study of lisaftoclax in combination with azacitidine (AZA) for the first-line treatment of elderly/unfit treatment-naïve patients with acute myeloid leukemia (AML) who were intolerant of standard induction chemotherapies; and a global registrational Phase III study of lisaftoclax in combination with AZA for the first-line treatment of newly-diagnosed patients with higher-risk myelodysplastic syndrome (MDS). "Ascentage Pharma's founding team has over 20 years of deep experience in developing apoptosis-targeted therapies and has made significant strides with the Bcl-2 target," said Dr. Dajun Yang, Chairman & CEO of Ascentage Pharma. "To date, only one Bcl-2 inhibitor has been approved globally, which is a reality underscoring the immense difficulty and challenges in this field of research and development. This NDA submission for lisaftoclax could potentially pave the way for lisaftoclax to become the first approved China-developed Bcl-2 inhibitor, thus marking another major milestone that is a culmination of the Ascentage Pharma's deep commitment and perseverant work in the past 15 years." Dr. Yang continued, "Globally, r/r CLL/SLL represents an area of urgent unmet clinical needs. To have successfully advanced lisaftoclax to this point, it is a true testament to Ascentage Pharma's robust capabilities in global pharmaceutical innovation. Moving forward, we will accelerate the global development of lisaftoclax in other indications to bring benefit to patients as quickly as possible. Remaining steadfastly committed to our mission of addressing unmet clinical needs in China and around the world, we will strive to develop more novel therapeutics for patients in need." References: 1. Yao, Y., Lin, X., Li, F., et al. The global burden and attributable risk factors of chronic lymphocytic leukemia in 204 countries and territories from 1990 to 2019: analysis based on the global burden of disease study 2019. Biomed Eng Online. 2022 Jan 11;21(1):4. DOI: 10.1186/s12938-021-00973-6 2. Liu Peng. Practice guidelines for the diagnosis and treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma in Zhongshan Hospital, Fudan University (v1.2018). [J]. Chin J Clin Med, 2018, 25(1): 157-160. DOI 10.12015/j. issn. 1008-6358. 2018. 20180 3. Li Jianyong, Qiu Lugui. Hematology Committee of Chinese Medical Association; Hematological Oncology Committee of China Anti-Cancer Association; Chinese Working Group for Chronic Lymphocytic Leukemia. The guidelines for diagnosis and treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma in China (2022). Zhonghua Xue Ye Xue Za Zhi. 2022 May 14;43(5):353-358. DOI: 10.3760/cma.j.issn.0253-2727.2022.05.001 About Ascentage Pharma Ascentage Pharma (6855.HK) is a global, integrated biopharmaceutical company engaged in discovering, developing and commercializing therapies to address global unmet medical needs primarily in malignancies. On October 28, 2019, Ascentage Pharma was listed on the Main Board of the Stock Exchange of Hong Kong Limited with the stock code 6855.HK. The company has built a rich pipeline of innovative drug candidates that includes novel, highly potent Bcl-2 and dual Bcl-2/Bcl-xL inhibitors, as well as candidates aimed at IAP and MDM2-p53 pathways, and next-generation TKIs. Ascentage Pharma is also the only company in the world with active clinical programs targeting all three known classes of key apoptosis regulators. The company has conducted more than 40 clinical trials in the US, Australia, Europe, and China, including 13 registrational studies (completed/ ongoing/planned). Olverembatinib, the company's first lead asset developed for the treatment of drug-resistant chronic myeloid leukemia (CML) and the company's first approved product in China, has been granted Priority Review Designations and Breakthrough Therapy Designations by the Center for Drug Evaluation (CDE) of China National Medical Products Administration (NMPA). To date, the drug had been included into the China National Reimbursement Drug List (NRDL). Furthermore, olverembatinib has been granted Orphan Drug Designations (ODDs) and a Fast Track Designation (FTD) by the US FDA, and an Orphan Designation by the EMA of the EU. To date, Ascentage Pharma has obtained a total of 16 ODDs from the US FDA and 1 Orphan Designation from the EMA of the EU for 4 of the company's investigational drug candidates. Leveraging its robust R&D capabilities, Ascentage Pharma has built a portfolio of global intellectual property rights and entered into global partnerships and other relationships with numerous leading biotechnology and pharmaceutical companies such as Takeda, AstraZeneca, Merck, Pfizer and Innovent; and research and development relationships with leading research institutions such as Dana-Farber Cancer Institute, Mayo Clinic, MD Anderson Cancer Center, National Cancer Institute and the University of Michigan. The company has built a talented team with a wealth of global experience in the discovery and development of innovative drugs and fully functional commercial manufacturing and Sales & Marketing teams. One pivotal aim of Ascentage Pharma is to continuously strengthen its R&D capabilities and accelerate its clinical development programs, in order to fulfil its mission of addressing unmet clinical needs in China and around the world for the benefit of more patients. Forward-Looking Statements The forward-looking statements made in this article relate only to the events or information as of the date on which the statements are made in this article. Except as required by law, Ascentage Pharma undertakes no obligation to update or revise publicly any forward-looking statements, whether as a result of new information, future events, or otherwise, after the date on which the statements are made or to reflect the occurrence of unanticipated events. You should read this article completely and with the understanding that our actual future results or performance may be materially different from what we expect. In this article, statements of, or references to, our intentions and expectations or those of any of our Directors or our Company are made as of the date of this article. Any of these intentions and expectations may alter in light of future development. SOURCE Ascentage Pharma WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

A newly evolved enzyme could one day make silicone compounds biodegradable. For the first time, scientists have engineered an enzyme that can break stubborn human-made bonds between silicon and carbon that exist in widely used chemicals known as siloxanes, or silicones. The discovery is a first step toward rendering the chemicals, which can linger in the environment, biodegradable. "Nature is an amazing chemist, and her repertoire now includes breaking bonds in siloxanes previously thought to evade attack by living organisms," says Frances Arnold, the Linus Pauling Professor of Chemical Engineering, Bioengineering and Biochemistry at Caltech and winner of the 2018 Nobel Prize in Chemistry for her pioneering work in directed evolution, a method for engineering enzymes and other proteins using the principles of artificial selection. Arnold and her colleagues, including Dimitris (Dimi) Katsoulis of Michigan-based Dow Inc. used directed evolution to create the new silicon-carbon bond-cleaving enzyme. The results are published in the January 26 issue of the journal Science. The researchers say that while practical uses for their engineered enzyme could still be a decade away or more, its development opens the possibility that siloxanes could one day be degraded biologically. "For example, natural organisms could evolve in siloxane-rich environments to catalyze a similar reaction, or further improved versions of laboratory-evolved enzymes such as this one could possibly be used to treat siloxane contaminants in wastewater," Arnold says. Katsoulis explains that nature doesn't use silicon-carbon bonds, "but we do and have been for about 80 years. The volatile nature of some of these compounds warrants health and environmental research to properly understand the degradation mechanisms of these materials in the environment." Siloxane chemicals can be found in countless products, including those used in household cleaning, personal care, and the automotive, construction, electronics, and aerospace industries. The compounds' chemical backbone is made of silicon-oxygen bonds, while carbon-containing groups, often methyl, are attached to the silicon atoms. "The silicon-oxygen backbone gives the polymer an inorganic-like character while the silicon-methyl groups give the polymer organic-like characteristics. Thus, these polymers have unique material properties, such as high thermal and oxidative stability, low surface tension, and high backbone flexibility among others," Katsoulis says. Siloxanes are believed to persist in the environment for days to months, and, therefore, ongoing research aims to provide greater scientific understanding of the health and environmental safety of silicone materials. The chemicals naturally start to fragment into smaller pieces, especially in soil or aquatic environments, and those fragments become volatile or escape into the air, where they undergo degradation by reacting with free radicals in the atmosphere. Of all the bonds in siloxanes, the silicon-carbon bonds are the slowest to break down. Katsoulis approached Arnold to collaborate on efforts to speed up siloxane degradation after he read about her lab's work in coaxing nature to produce silicon-carbon bonds. In 2016, Arnold and her colleagues used directed evolution to engineer a bacterial protein called cytochrome c to form silicon-carbon bonds, a process that does not occur in nature. "We decided to get nature to do what only chemists could do -- only better," Arnold said in a Caltech news release. The research demonstrated that biology could make these bonds in ways that are more environmentally friendly than those traditionally used by chemists. In the new study, the researchers wanted to find ways to break the bonds rather than create them. The scientists used directed evolution to evolve a bacterial enzyme called cytochrome P450. Directed evolution is similar to breeding dogs or horses in that the process is designed to bring out desired traits. The researchers first identified a variant of cytochrome P450 in their collection of enzymes that had a very weak ability to break silicon-carbon bonds in so-called linear and cyclic volatile methylsiloxanes, a common subgroup of the siloxane family. They mutated the DNA of the cytochrome P450 and tested the new variant enzymes. The best performers were then mutated again, and the testing was repeated until the enzyme was active enough to enable the researchers to identify the products of the reaction and study the mechanism by which the enzyme works. "Evolving enzymes to break these bonds in siloxanes presented unique hurdles. With directed evolution, we must evaluate hundreds of new enzymes in parallel to identify a few enzyme variants with improved activity," says Tyler Fulton (PhD '22), co-lead author of the study and a postdoctoral scholar at Caltech in Arnold's lab. One challenge involved the siloxane molecules leaching plastic components from the 96-well plates used to screen the variants. To solve the problem, the team created new plates made from common lab supplies. "Another challenge was finding the starting enzyme for the directed evolution process, one with even just a tiny amount of the desired activity," Arnold says. "We found it in our unique collection of cytochrome P450s evolved in the laboratory for other types of new-to-nature silicon chemistry." The final improved enzyme does not directly cleave the silicon-carbon bond but rather oxidizes a methyl group in the siloxanes in two sequential steps. Basically, this means that two carbon-hydrogen bonds are replaced with carbon-oxygen bonds, and this change allows the silicon-carbon bond to break more readily. The research draws parallels to studies involving a plastic-eating enzyme, explains Fulton, referring to a polyethylene terephthalate (PET)-degrading enzyme discovered in the bacteria Ideonella sakaiensis in 2016 by a different group of researchers. "While the PET-degrading enzyme was discovered by nature rather than by engineers, that enzyme inspired other innovations that are finally coming to fruition for plastic degradation. We hope this demonstration will similarly inspire further work to help break down siloxane compounds," he says.