Germline mutations in either MCM8 or MCM9 have been associated with primary ovarian insufficiency/failure (POI/POF), infertility, and more recently with somatic mutations in various cancers and cancer genomes. This suggests a link for the MCM8/9 complex in participating in genetic recombination processes in both meiotic and mitotic cells; however, the exact cellular or biochemical roles of MCM8/9 are not known. Knockouts of MCM8 or 9 are highly sensitive to crosslinking agents such as mitomycin-c or cisplatin, but we now find that MCM8/9 is also sensitive to and responds to the fork stalling agent hydroxyurea (HU). During fork stalling and reversal, MCM8/9 helps to protect stalled forks by loading and stabilizing Rad51 directly through the BRCA1 pathway. MCM8 or 9 deficient cells show increased degradation by Mre11 after stalling with HU; however, simultaneous knockdown of BRCA1 restores fork stability. Therefore, MCM8/9 helps to promote and stabilize reversed forks after genomic stress. These reversed forks are analogous to recombination intermediates found in meiotic and mitotic cells providing insight into their cellular functions in promoting meiotic genomic diversity and mitotic stability, impacting cellular aging.
Cancer is the second leading cause of death worldwide, and is predicted to rise to ~29 million new cases by 2040. Aging plays a role in the susceptibility of cancer, and studies have shown that aging is correlated with increased genetic instability, which is a hallmark of cancer. In human genomes, cancer-associated mutation “hotspots” have been identified; however, the mechanisms involved are unclear. Interestingly, we and others have found that alternative (i.e. non-B) DNA structures formed at repetitive DNA sequences are highly enriched at mutation “hotspots” in human cancer genomes, implicating non-B DNA in cancer etiology. For example, we have found that H-DNA and Z-DNA are mutagenic both in vitro and in vivo and stimulate the formation of DNA double-strand breaks, deletions, translocations and point mutations. Interestingly, these structures are processed in a mutagenic fashion by DNA repair proteins. We found that H-DNA is processed by the nucleotide excision repair (NER) pathway, while Z-DNA is processed by proteins from both the NER (ERCC1-XPF) and the mismatch repair (MSH2-MSH3) pathways. Although we have determined that NER proteins and MSH2-MSH3 and ERCC1-XPF complexes are recruited to H-DNA and Z-DNA sequences, respectively, to process them in a mutagenic fashion, we do not know how age affects the recruitment of these proteins to these sequences and/or the mutagenic processing of non-B DNA. To test this, we developed a novel transgenic mouse model to evaluate the processing of non-B DNA sequences with age. Experiments are currently being performed on tissues from these transgenic mutation-reporter mice at 2 months and 18 months of age, and our preliminary data suggest that non-B DNA-induced mutagenesis increases with age. Results from these studies will assist in the elucidation of the mechanisms involved in the mutagenic processing of alternative DNA structures with age, and the roles of DNA structure and aging in the generation of mutation hotspots.
Telomeres are protective nucleoprotein-DNA caps at chromosome ends that profoundly influence genome stability and human health. In most human somatic cells, telomeres shorten with division, eventually triggering senescence which blocks further division and drives aging-related diseases. Critically short telomeres in pre-cancerous cells drive genetic alterations that promote carcinogenesis. Previous studies show oxidative stress caused by an excess of reactive oxygen species (ROS), accelerates telomere shortening and dysfunction. Telomere TTAGGG repeat arrays are highly susceptible to ROS-induced conversion of guanine to the common oxidative lesion 8-oxoguanine, which has been proposed to accelerate telomere dysfunction. To study cellular consequences telomere damage, wedeveloped a precision chemoptogenetic tool that selectively produces 8-oxoguanine exclusively at telomeres with high spatial and temporal control. This tool allows us to unequivocally attribute phenotypic outcomes to the telomere damage, eliminating confounding effects of damage elsewhere. We discovered that oxidative base damage at telomeres is sufficient to drive hallmarks of telomere dysfunction, generating distinct cellular consequences in human cancer cells versus non-diseased cells. Chronic formation of telomeric 8-oxoguanine in human cancer cells accelerates telomere shortening and loss, resulting in chromosome fusions and bridges. Acute telomeric 8-oxoguanine damage in human fibroblast and epithelial non-disease cells is sufficient to trigger multiple hallmarks of p53-dependent senescence. In these cells acute damage fails to shorten telomeres, but rather generates telomere fragility indicative of failures in telomere replication. Our results indicate that 8-oxoguanine damage at telomeres is sufficient to drive telomere dysfunction-induced genomic instability in cancer cells, and cellular senescence in non-diseased cells.
Epigenetic markings in chromatin offer an important layer of regulation for transcription in response to metabolic changes, various stresses, and aging. In this talk, I will briefly discuss the various technologies we have developed to identify and study such pathways that discovered in recent years. In particular, I will focus on a class-II histone deacetylase, the HDA complex, regulates aging through its target of acetylated H3K18 at trehalose metabolic genes. We found that disruption of HDA results in resistance to DNA damage and osmotic stresses, as well as lifespan extension. The longevity effect of HDA is independent of the Cyc8 (Ssn6) – Tup1 repressor complex that has been previously shown to interact with HDA and coordinate transcriptional repression. Instead, we found that HDA deacetylated the promoters of genes regulating the synthesis of a storage carbohydrate, trehalose. Activation of this pathway offered protection for the cells against stresses, antagonizing aging and promoting longevity. Intriguingly, this longevity mechanism appears to be conserved in worms and fruit flies. These findings offer novel insights into how histone modifying enzymes regulate anti-aging mechanisms.
Cellular senescence is a cell fate triggered in response to numerous types of stressors, including, genotoxic stress. Indeed, many cancer therapeutics such as ionizing radiation are potent inducers of cellular senescence. Senescent cells are characterized by metabolic reprogramming, chromatin marks of chronic DNA damage, and irreversible cell cycle arrest. As such, senescence is a potent tumor suppressor mechanism. However, the down-side is that senescent cells have been shown to drive aging in mammals. Genetic or pharmacologic ablation of senescent cells in mice extends their median lifespan and attenuates a broad range of age-related diseases. This is thought to be mediated by the secretome of senescent cells, which is often pro-inflammatory and able to perturb the tissue microenvironment. Interestingly, the secretome of senescent cells can drive senescence in trans, enabling genotoxic stress to instigate aging in a cell non-autonomous mechanism. The cause and consequence of cellular senescence in particular with respect to environmental toxicants and aging will be discussed.
An inventor of a new technology that appears to have a significant commercialization opportunity is confronted with a dilemma – what to do next? There are many choices, including continuing to elucidate, develop and refine the technology, possibly license the technology or start a new company, among other options. This session will examine the various decisions the inventor faces and the implication of each choice.
Grants from NSF, NIH, DOE, etc. are an early and many times the first source of capital for early stage entrepreneurs. Grants are in many cases the source of funding to follow up on ideas from academic research even before markets are identified. Angel Capital is a major source of funding for early stage entrepreneurs after funding from Friends and Family and before Venture Capital. Angel Capital is personal capital invested mostly in an entrepreneur whereas Venture Capital is Institutional capital invested in a company. This talk will explore the various sources of capital for early stage entrepreneurs and will highlight the Chemical Angel Network (CaN), the only nationwide angel investing network for early stage chemical entrepreneurs. This network is an organization of angel investors who came together to source, evaluate and invest in early stage chemical entrepreneurs. CAN offers chemists, chemical engineers, and allied professionals a unique opportunity to participate in the growth of companies in the chemical and related industries by investing both intellectual and financial capital.
Starting a business requires many decisions. This session will describe the different types of businesses; sole proprietorship, partnership, LLC, an S Corp and a C Corp. Having decided to incorporate, the jurisdiction of incorporation will be reviewed as well as the importance of the Articles of Incorporation, the Bylaws; the equity structure, shareholder agreements and other important facets of creating and incorporating the company.
To ensure that a startup company will be successful, the founders must access the market opportunity for their technology, product or service. Where a market currently exists, there is, or may be, significant market data to profile competition, estimate pricing and your features and benefits relative to the marketplace. However, with new technologies and the related products or services, there may be little market information. That being the case, determining the potential for financially viable commercialization is much more challenging. This session will address those marketing challenges.
There is a long history of innovation and entrepreneurism in chemistry. There is also a great deal of confusion and disagreement about what it takes to successfully lead creative initiatives. Many of these misunderstandings are fueled by mythical sagas of men born of vision. While most of these people exist, and many of the details of their lives are true, alternate facts and expedient omissions have led to new fictions in science. We will discuss the most common myths of innovation and entrepreneurism in chemistry and look to new sources of truth in the chemical enterprise.
Technology commercialization offices within an academic setting help inventors and entrepreneurs to take their technology into the marketplace for the benefit of society. To achieve this, university technology commercialization offices help to evaluate, protect, market, and license technology developed at their institution to create value for countless stakeholders. The Office of Technology Commercialization (OTC) at The University of Texas at Austin has a robust organization committed to the success of its entrepreneurs which resulted in contributed to the 263 granted U.S. patents and over $370MM in gross revenue from intellectual property in 2020 from the UT System institutions. This session will enable attendees to better understand how organization like the OTC can be ideal partners as their attempt to commercialize their technology within the academic environment.
Many entrepreneurs equate the term “intellectual property” with patents. While Patents are one type of intellectual property, they are not the only one. There are others that are also very important to the entrepreneur. For example, an entrepreneur would also be wise to pay attention to trademarks, copyrights and trade secrets. Come learn about the various types of intellectual property and their relevance to entrepreneurs.
Product development groups sit at the nexus of business growth. Often, they act as the bridge between the commercial and operational functions. While the popular business literature focuses heavily on the product-market fit for technology, there is much less to be said for the detailed work in moving products past the grey area of scaleup and adoption by the greater operational side of the business. This crucial step is often mired in bureaucracy and hindered by real or imagined organizational silos.
Through a combination of theoretical approaches and real-world examples, we will explore approaches and general frameworks that can enhance the operational side of product development pipeline from design to sourcing and manufacturing. Incorporating these strategies into your product development process can improve time to revenue, initial product margin, and customer experience from new product introductions.
In view of the accelerated pace of multiple shifts (industry; sciences; society, including consumers and talents), companies like P&G are able to remain in the forefront of industry innovation by learning to transform the way to innovate, operating more as a start-up while building on its strengths: values and principles, depth and breadth in science, sound consumer understanding, and scale. This progressive journey into the future is made possible by embracing lean Innovation, digital transformation, a culture of continuous learning and intentionality to drive a constructive disruption mindset. P&G does not do this alone and always seeks to cultivate enduring partnerships with chemistry enterprises (university, entrepreneurs, industry, consortiums) to raise the bar on scientific advancements, transformative technologies and innovations to grow and lift our partners, and to better serve the consumers and the planet.
True innovation comes when solutions that broadly impact humanity are timely and delivered at scale. The need for innovation is greater than ever before in order to address some of the largest challenges the world has faced. The complexity and pace of innovation continues to accelerate. Research continues to become more global, yet with very local and evolving needs. Consumers are demanding both product performance and product sustainability, it is not an either or. Research tools are constantly advancing, providing new ways to look at problems. Researchers and the research community are continuously becoming more multi-disciplinary, diverse, and entrepreneurial. As such, innovation requires context, inclusivity, and feedback to be successful, impactful, and at scale. Good opportunities must be quickly seized and delivered. All of this requires a partnership, open-minded, risk-tolerant approach in order for research and development to be most effective. Collaborators across the value chain facilitate holistic solutions that no single participant could achieve alone. This talk will present several examples of how we focus our innovation efforts at Dow. A primary objective is that solutions must be simultaneously better performing and more sustainable. Customers and value chain partners, both small and large companies around the world, are critical partners to identify, prioritize, and address the most significant opportunities. Collaborations are vital to develop impactful solutions where each partner contributes complementary perspectives and unique-to-the-world capabilities. Collaborations with academics and government research labs are foundational to Dow to extend our expertise, provide the next generation of talent, and incubate nascent technologies.
With the largest R&D engine in AgTech, Bayer Crop Science innovates internally to bring the best products to market. Bayer also operates externally around the globe in the quest to support and enrich our R&D pipeline. This approach provides unique opportunities to find and cultivate innovations to support our customers, but it also provides a communication platform to position Bayer as a partner of choice and a thought leader in our industry. External engagement helps us to build new relationships and demonstrates our transparency and willingness to partner on innovation. Bayer develops collaborations and partnerships through a variety of vehicles, programs, and funding models. These varied approaches provide opportunities for outreach to diverse communities and ways to drive innovations though funding, investment, co-creation, co-location and in-kind support. Working and investing in this manner provides an unparalleled level of visibility into Bayer, helping partners understand who we are, and what we stand for. Additionally, by working directly with external parties, we can mitigate misinformation, reduce risk perceptions, and engage advocates. These external collaborations are a key part of our R&D efforts, making them also a key part of Bayer’s mission to enable Health for All and Hunger for None.
As an innovation leader, DuPont is constantly drawing from our 200-year experience to deploy scientific solutions that help the world to thrive. From safer, more efficient building materials, to innovations for electric and autonomous vehicles, or new technologies that enable advanced electronics and access to clean water, our businesses work closely with customers and industry partners to solve the problems that matter most. The way we innovate has evolved to adapt to today’s faster pace of change, to manage uncertainties around investment choices, and to maximize efficiency in implementation and commercialization through upgraded frameworks, skill sets and culture.
Typically, when starting a company, funding is required. There are many sources of funding, but they may not be positively inclined to offer funds. This talk will provide insights from an experienced venture capital investor regarding this new company and its founders’ attributes that lead to an investment.
Investing in startup and early-stage companies is both a science and an art. In an effort to select those companies that will have increased opportunities for success, professional investors use criteria for making those investments. This talk will discuss the process that successful investors employ and describe the new company attributes upon which they base their investment.
A successful serial entrepreneur discusses what he learned when starting several new companies. There are those things that were done well that helped the company be successful and decisions made that would be done differently with the next start up. One of the important lessons learned was that tough decisions should have been made much more quickly.
Starting a company is both exciting and challenging. There are many different projects that must be done, from market research and forecasting to budgeting and financial considerations. As a successful, serial entrepreneur, this session will provide insights regarding those activities that must be done in order to be successful as well as certain activities that one should not do to avoid mistakes and increase success.