Professor and Director at Northwestern University
Category of Humanitarian Benefit: Health and Medical
Short Biography/Background of the Nominee: Dr. Chad A. Mirkin is the Director of the International Institute for Nanotechnology and the George B. Rathmann Prof. of Chemistry, Prof. of Chemical and Biological Engineering, Prof. of Biomedical Engineering, Prof. of Materials Science & Engineering, and Prof. of Medicine at Northwestern University. He is a chemist and a world-renowned nanoscience expert, who has made discoveries in science and technology, with important implications in health and medicine, that are positively affecting humanity. Specifically, he has discovered and developed spherical nucleic acids (SNAs) and SNA-based biodetection and therapeutic schemes that have led to over 1,100 patent applications worldwide (over 310 issued) and his founding of multiple companies, including Nanosphere (now a part of Luminex), AuraSense, and Exicure (Symbol: XCUR). These companies have commercialized roughly 2,000 products in the life sciences and biomedicine with significant societal benefit. Mirkin has authored over 720 manuscripts, given 660 invited lectures worldwide, and educated over 260 graduate students and postdoctoral fellows (over 100 alumni are now faculty members at top institutions around the world).
Mirkin has been recognized for his research accomplishments and professional service with over 130 national and international awards. These include the Harrison Howe Award, the Remsen Award, Ralph N. Adams Award, the Dickson Prize in Science, the Wilhelm Exner Medal (Austria) the RUSNANOPRIZE, the Nichols Medal, the Dan David Prize (Israel’s Nobel Prize), the NAS Sackler Prize in Convergence Research, the RSC Centenary Prize, the Friends of the National Library of Medicine Distinguished Medical Science Award, the Thomson Reuters Highly Cited Researcher (2002-2012), the ACS Nano Lectureship Award, the Linus Pauling Medal, the Thomson Reuters “Nobel-Class” Citation Laureate, RSC's "Chemistry World" Entrepreneur of the Year Award, the Walston Chubb Award for Innovation, the Lee Kuan Yew Distinguished Visitor to Singapore, the ACS Award for Creative Invention, an Einstein Professorship of the Chinese Academy of Sciences, the $500,000 Lemelson-MIT Prize, the Havinga Medal, the Gustavus John Esselen Award, the Biomedical Eng. Society's Distinguished Achievement Award, a DoD NSSEFF Award, the Pittsburgh Analytical Chemistry Award, the ACS Inorganic Nanoscience Award, a NIH Director’s Pioneer Award, the Collegiate Inventors Award, the Raymond and Beverly Sackler Prize in the Physical Sciences, the Feynman Prize in Nanotechnology, the Leo Hendrick Baekeland Award, the ACS Award in Pure Chemistry, the PLU Fresenius Award, the Camille Dreyfus Teacher-Scholar Award, the Alfred P. Sloan Foundation Award, and the Beckman Young Investigator Award.
Mirkin served as a Member of the President’s Council of Advisors on Science & Technology (Obama Administration) for eight years, and he is one of very few scientists to be elected to all three US National Academies (Medicine, Science, and Engineering), and in addition, he is a Foreign Member of the Chinese Academy of Sciences. He is also a Fellow of the American Academy of Arts and Sciences, the American Association for the Advancement of Science, the National Academy of Inventors, the American Chemical Society, the Royal Society of Chemistry, the American Institute for Medical and Biological Engineering, and the Materials Research Society. Mirkin has served on the Editorial Advisory Boards of over 20 scholarly journals, including J. Am. Chem. Soc., Acc. Chem. Res., Angew. Chem., Adv. Mater., Biomacromolecules, Macromolecular Bioscience, SENSORS, Encyclopedia of Nanoscience and Nanotechnology, Chem. Eur. J., Chemistry & Biology, Nanotechnology Law & Business, The Scientist, J. Mater. Chem., J. Cluster Sci., and Plasmonics, and at present, he is an Associate Editor of Journal of the American Chemical Society. He is the founding editor of the journal Small, one of the premier international nanotechnology journals, and he has co-edited multiple bestselling books.
Mirkin holds a B.S. degree from Dickinson College (1986, elected into Phi Beta Kappa) and a Ph.D. degree in Chemistry from the Penn. State Univ. (1989). He was an NSF Postdoctoral Fellow at the MIT prior to becoming a professor at Northwestern Univ. in 1991.
Project Name and Description: I am thrilled to enthusiastically nominate Professor Chad A. Mirkin for a Rotary Humanitarian STAR Award, which recognizes outstanding achievements in Science and Technology, in the Health and Medicine category. He is being nominated for his discovery of spherical nucleic acids (SNAs), new structures that have led to ground-breaking advances in biology and medicine that benefit humanity and that have changed the way we think about and use DNA and RNA. Mirkin’s discovery of spherical nucleic acids (SNAs) is among the most important of the last quarter-century, with ramifications and implications that will fuel subfields of biology and medicine for decades. His work has shown that SNAs are a new form of matter comprised of nucleic acids - the molecules that Nature uses to store life’s blueprints. However, there are no known natural equivalents of SNAs and these structures, on a sequence-for-sequence basis, interact with living systems in ways that conventional nucleic acids do not. Mirkin has beautifully elucidated the fundamental origins of their unusual and highly useful properties and exploited them in the development of techniques and technologies that are positively changing and enhancing health and medicine worldwide. Further, he has made significant contributions to global science policy, professional service, and education; he is exceedingly worthy of this prestigious honor.
Mirkin prepared the first spherical forms of nucleic acids, in 1996 [Nature 1996, 382, 607]. These spherical nucleic acids, or “SNAs”, consisted of densely functionalized and radially oriented DNA affixed to inorganic gold nanoparticle cores. Since then, Mirkin has designed and developed dozens of different types of SNAs owing to the modular nature of the SNA architecture, including those with protein, liposomal, and polymeric cores, and core-less, hollow structures composed entirely of nucleic acids cross-linked at one end and those with DNA, RNA, LNA, and PNA shells [e.g., J. Am. Chem. Soc. 2011, 133, 9254; J. Am. Chem. Soc. 2014, 136, 9866]. Through painstaking analytical studies, Mirkin has elegantly shown that many of the chemical and biological properties of SNAs that set them apart from even the linear nucleic acids of the same sequence, including their rapid cellular uptake and increased resistance to nuclease degradation [Science 2006, 312, 1027; Nano Lett. 2008, 9, 308; J. Am. Chem. Soc. 2009, 131, 2072], stem from the dense layer of oriented nucleic acids and are core-independent.
Mirkin’s understanding of the fundamental features of SNAs gave way to his use of them in living cells as gene regulation and immunomodulatory agents and as probes for RNA analysis, challenging long-held paradigms in chemistry, biology, and the life and biomedical sciences. Mirkin pushed beyond simple proof-of-concept demonstrations to develop probes that could outperform conventional molecular structures. Striking examples are Mirkin’s 2000 and 2003 reports in Science [Science 2000, 289, 1757; Science 2003, 301, 1884] of how SNA structures can be used as high-sensitivity probes for the detection of nucleic acids and proteins with sensitivities rivaling PCR and ELISA; these are tour de force and defined a new standard. This work moved from the benchtop to the clinic at a rapid pace, and today, there are millions of tests run every year based upon this technology (see below, the Verigene system). These SNA-based diagnostic probes are allowing scientists to study and track diseases in new ways. Mirkin and his medical collaborators have used them to “redefine undetectable” levels of prostate specific antigen in patients after radical prostatectomy. Three-hundred times more sensitive than commercial assays,
SNAs come in many forms and have transformed materials science and engineering and related fields and resulted in over 2,000 commercial products (and counting) that are positively impacting and, in certain cases, saving lives.
Mirkin’s assay allows doctors to accurately forecast cancer recurrence, and it guides radiation therapy by monitoring dose responses that ordinarily could not be tracked. It is not an overstatement to say that Mirkin’s contributions have impacted millions of lives and saved many.
Mirkin also has shown how SNAs are extraordinarily useful intracellular gene regulation agents (antisense and siRNA [Science 2006, 312, 1027; J. Am. Chem. Soc. 2009, 131, 2072]), and SNAs are therapeutic lead structures for a wide variety of oncology treatments (e.g., glioblastoma multiforme (brain cancer) [Science Trans. Med. 2013, 5, 209ra152] and skin cancer [Proc. Natl. Aca. Sci. 2012, 109, 11975]. Mirkin has demonstrated that these nanostructures, despite their high negative charge, are naturally taken up by cells without the need for polymeric co-carriers [Angew. Chem. Int. Ed. 2010, 49, 3280]. This fundamental chemical discovery introduced a paradigm shift for this therapeutic field. The lore prior to Mirkin’s discovery of SNAs was that nucleic acids (and many drugs based upon them) would not efficiently enter cells without positively charged (often-toxic) co-carriers. SNAs, unlike their linear counterparts, complex scavenger proteins (Class A) that facilitate endocytosis. Mirkin worked out the mechanism for SNA cellular uptake [Nano Lett. 2007, 7, 3818; Proc. Natl. Aca. Sci. 2013, 110, 7625] and has shown that SNAs do not trigger an unwanted cellular immune response and cellular toxicity [Mol. Pharma. 2009, 6, 1934; ACS Nano 2010, 4, 5641].
Most recently, Mirkin has shown that SNAs can serve as potent immunomodulatory agents as well (stimulation or repression depending upon choice of sequence) [Proc. Natl. Aca. Sci. 2015, 112, 3892]. Mirkin found that SNAs have a three-dimensional structure that can be tailored to uniquely engage biological structures within the innate and adaptive immune systems, leading to beneficial therapeutic effects. For example, he has shown that SNAs are 100 to 100,000 times more effective than linear nucleic acids at engaging toll-like receptors (TLRs), which control immunity in living systems and that SNAs enter cells via endosomes, where many TLRs reside. The oligonucleotides that comprise SNAs are pre-aligned to support high-affinity binding. Mirkin also discovered that SNAs composed of immunomodulatory oligonucleotides and antigens (i.e., SNA-based adjuvants) induced a significantly higher adaptive immune response than the analogous free oligonucleotides utilized in conjunction with other commonly used adjuvants, ultimately leading to reduced tumor growth rates and dramatically increased survival. Mirkin has explored systematically how changes to the SNA architecture, including conjugation chemistry, can mediate these effects [J. Am. Chem. Soc. 2018, 140, 1227]. He found that the way in which antigenic peptides are chemically linked to the DNA strands on SNA surfaces ultimately dictates the form of the antigen and SNA in the intracellular environment and identified that certain SNA formulations lead to an eight-fold improvement in T-cell proliferation. The ability to chemically formulate the SNA platform with a near-infinite number of immunomodulatory oligonucleotides or biological adjuvants in different arrangements points to the promise of SNAs as vaccines for cancers and other diseases. Mirkin has already developed a high-throughput assay that when coupled with machine learning allows one to map the immune activation characteristics of libraries of SNAs (approximately 1,000 SNAs tested to date).
Finally, Mirkin synthesized and developed diagnostic versions of SNAs called NanoFlares – structures designed to enter live cells, bind target mRNA sequences, and concomitantly release reporter strands which can be detected via fluorescence [J. Am. Chem. Soc. 2007, 129, 15477]. This includes the ability to track and isolate live circulating tumor cells (CTCs) [Proc. Natl. Aca. Sci. 2014, 111, 17104], screen drug libraries for specific genes that are up- or down-regulated within a living cell in response to a drug candidate molecule, and identify rare cells, including stem cells and cardiomyocytes. In addition, Mirkin was able to formulate the NanoFlare platform to create the Sticky-Flare, an extremely useful tool for the quantification and real-time tracking of RNA in live cells [Proc. Natl. Aca. Sci. 2015, 112, 9591]. The Sticky-flare is valuable for investigating proper RNA function and its misregulation in disease, and it is making such studies accessible to a broader community, given the ease of its application in cell culture. Further, the Sticky-flare is improving analyses in other model systems where asymmetric RNA expression is an essential component, such as embryonic development, tissue and organ regeneration, and neurobiology.
Humanitarian Benefit: Humanitarian Benefits through Research and Translation. SNAs have enabled the first commercialized molecular medical diagnostic systems of the modern nanotechnology era, allowing the detection of genetic and other biomarkers for many diseases with a sensitivity and selectivity far exceeding that of conventional diagnostic tools. One such example is the FDA-cleared Verigene™ System (https://www.luminexcorp.com/the-verigene-system/). This product was originally developed by Nanosphere, a company founded by Mirkin, and recently Nanosphere was acquired by Luminex. Now sold in over 20 countries and a mainstay in the world’s top hospitals, the SNA-based Verigene can be utilized to detect infectious diseases, antibiotic resistant bacteria, and certain forms of cancer and identify new genetic markers for Alzheimer’s disease, HIV, and cardiac disease. The Verigene’s assay for warfarin sensitivity was the first ever approved by the FDA in support of its critical initiative on personalized medicine. Blood clotting is often treated with the drug warfarin, but it is the number two cause of adverse drug reactions; thus, this SNA-enabled assay is saving numerous patients from debilitating strokes, and even death, every year. Further, the Verigene system is revolutionizing patient care by transitioning molecular diagnostic screening from centralized, often remote, analytical laboratories to the local hospital setting, dramatically decreasing the time required for diagnosis. These medical diagnostics also constitute an important class of research tools that enable fundamental discoveries and empower physicians to make quick and accurate decisions about patient care regarding many diseases with a genetic basis.
Also, in the diagnostic arena, NanoFlares have been commercialized by Merck Millipore (in partnership with AuraSense (a company founded by Mirkin) under the trade name SmartFlaresTM (http://www.emdmillipore.com/US/en/life-science-research/genomic-analysis/SmartFlare-Live-Cell-RNA-Detection/ZdGb.qB.KCcAAAFLAQs0i.s1,nav) and provide the only way to sort live cells based upon genetic content (as opposed to external protein markers)), and thus allow enormous opportunities for diagnosing disease and studying cellular genetics. Approximately 1,600 versions of SmartFlaresTM have been commercially available to researchers around the world, and these are opening up new research capabilities in chemistry, biology, and the life sciences.
On the pharmaceutical side, Mirkin’s SNAs and the technologies that he has developed based on them are allowing us to tap into the full potential of digital medicine (where a new drug can be made simply by formulating a new oligonucleotide sequence on the SNA surface) and move drug development beyond small molecules and biologics to nucleic acids. Of course, the realization of digital medicine relies on multiple factors, including: 1) the ability to make nucleic acids at scale, 2) the ability to get them into tissues and cells of interest, and 3) a thorough understanding of their intracellular pathways to prevent and treat disease. Until Mirkin’s SNA work, tissue and cellular delivery remained a significant issue, so although the other two points were well-worked out in certain cases, the scope of utility of nucleic acid-based medicines was actually quite limited. Drugs based on nucleic acids were utilized predominantly to treat diseases of the liver, the site of accumulation upon systemic delivery. Remarkably, Mirkin has shown how SNAs meet all three requirements, paving the way for their use for a wide range of therapeutic indications historically not addressable with conventional linear nucleic acids. Through his discoveries, he has moved nucleic acid medicines beyond the liver, enabling the rapid identification and synthesis of target molecules, and importantly, permitting low-cost, accelerated development that will rapidly bring precision medicines to patients.
Mirkin and the company he co-founded, Exicure, have raised over 42 million US$ in R&D capital from high-level investor/philanthropists, including Mr. Bill Gates, Mr. Eric Schmidt, and Mr. Pat Ryan and are shepherding different versions of SNAs through four new human clinical trials. SNA drugs are being delivered topically in creams to treat skin diseases, systemically to treat patients with glioblastoma multiforme (GBM, aggressive brain cancer) (because SNAs cross the blood-brain-barrier), and locally to engage the immune system in the form of monotherapies and combination therapies with checkpoint inhibitors (http://www.exicuretx.com/pipeline/overview.php). One of these, AST-008, potently
stimulates the immune system and holds great promise in cancer treatment and vaccine development. It is effective in a wide array of models of breast, colorectal, and bladder cancers as well as lymphoma and melanoma, either as monotherapy or with checkpoint inhibitors. Total tumor remission has been shown as well as the development of long-term immunity, and this drug is being tested in patients. In another key example, Northwestern has initiated the first systemic use of SNAs via intravenous injection for GBM. Patients have responded well to the drug (NU-0129), and they are seeing accumulation in tumors and complete ablation of the target gene (BCL2-L12, which is upregulated in gliomas and implicated in apoptosis resistance). In short, Mirkin’s efforts thus far prove that SNAs represent a revolutionary way to design and build personalized, precision medicines that will change the face of health care.
Humanitarian Benefits through Education and Public Understanding. Mirkin has educated over 260 graduate students and postdoctoral associates and thousands of undergraduate students. Over 100 of these students and postdoctoral fellows are now tenure-track faculty at leading research institutions around the world, including MIT, Harvard, Northwestern, the University of California Los Angeles, and Duke. He is an award-winning teacher, who has taught the largest NU freshmen chemistry class throughout his entire career. He has contributed to, and in several cases led, some of the most important policy reports involving undergraduate and graduate education. He has helped establish new educational tools through extensive outreach and publishing activities. These include: a lay-friendly animation on SNAs that was recently awarded the 2013 International Science and Engineering Visualization Challenge People’s Choice Award (hosted by Science and the National Science Foundation), a nanoscience exhibit at Chicago’s Museum of Science and Industry (MSI), a discovery-based learning module for high school students that is being disseminated via the Materials World Module Program, the DiscoverNano website that engages the general public and introduces them to nanotechnology and the importance of chemistry in the field, and the first undergraduate journal on nanoscience and nanotechnology, Nanoscape: A Journal of Undergraduate Research in Nanotechnology.
Humanitarian Benefits through Service and Policy. Mirkin just finished an eight-year term as a member of the President’s Council of Advisors on Science and Technology (PCAST, Obama Administration) and has been actively involved in national and service geared towards shaping science policy decisions in the US and around the globe. He co-chaired the PCAST report titled, “Engage to Excel,” focusing on teaching and engagement issues involving students, who are in their first two years of undergraduate study at R-1, -2 and -4-year institutions and community colleges. Mirkin also was a key member of the Faulkner-led report, “Advancing Graduate Education in the Chemical Sciences,” which identifies the major changes that must occur in order to ensure that graduate education serves the needs and aspirations of students and society as a whole, and contributed greatly to it. This report urges graduate programs to prepare PhD candidates for present and future marketplace opportunities, promote stronger communication skills across disciplinary and cultural lines, and engage more women and students from underrepresented populations to bring new talent and energy to the chemical enterprise. In addition, Mirkin served as the PCAST ex officio member of the Advanced Manufacturing Steering Committee. The report produced by the committee calls for sustaining the investments in advanced science and technology that produced America’s innovation economy and the establishment of a National Network of Manufacturing Innovation Institutes. Finally, Mirkin has represented the US by participating as a Delegate at the Asia-Pacific Economic Cooperation (APEC) 2011 Summit (Honolulu, HI), with 21 world leaders, including former President Barack Obama and former Secretary of State Hillary Rodham Clinton, and representatives from Fortune 500 companies. At APEC, he served on a panel with the President of Chile, Sebastian Piñera Echenique, focused on, “Game Changing Technology Redefining the Region.” Mirkin has served as an Associate Editor of Journal of the American Chemical Society since 2015.
Humanitarian Benefits through the Advancement of Science and Technology Around the World. Mirkin runs collaborations with researchers at dozens of universities and institutions worldwide to promote aspects of science and technology. He launched and is deeply involved in the operations of the Nanyang Technological University (NTU)-Northwestern University (NU) Institute for Nanomedicine in Singapore, the Institute of Chemical Biology and Nanomedicine in China (Hunan University), and the Northwestern Cancer Center of Nanotechnology Excellence (CCNE). As a result of his global cooperation in STEM, he has been recognized with rare accolades that indicate the global reach and impact of his work. For instance, he has been named a Foreign Member of the Chinese Academy of Sciences, an Honorary Professor at four Chinese universities, a Lee Kuan Yew Distinguished Visitor to Singapore, and an Honorary Member of the Materials Research Society of India; he also has received an Honorary Degree from the Universidade Federal do Rio Grande do Sul in Brazil, South America.
Mirkin’s passions include both advancing fundamental science and technology and promoting clinical innovation in health and medicine. One of his main goals is to assure that the nanomaterials and processes developed in his laboratory are employed for the betterment of society. This approach led to the advances elaborated above and make him an ideal candidate for the Rotary Humanitarian STAR Award in the Health and Medicine category.