An Adventure with Light and Reflections on Science

Working at the frontiers of biotechnology, fiberoptics, lasers technique, and molecular spectroscopy, Tuan Vo-Dinh of Duke University has developed multiple sensor technologies for medical research and diagnostics. His contributions include the first antibody-based fiberoptics fluoroimmunosensor (FIS), the first antibody-based nanoprobe for monitoring biochemical species in a single living human cell, the first paper on the analytical use of surface-enhanced Raman spectroscopy (SERS) for chemical analysis, the development of a laser-induced fluorescence (LIF) technique for non-invasive optical biopsy, and plasmonic nanoprobe assays for early cancer diagnostics. Throughout this work Vo-Dinh and his research colleagues have brought spectroscopy to biomedical applications. In this second recent interview, Vo-Dinh talks about his research work and philosophy. Vo-Dinh is the winner of the 2020 Royal Society of Chemistry (UK) Sir George Stokes Award and will give a plenary lecture at the 2021 SciX conference, which will be held September 26 to October 1 in Providence, Rhode Island. A symposium is organized at SciX to honor Dr. Vo-Dinh’s award. This interview is part of an ongoing series with the winners of awards that are presented at SciX.

What is a major scientific discovery you are you working on at this particular time and why is it important?

Currently, the research in my laboratory at Duke is focused on several exciting projects. Given recent and ongoing genomics discoveries in the molecular profiles of many diseases, I believe this is an ideal time to link new knowledge to new strategies for rapid screening and early diagnosis. Of special interest to us are microRNAs, small RNAs that do not code for proteins, which regulate gene expression and have demonstrated great promise as an important class of biomarkers for early detection of various illnesses. However, these small microRNA molecules have not been adopted into early diagnostics for clinical practice because of challenging analytical aspects in the lab-based technologies, such as microarray-based technology, Northern blotting, sequencing, and PCR analyses. We are actively developing a unique class of generally applicable biosensing technologies for microRNA biomarkers associated with various illnesses ranging from cancers and cardiovascular disorders to infectious illnesses and Alzheimer’s diseases. We hope our technologies will lead to the inclusion of entirely new types of bioanalysis and diagnostics that are cost-effective and easy to perform and will have transformative potential in early disease diagnostics and screening at the point of care and for global health applications.

In addition to environmental and human health protection, we are also interested in sustainability-related research topics such as renewable energy and biofuels. For instance, plant biologists would like to understand exactly which genes turn on inside a plant, and when, thus allowing them to fine-tune plant growth for more efficient biofuel production. Usually, they have to extract samples from the plant in the lab and chemically analyze the extracted miRNAs from the plant to figure out which genes are active in controlling the growth phase of a plant’s life. Using our biosensing techniques, plant biologists could rapidly monitor microRNAs in living plants, select plants with preferred growth patterns, and examine their genes to learn how to induce those growth patterns in order to increase biofuel crops.

Several activities are based on our unique plasmonic nanoparticles called gold “nanostars.” These star-shaped nanobodies made of gold have the advantage of geometry due their multiple sharp spikes, which work like lightning rods, concentrating the electromagnetic energy at their tips and allowing them to capture photon energy more efficiently when irradiated by laser light. Teaming with medical collaborators, we have introduced a new cancer treatment modality, called synergistic immuno photothermal nanotherapy (SYMPHONY), which combines immune-checkpoint inhibition and gold nanostar–mediated photothermal therapy that can unleash the immunotherapeutic efficacy, eradicate the primary tumors as well as distant “untreated” tumors, and induce a “cancer vaccine” effect leading to immunologic memory in murine model. Currently, we are performing fundamental studies to achieve better understanding and optimal exploitation of the mechanisms underlying this synergistic treatment modality. Identifying and understanding the specific immune cells and molecular processes involved in this synergistic interaction will pave the way for successful treatment of locally advanced and metastatic cancer.

From your perspective, how is your research approach different from the work of other scientists you are aware of?

I would hesitate to directly compare different research approaches of different scientists because this depends very much on a multitude of factors, such as the type of research (fundamental research or applied technology), emphasis of the university (liberal arts or engineering), the career path of the researcher (early, mid, or late career), the resources of the institution (large research universities or small colleges), and so on. Not to mention the personality of the investigator, which plays a significant role as well. Scientists should follow their own approach adapted to their personal situations in order to conduct research that is most appropriate to them, their environment, constraints, and possibilities. There is no general modus operandi rule. In my case, I try to provide cross-disciplinary training to my students because I believe it is essential for young researchers who want to pioneer new fields of science. I usually give high-level guidance to my students and postdocs, encourage them to develop initiatives, give them intellectual freedom, support them to take risks, and advise them to be patient.

In a previous interview with Spectroscopy (1), you made the statement that “no single discipline can solve big problems.” Would you expand on what is meant by this?

We are now living in the most exciting time in science that reflects an epochal convergence of several scientific and technological revolutions of the 20th century: the quantum theory revolution, the technology revolution, and the genomics revolution, all starting in the 1950s. The merging of these important revolutions is still progressing today and has led to an acceleration of knowledge accumulation that span multiple scales, multiple systems, and multiple disciplines. More recently, the so-called information revolution, which has emerged from the technology revolution, triggers an exponential growth of data; this will bring a wealth of knowledge in many different scientific fields that can be combined to produce a more comprehensive perspective and understanding of many processes and systems, creating new approaches for solving complex problems heretofore invisible to us. But this enormous amount of data of different kinds reflects the complexity of many problems to solve and should instill in all of us a sense of scientific humility that “no single discipline can solve big problems” but a combination of them will provide the ultimate solution to address challenges of global significance.

Many research fields have benefited directly or indirectly from each other’s development in ways that we cannot predict a priori. For instance, quantum theory of atomic phenomena provides a fundamental framework for molecular biology and genetics because of its unique understanding of electrons, atoms, and molecules. Out of this scientific framework emerged the discovery of DNA structure, the molecular nature of cell machinery, and the genetic cause of diseases, all of which form the basis of molecular and precision medicine. In essence, our current knowledge in molecular biology of how molecules bind together, how the building blocks of DNA cause a cell to grow, and how disease progresses on the molecular level evolves from a combined knowledge of many different disciplines and has a fundamental basis in quantum theory of molecules. Who would have predicted this interrelationship seventy years ago? Today when a patient enters a hospital for cancer screening or checks into an emergency room with chest pains or severe headaches, a diagnostic test using X-ray computed tomography (CT) or magnetic resonance imaging (MRI) will be performed for detecting a possible tumor, heart attack, or stroke. The underlying science behind the photon of CT (X-ray photons) and MRI (radio-frequency photons) are based on quantum theory. Who would have foreseen that the seemingly “far-fetched” fundamental research in quantum theory in the 20th century would be critical to the development of life-saving medical imaging technologies a century later?

You have also stated that “[The] transition from a knowledge base of individual elements to a systems level is one of the major paradigm shifts of the 21st century, which can be achieved only by integrating multiple disciplines and different domains of knowledge.” Please explain.

The term systems could have different definitions and meanings for different people, in different contexts and for different disciplines and applications. Simply defined, systems could be considered as entities with a certain level of complexity, for example a cell, disease, or population, that are composed of simpler elements, such as atoms, electron, and molecules, linked together. In high-energy physics, the simplest elements would be elementary particles, such as leptons and quarks. Decades ago, scientific knowledge was focused on investigating and understanding simple elements due to the limits of available investigative tools. Nowadays, the knowledge base of systems has increased rapidly due to the advancement of instrumentation and the combined knowledge of multiple scientific disciplines. The systems approach allows us to look at the entire system. To give you a perspective, one example: The discovery of the DNA helix of a gene, considered here as the single element, has led to discoveries about the gradual buildup of genetic changes in a cell, and subsequent understanding of many diseases at the systems level. Acquisition of knowledge at the systems level of illness is made possible by scientific and technological achievements in multiple disciplines, such as bioimaging (photonics, CT, MRI, PET), nanosensing, microelectronics, optogenetics, and computational genomics, all contributing to identify specific subsets of genes encoded within the human genome that can cause the development of a disease. It is the combined use of all these tools and integrated knowledge of different disciplines (chemistry, physics, molecular biology, bioengineering, medicine) that allows the systems properties to emerge, such as identification of the molecular alterations distinguishing a cancer cell from a normal cell at the earliest stage. This cross-disciplinary and systems approach will give us powerful capability for efficient and preemptive therapy.At another systems level involving data in large patient populations, artificial intelligence tools can combine all collected raw data from different types of measurements to identify meaningful connections that can lead to a myriad of medical applications, ranging from drug synthesis, vaccine development, treatment strategies, and patient care and global health.

You have expressed some opinion about the interconnectivity between science and the humanities, such as art and philosophy. Could you explain more?

The interconnectivity between art and science is occasionally depicted in anecdotes of Leonardo da Vinci as a scientist and engineer, Albert Einstein as a violinist, or Erwin Schrodinger as a philosopher. If we take a closer look, the interconnection between art and science could be more deeply rooted. For instance, it is noteworthy that the quest for understanding light and color perception is not limited to spectroscopy and neuroscience but is also pervasive in many fields of the humanities beyond the realm of biophysics and molecular biology. In the early 19th century, the poet Johann Wolfgang von Goethe disclosed his thoughts on color perception in his work Theory of Colours and the philosopher Arthur Schopenhauer discussed the phenomenon of visual perception in the treatise On Vision and Colors. A century later, the philosopher Ludwig Wittgenstein presented his views in a collection of notes Remarks on Colour delineating the differences between the scientific basis of Newton’s optics and Goethe’s phenomenology of color.

The philosophy behind scientific thoughts and actions has been a topic of debate throughout the history of science. Whereas Rene Descartes advocated rationalism based on pure thought and reason, David Hume formulated a philosophy of empiricism, which regards empirical observation by the senses as the only reliable source of knowledge. Later on, Immanuel Kant erected a bridge between pure thought and sensory perception and reconciled the philosophical divide between rationalists and empiricists (the so-called “Battle of Descartes versus Hume”).

The connection between scientific and philosophical thought is often not well recognized but sometimes it could be closer than we may have realized, especially in quantum physics. The rules of quantum physics, which govern the subatomic world of “strange” probability clouds and blurry particles sometimes require a certain degree of “philosophical” contemplation and belief. In fact, scientists acknowledged that a complete understanding of physical reality lies beyond the capabilities of rational thought, a declaration known as the 1927 Copenhagen Interpretation of Quantum Mechanics. The quantum worldview implies that the structure of matter is often not mechanical or visible, and that the reality of the world cannot be explained by the physical perceptions of the human senses. Coming into full circle, this fundamental scientific concept of the 21st century rejoined some idea of Plato’s philosophy in 400 B.C., which referred to the concrete objects of the visible world as imperfect copies of the forms which they partake of. Until today, similarities between quantum physics and many metaphysical concepts in Eastern philosophies and Western religions have been a topic of great interest.

It is possible that the discovery of quantum physics affected some other fields beyond science, such as art. It is noteworthy that modern art, with its seemingly strange distortions of visual reality, also appeared in the 1930s during the emerging period of quantum physics. It might not be a coincidence that during the quantum revolution in science, Cubist and Surrealist art abolished realistic shapes referenced in fixed space and fixed time. The interdependence of science, technology, and art was well expressed in the 1950s by the Abstract Expressionist artist Jackson Pollock in the review Possibilities: “It seems to me that modern painting cannot express our area (the airplane, the atomic bomb, the radio) through forms inherited from the Renaissance and from any other culture of the past. Each area finds its own technique.”

In another statement you have said, “It is important for us to educate our students, the next generation of innovators and leaders, not only to solve scientific and technical problems but also to understand societal connections between various human activities, and create bridges between elements spanning multiple disciplines in order to ultimately build a better interconnected world.” Would you give some examples?

We are witnessing the advent of a new epoch of globalization. The forces of globalization are affecting every facet of our existence, from commerce, to transportation, research, and education. With this globalization, we will see a lot of changes. We will need to rethink how the structure of education and translation of research will be implemented in the service of society in the global context. For example, the interconnections between the innovation source in the academic labs to the outside chain of global outsourcing will need to be redistributed. The implementation and commercialization of technology will need to be reformulated in the global system and, ultimately, the education system will need to be reconceptualized in a global framework.

In this era of globalization, the Internet is empowering more and more individuals from different countries having different cultures from all corners of the globe to reach faster and farther than ever before. In this interconnected world, the future is now: A scientific idea conceptualized in a university in Palo Alto, could then be developed in a sister lab in Dublin, optimized by a collaborator in Mumbai, outsourced for fabrication in a partner plant in Singapore, and field tested in Nairobi. All these development and translational processes can now be vertically integrated and horizontally implemented through a hyper structure of universities, labs, companies, and individuals interconnected through the global cyberspace. Such a model would be unthinkable just a decade ago.

The forces of globalization will create new opportunities, but will also impose new rules and will require us to take important choices: choices on future directions of our research, choices on new rules for competition and collaboration, choices on new structures of our very fundamental educational system; especially, this will require us to acquire a new global consciousness and a deep understanding of societal connections between various human activities and cultures among different nations throughout the planet. This could raise interesting social and economic issues and challenges in a global context. It is important to articulate a vision of global interconnections based on multicultural respect, social fairness, and harmony. We can design new education systems to train, educate, and mold future generations of students and provide them the tools to change the world. Most importantly, we will instill in them the ideals to build a better world. I believe that we are at the crossroads of a paradigm-shifting epoch that could foreshadow the dawn of a new era in human connection and evolution. This is now our choice, a choice at a critical time, a choice with a far-reaching impact. And this choice will be our destiny.

What is the favorite part of your workday and why?

This could be any time of the day. It could be a brief half-hour moment or a longer period of several hours; it could happen anytime, in the morning, at lunch break, or late at night. This is the time when I am able to steal a precious moment from my busy schedule to have some mental peace, a time when I can totally devote my intellectual energy to contemplate the long-term needs of research, solve a pressing scientific problem, design a new method, or dream up an “out-of-the box” idea for a new research concept. These are very cherished moments in my workday as a scientist.

What are your plans for future research? What is one major scientific problem or challenge that you would like to understand or solve?

I believe that there is not one major scientific problem or challenge but that we all, as humans, are faced with a myriad of challenges. As it is often said, challenges also bring opportunities. I would say there are several areas for advancement. We are going to develop a series of cost-effective biosensing tools that can rapidly acquire large amounts of data in a simple and cost-effective way. For instance, there is now a need to collect information on genomics biomarkers from large populations around the globe in a rapid and inexpensive way, and put it in a computer server that would analyze and identify infectious disease hot spots. However, most DNA analyses are still performed using lab-based technologies, such as PCR, microarray-based technology, or Northern blotting. We will combine the latest advances innanotechnology, microdetectors, and miniature lasers to develop next-generation "sample-to-answer” diagnostics devices that are miniaturized, practical, inexpensive and capable to detect specific genomic biomarkers without lab-based assays for point-of-care, point-of-need, and global health applications. Such easy-to-use devices could help detect disease in population of underserved regions, or uncover early emergence of new pandemics in remote areas before they become global health threats.

With the tools of nanotechnology and molecular biology, we are interested in developing truly implantable devices such as “smart tattoos,” as tiny as the tip of a pen, that can directly monitor biomarkers in real time to forecast and prevent disease in a person before there are any clear outward signs of it. Another area of interest would involve collaboration with colleagues in other disciplines to combine our technologies with their systems in order to enable robots, optical sensors, and computers to receive natural emotional feedback and improve human experiences. These tools could help people communicate and express emotional information, and to better manage and understand the ways emotion impacts health, social interaction, learning, and memory. This is a fascinating area of science with many still-unanswered questions that could be transformed with a cross-disciplinary and systems approach.

In essence, the general focus of my research activities continues to be directed toward areas related to the development of advanced technologies for early detection and treatment of disease, protection of the environment, and enabling sustainability of our planet. Throughout my career, I have been fortunate to work with many dedicated collaborators, postdoctoral fellows, and students in our common quest of these exciting goals. I am always looking to learn new areas of research and open to apply my expertise to address the new challenges ahead.

References

(1) Jerome Workman Jr., “Spectroscopy for Medicine—From SERS, Laser-Induced Fluorescence, and Biosensors to Analytical Nanotools,” Spectroscopy, May 5, 2020. https://www.spectroscopyonline.com/view/spectroscopy-medicine-sers-laser-induced-fluorescence-and-biosensors-analytical-nanotools

Tuan Vo-Dinh is the R. Eugene and Susie E. Goodson Distinguished Professor of Biomedical Engineering, a Professor of Chemistry, and the Director of the Fitzpatrick Institute for Photonics, at Duke University. He has authored over 500 publications, is a Fellow of the U.S. National Academy of Inventors, and holds over 58 patents. ●