Office: MoSE G026

Phone: (404) 894-2761

Email: cicerone@gatech.edu

Marcus T Cicerone received his Ph.D. from the University of Wisconsin – Madison in 1994, under the direction of Mark Ediger. He spent three years at Johnson & Johnson Clinical Diagnostics, served as a visiting teaching professor at Brigham Young University for two years, and subsequently joined the National Institute of Standards and Technology in 2001, where he remained for 18 years, serving as a group leader and project leader. In January 2019 he joined the Georgia Institute of Technology as a Professor of Chemistry.

Professor Cicerone is a fellow of American Physical Society, and has received several awards for his efforts in coherent Raman-based biological imaging and for his work in dynamics of liquids and amorphous solids. These include a Johnson & Johnson Director’s Research Award, two Department of Commerce Bronze metals, the 2015 Washington Academy of Sciences Physical & Biological Sciences Award, and the 2017 Arthur S. Flemming Award.

Research Interests

Professor Cicerone works on development and application of spectroscopic coherent Raman imaging approaches and on dynamics of amorphous condensed matter. In the coherent Raman imaging work, his group introduced broadband (spectroscopic) coherent anti-Stokes Raman scattering (BCARS) microscopy in 2004. Since then he and his group have remained at the forefront of this field, introducing improvements such as a time-domain Kramers-Kronig transform to deal with non-causal signals for retrieving the pure Raman spectrum directly from the raw BCARS signal. The results of that work and other instrument design innovations utilizing impulsive vibrational coherence generation resulted in recognition as one of the top 10 innovations in BioPhotonics for 2014. His group has logged many imaging firsts, including the first to obtain quantitative vibrational fingerprint spectra from mammalian cells using coherent Raman imaging, and the first to identify specific structural proteins from coherent Raman imaging.

His work on dynamics of amorphous condensed matter focuses on the impact of picosecond timescale spatial and temporal heterogeneity in dynamics on transport and relaxation in liquids and glasses. In 2004, he used neutron scattering to show for the first time that chemical and physical stability of proteins encapsulated in glassy sugars could be predicted by the profile of ps-timescale dynamics. Since then, he has developed a framework for calculating transport and relaxation properties of liquids and glasses over 12 orders of magnitude in time, based solely on ps-timescale dynamics, and identified the molecular origin of a relaxation process (Johari-Goldstein process) that had been observed but remained enigmatic for 50 years. He has also developed benchtop approaches accessible to pharmaceutical labs for measuring the relevant dynamics, and developed a protein stability approach for drug delivery that encapsulates proteins in nanometer-sized droplets of vitrified sugar-based glass and makes them impervious to traditional processing steps, allowing retention of ~99% of protein function or titer after all processing steps. This approach has now been used successfully in large animal trials, and has also been shown to be effective for transdermal drug delivery due to the nanometer size of the encapsulation materials.

Broadband spectroscopic coherent Raman imaging

Broadband coherent anti-Stokes Raman scattering (BCARS) is a spectroscopic coherent Raman imaging method that my team and I introduced in 2004 and have been continuing to develop since then. We have produced many pioneering milestones that have laid the foundation for accomplishing our vision of a rapid, label-free spectroscopic imaging method that is easy to use and to extract information from. In addition to introducing BCARS, we have introduced many improvements in hardware and software, including engineered continuum laser pulses, a mathematical approach based on a time-domain Kramers-Kronig transform for retrieving the pure Raman spectrum directly from the raw BCARS signal, and a significantly improved utilization of impulsive vibrational coherence generation. The work resulting from the combination of these was recognized as one of the top 10 innovations in BioPhotonics for 2004. We have had many imaging firsts, including the first to obtain quantitative vibrational fingerprint spectra from mammalian cells using coherent Raman imaging, and the first to identify specific structural proteins from coherent Raman imaging.

Camp Jr, C. H., and Cicerone, M.T. Chemically sensitive bioimaging with coherent Raman scattering. Nature Photonics 9, (2015).

Gohad, N. V., Aldred, N., Hartshorn, C. M., Lee, Y. J., et al. Synergistic roles for lipids and proteins in the permanent adhesive of barnacle larvae. Nature communications 5,  (2014).

Camp Jr, C. H., Lee, Y. J., Heddleston, J. M., Hartshorn, C. M., et al. High-speed coherent Raman fingerprint imaging of biological tissues. Nature Photonics 8, 627-634 (2014).

Parekh, S. H., Lee, Y. J., Aamer, K. A. & Cicerone, M. T. Label-free cellular imaging by broadband coherent anti-Stokes Raman scattering microscopy. Biophysical journal 99, 2695-2704 (2010).

Kee, T. W. & Cicerone, M. T. Simple approach to one-laser, broadband coherent anti-Stokes Raman scattering microscopy. Optics letters 29, 2701-2703 (2004).

Basic transport phenomena in liquids and picosecond timescale dynamic heterogeneity

Most theories that describe liquid motion and transport above the melting temperature assume spatial and temporal homogeneity. Even leading theories of supercooled liquids (liquids below their melting point), such as mode coupling theory, take a homogeneous medium as their starting point. Consequently, experimental data from liquid systems has virtually always been analyzed with homogeneous models in mind. We have shown experimentally and by molecular dynamics simulation that, for timescales shorter than 100s of picoseconds, liquids cannot be considered truly homogeneous, and at timescales of less than 1 picosecond, there are stark differences between dynamic states of molecules in pure liquids, even well above the melting temperature. These findings have allowed us to derive an expression for molecular transport in liquids and amorphous solids based on easily measured or simulated picosecond dynamic quantities. These insights will allow materials scientists to more reliably design and calculate the properties of novel materials, including applications such as drug eluting stents, ionic liquids for battery applications, and optimized formulations for stabilizing freeze-dried vaccines and therapeutic proteins.

Cicerone, M. T. & Tyagi, M. Metabasin transitions are Johari-Goldstein relaxation events. The Journal of Chemical Physics 146, (2017).

Cicerone, M. T., Averett, D. & de Pablo, J. J. The role of hopping on transport above Tc in glycerol. Journal of Non-Crystalline Solids 407, 118-125 (2015).

Cicerone, M. T., Zhong, Q. & Tyagi, M. Picosecond Dynamic Heterogeneity, Hopping, and Johari-Goldstein Relaxation in Glass-Forming Liquids. Physical Review Letters 113, 117801-117801 (2014).

Fluorescence-based method for evaluating likely success of solid formulations to stabilize proteins and vaccines

As described below, my team and I introduced a robust relationship between stability of proteins in a freeze-dried state, and picosecond timescale dynamics of the freeze-dried excipient materials that encapsulate proteins. Although the relationship has been found to be very robust, and potentially useful to pharmaceutical formulation scientists, here was no way to characterize the picosecond dynamics of the freeze-dried materials other than through neutron backscattering – the way we discovered it. Neutron scattering is not suitable as a high-throughput method for evaluating candidate formulations. With this in mind, we demonstrated that a signal containing equivalent information to that from neutron backscattering could be obtained from analyzing light emitted from fluorescent molecules dissolved in the freeze-dried matrix. We have shown that this approach is predictive, and it is beginning to be used by pharmaceutical scientists. For this contribution we were awarded the 2014 American Association of Pharmaceutical Scientists Innovation in Biotech award.

Qian, K.K., Grobelny, P.J., Tyagi, M., Cicerone, M.T. Using the Fluorescence Red Edge Effect to Assess the Long-Term Stability of Lyophilized Protein Formulations, Mol. Pharmaceutics, 12 1141–1149 (2015)

Cicerone, M. T., Zhong, Q., Johnson, J., Aamer, K. A. & Tyagi, M. Surrogate for Debye–Waller factors from dynamic stokes shifts. The journal of physical chemistry letters 2, 1464-1468 (2011)

Nanoencapsulation approach to stabilize proteins for drug delivery applications

Drug delivery approaches have tremendous potential to deliver potent drugs primarily or exclusively to sites of interest, protecting the drugs from the effects of the body or vice versa, until they have reached their target, or providing a depot for long-time elution of drugs. A significant problem with drug delivery approaches involving therapeutic proteins or peptides has been that most (frequently > 99%) of the protein payload looses its activity when encapsulated by traditional methods. My team and I invented and demonstrated a way to encapsulate proteins in nanometer-sized droplets of vitrified sugar-based glass that makes them impervious to traditional processing steps, allowing us to retain more than 99% of protein function or titer in many cases. This approach has now been used successfully in large animal trials, and has also been shown to be effective for transdermal drug delivery due to the nanometer size of the encapsulation materials.

Giri, J., Li, W., Tuan, R. S. & Cicerone, M. T. Stabilization of Proteins by Nanoencapsulation in Sugar–Glass for Tissue Engineering and Drug Delivery Applications. Advanced Materials 23, 4861-4867 (2011).

Protein degradation in freeze-dried solids is gated by picosecond dynamics

For decades, pharmaceutical scientists have been freeze-drying proteins and vaccines to stabilize them for storage and application, although the mechanisms of stabilization have not been understood. As a consequence of the poor understanding of stabilization mechanisms, there has been no reliable systematic approach to successfully formulating the stabilizing matrix. Largely due to this, approximately 30% of pharmaceutical drugs fail in manufacturing. Further, the lack of clear understanding leads to long and risky formulation cycles. My team and I have demonstrated that none of the metrics traditionally used to predict efficacy of a stabilizing formulation is based in causality, and thus each of them have only small regions of utility. We also showed that picosecond dynamic processes can be used with high confidence to predict stabilizing efficacy. This work has led to collaborations with most of the major pharmaceutical companies, and adoption of our ideas in their formulation processes.

Devineni, D., Gonschorek, C., Cicerone, M. T., Xu, Y., et al. Storage stability of keratinocyte growth factor-2 in lyophilized formulations: Effects of formulation physical properties and protein fraction at the solid–air interface. European Journal of Pharmaceutics and Biopharmaceutics 88, 332-341 (2014)

Xu, Y., Carpenter, J. F., Cicerone, M. T. & Randolph, T. W. Contributions of local mobility and degree of retention of native secondary structure to the stability of recombinant human growth hormone (rhGH) in glassy lyophilized formulations. Soft Matter 9, 7855-7865 (2013)

Cicerone, M. T. & Douglas, J. F. β-Relaxation governs protein stability in sugar-glass matrices. Soft Matter 8, 2983-2991 (2012)

Cicerone, M. T. & Soles, C. L. Fast dynamics and stabilization of proteins: binary glasses of trehalose and glycerol. Biophysical journal 86, 3836-3845 (2004)

Dynamics in supercooled liquids and glasses is spatially and temporally heterogeneous

Glasses and supercooled liquids have been topics of keen scientific interest for centuries. Their transport and relaxation properties dictate the performance of many structural, storage, and separation materials. P.W. Anderson, a Nobel Laureate physicist declared that the mystery of glassy dynamics was the “most important unsolved problem” in condensed matter studies. The entirety of the problem remains unsolved, as even now, there are more theories for glassy motion than there are theorists. However, as a graduate student, I was able to convince my thesis advisor to allow me to do a series of experiments that led to a clear demonstration that dynamics in these materials is dynamically and spatially heterogeneous on timescales of many (sometimes millions of) seconds. Whether dynamics were homogeneous or heterogeneous had been a point of contention for decades, and the work I did demonstrated clearly that it was the latter case.  As a result of that work, the term “dynamic heterogeneity” describing glasses and supercooled liquids was popularized, and the verity of the heterogeneous scenario was solidified for this field.

Cicerone, M. T. & Ediger, M. D. Enhanced translation of probe molecules in supercooled o‐terphenyl: Signature of spatially heterogeneous dynamics? The Journal of chemical physics 104, 7210-7218 (1996)

Cicerone, M. T. & Ediger, M. D. Relaxation of spatially heterogeneous dynamic domains in supercooled ortho‐terphenyl. The Journal of chemical physics 103, 5684-5692 (1995)

Cicerone, M. T., Blackburn, F. R. & Ediger, M. D. Anomalous diffusion of probe molecules in polystyrene: evidence for spatially heterogeneous segmental dynamics. Macromolecules 28, 8224-8232 (1995)

Cicerone, M. T., Blackburn, F. R. & Ediger, M. D. How do molecules move near Tg? Molecular rotation of six probes in o‐terphenyl across 14 decades in time. The Journal of chemical physics 102, 471-479 (1995)