Dr. Carolyn Bertozzi pioneers bioorthogonal chemistry to study molecules within living systems

Dr. Carolyn Bertozzi. From the National Inventors Hall of Fame website.

The scientific discipline of chemical biology merges the fields of chemistry, biology and physics to serve in the study and manipulation of biological systems. Along with biochemistry, which is the study of chemical processes within and relating to living organisms, these two fields of science are very important in gaining a greater understanding of biological processes, especially those related to disease progression which can lead to the development of novel drugs or medications to treat disease.

However, most fields of chemical science designed to look at biological process involving living molecules suffer from a rather serious drawback— studying those molecules within a living body without interfering with any other processes. Over the past two decades, however, an entirely new scientific field has opened up which enables the study of chemical reactions occurring within living systems with no interference to any biochemical processes native to that living system. Bioorthogonal chemistry was pioneered by Dr. Carolyn Bertozzi, a 2017 inductee into the National Inventors Hall of Fame. This Thursday, October 5th, is the seventh anniversary of the date of issue of the patent for which Bertozzi has been inducted. As we often do, we’ll return to our Evolution of Tech series to see how this particular innovation was developed and how it helped to unlock a completely new field of scientific research.

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Carolyn Bertozzi’s Work in Immunology Earns Her a MacArthur Award at Age 33

Carolyn Bertozzi was born in October 1966 in Boston, MA. As a video profile of Bertozzi produced by the National Inventors Hall of Fame notes, Bertozzi’s father was a physics professor at the Massachusetts Institute of Technology with a great deal of mechanical expertise. Bertozzi spoke about how her father would fix home appliances himself, sometimes enlisting help from her or her siblings to do so. “I do remember some days spent under a lawnmower,” Bertozzi said.

Bertozzi would go on to graduate summa cum laude from Harvard University with a bachelor’s in chemistry; while at Harvard, she actually played in a band with Tom Morello, a guitarist who would go on to become a founding member of rock groups Rage Against The Machine and Audioslave. In 1993, Bertozzi finished her Ph.D studies in chemistry at the University of California, Berkeley, where she focused on the chemical synthesis of analogs to oligosaccharide, a polymer containing simple sugars which are important in cell recognition and cell binding and are used in immune system processes.

Bertozzi’s postdoctoral work started in the field of immunology, the branch of biology focused on immune systems in living organisms. Specifically, she focused on cell adhesion in immune cell trafficking which is mediated by glycans, which are compounds consisting of a large number of linked monosaccharides. Bertozzi’s research helped to contribute to the body of knowledge surrounding the activity of oligosaccharides which promote cell adhesion at sites of inflammation. During this time, she was also gaining a great deal of knowledge about cellular surfaces; this knowledge would be key to how she was able to unlock the world of bioorthogonal chemistry. For example, Bertozzi found a way to modify the cellular structure of living cells and tissues so that they more easily accept medical implants. In 1999, at the age of 33, she became one of the youngest people ever to receive a MacArthur Award for her contributions to increasing the body of knowledge regarding cellular interactions.

Bertozzi Develops Bioorthogonal Chemistry to Study Molecules in Living Systems

Many chemists work throughout their careers to discover new kinds of chemical reactions. Bioorthogonal chemistry, however, is not so much concerned with the discovery of new reactions as much as it is designed to encourage known chemical reactions within a living system. Such work carries with it the difficulty of ensuring very specific chemical reactivity in complex, often aqueous, environments without disturbing any other biological process surrounding the reaction. As Bertozzi wrote in a 2011 article published by Accounts of Chemical Research:

“[Bioorthogonal chemistry] was launched alongside the growing realization that the molecular details of biological processes can be most accurately understood by probing biomolecules within their native habitats, that is, in cells, or even better, live organisms. To interrogate biomolecules in such complex settings requires the means to selectively modify them with imaging probes, affinity reagents, or moieties that perturb function.”

Monoclonal antibodies and genetic fluorescent protein fusions used in previous decades went a long way in identifying the roles of specific proteins in dynamic cellular processes, Bertozzi noted, but the large size of some molecules introduced the risk that they would perturb many other cells which were not the target of research. Bertozzi began working with glycans instead of proteins as glycans are involved with immune system activities, although she had to overcome an issue in how glycans are programmed. Unlike proteins, glycans are not genetically programmed and thus cannot be labelled with the use of conventional genetic-based fluorescence techniques. The glycan-labelling techniques developed by Bertozzi were based on scientific discoveries nearly a century earlier by German organic chemist Hermann Staudinger who developed a type of chemical reaction between an azide (N3) and a phosphine (PH3). Bertozzi and colleagues adjusted the phosphine component of this reaction to create a type of reaction which can occur in water, is highly reactive but doesn’t react to other biological molecules because of the absence of both azides and phosphines from living systems. This new type of reaction helped Bertozzi and colleagues create smart probes which created a fluorescent marker only when the fluorophore reacted with an azide reporter in a target glycan.

The patent for which Bertozzi is being inducted into the National Inventors Hall of Fame is U.S. Patent No. 7807619, titled Compositions and Methods for Modification of Biomolecules and issued on October 5th, 2010. It claims a compound providing modified cycloalkyne compounds and the methods of using such compounds in modifying biomolecules in reactions that can be carried out under physiological conditions. Both the reaction and its compatibility with aqueous environments allow for both in vivo and in vitro application, addressing a need for additional mechanisms to modify biological molecules through a biocompatible reaction in a biological environment.

In 2008, Bertozzi and colleagues formed Redwood Biosciences as an entity to commercialize the site-specific protein modification technology which they named SMARTag. In October 2014, Redwood Biosciences was acquired by Somerset, NJ-based drug delivery firm Catalent after Catalent had acquired an exclusive license to SMARTag tech in April 2013.

As for Bertozzi, she continues her work at Stanford University in developing nanoparticles for both drug delivery and minimally-invasive cell study. The ‘619 patent is one of 50 U.S. patents which lists Bertozzi as an inventor. Along with the 1999 MacArthur Fellowship, she has received a great deal of career awards and recognitions including the Alfred P. Sloan Research Fellowship, the 2010 Lemelson-MIT Prize and the 2017 Arthur C. Cope Award. A member of the National Academy of Sciences since 2005, Bertozzi received the 2016 Award in Chemical Sciences from that organization.