Susan Band Horwitz

Susan Band Horwitz is an American biochemist and professor at the Albert Einstein College of Medicine^[1][2] where she holds the Falkenstein chair in Cancer Research as well as Co-chair of the department of Molecular Pharmacology.

She played a major role in the development of understanding the complicated mechanisms for camptothecin, epipodophyllotoxins, and bleomycin. However, her biggest contribution to the world of science so far is the work of her team on discovering the unique mechanism by which Taxol functions to arrest the cell cycle in its metaphase state.^[1] This therapy is now on the market and used widely as a means to treat ovarian, breast, and lung cancer. Her team was credited with establishing the existence of a novel category of anti-tumor drugs, in which drug molecules bind to microtubules in order to inhibit the further division of cells.^[3] Her team continues to look for similar therapies in natural products.

Personal life and education

Susan Band Horwitz was born in Cambridge, Massachusetts in 1937.^[3] She spent her childhood in the Boston area and attended a Boston public high school.^[1] She went to Bryn Mawr College for her undergraduate studies and graduated with a degree in Biology in 1958.^[3] Subsequently, Susan moved on to obtain her PhD. in Biochemistry at Brandeis University. It was here that she studied the activity of enzymes and enzyme kinetics under Nathan O. Kaplan. More specifically, she focused on hexitol dehydrogenases from several bacteria, including Bacillus subtilis and Aerobacta aerogenes.^[3] Following the completion of her PhD program, her next venture was in the Pharmacology department as a postdoctoral fellow at Tufts University Medical School under Roy Kisliuk. Here, she looked at bacterial assays to explore anti folate qualities present in novel compounds.^[3] She began teaching pharmacology to the dental students at Tufts. In 1965, Susan and her family moved down to Georgia where she accepted a position in the pharmacology department at Emory University Medical School. In 1967, she migrated back north again, this time to New York where she took a job as a research assistant under Arthur Grollman at the Albert Einstein College of Medicine.^[3] She has worked for the Albert Einstein College of Medicine ever since. In 1970, she moved to a full time job as an assistant professor in the department of pharmacology. From 2002-2003,^[1][2] she was the president of the American Association of Cancer Research. She has a membership in several different organizations including, The National Academy of Sciences, the Institute of Medicine of the National Academies, the American Academy of Arts and Sciences and the American Philosophical Society.^[1][2] Throughout the course of Susan's career, she has been published over 250 times.^[4]

Taxol mechanism discovery

Susan had been working on several anti tumor drugs in her lab that inhibited the cell cycle by binding to DNA. The National Cancer Institute (NCI) contacted her one day in 1977, and inquired whether she would be interested in working on a drug for them, called Taxol. This was a drug that had been obtained from the yew plant Taxus brevifolia. At the time there was only one published article about the drug from 1971. Susan happily complied to the offer and received 10 milligrams of the drug from the NCI. She planned to examine the drug with her graduate student, Peter Schiff, for a month. After the month was up, they planned to decide whether or not the project displayed enough promise to continue. By the end of the month, they were heavily invested in the drug due to its outstanding uniqueness. They had discovered that the molecule acted by interacting with microtubulin. They ran assays with the molecule to determine what cell cycle phase was arrested by its mechanism of action. The stoppage of the cycle turned out to clearly occur during mitosis. With this realization, they quickly discovered that there was a binding site for the molecule located on the tubulin, which led them to their next discovery that the microtubules were frozen in place when the molecule was bound in this site. The cytoskeleton was essentially stuck in place, which served to inhibit any depolymerization. Their next step in the process was to identify where the binding site was and how the molecule managed to bind effectively. At this point, Susan was being assisted by another colleague, George Orr. They used photo-affinity analogues to test for the interaction between the molecule and the tubulin. Obtaining these analogues was an arduous task for the team. After some time, they were able to scrounge up the appropriate analogues and were able to successfully use them in their study. The use of a radiolabel allowed the team to visualize where exactly the interaction was occurring. WIth collaboration from various other laboratories including help from Eva Nogales and Ken Downing at the Lawrence Berkeley lab in California, a large amount of electron crystallography was performed. Following this extensive research, the binding site was officially located on the ß-tubulin sub-unit. This revolutionary discovery initiated the search for similar molecules. Even though Taxol® is now a very widely accepted treatment for cancer patients, it is a very hydrophobic molecule and cannot be dissolved in saline for administration to patients. Instead, it must be given to patients in a different solubilizing substance, called cremophor. This is not an ideal substance for bodily injection and because of this, new therapies involving the combination of Taxol with various parts of other molecules are becoming a bigger frontier for research.^[1] Susan is continuing this research with her co-worker, Hayley McDaid.^[3]

Further research

With the search for similar microtubulin binding molecules, scientists explored many natural products in the ocean, specifically sponges. It took around 15 years until another molecule with a similar mechanism was found. In more recent years, the molecules that have been discovered have differing structures from Taxol, however the mechanisms still remain to be similar. One in particular is called, discodermolide. Dr. Horwitz and her team were interested in not only the binding site for the molecule on the microtubule, but also the possible allosteric effects that the molecule may have on other parts of the microtubule. In order to test for these effects, the team used a hydrogen-deuterium exchange process. The results showed that there was in fact several changes that occurred along the microtubule separate from the binding site when the molecule was bound. They found that normal microbtubule-associated proteins, or MAPs, were not able to bind to the microtubules in the normal way. When discodermolide and Taxol® were both tested together, the results displayed that they do bind in the same location on the microtubules, however they bind in unique ways from each other. This opened a new door for the team as they decided to attempt making hybrid molecules that would put together the active parts of both of these molecules into one super molecule.^[1][3]

Awards and honors

Horwitz has received many awards for her work over the years. These awards and honors include:

• C. Chester Stock Award from Memorial Sloan Kettering Cancer Center^[2]
• Warren Alpert Foundation Prize from Harvard Medical School^[2]
• Bristol-Myers Squibb Award for Distinguished Achievement in Cancer Research^[2]
• American Cancer Society's Medal of Honor^[2][4]
• AACR Award for Lifetime Achievement in Cancer Research^[2]

References

1. 1 2 3 4 5 6 7 Horwitz, Susan; Goldman, David (January 2015). "A Conversation with Susan Band Horwitz". Annual Review of Pharmacology and Toxicology. 55: 1–9. doi:10.1146/annurev-pharmtox-010814-124519. Retrieved 24 March 2016. 
2. 1 2 3 4 5 6 7 8 "Susan Band Horwitz". www.warrenalpert.org. 
3. 1 2 3 4 5 6 7 8 Davis, Tinsley (June 26, 2006). "Profile of Susan Band Horwitz". PNAS. 103 (27): 10163–10165. doi:10.1073/pnas.0604639103. PMC 1502428. 
4. 1 2 Erwin, Becky; Greenwell, Claire. "The Honorable Edward M. Kennedy, Mina J. Bissell, Susan Band Horwitz, and Jon M. Huntsman to Receive American Cancer Society Highest Honor". American Cancer Society. Retrieved 24 March 2016.