Alanna Schepartz: Exploring biomolecules nature never created

Alanna Schepartz Alanna Schepartz photographed at Yale.

By Michael Barnes

Driving east out of Manhattan through Queens on the Long Island Expressway brings you to Alanna Schepartz’s old neighborhood. Just before the turn toward the JFK airport on the Grand Central Parkway, you pass Rego Park. A few blocks past the bright red Costco, between 98th and 99th streets on the right, you can spot the five gigantic co-op apartment towers of Park City Estates. That’s where Schepartz grew up, and where her mother still lives today.

But Rego Park did not hold Schepartz for long. Instead, it became the launching pad for her ascendant talent; a talent that would alternately rocket her far away and then bring her back home again. By age 16 she was studying at the State of New York’s premier public university, SUNY Albany, a three-hour drive to the north. Next came graduate school at Columbia University in Manhattan, just 10 miles away. A postdoc flung her across the country to Caltech in Pasadena followed by her first academic appointment at Yale University, only 75 miles from Rego Park.

Now, after 31 years at Yale, the College of Chemistry welcomes her to the Berkeley campus. Upon her arrival in July 2019, Schepartz assumed the T. Z. and Irmgard Chu Distinguished Professorship in Chemistry and is a professor of molecular and cell biology. She brings with her an outstanding portfolio of scientific accomplishments. Nevertheless, she is the first to acknowledge how much she benefitted from extraordinary mentors at every stage of her career.

Says Schepartz, “I started college at SUNY Albany when I was 16. It was not fun being two years younger than everyone else. But I was lucky – I ended up in a class taught by Shelton Bank and fell in love with organic chemistry. I worked in his lab for two full years and every summer. I learned a ton of lab skills for sure, but mostly I started to learn how to function as an independent scientist.”

Bank suggested Schepartz apply to Columbia, which at the time had the best organic chemistry program in the country. She was accepted into the chemistry Ph.D. program in 1982. There she joined the lab of Ronald Breslow, winner of the 1991 National Medal of Science among many other awards. “Breslow was another phenomenal mentor,” says Schepartz. “He was very supportive but also very hands-off. He forced his students to become creative thinkers.”

After completing her Ph.D. in 1987, Schepartz switched coasts moving to a postdoc in Pasadena with Caltech organic chemist Peter Dervan. His group was doing research to create small molecules that could bind DNA sequence-specifically in living cells. “Like Breslow, Dervan encouraged his students to think about big, hard, important problems.”

After a year at Caltech, Schepartz joined the faculty at Yale University in New Haven, CT, less than two hours from Rego Park. Schepartz states, “I had loved living in Pasadena, so my Mom was very surprised when I ended up so close to home. She thought I would never leave California.” Back on the East Coast, Schepartz settled in and got to work. Her early research interests included tethered oligonucleotide probes and bZIP proteins, obscure-sounding topics that led to important discoveries.

Says Schepartz, “As a postdoc in Peter Dervan’s lab at Caltech, I helped design molecules that could report on ribosomal RNA structure and interactions with antibiotics. This research provided a very early view of which ribosomal RNA regions were located on the surface of this very complex molecular machine.  At Yale, I continued to design tools that could report on complex RNA structure by identifying proximal loops and helices. Although that project ended many years ago, it’s kind of amusing that the lab has now come full circle to work on the ribosome again, in collaboration with several labs including Jamie Cate’s in MCB.” In those early days, her lab also studied a family of helical DNA-binding proteins known as bZIP proteins and developed a strategy for site-specific protein cleavage.

Schepartz’s became an associate professor in 1992 and was promoted to tenure in 1995. She was the first woman granted tenure in Yale’s Department of Chemistry and the first female full professor in the physical sciences at Yale.

In the new millennium, Schepartz started exploring a new family of peptidomimetics known as beta-peptides. Beta-peptides resemble the natural amino acids found in all proteins but differ by the addition of a single -CH2- group in the backbone. Beta-amino acids do not form proteins in nature but have many potential applications in studying and controlling biological processes, including inhibiting errant signaling that can lead to runaway cell growth in cancers.

Researchers in Schepartz’s lab set out on a multi-year journey to study the chemistry and biology of beta-peptides. As they assembled longer and longer beta-peptides, these longer polymers began to fold into complex three-dimensional shapes, sometimes mimicking the shapes taken by natural proteins, and sometimes creating unpredictable, but stable, shapes all their own. By the beginning of 2007, the Schepartz lab had reported on creating the Zwit-1F structure, what could be considered the first beta-protein (JACS 2007, 129, 1532-33).

Since 2007, Schepartz has continued to expand her research repertoire. Her group’s work on beta-peptides continues; work that is constrained by the painstaking chemical processes necessary for constructing beta-peptides. These processes cannot rival the speed and versatility of the ribosome, the macromolecular machine that is the cell’s protein foundry. Ribosomes rapidly create proteins by linking together amino acids according to the code provided by messenger RNA.

In nature, ribosomes produce only alpha-proteins. Along with several other collaborators, including the lab of Berkeley’s Jamie Cate, the Schepartz group is working to modify the ribosome to produce beta-proteins and ultimately many other biopolymers. If scaled up, ribosomal factories could produce many synthetic polymers: catalysts, biofuels, pharmaceuticals and other chemicals.

The Schepartz lab has also taken on developing potential treatments for cancer, based on a novel way to interfere with signaling cascades that lead to tumor formation. Epidermal growth factor (EGF) is a protein that stimulates cell growth and differentiation by binding to the epidermal growth factor receptor (EGRF). EGRF is a transmembrane protein that transmits chemical signals through the cell membrane, starting a signaling cascade that leads to cell proliferation.

EGRF is a member of a family of receptors that includes HER2, a receptor that is involved in aggressive forms of breast cancer. It is often successfully treated with Herceptin (trastuzumab), a monoclonal antibody drug. EGRF mutations are implicated in many cancers, including many adenocarcinomas of the lung and glioblastomas of the brain. The mutations involving EGFR lead to its constant activation, which produces uncontrolled cell division.

Say Schepartz, “My lab has created molecules that inhibit mutant EGFR receptors through allostery, which is like a remote-control switch for enzymes. If you can find just the right effector molecule, it can bind to a remote site on an enzyme molecule and turn the activity of the enzyme’s active site up or down. In this case, we have found allosteric regulator molecules that prevent the formation of critical downstream intermediate products, jamming the signaling cascade. The result, we hope, will be slow growth, or no growth, of cancer cells.”

Schepartz can look back with satisfaction at her scientific breakthroughs to date. But what often goes unheralded are the foundations of those breakthroughs: the efforts of the many students and postdocs, and the hours spent at step-by-step work at the bench. One of the most important products of a research group is the training and mentoring of the next generation of scientists. Says Schepartz, “The nicest thing that I heard about my mentoring is that I push people to accomplish more than they themselves thought possible. Mostly, I’m proud of how incredibly well my students have done. I’m very fortunate to have worked with such amazing people.”

Now that Schepartz is back on the West Coast, the inevitable question arises: does she miss New York City? “Do I miss New York? Who wouldn’t? I miss the Mets and the Metropolitan Opera, mostly. But Berkeley is a magical place in so many ways. I am incredibly excited to be here.” she adds with a smile.

With these two loyalties, Schepartz embraces several aspects of the scientific enterprise: The appreciation of beauty, skill, precision and passion that marks a fan of the Metropolitan Opera, joined with the enthusiasm, eternal optimism and the patience of a New York Mets baseball team fan. All good qualities for a Berkeley research scientist.