I went to graduate school more or less because I wanted to be Jean Chmielewski. So when she asked me recently if I could create cover art for a themed issue of The Journal of Peptide Science, of course, I immediately agreed.
She and her graduate student Michael Jorgensen were publishing a paper in that issue on reversible encapsulation of cells in a 3D matrix that mimics their native environment — the extracellular matrix. Taking cells out of their native environment leaves them a bit lost, but Chmielewski and Jorgensen had engineered a support system for them.
I was a year and a half into my chemistry major at Purdue, a pre-med by default since I had no clue what chemists actually did, when a classmate told me that undergraduate research experience would look good on my medical school application. I asked an assistant professor named Bruce Morimoto if I could join his lab, and despite the fact that I naively told him my motivation for it, he welcomed me anyway. I spent the holidays reading his papers and then got to work.
The support system that Chmielewski and Jorgensen devised uses a helical peptide that gently twists together with two of its identical twins to form trimeric coiled coils like very short lengths of rope. They equipped each peptide with multiple metal-binding arms. When metal is added to the solution, each metal ion can bind to two separate arms, forming bridges between neighboring peptide trios that enable them to self-assemble into larger and larger 3D structures. When cells are present, these structures assemble themselves around the cells like a molecular scaffolding.
In the Morimoto Lab I was delivered into the capable hands of a warm and knowledgeable graduate student who taught me how to clone a gene and sequence DNA, decoding it old-school style from spots on a sheet of photographic film the size of a Denny’s menu. She invited me to her home and cooked Indian food for me — the first and still the best I’ve ever had. But about 6 months in, Morimoto left academia for biotech.
At any moment, the peptidic 3D support system can be immediately disassembled simply by adding a metal chelator that sponges up the bridging metal ions, dispersing the trimeric peptidic coiled coils and leaving the cells to fend for themselves again.
I met Professor Chmielewski at a summer BBQ where in between volleyball games she asked me if I wanted to join her lab. When I overheard her husband, Professor Mark Lipton, declare that the volleyball he’d lobbed over the net was out of bounds by only angstroms, I knew I’d found my home in the 35,000-student university. Chmielewski showed me around her lab and cleared an available desk that had accumulated books, papers, and random lab equipment, musing aloud to herself, “Nature hates a vacuum.”
Adding metal back to the system causes coiled coils to immediately re-assemble around the momentarily floundering cells, once again mimicking the supportiveness of the extracellular matrix like a surrogate family.
I often can’t remember why I walked into a room, but the sequence of the first peptide I ever synthesized is inexplicably lodged in my brain. Its 1-letter amino acid code was HCKFWW. It was designed to prevent the two halves of HIV-1 Integrase from coming together to insert the virus’s genetic code into human host DNA. The grad student who trained me betrayed not a hint of annoyance when I repeatedly sought him out on his cigarette breaks to tell him an experiment I’d done hadn’t worked.
The nature of the 3D matrix formed by the cross-linked coiled coils makes it highly conducive to growth. The cells can expand in all directions, and the matrix harbors cavities that allow them room to grow.
I eventually became more independent and set up an assay for the lab to measure HIV-1 Integrase’s activity. After repeated failures, I finally got it to work. Seeing the result while alone in the darkroom with only the developer whirring its congratulations, you’d have thought I’d discovered penicillin. Later, without a whiff of patronizing, Chmielewski heartily joined me in celebrating this meager accomplishment.
With this kind of steady support for the cells, one could imagine the possibility of growing organoids—miniature organs that grow in 3 dimensions and resemble a real organ—for research purposes.
One grad student in the lab and his friend from the Fuchs lab down the hall invited me to join them for their weekly Taco Tuesday lunches at Taco Bell. They giggled on the way back to lab one Tuesday after we’d run into one of my roommates there, still wearing her clothes from the previous night out, make-up smeared, desperately seeking relief from her hangover in a 7-layer burrito. (Which is not to suggest that I was any stranger to a hangover myself.)
Another grad student in the lab, now an environmental health scientist at the CDC, presented me with an award for undergraduate research at a small ceremony, and then hours later, returned with me to the same spot to re-enact the scene for my other roommate (and best friend of almost 30 years now). My friend couldn’t make it to the ceremony earlier but insisted on getting a photograph. I would not have remembered that moment had my labmate and roommate not staged this reenactment. And I certainly wouldn’t have known how important it apparently was for me at the time, if not for the photographic evidence that I had actually put on a dress.
The real beauty of the 3D coiled-coil assembly is its reversibility. If one used it to grow an organoid, for example, the metal ions could be removed when the fledgling mini-organ was ready to carry out its intended function, and the scaffolding would fall away.
On the day of my graduation, the lab held a small celebration, including a tradition typically carried out by newly minted PhDs after the thesis defense—popping a champagne bottle and trying to break the record for distance traveled by the cork down the hallway outside the lab. A senior grad student in the lab gifted me a leather-bound composition book for taking seminar notes. On the inside back cover is a lovely inscription, at the end of which he quips, “I hope this small token of my gratitude will serve you well in your scientific journeys as a storehouse of knowledge and inspiration. Now get back to work.” It is now filled with seminar notes dating from 1999-2005 alongside drawings of speakers and assorted audience members. A grad student from another lab on the same floor who is now a scientist at Eli Lilly gave me a copy of All the King’s Men by Robert Penn Warren. On the inside cover, she congratulated me for going to MIT for grad school, and told me not to forget about all of them at Purdue. I didn’t.
I also didn’t become Jean Chmielewski. She is one of a kind. But when I think back to what seemed most appealing to me about her job, one single image comes to mind. It is of her sitting in her quiet office, illuminated only by natural light from the window. She is surrounded by stacks of journals and she’s reading one of them, sipping tea with her Teva-sandaled feet propped up on a nearby chair. (Clearly I was shielded from the administrative duties and endless cycle of grant proposal writing.) I realize now that what I really wanted all along was the opportunity to read about science and try to come up with creative ideas, as she did, and continues to do. So I guess I did get my wish, and now, every so often, I get to do that with my mentor.
Jorgensen, MD and Chmielewski, J, Reversible crosslinked assembly of a trimeric coiled-coil peptide into a three-dimensional matrix for cell encapsulation and release. J. J. Pept. Sci. 2022, 28(1)
