Big Picture Thinking

Thursday, September 14, 2017

If you peer closely at a drop of pond water with a microscope, what do you think you’ll see? If your answer is an amorphous amoeba, or perhaps a furry paramecium, you’re correct.

But if you’re lucky and patient, in time the shadow of a much, much larger creature will slide into view. It’s so large that you might need to put the scope aside and look with your eye.

It is Stentor, a trumpet-shaped gentle giant and the baleen whale of this tiny world, waiting peacefully for tiny bits of food to come along.

If you’re in a foul mood and particularly deft, and you cut it in half, you’ll be amazed to see that it won’t die, but will regenerate. Now there are two!

How does this creature persevere in the face of such a blow? Is it merely size, or other intrinsic, gritty qualities? What can this ability teach us about the inner workings of all living cells, everywhere?

These are the questions that have always captured the imagination of UCSF professor Wallace Marshall. From a very young age, Marshall had the makings of a scientist.

“In third grade my teacher, Miss Kittles, used to call me Professor,” he said.

By sixth grade his twin interests were biology and computers, two fields that at this time were not yet seen as complementary.

For Christmas that year, his parents gifted him a fetal pig dissection kit. Marshall also recalls soldering electronic bits side-by-side with his father in the basement laboratory.

His ambition and curiosity soon drove him higher, beyond the home, to his school’s computer club. But there was a problem.

“I was told that I could not join the computer club because I was in sixth grade, I was too young. And I remember going completely berserk when I went home... and vowing that I was going to show them! I was going to build my own computer!”

This early setback solidified a lifelong ambition: to understand the building blocks of biology, cells, in the same way that engineers understand the computers that they design and build. He planned to achieve this through the careful study and construction of both biological and electronic systems.

After devouring Experiments with Microscopic Animals cover-to-cover, Marshall became wise to Stentor’s resilience, its ability to regenerate, and the potential for experimentation.

With a big, regenerating cell like Stentor, parts could be systematically and easily cut away, and he could observe how the cell recovered. In this way, he could determine if certain parts were required for the cell’s normal function. Were there parts that when removed would be akin to removing the heart or brain of an animal?

“The idea that you could have a single cell that would develop like an animal and behave like an embryo was just so mind-blowing,” Marshall said.

But while his dream was in-hand, the path of his career would not be easy.

Like many science-minded kids he faced pressure to drop his intellectual pursuits and conform to his peers. Fortunately for him, he’s always been big, and not easily bullied.

“I saw students who dropped their scholarly interests because they didn’t want to fight with people; whereas, I just got in fights,” Marshall said, clearly not relishing the memory of these middle-school encounters. “It was good that I was bigger than most of [the bullies].”

Finally, after high school, Marshall decamped with his ambitions to the academic enclave of SUNY Stony Brook, where he could remain close to his family, yet receive a world-class education affordably.

Did he reign in his ideas, chastened by the intellects of his fellow college students?

Marshall thought for a moment, then with a spark in his eye.

“On the first week in college, I had to meet with my undergraduate academic advisor. He sat me down and said, ‘So what is your plan?’ And I said, ‘Oh! My plan is to invent circuitry that can grow inside of a living cell, and then I’ll make an arbitrarily large computer by having the cells grow.’ He said ‘Well, I kind of meant what classes are you going to take this semester.’”

From college to grad school, his path was happily one of full-time study and research. He did, however, need to help his family make ends meet, and doing so put his powers of grit and creativity to the test.

“My mother wanted a job as an organist at a church that was near our house, but she was still under contract as an organist at another job, so I took the job to hold it open for her. But, I actually didn’t know how to play the organ! My mom had taught me how to play the piano, and so I bluffed my way through the organ.”

He added, “Even if I couldn’t play the organ fully, I was able to play the music that they needed me to play. I was able to do what I needed to do.”

Marshall carried that can-do attitude to a PhD at UCSF, where he studied the biophysics of DNA packaging in cells, under John Sedat. From there is was a postdoc at Yale, a homecoming to UCSF as a faculty member, and finally the Directorship for the Center for Cellular Construction.

This collaboration of UCSF, Berkeley, Stanford and several other companies and institutions, was created to help engineer living cells into “modules of novel self-organizing devices,” such as computers. It is a job that is the end-product of his tireless perseverance.

“Between working on Stentor, and having the Center for Cellular Construction, I’m literally living my middle school childhood dream,” Marshall said. “That’s incredible, right? It makes me really happy.”

But he’s not done.

Take a look at that drop of water again, and wait patiently for moment. Eventually Stentor will roll out of view. Slowly, you’ll begin to make out other, strange microscopic forms, as alien as anything you’ll find on the ocean floor or some faraway exoplanet.

There’s Lacrymaria, a microscopic giraffe with an impressive, craned neck foraging for tidbits; to the right, a species of Dinoflagellate with a structure resembling an eye that, incredibly, may form an image inside a single cell, in a manner completely analogous to our multicellular, macroscopic eye; and here, in the foreground, is tiny Euplotes, a single-celled creature that appears to have feet, and the ability to walk.

“We have evidence that this little cell [Euplotes] has a coordinated gate, like an animal, even though there’s no brain,” Wallace says, almost breathless.

Marshall swallows hard, leans back in his chair, and looks to the ceiling.

“How much can cells ‘think’ without a brain? That’s super interesting to me.”

“If you could classify the behaviors, and then ask how it decides which one to do when, could you do a psychological analysis on a cell?” Marshall said.

It is all fantastic and beautiful. But with interests that include enormous cells, walking cells, cells that might spy on their neighbors and cellular "thought" without brains, what is Wallace's grand vision? Where does it lead?

Marshall smiles, rests comfortably on his elbow and takes a swig from his bottle of water.

“Synthetic Histology,“ he says. “What if you could make every possible change within a cell, and see which ones give you the behavioral changes observed by [cancer pathologists]?”

This, he explains, could enable a more accurate prediction of therapeutic outcomes and disease progression in cancer, through an application of his cellular psychological theory.

Of course, these are breakthroughs that might, or might not, happen in the future. Right now it is Friday afternoon, and a holiday barbecue awaits. Marshall will take a rare break.

Undoubtedly he will be back to work soon, turning setback into opportunity, and ushering his scientific dreams into reality.