Harvard University - Department of Molecular & Cellular Biology

AFTER MUCH TRAVEL, NEW PROFESSOR ALIGHTS IN CAMBRIDGE

by Sebastian Stockman

January 6th, 2009


Vlad Denic

Vlad Denic has been around. He's lived in Belgrade and Baghdad. He went to college in New Zealand and did his graduate work in San Francisco. At the beginning of the semester, he was installed in a fourth-floor office in the Northwest Labs building.

Denic, an Assistant Professor in Molecular and Cellular Biology, is one of MCB's five new faculty appointments this year. He's hard-pressed to pin down his exact research interests - but he finally gives it a shot.

“Some people will tell you they're working on a particular protein,” Denic (pronounced DEN-itch) said. Instead, his scientific interests span a range of areas of cell biology that are “connected loosely by the fact that they all have to do with cellular membranes.”

One of his projects involves studying the synthesis of a class of functionally diverse lipid molecules that are required for building eukaryotic membranes. These lipids come in a large variety of distinct but related structures, and Denic is “looking at how you make them and stuff like that. ...” which he says is “fascinating from a perspective of - how do you create diverse building blocks that are supposed to fill in very specialized functions?”

Another big question Denic considers in his research is “how do you put things into membranes?”

“Because cellular membranes are active only in combination with the proteins that are inside of them,” Denic said. “On their own they have a relatively narrow spectrum of things they can do. So the other question is: how do you insert proteins into membranes?

“That is something that, in some ways, seems obvious, because the way that this happens in the end is you have a very hydrophobic segment of a protein that gets inserted into the hydrophobic core of a membrane - so it's certainly something that looks favorable from a thermodynamic perspective... but it doesn't seem to occur efficiently on its own. So even though something can be ultimately favorable, there are barriers to getting it to happen fast enough on a biological time scale. So another thing that I'm studying is how a particular protein machine that is found in the endoplasmic reticulum membrane can recognize the hydrophobic segments of a certain class of membrane proteins and then, using energy, actively insert these hydrophobic anchors into lipid bi-layers [membranes].

“One of the newer things I'm getting into now is how do you assemble membranes? So when I talked about membranes before [in the other work] ... these were always pre-existing membranes. One of the classic tenets of cell biology is that most structures arise from pre-existing structures. ... A plasma membrane, if you wanted to make a daughter cell, has to double in size and then it has to pinch in two.”

However, in some cases, these intracellular membranes seem to assemble themselves from scratch, which can be beneficial from the perspective of the cell's self-defense.

“So, under certain circumstances, let's say you wanted to destroy some large thing inside the cell, the way this happens is you somehow create a membrane that envelops it, and then deliver it to a place in the cell where it gets destroyed. ... For example, this is beneficial when you have a bacterium inside your cell or if you had a potentially toxic neuro-degenerative protein aggregate, this could be a way of eliminating them.”

This is a phenomenon that can be observed, but it's not well understood.

“It's not understood mechanistically,” Denic said. “In terms of how do you get lipids to self-assemble into these sheets, and then how do these sheets grow to then envelop their targets and finally fuse with themselves? That's a very challenging question: [the] large-scale coordination of lipids.”

A Bold Introduction

Denic's interest in membranes cell biology grew out of one his first encounters with science “in the wild,” as he put it. On one summer break from the University of Auckland, Denic found himself staying at his great uncle's house in San Francisco, when he decided to take advantage of the library at the University of California at San Francisco.

“It was this summer thing where I was basically deciding what to do,” Denic said. “And I was mostly focusing on chemistry and stuff, and I was only getting into biology towards the end.”

Rather than reading about scientific findings that had been digested by textbook editors - which is how he'd been studying science in New Zealand - Denic availed himself of the library's large journal collection.

By doing this he hoped “to see how you go from raw data to some kind of conceptual framework you read about in a textbook.”

He encountered rough sledding at first: “It was hard to understand a lot of the papers I was reading.”

Eventually, he came across a paper on the so-called unfolded protein response in the endoplasmic reticulum, and a light went on.

“And I was reading it, and it took a long time,” Denic said. “But I was getting it, and I was like, 'wow, this is kind of awesome...' And I was wondering who did this, and it turns out it was this guy at UCSF called Peter Walter.”

Many of us might simply see that information and file it away, but Denic - still an undergraduate, remember - saw an opportunity. When he got back to New Zealand, he wrote to Professor Walter - but it wasn't just a fan letter.

“And I wrote him, you know, some suggestions,” Denic said, chuckling. “Maybe you guys should consider doing some of these experiments I thought up, and I would be willing to offer my services.”

Denic didn't hear from Walter, though, so the undergrad picked up the telephone.

“And so I called him eventually, and got him on the phone,” Denic said. The result of that phone call was Walter's acceptance of Denic as a summer intern in his lab.

As it turned out, Professor Walter had a rival in the field who moved to Australia, so when Walter received an unsolicited communiqué from that side of the world, he wasn't sure what to make of it.

“There's all of a sudden this kid who's writing me from New Zealand, and what if he's a mole intended to bury itself in my organization?” Denic said.

So, once Walter figured out that what he really had on his hands was just an eager kid, writing on his own initiative, did he take a look at Denic's suggested experiments? Well... not exactly.

“I'm sure they were very na\0xEFve,” Denic said of his long-ago ideas. “I'm sure they were not very reasonable at all.”

Denic had a great time as a lab assistant, and when it came time to apply to graduate schools, Professor Walter wrote him a recommendation. Denic had his pick of institutions, but he elected to stay at UCSF.

“I just loved UCSF,” Denic said. “It was just magical.”

Denic ended up spending eight years there, all told, including his Ph.D. work and his postdoctoral studies. At the end of that time, he picked up and moved across the continent, which was nothing new for him.

Globetrotter

Denic grew up in Belgrade, Yugoslavia (now Serbia), before the war. His parents were doctors, so they were relatively well off - but still, it “was a different world.”

“Because it was very Communist before the war,” Denic said. “So you have to imagine a system where, depending on your party affiliation, your career could either be heavily advanced, or it could be ruined.”

Money was tight, too, for many people. One day, Denic was home by himself while his parents were at work, when his mother received an unusual form of payment for her medical services.

“We lived in this Communist building in Belgrade, that's got 30 stories of concrete,” Denic said. “And we're on the 20th floor. The doorbell rings and I open the door - and this was already when inflation was getting very bad - and there's this farmer guy, a peasant, with this pig on a leash.”

The farmer asked if he had Vlad's mother's house, and then explained that Vlad's mother had saved his wife's life, but there was no money with which to pay her. He handed over the pig to Vlad.

“And so I put it on the balcony overlooking Belgrade,” Denic said.

It didn't get too bad in Belgrade during the war - it wasn't Sarajevo - but there were still air-raid warnings and a lot of anxiety. Eventually, his mother and stepfather moved to New Zealand - which was offering refugee status to people fleeing the Yugoslavian conflict - and that's how he ended up at the University of Auckland.

Before that, though, Denic spent a short amount of time living in another not yet war-torn capital: Baghdad.

This was back before the first Gulf War, in 1990. Denic's father was working at an Irish hospital in the city, and so he and his son enjoyed a relatively privileged status.

“We were sequestered,” Denic said. In “a place where all the foreign government people lived. It was a gated community - but it was in the heart of Baghdad, and you know, we wouldn't really interact on the street. ... We would mostly be at home, or then get in a car and go to these fancy hotels.”

At least one of those fancy hotels - the al-Rashid - was much in the news more than a decade later, but for Denic it was where he went to swim, play tennis, and eat at restaurants.

“You were part of a very privileged layer of society” as a foreigner in Baghdad, Denic said. “It was a weird place - you would go down these boulevards and there would just be these enormous pictures of Saddam Hussein, in various poses and with various outfits. ... Our life was very good there, before the war.”

Then Iraq invaded Kuwait, and everything changed. Denic's father put him on a bus, which went to the Iraq-Jordan border, where Denic and the other passengers crossed the desert on foot, before getting on another bus that would take them to Amman, Jordan's capital. From Amman, Denic got a flight to Belgrade, where he could wait until that war broke out, two years later.

“Duck for cover,” Denic joked. “It seems to follow me everywhere I go.”

View Vlad Denic's Faculty Profile