As a junior in college around the turn of the century, Qi Zhang wanted to know how proteins worked. He wanted to see them work. He wanted to see how these ingenious little engines folded to perform a function vital to human health. So, of course, he created software – a computer program that could model how these tiny enzymes morphed their structure to affect change in the body.
To some people, that step from wanting to know something to creating a way to know it might seem like too large a leap. But that’s how Qi Zhang’s mind has always worked. Biochemistry, to him, is a world of movement in need of further exploration. Ever since he was a boy growing up in eastern China, he has been intrigued with how things are built and how they move.
Now, as an assistant professor of biochemistry and biophysics at the UNC School of Medicine, Qi Zhang, PhD, is creating new ways to explore how the tiniest things that make us human change and move. At the heart of his research is the fundamental question: how do tiny pieces of genetic code called microRNA (miRNA) keep us healthy and sometimes cause disease.
For his work, Zhang earned a UNC School of Medicine Jefferson-Pilot Fellowship in Academic Medicine, which includes a $20,000 prize to support his scholarly endeavors. We sat down with Dr. Zhang for a Five Questions feature to discuss his love of science and math, his creation of novel technologies to study microRNA, his coming to UNC, and the importance of his research in understanding human health and disease.
How did you become interested in science and biochemistry in particular?
I was not only interested in science as a kid, but also technology, engineering, and math. I was a real STEM kid. I liked to build things that move. I’d make model cars, airplanes, and boats. I’d buy little pieces and follow instructions (and sometime not) to put them together and make sure the things would move like they were supposed to. It was quite an expensive hobby and these projects took a lot of time. I was 10.
When I wanted to buy a computer for gaming, my parents – who were far from rich – said they couldn’t afford that. But when I said I wanted to build things, they were very supportive because they loved putting things together, too!
Eventually, I really wanted to know how all these pieces moved and the secrets (science and math) behind them. This is when I got into chemistry, which is a field that combines science, math, and movement. Chemistry is all about dynamics; you mix things that are moving around, and something else is created. Ultimately, I realized that the human body is indeed an amazing stage where exciting chemistry happens; proteins, RNAs, and DNAs are constantly moving, communicating, and at the same time, new proteins, RNAs, and DNAs are being created. I wanted to know why and how.
You began as a chemistry student at Fudan University in China and then a graduate student at the University of Michigan. Why did you decide to come to the United States?
In the early 2000s, the Human Genome Project was booming, and biology was booming. I realized that biological processes are basically chemistry, a more complicated world of chemistry. Studying the chemistry of biology – biochemistry – seemed like fun, something I’d like to pursue.
In my third year, I decided to do research. This is when I wrote my own computer programs to see how proteins folded. Proteins are made from various building blocks called amino acids; they start as random things and turn into unique shapes. I wanted to watch these proteins fold. But in China at the time, there wasn’t much technology available to do this. The most accessible technology was computer models, but there was no software available to make them. So I had to write my own software, which the principal investigator in the lab was happy to let me do. I did two years of this pretty much by myself, and it allowed me to create models and “watch” how proteins became folded molecules.
But writing my own software to accomplish this was the most I could do in China. I didn’t have access to any other technologies to help me validate what I was doing. I graduated in 2001 and realized I had to go to the United States, a place full of state-of-the-art technologies that could help me create images of proteins folding.
The University of Michigan was at the center of using nuclear magnetic resonance (NMR) spectroscopy to study how biomolecules function and how proteins fold to change their structures. When I arrived, I saw that this young professor, Hashim Al-Hashimi, who had just arrived in Ann Arbor, wasn’t doing normal protein work. He worked on RNA –chains of building blocks with ribonucleic acids, which are very similar to DNA.
This was not long after the Science paper on the human genome project was published. We could finally see the entire human genome, and there looked to be all this genetic material that didn’t do anything. It was called junk DNA. Well, it turns out it isn’t junk at all. They turn into RNA. So, Hashim was this young guy winning awards who thought that RNA was the future. And I thought he was right.
Only about 1.5 percent of the genome codes for proteins. About 98.5 percent involve the things that make us human. If those things are all RNA, then that’s the future. It has to be important for health and disease. That’s how I wound up in the field.
Why did you come to UNC?
I think UNC is a unique place when it comes to RNA, biophysics, and biochemistry. Our department is very collaborative, people are very collegial, and students are very active and enthusiastic. We all understand each other. Leaders in the department, [the UNC Lineberger Comprehensive] Cancer Center, and the School of Medicine are all very supportive. We have a fantastic atmosphere here. We also have state-of-the-art techniques and facilities that are essential for developing my technologies. Our NMR people have done so much work to make this place a very exciting place to work. And then there’s the RNA work; I think UNC is one of the top universities in this field.
Also, there’s the environment of the neighboring universities plus NIEHS [the National Institute for Environmental Health Sciences]. I would say, for me, UNC is the perfect spot for technology development and for the kind of research I want to do with that technology.
What is x-ray crystallography and nuclear magnetic resonance spectroscopy, and how do you use these techniques, as well as computational and biochemical approaches, in your research?
The critical aspect of my work involves building new techniques to study miRNA instead of relying on existing techniques. When I was in graduate school, we developed new techniques that allowed us to make a video to see how RNA moves.
As a postdoc I built more techniques. And now here at UNC, I’m still developing new techniques based in NMR spectroscopy that allow us to show RNA movement at a slower time scale. This cannot be done by any other techniques.
NMR is like MRI (magnetic resonance imaging). The difference is that MRI shows images of the body. NMR images atoms. It’s at a much higher resolution. NMR allows us to look at every single atom so we can determine the structure of a molecule that can control gene expression. We can create images in three dimensions on a nanometer scale. We can show its very interesting shape.
X-Ray crystallography involves the same principle. Instead of creating x-rays of bones, we x-ray atoms to look at molecules at the atomic level
Our techniques allow us to look at atoms at a specific time and to “watch” how the atoms move. We can generate a video. That’s what we want – not only what a molecule looks like but how it acts while it performs a function. This is important because everything in biology is moving. Molecules have to communicate with each other. They need to change shape depending on whether there’s an intruder or not, or during cancer. So, NMR is a powerful tool.
Think of it like this: if we really want to understand how a story is developing, it’s ok to see a couple photos, but it’s better to watch a movie to see how it starts, how it ends, and what happens in between. So, for us – as researchers – motion pictures are better when studying human biology and how disease occurs. We can take high-resolution motion pictures so we can know how molecules respond to different environments and how they work. And when something goes wrong, we can see it and search for a way to repair it.
This is why computer programs are crucial. Once we generate motion pictures, we have to be able stitch them together so we can see how molecules work on the atomic level and find a way to repair them. If molecules are dysfunctional, they cause disease. This is why basic science is so important. It describes the fundamentals of all biological processes, and when something goes wrong you end up in a kind of disease state. That’s what we’re interested in.
What has your research revealed thus far, and why is this kind of work important for improving health and treating diseases?
We want to use research techniques we’ve developed to solve biological puzzles. We’re trying to study how “misregulation” of genes contributes to major diseases, such as heart disease and cancer. One thing we study is that if you get rid of a particular microRNA, a tumor disappears. That means it’s an oncogene. This little bit of RNA – 22 nucleotides – once thought of as genetic junk or noise turns out to be very important.
We’re trying to understand how this tiny piece of RNA wound up here and to be so important for human health. How are miRNAs made? A lot of people study what miRNA strands do and how they affect other biology. We’re interested in that, too, but we’re more interested in how the miRNA winds up in the role of regulation. We’re interested in the upstream situation of a disease state – can we prevent that miRNA from being the cause of a problem? To us, that’s a more important, and a more fundamental scientific question.
What we’ve found, when studying miRNA from its origin, is that these strands are very dynamic. They move around. A lot of miRNAs as regulatory genes are very dynamic. Now we want to watch how they move and identify different proteins that can use this moving target as a regulator for a downstream effect to cause disease. It is no doubt very complex.
The human condition is astonishing to think about. The better we get at figuring out what’s going on inside a healthy person, the more we reveal how much we don’t really know. I think the more we know about biology the more it seems almost like magic. I have two boys, and it’s almost magic to see that they were born healthy. An incredible number of things could go wrong, but they usually don’t, even though the human body is an intense synergistic system. All the parts of the body talk to each other to make sure every part of our body works. It’s really amazing. The more I do science the more I find that every single living species is just amazing. That motivates me even more to do science, to understand what’s going on, and to find a way to restore that synergy for people who have a disease.