A Structured Environment
Annie Vemu studies microtubules, the skeleton of the cell
Microtubules provide the fundamental structure of a cell. They’re small, cylindrical structures that contribute to its shape. Microtubules also work like mini-highways within a cell, transporting cargo from one place to another so cells can survive and adapt to an ever-changing environment.
At Johns Hopkins, fifth-year Ph.D. student Annie Vemu looks at how microtubules get their shape, what happens when this skeleton of the cell gets pulled apart, and how it can be changed. She’s part of the Hopkins-National Institutes of Health (NIH) GPP program: Although she attends classes at Hopkins, all her research is done at the NIH.
The shape of things
All cells have different shapes. For example, a neuronal cell is long, which supports transport of information. And although all cells have microtubules, they’re not all the same. They aren’t static structures that sit around during the lifetime of a cell.
Because the cell is experiencing different environmental cues throughout its life, its microtubules are constantly growing and shrinking.
A microtubule’s basic building blocks are called alpha- and beta-tubulin heterodimers, which interact with each other to form dynamic polymers. Upon closer inspection, Vemu says, microtubules are actually quite heterogeneous. There are different tubulin isoforms that are decorated with diverse post-translational modifications. And in certain cells, such as cancer cells, when certain types of tubulin become over-expressed, the dynamics of the microtubules change, and they become resistant to chemotherapeutic agents.
Vemu says that although tubulin was discovered about 50 years ago, researchers are still trying to understand how a single tubulin isoform or single post-translational modification affects microtubule dynamics and microtubule associated protein recruitment in the cell. Research has involved developing a protocol to isolate and purify single tubulin isoforms to understand how just a single tubulin isoform could change the microtubule dynamics of cells and the whole body ecosystem.
Vemu’s Ph.D. thesis, she says, was inspired by her time evaluating microtubule severing enzymes: spastin and katanin. They are essential for the maintenance and organization of microtubule arrays found in mitotic and meiotic spindles and neurons; if their activity is disrupted, she explain, it can lead to neurodegenerative conditions such as hereditary spastic paraplegia and microcephaly.
“When you remove those enzymes, you get disregulation of organelle trafficking as well as decreased neurotransmitter release,” Vemu says.
When the enzymes break the microtubule, they pull out tubulin dimers within the microtubule; this creates potholes within the microtubule lattice, Vemu explains. But within the cell, there is so much free tubulin floating around, the potholes could be plugged quickly by the tubulin that’s in reach. Also, this new tubulin that plugs up the potholes prevents the microtubule from falling apart and facilitates the growth of new microtubules.
Also, location matters. “The prevailing thinking until recently was that tubulin addition and removal happened only at the tips of the microtubules. But what we have found is that tubulin addition occurs all along the microtubule, because of the severing enzymes’ activity on the microtubule lattice. One advantage this could provide is that instead of completely destroying the microtubule array, you could take out old tubulin and put in new tubulin to rejuvenate the microtubule lattice. This would be much less energetically costly,” she explains.
The long-term implications of this work are meaningful for neurodevelopment, Vemu says. The activity of these enzymes can help explain how cells like neurons develop. And now that we understand that this enzymatic action occurs throughout the microtubule, we can shift our focus to all over, not just the tips.
Because, Vemu says, sometimes cells need to make a lot of microtubules very fast. “Let’s say there is a neuronal injury, and the cell body or microtubule organizing center is far away from the end of an axon. To make the microtubules, you will have to make the cell body, make the microtubule and then transport it all the way to the axon. But if you have severing enzymes, you can make microtubules quickly and not have to wait for a signal from the cell body,” she says.
Background and next steps
Vemu works in Antonina Roll-Mecak, Ph.D.’s lab at the NIH. Prior to coming to Baltimore, Vemu was a biochemistry/chemistry major at the University of California San Diego, where she also received a master’s degree in chemistry.
“I really enjoyed getting to the mechanistic perspective and the basics of things,” she explains. “And then when I went to Hopkins I got the opportunity to study things like genetics and development. That gave me a different perspective on science, which I never would have gotten if I were in the bubble of doing only biochem.”
Although she has spent a lot of time looking at the mechanical side of things, she’d like to take on another layer once she’s through with the program. Perhaps something less basic and more translational, she says. Maybe integrating neurobiology. Regardless, she’s happy to do something she’s enjoying and encourages prospective students to do the same.
“Working on something you really enjoy takes 90 percent of the struggle out of it. When experiments don’t work—and they won’t sometimes, that’s just how it is—when you are doing something you are curious about, you will be resourceful enough to figure out a way. That helped me get over the bad experiment days. Even if they don’t work, they still tell you something,” she adds.