Cells divide and organisms grow. We learn this early in science classes. But what happens when an organism is done growing? How do the cells know when to stop dividing? What do cells do if they make a mistake?
“In our cells, we have proteins that are made all the time, and sometimes those proteins need to be destroyed,” explains Assistant Professor of Biology VJ Rubenstein. “Some proteins you want to have around only for a little period of time – for instance, proteins that tell your cells to divide. You want those cells when you’re developing or healing, but you don’t want those around all the time or you get cancer. The cell has in place a way to say, ‘That protein’s job is done. We’re going to destroy it.’”
Deliberately triggering that reaction in cholesterol is Rubenstein’s goal. He has been investigating what specifically activates it through a study called Seek and Destroy: Reducing Cholesterol by Enhancing Protein Destruction.
“We say cholesterol as though it’s one simple thing, but cholesterol is actually several molecules together,” Rubenstein explains. “Cholesterol itself is a lipid, but the cholesterol that’s moving in our blood is little particles of a protein bound up with all these little lipids. If we can find a way to tell our cells to recognize and destroy this protein, then we can reduce the levels of cholesterol in our blood.”
To find a way to tell cells to destroy that protein, Rubenstein is tapping the power of a resource common in genetic research: yeast.
“Most of the systems functioning in your cells right now are functioning in almost every other cell that lives,” Rubenstein says. “We all do the same thing – we all have DNA, we all have protein, we all make RNA from DNA molecules and use the RNA as a template to make new protein molecules, and we have ways to detect and destroy proteins when we don’t need them anymore.”
Because of this, yeast can act as a model organism – results found through yeast research can usually be applied to larger, more complex organisms, such as humans.
“Yeast cells don’t necessarily have cholesterol, but they have proteins that are recognized and destroyed in the same way. In my lab, we are trying to understand how yeast cells destroy proteins and using that as a model for the major protein component of cholesterol,” Rubenstein says. “If we can piece together how this works in yeast, we might be able to provide some insight to people who are studying this field in a mammalian system – people working with mice, ultimately working up to humans.”
Yeast cells appeal to researchers because they yield results quickly.
“If I have a hypothesis that Gene X is required to destroy this protein, I can very, very easily go into the yeast’s DNA and erase that sequence. So I can get rid of that gene and then we have a yeast cell that lacks Gene X. I can ask, ‘Can this cell that lacks Gene X destroy this protein?’ and very easily I can say yes or no, Gene X is or is not required to destroy this protein,” Rubenstein explains. “That’s a lot harder to do in animals. I can make a yeast strain that lacks Gene X in a matter of two weeks or a month. To make a mouse that lacks Gene X could take a year.
“There’s this idea in the yeast community: the APOYG – the Awesome Power of Yeast Genetics – because we can very readily do what I’ve described. There are all kinds of fun things that we can do in yeast cells – we can look at individual genes or start looking at the entire genome, the entire collection of genes, and knock out one at a time and ask ‘what is the effect?’”
Rubenstein has been working with yeast since 2003. He says his interest in the unicellular organisms came about because they are great for studying basic processes and for conducting research with undergraduate students.
“In almost every basic area of biology, the initial studies were done on yeast,” Rubenstein says. “My lab works on yeast, some other labs work on animals, some other labs work on human cells, and we all kind of work together to build this body of knowledge.”
The National Institutes of Health recognize Rubenstein’s contribution to this body of knowledge and recently awarded him a three-year, $310,688 grant to study the process by which cholesterol proteins are destroyed. His goal is to provide understanding that will lead to improved treatments for cholesterol-related diseases.