A summary of Dr. Gottschling’s talk at RU, targeted at a non-science audience.
Comments, critiques, etc.. are more than welcome. Is it understandable? Too simplified? etc..
The version targeted at scientists is now up on the The Incubator.
Studying the Deep, Deep Details of How We Age
As cells–or people–age, processes break down and things go wrong. Generally, this occurs through the appearance of mutations in our genes (this is a scientist’s way of saying that the “recipes” that code for important parts of our cells start to accumulate mistakes). Many studies on aging have worked to identify these aging-associated mutations. But, what is actually happening in an aging organism that is causing these mutations to occur? This is the question Dr. Dan Gottschling from the Hutchinson Cancer Research Center hopes to answer, and he has designed some pretty cool experiments to do so.
Dr. Gottschling does not study aging humans, but instead uses a model system: yeast. Yeast are an entire organism made up of a single cell (and the force behind both beer and bread). Why study yeast and not a person? People are made up of billions of cells, each of which functions just like a yeast cell (or close enough). When you see your forehead wrinkling, or an age spot appears, it is because the individual cells that make up your skin are aging. To understand what is happening that causes these cells to age, we need to look at the cells themselves, and yeast are a great way to do this.
But do yeast age? The answer is yes. Yeast “reproduce” by duplicating their DNA, moving it to one side next to their outer skin (membrane), and then pinching off a smaller, identical version of themselves (a daughter cell, from a mother cell). The mother, however, cannot live forever. After budding off about 40 of these daughter cells, the mother becomes too old, and dies.
Aging causes cancer, or at least that is the theory that inspired Dr. Gottschling’s first work. Other than some specific exceptions, there is strong data that the incidence of tumors correlates strongly with age. Tumors generally appear when something “funky” happens to your DNA, one outcome of which could be not duplicating properly into the daughter cell (scientists call this nuclear genomic instability, but we can stick with funky). So, Dr. Gottschling developed an experiment to see whether something funky was occurring to the mother cell DNA, as she continued to bud and age.
To do this, Dr Gottschling relied on something called dominant and recessive genes. Each gene we have has two copies, and each of these copies can be different. Sometimes the difference is dominant (G), which means you only need one copy (G/g) to see an effect in the cell, while sometimes it’s recessive (g) and you need both copies (g/g) to see the effect. So, Dr. Gottschling created yeast cells that were (M/m) with a mutation (m) that makes them turn red (this is one of many super-cool tricks scientists can do with yeast, which is why they love it so much—and not just in its drinkable form).
And this is where the crazy science experiment began for real, Dr. Gottschling’s students would sit by a microscope, and watch the mother cell reproduce (another reason yeast works better than people, or even mice). Whenever a daughter appeared, they would very carefully move her to a different plate. By the time the mother died, all 40 or so of her daughters had grown up their own little families (colonies) in a row on a separate plate. What they saw was that around the 25th bud (middle-age for Mom) the daughters were turning red. This meant that instead of being M/m, as they should be, the daughters were becoming m/m, or even losing a copy altogether and becoming m/-. This was the visual proof that “something funky” (or genetic instability) was occurring in Mom as she got older.
Dr. Gottschling’s lab now not only had evidence that getting older was linked to “funky” DNA, but a way to score what is called “a phenotype” of aging. He could change various processes within the mother cell, and see whether this prevented, or encouraged, the daughter cells to turn red. Or, he could correlate dysfunction in other processes with the emergence of red daughter cells. This second approach led him to the discovery that mitochondria, which are called the powerhouses of the cell (think- little machines that make the fuel), weren’t working properly in the red, funky, daughter cells. Further experiments showed that a specific process was breaking down in the mitochondria, which was responsible for building a chemical subunit (iron sulfur clusters: ISFs). And the best part of this punchline: three parts of the cell that need ISFs to work properly, are involved in processes that keep your DNA from going funky.
But, will any of this ever help with my own wrinkly forehead, or help prevent cancer as we age? Dr. Gottschling, and the scientific community, think yes. The three genes that he identified in yeast are also present, and important, in all human cells. Dr. Gottschling’s work is typical of what is called basic science. He is not looking to make medicine, or cure aging. Instead, he hopes to help us understand as thoroughly as possible what happens as a cell ages. And I think we can all agree; we can’t fix what we don’t understand.