The Mountaineer

By Eric Sauter

Kristin Baldwin came to The Scripps Research Institute just about a year ago, after she and her colleagues at Columbia University and the Massachusetts Institute of Technology managed to do something no one had ever done before—clone a mouse using mature olfactory neurons as the source of genetic material.

Aside from being a spectacular bit of science, her feat also had a built-in media hook. The experiment, or so the scientists said at the time, was inspired by Woody Allen's Sleeper, a slapstick comedy in which a group of scientists attempt to clone a dead dictator from his nose, the only part that survived an assassin's bomb.  The 2004 study clearly showed that animals could, in fact, be derived from the nucleus of mature neurons following transfer into an egg cell. Earlier attempts at using post-mitotic cells like neurons had failed; so did the Sleeper attempts. In the film, the nose gets run over by a 200-year-old Volkswagen. Not so with Baldwin's olfactory neurons.

Currently an assistant professor of cell biology at Scripps Research, Baldwin is still working on olfactory neurons—and others—trying to unravel the mind-bogglingly complex system they inhabit.

"In our olfactory system, hundreds of different types of neurons in the nose detect the individual components of particular scents, such as fresh grass or baking bread, and they send this information to the brain," she said. "We now have a good understanding of how this works, but we really have no idea how cortical neurons link together the components of different scents to allow us to know what the nose is smelling. Even more mysterious is how these odor codes are conveyed to the parts of the brain that determine whether you enjoy a particular scent or not."

Unraveling Complexity

The Baldwin lab is currently trying to visualize the neural circuitry of smell as a first step in the effort to hunt down the genes and molecular mechanisms that help to build these circuits.

In one line of research, the group is trying to broaden their initial success with neuronal cloning by attempting to replicate the process with cortical neurons. While some researchers have suggested that cloning cortical neurons is impossible, Baldwin hopes to prove otherwise.

In a way, cloning or somatic cell nuclear transfer is relatively simple, yet terribly inefficient. This is the same technology that created Dolly, the sheep heard around world, a few years ago. In this process, the nucleus of an adult cell is injected into an egg cell whose nucleus has been removed. Although no one knows how, the egg cell then erases any changes to the adult cell chromosomes, producing the original genome, a kind of chromosomal tabula rasa, which then develops into a normal adult—a genetic duplicate of the original.

Until Baldwin's nose experiment, however, clones had only been produced from cells that could divide, the most common choice being skin cells. In fact, many scientists had simply given up, suggesting that non-dividing cells such as neurons had irreversible changes in their chromosomes that the egg could not erase. Baldwin's successful cloning of mice from non-dividing olfactory neurons established the notion that chromosomal changes could be reversed, even in highly diversified cells like neurons.

"Cloning from neurons takes adult DNA that has been altered many times throughout development—and which normally can never revert to a less differentiated state," she said. "Somehow the egg strips off the marks of differentiation and resets the chromosome. This process is inefficient and not well understood but, amazingly, it works frequently enough to produce adult clones about one percent of the time. Logically, researchers thought that the more differentiated a cell was, the harder it would be for the egg to reprogram the DNA. If a cell had stopped dividing altogether, many thought that it would be impossible to clone from that cell, but our original experiment showed that assumption was wrong, at least in the case of olfactory sensory neurons. Now, our new work aims to extend these findings to other neurons that are even more highly differentiated than olfactory neurons."

Baldwin's latest experiments will focus on what happens to the chromosomes of neurons when they differentiate and how well neurons preserve their DNA throughout the life of an animal. A better understanding of that, Baldwin points out, could have wide-reaching applications for any number of diseases, including neurodegenerative diseases such as ALS, Huntington's, Alzheimer's, and prion disease.

Climb Every Mountain

While the work has therapeutic potential, like a climber staring up at the mountain, Baldwin's interest in the process stems partly from the simple fact it's there. Outside her lab, she also relishes challenges, skiing, riding mountain bikes, and learning how to surf.

"Some of my interest in cloning comes from the fact that this is a brand-new science," she said. "There's an attraction to succeeding where others have not. By successfully cloning neurons, we can look at the whole genome at once, something we haven't been able to do before, and reveal mechanisms that generate neuronal diversity that are currently unknown."

Baldwin grew up in small-town Ohio, and was motivated early on by what she described as a deep-seated curiosity about things, particularly science and math. She was lucky to have her parent's support in fueling that curiosity, and attended summer camps with extra math and science classes. Baldwin left Ohio for undergraduate work at Duke University, where she first studied economics before coming to the conclusion that in order to understand actual human behavior, not just the utilitarian Homo economicus, you had to first understand DNA and the brain.

"I did my Ph.D. in immunology at Stanford," she said, "studying how T cells diversify to form a system that is able to recognize that some things are bad for you and some are not. From there, I became interested in how a different set of cells—our neurons—diversify to form the brain, which is the most complex cellular system in the body and also has to discriminate between the good and the bad."

Now at Scripps Research, Baldwin is still reveling in opening up new territory.

"We really want to build nuclear transfer technology at Scripps Research," she said. "Once we generate proof of principal, we have a rationale to clone from neurons of many types. We could begin to clone from diseased cells to see how they maintain their genome and how that might contribute to disease. What helps make all this possible is that we have such incredible resources here. We can do so much—from producing genetically altered mice, to analyzing them, to using advanced genomic technologies to study them."

Baldwin is hoping to have some early answers in her new neuron cloning work in the next several months. "Right now," she said, "the numbers don't say it's impossible."

In other words, the mountain is looking pretty good.

Send comments to: mikaono[at]scripps.edu

"Some of my interest in cloning comes from the fact that this is a brand-new science," says investigator Kristin Baldwin. Photo by BioMedical Graphics.

"By successfully cloning neurons, we can look at the whole genome at once, something we haven't been able to do before, and reveal mechanisms that generate neuronal diversity that are currently unknown."

—Kristin Baldwin