Cells are the basic unit of biology: the site where energy is transformed. It is the locale where DNA, RNA and proteins perform the timeless dance of cellular reproduction.

But cells are small (a mammalian cell is about 10,000 nanometers in diameter, which sounds large until you remember that one million nanometers equals one millimeter).

Photo: © Science/AAAS

That angled piece of ultra-slender wire at the end carries a transistor, and is about to slip inside one of the cells just above it. The two legs allow current to flow through the transistor.

Tracking events inside individual cells may get a lot easier, courtesy of a new transistor that is engineered to slip easily inside a cell and is just 50 nanometers wide.

This transistor, mounted on a much-thinner-than-a-hair wire, can detect and amplify faint electrical signals inside cells.

Several innovations from chemistry and material science were needed to construct ultra-mini transistors on a hairpin-shaped piece of wire, says Charles Lieber, a professor of chemical biology at Harvard University.

The nanowire itself is silicon, the basic material of solid-state electronics. To give the wire its hairpin shape, the researchers created two 120-degree bends, which had never been done before with nanowire, says Lieber.

To form a tiny transistor at the bend, Lieber, Bozhi Tian, who’s now a post-doctoral fellow at MIT, and colleagues “doped” the silicon wire with precise dollops of elements.

Small is indeed beautiful

The invention has advantages over the “patch clamp,” which was developed more than 25 years ago to measure voltage at ion channels on the cell surface, says Lieber.

Photo: The Athlete’s Heart Blog

Because the transistor “is an active device that amplifies the signal,” it can be much smaller than the patch clamp, Lieber says. The new probe is so small, he adds, that “you could envision putting several of these into the same cell to measure things on a scale that’s never been measured.”

The fabrication techniques impressed Xudong Wang, an expert in nanowire at the University of Wisconsin-Madison. “In making nanowires, it’s most difficult to grow a certain shape, and to put a specific function at a specific location.”

Although most early nanoelectronics are planar, Wang adds, “They made this part that is three-dimensional, so you can study something in 3D space.”

A matter of the heart

Because heart muscle cells exhibit an electrical rhythm that causes spontaneous contractions, Lieber’s research group used the probe to examine chicken heart cells in the lab. Inserting the nanowire did not seem to affect the cells, Lieber says. “The cell is beating, and as the device goes in, there is no change in the beat frequency or in the electrical potential.”

In contrast, harpooning a cell with a pipette — the slender glass tube used in the patch clamp — often disturbs it, Lieber says. And because that pipette also contains a liquid, “You will always have an exchange of medium from the measurement tool and the cell.” The new probe uses no fluids.

Photo: © Science/AAAS

Inside a single cell, this nanowire probe can measure electricity and may eventually be able to detect proteins and RNA.

King of nano-camo?

Photo: © Science/AAAS

To help the ultra-small probe enter cells, the researchers coated it with a layer that resembles a cell membrane, which causes the probe to be pulled into the cell. Cells use a similar process to devour viruses and bacteria.

Beyond measuring voltage inside a cell, Lieber suggests that the transistor could carry receptors for proteins or RNA, enabling it to measure chemistry in real time inside cells. That, in turn, would open a window on many basic biological mechanisms.

“It’s almost like a dream to be able to wire up a transistor, which is the fundamental unit in digital electronics, with a cell, which is the basic unit of information processing in biology,” says Lieber. “It does not take a lot of imagination to think there will be a lot of wild things that one can do with this technology.”

– David J. Tenenbaum

Learning is about connections: when the pathways between neurons get stronger, information flow is faster and smoother. We get better at triple toe-loops on the ice, or crooning a romantic ballad for “American Idyll.”

Nice notion, but what, exactly, is changing? Here, we get help from a singing bird that may never get beyond YouTube: the zebra finch.

In a study in Nature, Richard Mooney, a professor of neurobiology at Duke University, used a laser-powered microscope to peer into the brains of male zebra finches 60 days after hatching. Mooney and colleagues studied the birds’ first exposure to the song of their species, and correlated the amount of learning with changes in tiny spines on the dendrites of nerve cells, or neurons, in a motor circuit for singing in the bird’s brain.

Dendrites are branch-like structures on neurons that detect chemical signals, known as neurotransmitters, released from other neurons. When a neurotransmitter diffuses across a tiny gap, called a synapse, it is often received on tiny “dendritic spines” that, in their billions, define the neural wiring and thus the computational properties of the brain.

More and larger dendritic spines make stronger synapses, and that makes stronger and more reliable brain circuits.

Learning: All a matter of spines

In the study, Mooney, Todd Roberts, Katherine Tschida and Marguerita Klein labeled certain neurons so they would glow when viewed under a microscope; they then watched these neurons in living finches and measured what percentage of the dendritic spines appeared or disappeared over a two-hour interval.

The next day, these juvenile birds were allowed to hear the song of an adult male “tutor” of their species. Afterwards, the researchers looked at the spines again, noting that some had appeared, disappeared or changed size. In the following weeks, these birds never again heard their characteristic song, although some went on to learn it.

The birds with the highest spine turnover before hearing the tutor had a significant increase in spine size and stability immediately after tutoring. Eventually, these birds also did the best job of copying the tutor’s song.

Image: Todd Roberts

These tiny structures, called dendritic spines, receive inputs from neighboring neurons, and are an essential part of the brain’s wiring. A new study showed that these spines got stronger and larger as a bird learned to sing.

“We made an average measure of the turnover rate, and found some juveniles with high turnover and others with low turnover, and asked what their learning outcomes were, many weeks later,” says Mooney. “Those with high turnover before hearing a tutor song eventually learned more, and those with low turnover essentially learned nothing from their tutor. Apparently, if you have more dynamic spines, you are better equipped to encode and learn from experience. That’s a pretty important message, and this is the first time that relationship has been established in the context of learning a new behavior.”

Spinal tapestry

The pre-test differences in spines proved to have long-lasting influence, Mooney told us. “We are seeing changes in the brain that occur really quickly, within hours, even though the process of learning that is unfolding will take many weeks to complete. It’s not like the animal hears the tutor, and has mastered the song by the time we see the change.”

Image: Todd Roberts

After this zebra finch was “tutored” in singing by an adult finch, dendritic spines (the tiny white branches) emerged from the dendrite (green arrows) or enlarged (blue arrow). Both changes helped the birds remember the song.

And what makes a dumb bird? A fixity in the number of dendritic spines, Mooney says. The fact that spines tend to become fixed in mature birds could explain why birds cannot learn to sing if they wait too long to hear another bird’s song.

The same phenomenon could explain why it’s difficult or impossible for adult people to become fluent in a new language.

The study not only provides support for the notion that certain neural pathways grow stronger during learning, but it also explains how this could happen. A better distribution of dendritic spines eases the flow of nerve signals across synapses, which helps the bird remember how to sing like another zebra finch.

In essence, the mechanism that Mooney was watching comes down to a neural hybrid of use-it-or-lose-it and trial and error. “The spines are asking, ‘Am I needed? If no, I go. If yes, I stay,’” says Mooney. “They are waiting for a signal, and when it comes through, they are almost like a piece of photographic film. They respond and the synapse is permanently altered.”

Watching – and learning

Humans have many forms of learning, Mooney admits, “But bird song is imitative learning, and imitation is not only the sincerest form of flattery; it’s also basis of much of our culture,” such as speech, art and music. “Finding an animal model in which you can study cultural transmission of behavior is a really powerful way to explore how the brain responds to modeling of behavior by another animal.”

Smart brains are flexible brains, Mooney found. “We were able to see differences in juvenile brains in animals that were the same age, but some could learn and some could not. This suggests that if the brain is in a highly stable condition, you can get stuck.”

David J. Tenenbaum