Think of your memories: a first kiss, a broken bone, a heart-wrenching good-bye. They all changed your DNA.
Neuroscientists have long sought clues to memory — what we remember, what we forget — and increasingly, they find genomics plays a key role, says University of Florida neuroscientist Leonid Moroz.
For the brain to hold onto something for 20 years, 30 years, a lifetime, what is happening?
“It’s a fundamental question in neuroscience: How do you remember your first kiss for the rest of your life?” says Moroz, distinguished professor of neuroscience, genetics, chemistry and biology in the UF College of Medicine and the Whitney Laboratory for Marine Biosciences. “How does it fundamentally change you, modify something in your brain, and how is this modification maintained, if you’re lucky, for 60 to 80 years?”
For answers to this and other questions about the human brain, Moroz has turned to the sea.
In Aplysia, also called the sea slug or sea hare, he uses neurons, the largest in the animal kingdom at up to 1 millimeter in diameter, visible even without a microscope. In the ctenophore, or comb jelly, he has discovered a different evolutionary path to neural complexity, with a different chemical language. Recently, he has turned his attention to the cephalopod, or Octopus, in hopes of discovering how it developed an elementary intelligence independent of mammals.
The brains of these creatures, though complex, do not approach the complexity of the human brain with its estimated 86 billion neurons, but they can present alternative solutions to help scientists test theories and learn more about brain functions and origins. A census of cell types in the brain is one of the program areas at the UF McKnight Brain Institute, with which Moroz is affiliated. And with the federal BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative swinging into gear, now is the perfect time to forge ahead.
With the help of sea creatures, Moroz says, great strides are possible.
The Not-so-common Sea Slug
The sea slug, Aplysia californica, holds the distinction in the animal kingdom of having the largest brain cells. These colossal cells make Aplysia an excellent paradigm for the study of neurons as they learn and remember, Moroz says.
Early in his research, Moroz says, he became frustrated with white lab rats and dropped them to study genomics of sea slugs with their giant neurons, against the strong advice of more senior scientists. Then, on Christmas Eve 2002 he was working in his lab when he got a call. He figured it was his wife, telling him to come home, but it was Nobel Prize-winning neuroscientist Eric Kandel, suggesting a collaboration.
“My jaw dropped,” Moroz says, especially after the years of being discouraged from studying sea slugs and neurogenomics.
Kandel shared the Nobel in 2000 for research using sea slugs as a model for human memory formation, and was interested in the work Moroz was doing to sequence individual neurons. The research team reported in Cell in 2006 that more than 10,000 genes in a single sea slug brain cell could be expressed at one time. They also found that sea slugs and humans share more than 100 genes associated with common neurological disorders, a finding that could help in the study of degenerative diseases like Alzheimer’s or Parkinson’s.
The ability to sequence individual neurons in memory circuits could shed light on fundamental questions: how neurons work and why they work in a particular way, Moroz says.
One of the goals of the research is explaining why memories are stable, although the environment of the brain is not, with most of its molecules replaced every week or so. Memories, Moroz said, change the connections between brain cells morphologically, creating a structural basis for memory. But what are the molecular bases for long-term persistence of memory? He was surprised by what he found in Aplysia.
“Half of the Aplysia genome in neurons is chemically modified within two hours of memory forming,” says Moroz. “Memory, indeed, has a home in DNA.”
The challenge, Moroz says, is figuring out how, so quickly, signals that travel from your eyes or ears pierce the neuronal membrane to reach the nucleus and modify half the genome in a specific cell. Via computer analyses, scientists can monitor the activity of the entire genome in each cell of Aplysia memory circuits as they learn and remember, and “already we see it’s not random,” Moroz says.
Although the nervous system in the sea slug is simpler and has only about 10,000 neurons, that actually is ideal, because it is more easily studied. With their huge neurons, sea slugs provide an opportunity to do genomic analysis of the entire brain and combine it with physiology and memory studies, perhaps pointing the way to help scientists better target research in humans.
Paraphrasing a quote, Moroz says, “It’s not the days you live, it’s the days you remember.’
“How does the brain do it?”
In typical style, human hubris extends to evolution, the common belief being that simple organisms are at the bottom of the tree of life and humans, with their neural complexity, at the top. The fragile ctenophore, however, achieved neural complexity following an evolutionary path all its own, a recent finding by Moroz and a research team that challenges 100 years of textbooks on evolution of neural complexity.
Comb jellies, in fact evolved traits that human brains did not: the ability to regenerate, even multiple times.
Moroz has studied the sea creatures for years, often finding his work stalled by specimens that declined so quickly after collection that they were dead or deteriorated by the time they reached the lab. The waste of the beautiful creatures saddened him — he was forced to collect extra samples in hopes of some surviving — and the delay in collection, examination and research was frustrating.
His solution: take the lab to sea. The idea was simple but the execution was complicated. Without major funding, he needed to convince someone else the idea would work, and he found a receptive ear in UF College of Engineering alumnus Steven Sablotsky, who was willing to turn his 141-foot yacht into a research vessel.
The Copasetic went to sea in February and March. Moroz collected comb jellies, and processed and sequenced them onboard in his Ship-Seq mobile lab, which was linked by satellite to UF’s newest high-performance supercomputer, HiPerGator. In hours, he had the data — and proof that an at-sea genomics lab could work.
As his work progressed, he and his team discovered the secret the fragile ctenophore had been guarding was its own, very different, evolutionary path, so different, in fact, that Moroz calls them aliens of the sea. The work was published in Nature.
“Our concept of nature was that there was only one way to make a complex brain or neural system. We oversimplified evolution,” Moroz says. “There is more than one way to make a brain, a complex neural system.”
The ctenophores’ novel genomic toolkit with its rapid regenerative capabilities could reveal new ways to look at brain diseases, which Moroz describes as a “one-way ticket” to decline.
“Ctenophores show us there is more than one way to build a neuron and a complex nervous system.”
Moroz likens the study of genomics and the brain to the study of dark matter and dark energy in physics. The universe we observe is 5 percent of what exists; the rest is dark energy and dark matter. Genomics, too, has come to a similar conclusion about DNA.
“We used to think all the major stuff was proteins and protein-coding genes, the rest of it was garbage. Then garbage was upgraded to junk, and now junk turns out to be a key player,” Moroz says. “So we do have dark matter and dark energy in the genome, and amazingly, this dark matter and dark energy in the neural genome contributes substantially to everything we can imagine about our brains: wiring, learning, memory, diseases, aging, mortality. The dark matter, dark energy of the genome, the so-called non-coding RNAs, tells us a lot about function.”
The Ocean as Testbed
An Octopus, like a dog, has about a half billion neurons. An Octopus is capable of learning by watching, and it is highly adaptable. The cephalopod memory center has 20 times more neurons than the memory center of mice, and they can perform some tasks more efficiently than rats or rabbits. Their arms can do much more than other appendages in the animal kingdom, even learn. Moroz says some may exhibit personality, and although the analysis of cephalopod cognitive function is still new, cephalopod neural machinery is remarkable.
Moroz is hoping to get funding to further study cephalopods, which he calls primates of the sea. The creatures develop memory centers apparently independently from other creatures, and Moroz is hoping to figure out how their form of intelligence works.
The Octopus, he says, is just one of the billions of experiments nature has already performed, awaiting discovery by scientists. Life on this planet, Moroz says, is an experiment 3.5 billion years in the making.
Studying different organisms and their adaptations to different environments is important because it could reveal a variety of evolutionary solutions to performing the same task, like learning and memory.
“Nature has performed countless numbers of experiments for us,” Moroz says. “The advantage of genomics is that we can obtain the genetic blueprint of virtually any creature in the sea to study these experiments. Different cells learn differently, but also different cells age differently. Some neurons in the sea slug age fast, some never age at all, they have already discovered Fountains of Youth. Some animals can regenerate their elementary brain, like comb jellies, some don’t, so nature provides us with millions of enormously efficient experiments already done.
“This is why biodiversity is so important.”
Moroz points out that eyes have evolved about 40 times independently in the animal kingdom. If there is more than one way to make an eye, it stands to reason, he says, that there would be more than one way to make a brain, a neuron, a memory circuit. Looking at the solutions nature puts forth, he says, can help humans. If something is broken in the human brain, nature may show an alternative way to fix it.
“We need to look at these alternative designs,” Moroz says. “We are brainwashed to look for similarity but I say vive la diversité. The differences tell us more.”
Working only on humans, or lab rats, is not the most efficient path to discovery, Moroz says, adding that work on starfishes led to understanding of immunity. The creatures of the sea hold potentially unique solutions for all branches of science and medicine. Moroz points out that about 50 percent of drugs today are derived from natural products — bacteria, algae, plants or animals. With 70 percent of the planet covered by oceans, scientists estimate that 14 million to 20 million compounds remain to be discovered at sea.
The discoveries, however, hinge on public and agency support of research, Moroz says.
“Some people still think of slugs and jellies as freaks of nature. They do not feel these guys are our cousins, our friends to help with disease,” Moroz said. “We have to see the ocean’s animals not as freaks of nature but as a friend.”
There is no time to waste; scientists estimate a species is lost every six hours. Moroz laments the natural heritage being squandered, along with the opportunities to learn. Who would have predicted, he asks, that ctenophores would be so neurally different, but it took five grant applications before that research was funded and the support of private organizations.
Science, technology and computing power have converged today, creating new possibilities. In 2001, Moroz says, scientists were working manually, and sequencing a thousand genes took several weeks. Today, on a flat, one-inch chip, a whole genome can be sequenced in a few hours, with data feedback an hour later. One of the chips he uses today has 160 million reactors to sequence DNA. The next chip in development will be able to do six times more, he says.
Questions can be asked today that could not be addressed 10 or even two years ago, he says; it would have been like trying to “use a steam engine to fly to the moon.” It is possible now, he says, to get the genomic blueprint of all the animals in the sea, and he chafes at the delays in the race to save species. The molecular heritage of the planet is in our hands.
“We have capabilities we are not maximizing,” Moroz says. “The technology is here, the animals are here, the opportunity is here. If we wait, on a global scale, think what we lose. We need to do this faster, do it today, and disseminate the information at the speed of light using supercomputers and satellites.
“What are we waiting for?” Moroz asks. “We need to shake the tree of life.”
Leonid L. Moroz, Distinguished Professor of Neuroscience, Genetics, Chemistry & Biology, (904) 461-4006