Human cells have 46 chromosomes that determine who we are — a factory for replication and reproduction that forms our body, traits and aging.
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Your typical organizational consultant would be thrilled by the way this factory operates. Within this 10-micrometer cell sits a jumble of 46 segments of DNA spirals that would stretch three meters if they were strung together.
“Just to understand the proportions, it’s like taking a bowl of spaghetti and making it into one long strand that’s about 10 kilometers long,” says Prof. Yuval Garini of Bar-Ilan University’s physics department and head of its Institute for Nanotechnology and Advanced Materials.
“The chromosomes in the nucleus are inside a fluid. If there’s no mechanism for maintaining order there, the cell will die and won’t be able to complete the division stage.”
When it comes to the random mixture of chromosomes, every consistent genetic process is a kind of miracle that lets us pass on our genetic code and produce proteins and cells.
Garini focuses on what makes the order and stability out of the jumble; he recently published an article in Nature Communications on the matter. It took five years of research, with the aid of research students Irena Bronshtein and Eldad Kepten, in collaboration with Prof. Yaron Shav-Tal of Bar-Ilan’s Exact Sciences Department.
“We’re presenting a significant, logical, catchy and simple solution to the question of chromosome-system stability,” Garini says. “In small biological systems, at the single-cell level, there is no brain, there are no sensors, there is no intelligent being that views and directs all the players separately.”
According to Garini’s research, the “arms” connecting the chromosome parts in the cell are basically proteins known as Lamin A.
In recent years, a direct connection was found between Lamin A and several diseases, among them muscular dystrophy, diseases tied to the peripheral nervous system and diseases causing accelerated aging. The most famous is Hutchinson-Gilford progeria syndrome, which causes rapid aging in children and is induced by a Lamin A mutation.
The list also includes Emery-Dreifuss muscular dystrophy and Dilated Cardiomyopathy, which causes the heart to enlarge and restricts its ability to supply the organs with blood.
“The exact reasons tying Lamin A proteins to these diseases is still not fully known,” Garini says. “They’re almost certainly tied to a distortion in the protein structure that prevents normal functioning, as well as interruptions in the organization of the DNA in the nucleus and the way it affects the creation of other proteins.”
Jumble of coils
While science already assigned a role to Lamin A proteins in stabilizing a cell’s genetic system, some scientists were convinced that Lamin A was only found on the internal wall of nuclei, tied to the extremities of the jumble of coils.
As a physicist, Garini believed that other components in the nucleus were required to create a stable and effective network.
“We didn’t start out working in a vacuum,” he says. “Lamin A is well known, and it was known that it lines the nucleus’ internal walls. But we believed this wasn’t enough to explain the existing order in the nucleus.”
In their research, Garini and his colleagues showed that Lamin A is found not only on the walls but also in the nucleus. And it connects the chromosomes, turning them into a stable network. To do this, the scientists had to take special measurements in living cells.
According to the research, the physical connection via the protein takes place at many points in the nucleus — both on chromosome extremities (telomeres) and on other parts of chromosomes. Previous studies showed that two Lamin A proteins are tied by their tails and create a two-armed, T-shaped structure, so that each can send an arm to another chromosome and connect with it.
The result is a raft of connective junctions that generate a stable and consolidated network, necessary for coding and genetic replication.
Looking good on the dance floor
To understand Lamin A’s decisive role in creating order, the researchers used the process of elimination. They disrupted Lamin A activity in some cell groups, preventing it from doing its job. The differences from the normal cell were dramatic. The chromosomes began moving randomly, faster and across a larger area.
It’s hard to imagine a desirable outcome emerging from this chaotic activity. The discovery assigns the protein a more central role than previously thought. Garini paints the picture in an interesting way.
“I compare this to a disco. Think about a group of young people blowing off steam to trance music, with each going wild and every time heading to a different part of the dance floor. But when people who are more disciplined or know each other and haven’t seen each other in two years enter the dance floor, they’re closer; they meet and shake hands,” he says.
“Now imagine that each of them has more than two arms and they shake hands with more than one person at a time. A kind of network is created that moves but is relatively static. This description is an allegory, but it’s not much different from what goes on in a nucleus in a healthy situation.”
The work of Garini and his colleagues is another example of the fruits of cooperation between physics and biology. In this interdisciplinary approach, biophysics, physics answers biological questions.
In the Lamin A case, Garini’s research question was basically physics-oriented, trying to understand the components and forces operating to maintain stability in a network of DNA segments. The answer wouldn’t have been reached without biology.
“The biophysical concept has existed for 50 years, but until recently the significance was that physicists were the people who develop microscopes and other analytical instruments, while biologists were the ones using them,” Garini says.
“In recent years, this has changed, and physics is being assimilated into the research of classical biologists. Collaboration between the two areas was intensive in our research.”
Thus, for example, for the researchers to follow certain sites in the nucleus, they had to mark them. Here biology provided the solution.
The researchers isolated a fluorescent protein originating from marine organisms and attached it to another protein characterized by attaching to chromosome edges. These proteins were inserted into the nucleus, marking the desired areas with points of light.
“Without this solution, which comes from the world of biology and genetics, we couldn’t have done the necessary optical measurements,” Garini says. “There’s an understanding now that physics is an inseparable part of biological systems, and many research directions combine them.”