Latent Cell Memory

Artistic impression of nucleosomes interaction.
Credit: Mette Høst, CMOL, Niels Bohr Institute, University of Copenhagen

New Danish research has examined the mechanisms behind latent cell memory, which can come to life and cause previously non-existent capacities suddenly to appear. Special yeast cells for example, can abruptly change from being of a single sex to hermaphrodite.

Researchers from the Niels Bohr Institute at the University of Copenhagen have used mathematical models and computer simulations to examine fundamental mechanisms of cell memory. The research is an interdisciplinary cooperation between molecular biologists and physicists and has just been published in the journal CELL (article by Dodd et al., 18 May issue).

Dormant capacities

Our genetic material - DNA -- is a blueprint for how we look and are. This genetic material is very stable and it is faithfully transmitted to our descendants. Once in a while though, a change occurs to the DNA, either large or small. Such changes are at the origin of the immense and varied animal and plant life on earth. Constructive changes in the DNA, that is, changes creating new functions, normally arise by a slow and gradual process that involves natural selection operating over many generations.

Sometimes however, dramatic and very sudden changes are observed in one individual in the absence of any kind of change to the DNA. This happens in fact in all of us as our body develops: cells with identical genetic information adopt very different fates, forming tissues that have apparently very little in common with each other, such as skin, brain, or bones. Mechanisms at the origin of this so-called cellular differentiation are those for which researchers at the University of Copenhagen have a possible clarification.

"The explanation for the sudden changes is that it is not the DNA itself that is altered - it is its immediate surroundings that change and thereby cause a cell to activate some of its dormant capacities" says Kim Sneppen, professor in Biophysics at the Niels Bohr Institute, University of Copenhagen .

The environment controls the DNA

The DNA coils itself around protein complexes called nucleosomes. Importantly, nucleosomes can carry various chemical modifications that either allow, or prevent, the expression of the DNA wrapped around them. Every time a cell divides into new cells, its double-stranded DNA splits into two single strands, which then each produce a new double-strand.

Nucleosomes though are not duplicated like the DNA-strands. Rather, they are distributed between the two new DNA double strands and the empty spaces are filled by new nucleosomes. Cell division is therefore an opportunity for changes in the nucleosomal composition of a specific DNA region. Changes can also happen during the lifetime of a cell due to chemical reactions allowing interconversions between the different nucleosome types. The effect of these changes can be that a latent capacity that was dormant comes to life, or, conversely, that a previously active capacity shuts down.

Same inheritance -- different traits

In the practical experiment molecular biologists used a mutant of a yeast cell which was bi-stable, in that it could become either of a single sex or hermaphrodite. The experiment showed that a spontaneous change occurred in the yeast cells about every 2000 cell-generations. By building a mathematical model based on positive feedback from the microscopic state of the nucleosomes, the research group could simulate the experimental results and in this way gained insight into the mechanisms by which living cells with identical DNA can achieve extreme differentiation.

The research at the 'Models of Life' Basic Research Center at the Niels Bohr Institute has shown that communication between nucleosomes and positive feedback are likely to constitute fundamental memory mechanisms in individual cells. The mechanism gives both stability and openness to new influences which the cell could need to change state. Nature has a partner which controls the cells latent memory.

Latent Memory Of Cells Comes To Life
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Nanomedicine & Nerve Cells

Nanomedicine Opens The Way For Nerve Cell Regeneration

Credit: Stockphoto - Sebastian Kaulitzki

The ability to regenerate nerve cells in the body could reduce the effects of trauma and disease in a dramatic way. In two presentations at the NSTI Nanotech 2007 Conference, researchers describe the use of nanotechnology to enhance the regeneration of nerve cells.

In the first method, developed at the University of Miami, researchers show how magnetic nanoparticles (MNPs) may be used to create mechanical tension that stimulates the growth and elongation of axons of the central nervous system neurons. The second method from the University of California, Berkeley uses aligned nanofibers containing one or more growth factors to provide a bioactive matrix where nerve cells can regrow.

It is known that injured neurons in the central nervous system (CNS) do not regenerate, but it is not clear why. Adult CNS neurons may lack an intrinsic capacity for rapid regeneration, and CNS glia create an inhibitory environment for growth after injury. Can these challenges be overcome even before we fully understand them at a molecular level?

Dr. Mauris N. De Silva describes the novel nanotechnology based approach designed that includes the use of magnetic nanoparticles and magnetic fields for addressing the challenges associated with regeneration of central nervous system after injury. "By providing mechanical tension to the regrowing axon, we may be able to enhance the regenerative axon growth in vivo." This mechanically induced neurite outgrowth may provide a possible method for bypassing the inhibitory interface and the tissue beyond a CNS related injury.

Using optic nerve and spinal cord tissues as in vivo models and dissociated retinal ganglion neurons as an in vitro model, De Silva and his colleagues are currently investigating how these magnetic nanoparticles can be incorporated into neurons and axons at the site of injury. Although, this study is at a very preliminary stage to explore the possibility of using magnetic nanoparticles for enhancing in vivo axon regeneration, this work may have significant implications for the treatment of spinal cord injuries, and is a vital "next step" in bringing this new technology to clinical use.

The second presentation focuses on peripheral nerve injury, which affects 2.8% of all trauma patients and quite often results in lifelong disability. Since peripheral nerves relay signals between the brain and the rest of the body, injury to these nerves results in loss of sensory and motor function. Upper extremity paralysis alone affects more than 300,000 individuals annually in the US. The most serious form of peripheral nerve injury is complete severance of the nerve.

The severed nerve can regenerate; the nerve fibers from the nerve end closest to the spinal cord have to grow across the injury gap, enter the other nerve segment and then work their way through to their end targets (skin, muscle, etc). Usually, when the gap between the severed nerve endings is larger than a few millimeters, the nerve does not regenerate on its own. If left untreated, the end result is permanent sensory and motor paralysis. A few hundred thousand people suffer from this debilitating condition annually in the US.

Currently, the most successful form of treatment is to take a section of healthy nerve (autograft) from another part of the patient's body to bridge the damaged one. This autograft then serves as a guide for nerve fibers to cross the injury gap. Although successful, this autograft procedure has major drawbacks including loss of function at the donor site, multiple surgeries and, quite often, it's just not possible to find a suitable nerve to use as a graft. Various synthetic nerve grafts are currently available but none work better than the autograft and can't bridge gaps larger than 4 centimeters.

Researchers at the University of California, Berkeley have developed a technology that has the potential to serve as a better alternative than currently available synthetic nerve grafts. The graft material is composed entirely of aligned nanoscale polymer fibers. These polymer fibers act as physical guides for regenerating nerve fibers. They have also developed a way to make these aligned nanofibers bioactive by attaching various biochemicals directly onto the surfaces of the nanofibers. Thus, the bioactive aligned nanofiber technology mimics the nerve autograft by providing both physical and biochemical cues to enhance and direct nerve growth.

This technology has been tested by culturing rat nerve tissue ex vivo on our bioactive aligned nanofiber scaffolds. When the nerve tissue was cultured on unaligned nanofibers there was no nerve fiber growth onto the scaffolds. However, on aligned nanofiber scaffolds, they not only observed nerve fibers growing from the tissue but the nerve fibers were aligned in the same orientation as the nanofibers. Furthermore, when there were biochemicals present on the nanofibers, the nerve fiber growth was enhanced 5 fold. In a matter of just 5 days, nerve fibers had extended 4 millimeters from the nerve tissue in a bipolar fashion on the bioactive aligned nanofiber scaffolds. Thus, this technology can induce, enhance and direct nerve fiber regeneration in a straight and organized manner.

In order to make the technology clinically viable, they have also developed a novel graft fabrication technology in their laboratory. The most common method for fabricating polymer nanofibers is to use an electrical field to "spin" very thin fibers. This technique is called electrospinning and can be used to make nanofiber scaffolds in various shapes such as sheets and tubes. They have made a key innovation to this technology that enables us to fabricate tubular nerve grafts composed entirely of polymer nanofibers aligned along the length of tubes. This technology also allows customization of the length, diameter and thickness of the aligned tubular nanofiber grafts. The group will evaluate the performance of these aligned nanofiber nerve grafts in small animal pre-clinical studies starting in mid-May.

The technology presented herein is being patented by the University of California, Berkeley and has been licensed to NanoNerve, Inc.

According to Principal Investigator, Shyam Patel, "Speed is the key to successful nerve regeneration. Our aligned nanofiber technology takes full advantage of the fact that the shortest distance between damaged nerve endings is a straight line. It directs straightforward nerve growth and never lets them stray from the fast lane."

The presentation on magnetic nanoparticles is "Developing Super-Paramagnetic Nanoparticles for Central Nervous System Axon Regeneration" by M.N. De Silva, M.V. Almeida and J.L. Goldberg, from the University of Miami. The talk on aligned nanofibers is "Bioactive Aligned Nanofibers for Nerve Regeneration" by S. Patel and S. Li, from the University of California, Berkeley, CA.

Story adapted from a news release by Elsevier Health Sciences.
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