Sunday, May 29, 2011

Advances in cytosolic drug delivery

Nanoparticles (particles smaller than 100 nm where materials display different properties than at the bulk state) are frequently used in nanomedicine for drug delivery and other purposes. The sophistication and specificity of nanoparticle use is growing, particularly for delivering drugs past the lipid bilayer barrier of the cell wall to the inside of cells (cytosolic drug delivery) where they can target biophysical processes more easily. Two advances focus on cytosolic drug delivery, using light and peptides to break the endosomes (carrying vehicles) to release drugs directly into the cytosol.

1) Light-mediated endosomal breakage
One advance is in the development of nanoparticles (size-tunable (30-200 nm) highly monodispersed mesoporous silica nanoparticles) that can be loaded with a variety of compounds and released into the cytosol via light-mediated endosomal breakage, as illustrated in Figure 1 (Febvay et al, Nano Lett, 2010).

Figure 1: Nanoparticle cargo discharge through light-activation.

2) GALA peptide endosomal breakage
A second advance is in cytosolic drug delivery with nanoparticles using a peptide, GALA, to encourage endosomal breakage. GALA (comprised of repeating sequences of Glu-Ala-Leu-Ala) mimics the function of viral fusion protein sequences that mediate escape of virus genes from endosomes (Nakase et al, Methods Mol Biol, 2011).

Sunday, May 22, 2011

Anti-aging research developments in rapamycin, sirtuins, and stem cells

The Third Bay Area Aging meeting was held at Berkeley on May 8, 2010.

One highlight was the emperor’s new clothes statement “Maybe C. Elegans (e.g.; worm) is not the correct model organism for human aging!

A variety of research was presented, with four themes amongst the most interesting:

1. Role of rapamycin in preventing inflammation
Rapamycin (more technically known as the mammalian target of rapamycin (mTOR)), has long been examined in aging since it is a protein that regulates a range of cellular behavior including growth, proliferation, motility, and survival. Initially hoped to be useful in treating cancer, rapamycin later turned out not to kill tumors due to systems biology; when mTOR is given and the TOR pathway is knocked out, the ERK pathway is upregulated instead.

However new research presented by Remi-Martin Laberge (Buck) shows that there is hope for rapamycin in the context of inflammation prevention. The normal process is that DNA damage response leads to NF-kB (a protein controlling DNA transcription) activation which leads to IL-6/8 (inflammation-related proteins) buildup, but with an mTOR introduction of rapamycin, instead IL-1a (an immune-response regulator) is obtained which prevents inflammation.

The prevention of inflammation is thought to be critical in anti-aging as many aging pathologies start with inflammation which later escalates to waste-build up and tissue break-down. This work is part of ongoing SASP (senescence-associated secretory phenotype) research by the Campisi lab (recent papers on p53 and p38MAPK).

2. Role of recently discovered SIRT7 in oncogenesis
Matt Barber (Stanford) presented work regarding a recently discovered SIRT (Silent Information Regulator) protein. SIRT7 is a chromatin-associated protein and site-specific histone H3 K18 deacetylase. There is a potential connection with SIRT7 and oncogenesis in that SIRT7 interacts with ELK4 (a pathway upregulated in cancer) to suppress a tumor suppressive gene expression network and helps stabilize aggressive cancer phenotypes.

3. Enhanced stem cell therapies
Randy Ashton (Berkeley) showed research regarding the increased ability to dopaminergiacally pattern hESCs to facilitate regenerative therapies for Parkinson’s disease. This was accomplished by making a protein important in neural development, sonic hedgehog, more sensitive through polyvalency.

4. Protein homeostasis and proteasome activity necessary for long lifespan
Brett Robison (Buck) presented work suggesting that normal proteasome function is required for full lifespan in yeast. The proteasome is an important location for waste degradation in cells. Aging cells showed impaired protein homeostasis and decreased proteasome function but it is unclear if this is cause or effect. Theodore Peters (Buck) also showed that maintaining protein homeostasis is important for healthy aging.

Sunday, May 15, 2011

Genomic polymorphisms trigger phantom limb pain and synesthesia

Well-known cognitive neuroscientist V.S. Ramachandran (“Phantoms in the Brain”) has been extending his original phantom limb pain research into new realms over the last several years, facilitated by the advent of new tools such as fMRI and genomic analysis.

It turns out that phantom limb pain is related to other anomalies such as synesthesia, a ‘mis-wiring’ of the senses such that stimulation to one sense results in an experience in another (for example, someone may see Monday as red). In all of these cases, there is an overabundance of neural connections in the brain. Genomic polymorphisms prevent these connections from being pruned normally.

Synesthesia is 7-8 times more common in artists, which begs the question of creativity measurement. A synesthete’s depiction of the world he or she sees may look like creativity to non-synesthetes, but is it reporting or creativity from the synesthete’s viewpoint? Synesthetes of the same type would need to assess creativity.

Sunday, May 08, 2011

App fever at Mobile Health 2011

This year’s attendance was double last year’s at the Mobile Health conference, held at Stanford University May 4-5, 2011. The main theme last year was monetizing mobile health apps, without any real ideas of how to do so. This year the main theme was app fever – everyone either having or thinking that they need to have an app. No one seemed to be immune - large and small health service providers, physician groups, insurers, and entrepreneurs alike are scrambling to launch apps.

Rather than having each organization struggle through multi-platform app development,

what is needed is the GeoCities of mobile apps,
a plug and play platform where app creators can select different widgets for app customization. The most obvious mobile health app widgets would be for appointment scheduling, prescription management, lab test results, physician interaction, and EMRs.

Since app fever reaches far beyond the health sector, GeoCities/Dreamweaver-level platforms, much more accessible to the layperson than Google App Inventor and unified mobile code base tools, could cause even greater activity in the already booming mobile sector.

Sunday, May 01, 2011

How small is small? the pico, femto, atto world

Man continues to master the manipulation of matter and timescales further up and down the chain from observable quotidian life. Regarding time, ultrafast materials is the area of science that deals with phenomena occurring in picoseconds and faster.

The familiar time scale is one second, easily measurable with a stop watch. A picsecond is 10-12 of a second or 0.000000000001 seconds, a timescale used in high speed electronics. A femtosecond is 10-15 of a second, the timescale of molecular vibrations and carrier interactions in solids. An attosecond is 10-18 of a second, the timescale of electron motion at atomic levels.

Scientists are now finding in nature that most energy transfer and charge transfer transactions are typically taking place at the vibrational range, at the femtosecond timescale. A prominent example is the rhodopsin photoreceptor for vision. Traditional models for describing these dynamics, e.g.; Bloch’s single-electron band structure model, work for condensed matter but not for regular matter.

New models are needed to understand the interplay between atomic structure and electronic structure. Atomic structural dynamics deal with ultrafast chemical reactions,
ultrafast phase transitions, and ultrafast biological processes. Electronic structural dynamics deal with bond dynamics, valence charge flow, charge transfer, and electronic phase transitions.

One new tool being applied is the femtosecond X-ray. Since femtosecond X-rays interact with atomic cores, they are useful for obtaining direct information about atomic positions as compared with traditional optical measurements which only provide indirect information. This has immediately transferable implications in electronics manufacturing and biological applications.

Moving beyond the femtosecond scale, a next-generation light source at the attosecond time scale is being planned for the 2020 timeframe at Lawrence Berkeley Lab.