105 replies to this topic

[Lazarus Long]

A side issue of immense importance to all the medical technologies that we are attempting to integrate with regard to the goal of longevity is the specific technologies that allow for manipulation of the genome. These can include hypothetical applications of nanotechnology as well as proven uses for mutagenic transcriptases and phages. This should also examine methods that allow for isolation of episomal genetic material and cross species and phylum insertion for the numerous purposes from artificial adaptation for disease resistence to creating interface technology for cybernetic augmentation, from the creation of xenotransplant organ tech to GM food/fuel/ and waste reduction tech.

To add to the mystery and what we know, there appears to be some subtle mechanisms for the genes themselves to do this but we have only been able to observe this in simpler organisms. But more than a simple Natural Selection process is at work for example with the Darwin Finches of the Galapagos.

Why do I make such an outragous claim?

Because of speed and focus with which the adaptive characteristics of their beaks is possible. There appears to be some genetic regulator that increases the opportunity for successful mutation in relation to environment. If this observation and assumption are ever validated, then a gene, or set of genes may be found that turn on and off the ability to mutate in relation to specific stresses. This could then provide a natural method of doing what we are trying to do with the following methods artificially.

That said the focus of this thread is to identify and compare existing methods for manipulating the genome and perhaps as I am doing with this introduction to suggest alternative methods and areas of investigatin for new methods.

We should also take a little time to analyze the limits of these methods and theorize how some methods may overlap or be integrated to provide more powerful tools for treatment. I believe we should begin by nitroducing articles and select technical references for review and then begin a comparative discussion after assembling sufficient data.

The following article to start with is about a method of inserting genes that is now being tested utilizing a viral carrier to insert the genes to repair Parkinson's Disease. It is one of a number of new methods that we should be scrutinizing more closely.

LL/kxs

PS. I have to go back and review but follow up on this first article is now required. Some data has been collected and anyone who finds it before I do please post it. Also I have decided to make this a CIRA topic and expect any and allto spin off the thread for more personalized examinatinos of this theme.

My thanks to Helix for getting me to come back to this.

LL/kxs

Doctors to Start Gene Therapy in Parkinson's Patients

Doctors to Start Gene Therapy in Parkinson's Patients
Thu Oct 10, 2:04 PM ET
By Maggie Fox, Health and Science Correspondent

WASHINGTON (Reuters) - Gene therapy worked to stop the damage of Parkinson's disease (news - web sites) in rats, and the experiment was so successful that the operation will now be tried on a few people, researchers said on Thursday.

The researchers, in the United States and New Zealand, put new genes into the brains of the rats that stopped the symptoms that mark Parkinson's.

"We are using gene therapy to 're-set' a specific group of cells that have become overactive in an affected part of the brain, causing the impaired movement and other symptoms associated with Parkinson's Disease," Dr. Matthew During, a neuroscientist at the University of Auckland in New Zealand who led the study, said in a statement.

In Parkinson's, which affects up to 1.5 million Americans, brain cells that make an important message-carrying chemical called dopamine are destroyed. No one is sure why, but the result is a progressive and incurable disease that usually starts with mild tremors and eventually leaves patients virtually paralyzed.

Other brain cells become overactive because of the loss of dopamine, and this seems to cause many of the symptoms.

Treatments such as levodopa can help for a while, but eventually the brain damage cannot be reversed. There is an experimental therapy called deep brain stimulation (DBS), in which electrodes are inserted into the brain.

That seems to help, but it is only used in extreme cases, said During, who also works at Jefferson Medical College in Philadelphia. His gene therapy is meant to mimic the effects of deep brain stimulation.

"At this stage the effect of DBS doesn't seem to be wearing off," During said in a telephone interview. "The main downside is that there are certain side effects associated with leaving devices hooked up to a patient -- batteries fail, leads disconnect."

Writing in Friday's issue of the journal Science, During and colleagues said they used an adeno-associated virus to carry a gene called GAD into the brains of rats. GAD is responsible for making a compound called GABA, which is released by nerve cells to slow activity.

The rats showed fewer symptoms of Parkinson's and examination of their brain activity suggested the gene therapy did slow down the overexcited neurons, During's team reported.

It also seemed that the treatment actually stopped the destruction of their dopamine-producing cells.

The team, which founded a small Delaware-based company called Neurologix Inc., now has approval from the U.S. Food and Drug Administration (news - web sites) to test the treatment in people.

During said they would recruit 12 volunteers with relatively advanced Parkinson's and put a drop of the gene-carrying virus into the damaged areas of their brains.

The patients will be followed closely with MRI and PET scans to monitor brain activity, and careful clinical exams.

"At the end of one year we will analyze the data," During said.

Despite Cancer Risk, U.S. Gene Therapy Gets OK

[Lazarus Long]

Diffraction gradient lithography aids nanofluidics
11 October 2002

Small fluidic structures are important tools in the emerging field of bionanotechnology, but it can be difficult to stretch out long molecules such as DNA so that they can enter the nano-sized channels. Now, researchers from Princeton University, US, have developed a relatively cheap technique for making devices that gradually uncoil the molecules before guiding them into the channels.

"If the long strings of genomic DNA molecules are not uncoiled gradually, it is like dumping a pot of long spaghetti noodles into the sink and hoping they'll all go down the drain smoothly," Han Cao, a researcher at Princeton, told nanotechweb.org. "It's hard."

Fabricating a micropost array in front of the nanochannels helps to pre-stretch the long DNA molecules, as they must partially unwind to negotiate a path through the posts. The Princeton team reckoned that applying a gradient to the micropost region - so that the pathways become gradually shallower and narrower as they near the nanochannel region - would stretch out the molecules more effectively.

But making the structure easily and cheaply was a challenge. "You could spend hundreds and thousands of dollars and hours to write patterns with e-beam lithography, but it is prohibitively expensive and hard to scale up," said Cao. Conventional photolithography, meanwhile, struggles to produce features below a few hundred nanometres.

Not daunted, Cao and colleagues came up with a modified photolithography technique that they dubbed diffraction gradient lithography. To create the micropost region and gradient structure they applied a photoresist onto a silicon substrate chip containing large arrays of nanochannels made by nanoimprinting lithography. Then they used a photomask containing the post array pattern and, in the crucial step, added an aluminium blocking mask above part of the photomask.

This blocking mask both protected the region where the nanochannels were to remain and caused light diffraction along its edge. The diffraction led to a gradient in light intensity on the photoresist surface. And, following further treatment, such as development of the photoresist and reactive ion etching, this resulted in a gradient in the thickness of the silicon substrate in the area next to the remaining nanochannels.

"The whole industry has spent billions of dollars trying to minimize the feature/resolution-limiting optical light diffraction in making smaller and smaller structures, and I actually use diffraction to make smaller features," explained Cao. "The best part is, it costs nearly nothing and can be compatible with current industry-standard platforms."

The researchers reported their work in Applied Physics Letters.

About the author Liz Kalaugher is editor of nanotechweb.org.

LINKS

Nanostructures Laboratory, Princeton
Applied Physics Letters

[Cyto]

This isnt a gene insertion method but when a reliable vector is produced here is something we can correct...umung other things (chuckle).

RNA "Taught" to Act As Decoy in Living Cells

NF-kappaB (pronounced "en-ef-kappa-bee):

*activates genes that promote cancer-cell survival

*enables the HIV virus to reproduce, contributing to the onset of AIDS

*promotes the inflammation process involved in many chronic diseases, such as rheumatoid arthritis

Using a new approach, Mayo Clinic researchers have successfully "taught" an RNA molecule inside a living cell to work as a decoy to divert the actions of the protein NF-kappaB, which scientists believe promotes disease development. The findings are published in the current issue of Proceedings of the National Academy of Sciences.

[Cyto]

Gene therapy may switch off Huntington's

Using gene therapy to switch off genes instead of adding new ones could slow down or prevent the fatal brain disorder Huntington's disease. The method, which exploits a mechanism called RNA interference, might also help treat a wide range of other inherited diseases.

[Cyto]

Something to know...

Seattle home to cutting-edge gene therapy research

First, the elation: Nine doomed babies with "bubble boy" disease are cured with gene therapy.

Instead of imprisonment in an aseptic life and death before their first birthdays, the French children were restored to a normal life with a healthy, intact immune system.

Finally, it appeared that the promise of gene therapy -- fixing the body by rewriting its own instructional code -- was about to be realized.

Then the cruel sequel: Last summer, one of the boys in the 4-year-old trial developed leukemia, a terrible but known risk of the experiment. Months later, a second child developed an identical leukemia. The odds against that happening by chance were astronomical.

[kevin]

This isn't insertion but it is a way to get genes into the brain and probably a method that could be used to get transposons or some other splicing mechanism into cells to get gene insertion to work..

Undercover genes slip into brain


A MOLECULAR Trojan horse that can slip past the brain's defences has proved to be very effective at delivering genes to the brains of primates. It could be used to treat a host of brain disorders, from Parkinson's to epilepsy.
Treating the brain is very difficult because of the "blood-brain barrier" created by the tight junctions between the cells lining the capillaries. Only molecules recognised by the cell receptors can get in, unless they are very small. The viruses most gene therapists use to deliver genes are too big, and have to be injected directly instead. Even then, the genes are not expressed widely and evenly throughout the brain.

"Quite frankly, the existing delivery systems have been woeful failures," says William Pardridge of the University of California, Los Angeles. Instead, his team has been perfecting a way to get genes into the brain hidden inside fatty spheres called liposomes.

First the team coats the liposomes with a polymer called polyethylene glycol (PEG), without which they would be purged from the blood within minutes. Next, antibodies that latch on to some of the brain-capillary receptors are tethered to a few of the PEG strands. The antibodies trick the receptors into letting the liposomes pass, where they can deliver their cargo to brain cells.

Pardridge's team has already shown that the technique works in rats, by delivering the gene for the luminescent protein luciferase (New Scientist, 10 June 2000, p 10). Now the team has tested the liposomes in rhesus monkeys, using antibodies specific to primate brain receptors. Not only did it work, but the amount of luciferase produced was 50 times greater than in rats (Molecular Therapy, vol 7, p 11).

"I haven't seen anything like this for viral or non-viral vectors," says Savio Woo, director of gene therapy at the Mount Sinai School of Medicine in New York. "To reach the central nervous system through the blood-brain barrier in a non-human primate with this kind of efficiency- that's absolutely fantastic."

The liposomes do not appear to have any toxic side effects, though they do deliver genes to other organs besides the brain. But the team has shown that by choosing the right switch to turn on the gene, the gene will be active only in the desired tissues.

Because the genes are not integrated into the genome, weekly or monthly injections would be needed for long-term treatment. But Pardridge sees this as an advantage, because there's no risk of genes lodging permanently in the wrong place and triggering cancer- a worry with some gene therapy viruses.

The method shows promise for treating Parkinson's. The team gave rats a neurotoxin that causes Parkinson's-like symptoms by cutting production of the key enzyme tyrosine hydroxylase. Four weeks later, the team injected the rats with liposomes containing a gene that boosts production of the enzyme. Three days after that, the rats' abnormal movements were reduced by 70 per cent.

The liposomes can also deliver cargoes other than genes, including drugs and "antisense" RNA. The lifespans of mice with brain tumours doubled when the liposomes were used to deliver antisense RNA to block production of a growth factor. And in studies yet to be published, the team has exploited a mechanism called RNA interference (New Scientist, 15 March, p 20), delivering fragments of double-stranded RNA that "silence" cancer genes.


###
Anil Ananthaswamy, San Francisco

New Scientist issue: 22nd March 2003

Edited by kperrott, 21 March 2003 - 12:54 AM.

[Cyto]

A paper titled High-Level Sustained Transgene Expression in Human Embryonic Stem Cells Using Lentiviral Vectors [1] has given a pleasant glimpse at how we can control stem cells to execute desired operations (our stem cells not the mice).

[2]

Morphology
Virions enveloped; slightly pleomorphic; spherical; 80-100 nm in diameter. Surface projections of envelope small (surface appears rough), or barely visible; spikes (of about 8nm); dispersed evenly over all the surface. Nucleocapsids core isometric. Nucleoid concentric and rod-shaped, or shaped like a truncated cone. [2]

Physicochemical an Physical Properties
Buoyant density 1.16-1.18 g cm-3 in sucrose. Virions sensitive to heat, detergents, and formaldehyde. Infectivity not affected by irradiation. [2]

Since ESC can be differentiated without any known limit this ability to hack the system may prove useful in aggressively altering genetic behavior. "The lentiviral vectors used in this study are third-generation, self-inactivating (SIN), HIV-based constructs containing a 400-bp deletion in the U3 region of the 3' LTR following the reverse transcription and chromosomal integration." [1]
To clarify this we have a HIV vector that interacts with human cells. The self inactivating feature is brought on by the 400-bp deletion, Long Terminal Repeats are an overriding promoter that takes over the transcriptional machinery (RNAPII?). By taking most of this out down regulates the effectiveness. The reversetranscription section turn it from RNA to DNA and the chromosomal integration is self-explanitory.

The cells expressed the gene (Green Flouresence Protein) continuously even after 60 days of culture - differentiated into hematopoietic (CD34+) there was "minimal silencing" [1].

Overall this looks good, and no mention of cancer starting up.

[1] HERE
[2] HERE

Edited by XxDoubleHelixX, 30 March 2003 - 05:49 AM.

[Cyto]

_____________________________________________
______________________________________________
-=GENETICS OF STEM CELLS Lead to Gene Therapy?=-
Remeber the reports on hASC fusing with other cells and increasing chromosome numbers? Now some researchers are proposing that we step back and look at how they do this before injecting humans with the stem cells. And if you think about it that is a good idea. If we apply this fusion we may be able to make single or multiple instertion without the need of strong promoters (LTRs) of viral instertion methods.

"If stem cells are fusing, that could be good news for gene therapy researchers, who are trying to find effective ways to deliver new genes to cells."

“This could be a safe way to transfer a normal gene,” says Terada. “You could put a gene into an engineered stem cell and take advantage of cell fusion to cure a genetic deficiency.”

Source Here
_____________________________________________
______________________________________________

[Lazarus Long]

As promised elsewhere I am posting this article here as a significant example of a posible breakthrough both in specific application and methodology for gene insertion. I am curious to see us outline both HOW this was accomplished and a clear explanantion of WHY it works.

The apparent regeneration of complex neural interfacing alone bears merit but the implication that the process was applicable to adjacent unrelated tissues is a remarkable, if not entirely expected result and metaphorically like growing "hair on a billard ball".

Joke please. )

I understand these hairs have little to nothing to do with what most people associate with "alopecia." In fact this study is about a much more profound regeneration of a fundamental sensory organ system.

http://story.news.ya...me/hearing_loss

Scientists Regenerate Cell for Hearing
Sat May 31, 8:06 PM ET AP
By MALCOLM RITTER, AP Science Writer

For the first time, scientists have made mature mammals regenerate a type of inner-ear cell important for hearing, a key step toward a treatment that might someday help millions of people with hearing loss.

The researchers made adult guinea pigs grow new sound-sensing cells, called hair cells, in the spiral-shaped chamber called the cochlea.

Some 30 million Americans have significant hearing loss, and scientists say most of these cases — perhaps more than 90 percent — are due to lost or damaged hair cells. The cells can be damaged by aging, infection, loud noise, genetic conditions and exposure to certain medicines.

People normally develop about 16,000 hair cells in the cochlea of each ear, but they can't replace lost or damaged ones. The cells are critical to hearing because, using their hairlike projections, they convert sound waves into nerve impulses that go to the brain.

The new work is an early advance toward developing a therapy that might help restore hearing, said researcher Yehoash Raphael of the University of Michigan Medical School. He and colleagues present the results in Sunday's issue of the Journal of Neuroscience.

Edwin Rubel, who studies hair-cell regeneration at the University of Washington, called the results "a very, very important step. ... I wish I had done this study."

Raphael emphasized that the work is at an early stage and far from testing in humans. The researchers don't yet know how long the newborn hair cells can survive or even whether they can function. The scientists have just begun work to see if they can restore hearing to deaf guinea pigs.

For the reported study, Raphael and colleagues worked with a gene called "Math1," which must be active for a fetus to develop the initial supply of hair cells. In a surgical procedure, they squirted a solution containing Math1 genes into cochleas of adult guinea pigs. The genes had been placed inside viruses, which acted like shuttles to get the genes into the animals' cells.

One and two months later, the researchers examined the cochleas of 14 treated animals. All showed immature hair cells, usually between 25 and 50. Apparently, the treatment had transformed some non-sensory cells into hair cells, Raphael said.

Many of the immature cells were outside the region where hair cells normally grow, so those clearly resulted from the treatment, Raphael said. Despite their odd location, it's possible that at least some of them might be able to function, he said.

Other immature-looking cells were mingled in with the animals' original hair cells, and it's not clear whether they were new, or whether they were simply original cells recovering from the trauma of the surgery. Raphael speculates they were new cells that resulted from the treatment.

The researchers were encouraged to see nerve fibers growing toward some of the immature cells. That indicates the nervous system might be able to hook up with the new cells and transmit their signals to the brain, Raphael said.

Without such connections, the new hair cells would be useless. But the observed response of the nerve fibers to the new cells "is strong circumstantial evidence there will be an interconnection between the two," said hair-cell expert Dr. A.J. Hudspeth of The Rockefeller University and the Howard Hughes Medical Institute.

___

On the Net:

The Journal of Neuroscience: http://www.jneurosci.org


Information on hearing disorders: http://www.nidcd.nih.gov

Edited by Lazarus Long, 01 June 2003 - 07:18 PM.

[kevin]

From Eurekalert.org we have a press release which outlines the use of a new technology that uses differences in the way the surface tension of fluids behaves according to temperature to produce new microfluidic devices that are programmable. At the moment 'lab on a chip' devices, which are instrumental in using computers to help in profiling gene expression as well as discovering protein interactions, are dependent on channels etched in silicon to allow minute quantities of solutions to be used. The new technique uses heat energy to change the velocity and direction of a migrating fluid over a chip using programmable optical technology, eliminating the need for channels to be etched and increasing the speed of analysis manyfold. If we thought things were moving fast in the biological discovery area before, this technology promises to ramp it up even more.


http://www.eurekaler...t-oct080503.php

------------------------------------
Public release date: 5-Aug-2003
[ Print This Article | Close This Window ]

Contact: John Toon
john.toon@edi.gatech.edu
404-894-6986
Georgia Institute of Technology Research News

Optical control technique could enable microfluidic devices powered by surface tension
Reprogammable microarrays

Physicists at the Georgia Institute of Technology have demonstrated a new optical technique for controlling the flow of very small volumes of fluids over solid surfaces. The technique, which relies on changes in surface tension prompted by optically-generated thermal gradients, could provide the foundation for a new generation of dynamically reprogrammable microfluidic devices.
A paper describing the technique is the cover story for the August 1 issue of the journal Physical Review Letters. The research has been supported by the National Science Foundation and the Research Corporation.

Existing microfluidic devices, also known as "labs-on-a-chip," use tiny channels or pipes etched into silicon or other substrate material to manipulate very small volumes of fluid. Such "micropipe" devices are just beginning to appear on the market.

The Georgia Tech innovation could allow production of a new type of microfluidic device without etching channels. Instead, lasers or optical systems similar to those used in LCD projectors would produce complex patterns of varying-intensity light on a flat substrate material. Absorption of the light would produce differential heating on the substrate, creating a pattern of thermal gradients. Surface tension, a relatively strong force at micron size scales, would then cause nanoliter volumes of fluid to flow from the cooler areas to warmer areas through thermocapillary action.

"We envision that this could move multiple droplets or packets of fluid simultaneously, allowing arrays of drops to be moving at the same time at multiple locations," said Michael Schatz, a Georgia Tech associate professor of physics. "We could avoid putting detailed architectures onto the substrate. Instead, we would take advantage of advances in the miniaturization of optoelectronics to pattern the substrate with surface tension forces."

Because the temperature gradients would be formed by computer-controlled light patterns, pathways for the droplets could be quickly changed, allowing a reconfiguration not possible with existing microfluidic devices. And because the surface tension effects are strong at the micron scale, they could produce flow rates higher than channel-based microarrays, which must overcome large frictional forces. Finally, the substrate could be easily cleaned between uses, avoiding contamination.

In their paper, Schatz and colleagues Roman Grigoriev and Nicholas Garnier report their studies of how thermal gradients affect thin films of silicone oil on a surface of glass. The bottom of the glass had been painted black to absorb light, and a heat sink provided to prevent overheating.

The technique could theoretically also use liquid surfaces, where droplets of an immiscible liquid would be moved across a "substrate" fluid by the same surface tension forces. In a liquid-on-liquid system, the underlying fluid would also move, allowing higher flow rates.

In biological applications, fluids of interest are based on water, but Schatz says the optical principle could apply to most liquids. "This technique could apply to many fluid systems because it builds on an intrinsic property that nearly every fluid has – the temperature dependence of surface tension," he noted.

Though many technical hurdles remain, Schatz and his collaborators believe their technique could be the basis for a miniaturized lab-on-a-chip used for genetic or biochemical testing in the field. The easily reconfigurable system would be able to transport, merge, mix and split off streams of fluid flowing across a flat surface.

"If we can build devices that move fluids at small scales in a reconfigurable way, then in principle we can do all kinds of assays in the field at very high densities," Schatz explained. "This approach could be applied in a lot of different conditions."

Ultimately, the miniaturization of microfluidic devices could do for fluid handling what the modern semiconductor technology has done for electronics, allowing assays, chemical studies and other macro-scale processes to become smaller, cheaper and faster. "The shrinking of devices using microfluidics could be as revolutionary to our daily lives as microelectronics has been," Schatz said.

Unlike microelectronics, however, the drive to make microfluidic devices smaller and denser faces an immediate fundamental limit – the size of cells, DNA samples or protein molecules. If those are to be moved in fluid form, the microarray features can't be much smaller than a few microns.

Among the challenges ahead for building optically-driven microfluidic devices are controlling evaporation, developing interfaces to get the tiny volumes of liquid onto the surface, and choosing the right combination of substrate and heat sink to provide distinct temperature gradient patterns without overheating the fluids, notes Grigoriev, an assistant professor in the School of Physics.

"We are at the point of testing strategies for constructing the building blocks, much like the transistors of microelectronics," he said. "Once those pieces are in place, it will be much more straightforward to bring them together into a working microfluidic device."


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Technical contact: Mike Schatz (404-894-5245); E-mail: (michael.schatz@physics.gatech.edu)

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[kevin]

The expression of FoxM1B diminshes with age and it's effect has been discussed in the thread Aging Theories (cira).

The FoxM1B gene is involved in the turnover of cells and it's expression in the body diminishes as we age. In previous studies, Robert Costa in Chicago, has detailed how inserting this gene into the liver tissue of aged rats greatly enhances their recovery from hepatic/liver inury.

"By restoring the expression of this gene, we were able to achieve normal replication of cells like they were young again," said Costa, lead author of the study. He said he's hopeful that the study could lead to human benefits in less than five years.

Here's an update from the Life Extension Foundation that details a study by the same researcher who has engineered mice who have the gene througout their bodies. He will be looking for rejuvenation and longevity. Perhaps he should apply for the Methuselah Mouse Prize.

Link to Article

[kevin]

You might have seen before the discovery that a mutation in the Lamin A gene, which codes for a protein involved in the integrity of the cell nucleus, was involved with the premature/accelerated aging found in young children with progeria. Mutations in Lamin A were also implicated in the formation of skeletal defects in the syndrome mandibuloacral dysplasia (MAD). A few of the people exhibiting MAD however did not have mutant Lamin A, so further investigation was required, yielding the discovery that mutations in zinc metalloproteinase can cause the same development problems.

Zinc metalloproteinase is a bone development protein that has been implicated in the development of osteoarthritis as well as osteoporosis and premature aging.

------------------------------------------------
Public release date: 15-Aug-2003

Contact: Amy Shields
amy.shields@utsouthwestern.edu
214-648-3404
University of Texas Southwestern Medical Center at Dallas

Researchers identify second gene responsible for rare syndrome associated with skeletal defects
DALLAS – Aug. 15, 2003 – UT Southwestern Medical Center at Dallas researchers have discovered a second gene responsible for a rare syndrome that causes the loss of bone from the lower jaw, fingers, toes and collarbone.
The researchers isolated the gene, zinc metalloproteinase (ZMPSTE24), in a patient who had all of the classic characteristics of mandibuloacral dysplasia (MAD) but did not have a mutation in the LMNA gene, previously reported as a cause of the disorder.

In addition to causing MAD, mutations in this newly discovered gene may also lead to progeroid features, or premature aging, generalized loss of body fat and early death, the researchers report. The study appears in today's publication of the journal Human Molecular Genetics and also is available online.

"It was known that a mutation in LMNA caused MAD, but in several of the individuals that we studied LMNA was normal," said Dr. Abhimanyu Garg, professor of internal medicine and the study's senior author. "This led us to look at other genes that were associated with lamin A production. We considered ZMPSTE24 as a candidate gene based on recent reports that deletion of this gene in mice resulted in the development of similar physical features of the human form of MAD."

The LMNA gene encodes two proteins, lamin A and lamin C, which are components of the membrane of the cell nucleus. The zinc metalloproteinase enzyme is essential for producing the active form of lamin A. Besides MAD, LMNA mutations are linked to several conditions including a body-fat disorder called familial partial lipodystrophy, muscular dystrophy, cardiomyopathy and a premature aging disorder called progeria.

"It is likely that minor changes in these genes may predispose individuals to premature aging, a change of body-fat distribution, as well as osteoporosis," said Dr. Garg.

The researchers studied six individuals with MAD and found a mutation in LMNA in two. Of the remaining four individuals, who did not have a mutation in the LMNA gene, one was found to have mutations in ZMPSTE24. Dr. Garg is currently searching for mutations in other genes that are involved in processing of lamin A in three of the patients who did not have mutations in either LMNA or ZMPSTE24.


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[kevin]

Link: http://www.eurekaler...a-fpo082503.php
Date: 08-28-03
Author: -
Title: First production of a human protein with complex glycosylation in genetically modified yeast
-------------------------------------------------------------

Public release date: 28-Aug-2003
Contact: Jennifer LaBerge
jlaberge@glycofi.com
603-643-8186
GlycoFi

First production of a human protein with complex glycosylation in genetically modified yeast

LEBANON, NEW HAMPSHIRE (August 28, 2003): Yeasts and other fungi are reliable, cost-effective workhorses for the production of many industrial enzymes. However, biopharmaceutical companies currently manufacture few human therapeutic proteins using these organisms. The inability to correctly decorate human proteins with complex sugar molecules – a process known as glycosylation – has been the main obstacle that has prevented the use of fungal hosts for the expression of human therapeutics.

Today a team of scientists at GlycoFi, Inc. and Dartmouth College report the successful reengineering of the glycosylation pathway in the yeast Pichia pastoris. Published in the latest issue of Science, these results constitute the first fungal organism able to secrete a human glycoprotein with complex human glycosylation.

"The vast majority of therapeutic proteins are glycosylated and most require complex, human-like glycosylation to ensure therapeutic efficacy," said GlycoFi's Stephen Hamilton, Ph.D., lead author of the publication. "Mammalian cell lines can replicate human-like glycoprotein processing to a large extent, and so have traditionally been used to produce most protein therapeutics. However, mammalian cell culture systems have significant drawbacks including low protein yields, long fermentation times, production of a mixture of protein glycoforms, and ongoing viral contamination issues."

"Being able to produce human glycoproteins with homogenous N-glycan structures in a fungal host allows us to take advantage of the inherent commercial advantages of yeast and other fungal production systems," says Dr. Tillman Gerngross, GlycoFi chief scientific officer and associate professor of biochemical engineering at Dartmouth College. "Moreover, the ability to produce a homogeneous glycoprotein in yeast offers the biopharmaceutical industry a new tool for further understanding the structure-function relationships of glycoproteins and for potentially creating safer, more effective therapeutics."

Humanizing the Yeast Glycosylation Pathway

The GlycoFi team began their work with the yeast P. pastoris, a robust organism commonly used in fermentation processes, which can be grown to high cell density in a chemically defined growth medium. This yeast normally produces non-human N-glycans of the high mannose type, which have no therapeutic value for humans. The scientists modified the yeast by first eliminating endogenous yeast glycosylation pathways, while sequentially engineering into the organism five active eukaryotic proteins, including mannosidases I & II, N-acetylglucosaminyl transferases I & II and UDP-N-acetylglucosamine transporter. The targeted localization of these enzymes enabled the generation of a synthetic in vivo glycosylation pathway that enabled the yeast to produce a complex human N-glycan, GlcNAc2Man3GlcNAc2, in vivo. However, unlike the glycosylation pathway in mammalian cell lines, which typically produces an array of glycoforms, the genetically modified yeast yielded essentially homogeneous glycoforms.

"We have essentially been able to humanize the yeast, where it is able to make a single glycoform of exceptional uniformity," Dr. Gerngross said. "Unfortunately, using mammalian cell culture, it is difficult to isolate individual protein glycoforms and even more difficult to produce specific structures at a commercial scale. The ability to express a single protein in a library of genetically engineered yeasts – each producing a defined and uniform glycoform – will enable the generation of glycoprotein libraries that can be used both to elucidate specific structure-function relationships and to identify the most efficacious molecule for a particular therapeutic use. Moreover, once identified, a particular protein glycoform can be readily produced at industrial scale using the relevant yeast, due to the well-established rapidity with which yeast fermentations can be scaled up."

About GlycoFi

GlycoFi, Inc., privately held, was founded in 2000 with the mission of dramatically improving the capacity and cost of producing human therapeutic proteins, while simultaneously enhancing their efficacy and safety as therapeutics. The company harnesses the inherent advantages of yeast and other fungal-based protein expression systems by engineering these systems to produce correctly glycosylated human therapeutic proteins, thus greatly increasing the efficiency, fidelity and scalability at which those proteins can be made. For more information on GlycoFi, please visit the company's website at www.glycofi.com.


###
Note to Editors: This work was in part funded by a grant received from the National Institute of Standards and Technology's (NIST) Advanced Technology Program (ATP). GlycoFi received the ATP grant in October of 2002 to pursue a three-year project entitled "Production of Therapeutic Proteins through Metabolic Engineering of Yeast". ATP is designed to support high-risk research and development projects that, if successful, will lead to revolutionary new products and contribute significantly to the nation's economy.

Press Contact:

Jennifer LaBerge
GlycoFi, Inc.
jlaberge@glycofi.com
603-643-8186 x 122

Joan Kureczka
Kureczka/Martin Associates
jkureczka@aol.com
415-821-2413

--------------------------
Notes:
website: http://www.glycofi.com

[kevin]

Link: http://www.eurekaler...c-uom091203.php
Date: 09-12-03
Author: Warren Froelich
Source: American Association for Cancer Research
Title: U of MN researchers find genetic variations may predict treatment responses for myeloma

---

Public release date: 12-Sep-2003
Contact: Warren Froelich
froelich@aacr.org
215-440-9300
American Association for Cancer Research

U of MN researchers find genetic variations may predict treatment responses for myeloma

Researchers from The Cancer Center at the University of Minnesota have demonstrated that variations in genes may determine the outcome and toxicity of treatments for myeloma cancer patients. The findings support thinking that physicians may optimize care by adjusting treatment according to a patient's specific genetic condition. The findings will be presented September 15, 2003 at the American Association for Cancer Research (AACR)-sponsored specialty meeting on "SNPs, Haplotype, and Cancer: Application in Molecular Epidemiology."

Although chemotherapy drugs can be effective against myeloma in many patients, they can be less effective or even lethal in others. By determining a patient's toxic susceptibility to drugs through analysis of specific genetic variances, or single nucleotide polymorhphisms (SNPs), in genes known to promote myeloma growth, clinicians can adjust dosage levels or choose alternate, safer drugs to benefit the patient.

Led by Brian Van Ness, Ph.D., professor of genetics and a member of The Cancer Center, researchers analyzed patient samples from an Eastern Cooperative Oncology Group Study on myeloma chemotherapy treatments for 700 patients between 1987-1994. For this particular investigation, researchers examined 400 patient DNA samples for SNPs in genes that promote myeloma growth. Those patients with the SNPs that result in low production of the growth factor, generally had better outcomes to the chemotherapy and increased survival times.

"These data confirm that our research on genetic variances and their effect on treatment outcome is headed in the right direction," said Van Ness. "This important first step means we can start developing clinical trials based on genetic conditions that can lead to more effective treatments and help to evaluate new, targeted therapies."

Myeloma is a cancer of plasma cells, which are antibody-producing cells normally present in the bone marrow. More than 1,000 new cases or myeloma are diagnosed daily around the world making this the second most common form of blood cancer after lymphoma.


###
Co-authors of this study are William R. Kiffmeyer, Ph.D., Fangyi Zhao Ph.D. and Martin Oken M.D. of the University of Minnesota, and Emily Blood and Montse Rue, Ph.D. of the Easter Cooperative Oncology Group. The International Myeloma Foundation, through its Bank on a Cure project, will considerably expand this study in the future.

The Cancer Center at the University of Minnesota is a National Cancer Institute-designated Comprehensive Cancer Center. Awarded more than $80 million in peer-reviewed grants during fiscal year 2003, the Cancer Center conducts cancer research that advances knowledge and enhances care. The center also engages community outreach and public education efforts addressing cancer. To learn more about cancer, visit the University of Minnesota Cancer Center Web site at http://www.cancer.umn.edu. For cancer questions, call the Cancer Center information line at 1-888-CANCER MN (1-888-226-2376) or 612-624-2620 in the metro area.

Additional Contacts:
John Weiner
USC
323-442-2830

Todd Matthew
The Cancer Center (University of Minnesota)
612-624-6165

[kevin]

Link: http://www.eurekaler...c-gcm091203.php
Date: 09-12-03
Author: Warren Froelich
Source: American Association for Cancer Research
Title: Genetic clues may show which women face breast cancer risk from HRT

---

Contact: Warren Froelich
froelich@aacr.org
215-440-9300
American Association for Cancer Research

Genetic clues may show which women face breast cancer risk from HRT

USC study shows genetic variant can predict breast density changes in postmenopausal women using hormone therapy

A genetic clue may eventually help physicians identify certain women who would face an increased risk of breast cancer from using hormone replacement therapy, according to researchers from the Keck School of Medicine of the University of Southern California.

Keck School scientists obtained mammograms on more than 200 women and found that those with a genetic variant developed denser breast tissue after using estrogen and progestin therapy than women without the variant.

Mammographic density is a risk factor for breast cancer and has been proposed as a marker for breast cancer risk.

"Our research is promising. We already know that only some women who use hormone replacement therapy with estrogen and progestin go on to develop breast cancer," says Giske Ursin, M.D., Ph.D., associate professor of preventive medicine at the Keck School and one of the study authors. "If we could have a way of picking out the subset of women who are at risk for breast cancer from using standard hormone replacement therapy, we could offer these women some other treatment for their postmenopausal complaints."

The researchers presented their findings at a meeting called "SNPs, Haplotype, and Cancer: Application in Molecular Epidemiology," sponsored by the American Association for Cancer Research. SNPs is scientific shorthand for single nucleotide polymorphisms, which refer to differences in specific genes within the human genome.

Researchers explain that 99.9 percent of the genome is identical in all humans. But the rest of the genome is where it gets interesting--and where SNPs can be found. These polymorphisms are bits of the genetic blueprint that exist in different varieties within the population. They may account for characteristics as obvious as hair color or as complicated as the body's ability to break down hormones.

In their study, Keck School researchers aimed to find out which polymorphisms might link female hormones to increased breast density. They obtained mammograms and DNA from 233 postmenopausal women ages 45-75 who were randomly assigned to take either estrogen-and-progestin therapy, estrogen-only therapy or a placebo.

Scientists checked each participant's DNA for the presence of five genetic polymorphisms associated with progesterone action or the body's ability to break down estrogen or progesterone. Because of the way genes are inherited from both parents, each participant could either have two copies of the polymorphism, one copy or no copies.

When researchers took women's mammograms after 12 months on the trial and compared them to mammograms taken at baseline, they saw something striking. They found that among women on estrogen-and-progestin therapy, those with either one or two copies of a polymorphism in one of the genes that break down progesterone had a substantially greater increase in breast density than women who had no copies of that polymorphism.

The bodies of women with this genetic variant may not be able to break down progesterone as well as those without the polymorphism, researchers theorize. They did not see the same effects in women using estrogen-alone therapy.

Among study participants as a whole, those on estrogen-and-progestin therapy saw their breast tissue grow 7 percent denser, while those taking estrogen alone had somewhat less of an increase in breast density. Women on placebo had no increase in breast density.

We do not yet know whether an increase in breast density translates into an increase in breast cancer risk. However, breast density may be a measure of breast cell multiplication. Researchers believe the more breast cells multiply over a lifetime, the greater the breast cancer risk. The estrogen and progesterone naturally present in young women cause breast cells to multiply, but as a woman enters menopause, hormone levels plummet and breast cell multiplication slows.

Hormone replacement therapy in postmenopausal women introduces hormones present in very small amounts in such women. That means additional breast cell multiplication--and potentially greater breast cancer risk.


###
Additional Contacts:
John Weiner
USC
323-442-2830

Todd Matthew
The Cancer Center (University of Minnesota)
612-624-6165

[kevin]

Link: http://www.eurekaler...l-atb091603.php
Date: 09-16-03
Author: Heather Cosel
Source: Cold Spring Harbor Laboratory
Title: And the beat goes on: New insight into the genetics of congenital heart disease

---

Public release date: 16-Sep-2003
Contact: Heather Cosel
coselpie@cshl.org
Cold Spring Harbor Laboratory

And the beat goes on: New insight into the genetics of congenital heart disease

Using a sophisticated approach to alter gene activity in the embryo, scientists have identified a potential culprit for one of the most common human congenital heart malformations, AVCD (atrioventricular canal defect). As Dr. Kai Jiao and colleagues report in the October 1 issue of Genes & Development, proper expression of a single gene, called Bmp4, is essential for normal mouse embryonic heart development – even a 50% reduction leads to AVCD-like defects.

In its most severe form, AVCD is characterized by a large hole in the wall (the septum) that partitions the heart into upper and lower chambers (atria and ventricles, respectively). This defect disrupts the unidirectional flow of blood through the heart, allowing oxygen-rich blood traveling through the left chambers to re-enter the right chambers. The mixture of oxygenated and deoxygenated blood in the right chambers increases the overall volume of blood that the right ventricle must pump to the lungs. This increased blood volume taxes both the heart and lungs, causing heart enlargement, high blood pressure, and, eventually, pulmonary blood vessel damage (i.e. lung disease).

Dr. Jiao and colleagues now show that the reduced expression of Bmp4 may underlie AVCD.

Dr. Hogan, the senior author, now at Duke Medical Center, says: "We quessed that Bmp4 was critical for heart development more than 10 years ago because it is expressed there at high levels. But the gene is also needed by the embryo very early, before the heart has formed. Dr. Jiao hit on the idea of knocking the Bmp4 gene out just in the embryonic heart muscle (cardiomyocytes), leaving it intact everywhere else. What is more, he manipulated the system, using 'conditional tissue specific gene inactivation', so that Bmp4 activity could be titered down to different levels." (very cool.. KP)

Dr. Jaio observed a direct correlation between the level of Bmp4 activity and the ability of the septum to correctly partition the upper and lower heart chambers – what the researchers call "atrioventricular septation": the less Bmp4 present in cardiomyocytes, the more severe the septation defect.

By varying the level of Bmp4 expression, Dr. Jiao and colleagues were able to recapitulate the entire spectrum of defects seen in AVCD patients. They found relatively mild septation deformities in mice whose cardiomyocytes had slightly less-than-normal levels of Bmp4, while mice whose cardiomyocytes were completely devoid of Bmp4 displayed severe AVCD --making these mice useful models for AVCD research.

The researchers note that mice with Bmp4-deficient cardiomyocytes are, in fact, the first and only genetic model with AVCD as its primary defect.

Since AVCD is a common feature of Down syndrome, these mice will also be useful to study the cardiac defects associated with Down syndrome – perhaps even more so than existing Down syndrome models. While the classic animal model of Down syndrome (Trisomy 16 mice) does effectively portray many aspects of this disease, it does not wholly recapitulate the range of cardiac defects seen in Down syndrome patients. Mice with Bmp4-deficient cardiomyocytes do.

Dr. Hogan observes, "Knocking down genes specifically in some heart cells and not in others, and at different times, is becoming an increasingly important tool. Dr Jiao, as well as scientists here at Duke Medical Center, are using this approach to alter the levels of other genes besides Bmp4. As the big picture emerges it may reveal new insights into congenital heart malformations and perhaps ways to treat or prevent them."

Dr Kai Jiao continues his investigations at Vanderbilt University Medical Center.

[Lazarus Long]

Now add stroke to the list related to genes. This article is from today's New York Times but I will try and add the link to Nature as soon as I find it.
LL/kxs


http://www.nytimes.c.../22STRO.html?hp
Scientists Discover First Gene Tied to Stroke Risk
MONDAY, SEPTEMBER 22, 2003 7:32 AM
By NICHOLAS WADE

Researchers in Iceland say they have discovered the first gene that underlies common forms of stroke, a disease that affects more than 600,000 people a year in the United States.

People with a particular version of the gene have a three to five times greater risk of stroke, said the researchers, who are at Decode Genetics, a company based in Reykjavik. This is as large as or larger than known environmental risk factors like high blood pressure, high cholesterol and smoking.

Dr. Kari Stefansson, the chief executive of Decode, said that the new gene makes an enzyme that is a good target for drugs, and that the Roche pharmaceutical company in Switzerland was already testing several such drugs in laboratory rats.

The new gene was identified by a team led by Dr. Solveig Gretarsdottir. The gene had not previously been implicated in stroke, and its detection may open new insights into the mechanisms of the disease. Decode's work, reported today in the journal Nature Genetics, is a "tour de force" and "highly, highly significant for the stroke field," said Dr. Jonathan Rosand, a stroke specialist at Massachusetts General Hospital.

But the study is unlikely to yield new treatments any time soon and needs to be confirmed by other researchers in other populations, Dr. Rosand added.

Decode Genetics has identified 15 genes involved in 12 common diseases and has mapped the general locations on the genome for an additional 20, Dr. Stefansson said last week. All have been identified among the Icelandic population, which is particularly suitable for genetic studies because of its excellent genealogical records and uniform health care system, and some have also been identified in other populations.

Some diseases, like sickle cell anemia or cystic fibrosis, are caused by mutations in a single gene, and are relatively rare. Common diseases like stroke, diabetes and cancer are thought to be promoted by several different genes acting in concert.

Since each of the contributing genes in these multigenic diseases has a small effect, they are hard to pick up from family pedigrees. Identifying such genes was expected to be one of the major fruits of the Human Genome Project, which was financed by the United States government and other countries. But so far only a handful of such genes have been identified, with Decode's reported tally being far larger than anyone else's.

Dr. Rosand said the company had several advantages, including its use of extremely sophisticated technology, and the helpful genetic history of the Icelandic population, which ensures that many patients with a given disease may have inherited the same genetic variation from a single ancestor in the distant past. The population is a mix of Norwegian and Celtic, as the country was founded in the 10th century by Vikings from Norway who stopped first in Ireland to gather several wives apiece.

Dr. Stephen T. Warren, editor of The American Journal of Human Genetics, said other groups were making good progress in detecting the genes for specific complex diseases, but Decode was more visible because it was working on many diseases at once.

The disease-causing version of the new stroke gene has come to light among Icelanders, but its finders hope it may have a wider significance.

"My prediction is that we will find this in all populations we look at because," Dr. Stefansson said only partly in jest, "I am convinced that Icelanders are a good animal model for Homo sapiens." Other populations will have different genetic changes, but in the same gene, he suggested.

In addition, the drugs Roche is developing to target the stroke gene's enzyme might be useful for everyone at risk of stroke, whether or not they carry the same genetic variant found among Icelanders, said Dr. Jonathan Knowles, Roche's president of global research. Roche paid for some of Decode's research and has rights to certain discoveries.

Decode's data from its Icelandic patients shows that certain variations in the new stroke gene are highly associated with both the carotid artery and heart-associated forms of stroke. The gene is known as phosphodiesterase 4D, or "dunce" because it was first discovered in fruit flies with learning issues. But it is not yet clear how the variant form of the gene is involved in stroke. The dunce gene operates in the cell's internal signaling system and causes certain types of cells to be activated. These include the smooth muscle cells of the arteries.

Dr. Stefansson says he believes that in patients with the variant form of the dunce gene the muscle cells of the artery walls may proliferate, causing the blockage known as plaque. Dr. Knowles said that or other mechanisms were possible. Dr. Rosand said the variant gene might instead impair the brain's normal response to a stroke, which is to increase blood flow to regions affected by a blockage.

Many genetic diseases are caused by mutations, or changes in the DNA sequence of a gene, that make it produce a dysfunctional protein product. The change in the dunce gene is more subtle. The gene produces several different proteins, known as isoforms, depending on which of its subunits is involved in the protein manufacturing process. Decode's researchers could find no defects in these isoforms. The only change attributable to the variant form of the dunce gene was that it made different quantities of three of the gene's isoforms. This minute change is apparently enough to lead to disease. It is not yet clear what features in the variant gene cause the different production of its isoforms.

Dr. Stefansson said that there were probably several other genes involved in stroke, but that the dunce gene variant made the strongest contribution. His method of gene hunting is not powerful enough to pick up every gene relevant to a disease, but the ones it does flag are likely to be the most important, he said.

Discovery of the dunce gene's role at least gives researchers a new starting point for trying to understand the mechanism of stroke, even though the exact chain of cause and effect remains unclear.

"Genetics doesn't tell you the answer; it tells you that somewhere in here an answer lies," Dr. Knowles said.

[kevin]

Premature Aging Syndrome Genetically Identical to Normal Aging
Dwayne Hunter
Betterhumans Staff
Monday, September 29, 2003, 4:23:13 PM CT

Mitch Doktycz/Oak Ridge National Laboratory

Chipping away: In an advance for biogerontology, DNA microarrays have genetically linked Werner's syndrome and normal aging

Gene activity for a premature aging disorder is the same as for normal aging, suggesting that the condition accelerates the aging mechanism and that studies of it could provide valuable information for developing antiaging interventions.

Link to Article

[Lazarus Long]

Well I must admit it is nice to be vindicated by evidence. Peter (Ocsrazor) I think we need to return to the discussion about genetic clocks. Though I would anticipate that what he is going to say is the causal aspect is not necessarily viewed as a chronological decay issue as much as a consequential one to general systems being shut down by the genes {prematurely ) }.

However I still argue that for genes to regulate such complex long term processes we must start viewing them as programs with various levels of interdependent complexity and as such they must logically be interacting off a meter somewhere (a sort of biological internal clock like what we set in the CMOS for BIOS) to be able to compress the overlapping sequences in order.

It is also a consideration that there could be a regulator enzyme the mutation causes to either not be expressed, or is over expressed. If such a compound(s) exists we would be most lucky for that would be a crucial substance to isolate.

Either way Kevin I expect to hear more about this. As the genetics of Werner Syndrome is resolved for how to moderate the symptoms we are going to see some remarkably specific targeting of genes and their RNA that activates various aspects of the aging process. From that it will still have to be seen of using those regulators on normal populations has the effect of retarding growth, or causing unforeseen severe side effects.

This thread is relevant to the discussion:
http://imminst.org/f...&f=44&t=1153&s=

I would link to back to the original thread where I posted extensive references to Progeria and Werner's Syndrome and began our discussion of the highly unfashionable biological clock theory but apparently simpler and overly parochial minds have thought to erase that effort. This does annoy me since it isn't even in the catcher and its link have been made to go dead herein the forum. The thread(s) in question also referenced other articles on menstruation, circadian rhythms as well as an internal cell timing mechanism. I thought we agreed, no erasing the old threads?

I understood that we were consolidating aspects of the previous threads to create the CIRA aging subject but there was never any reason to erase the original threads. This quote from Peter is in the above linked thread to corroborate my concern:

EE) Weismann Aging Theory in the Goldsmith Article
Kevin-
This is literally the oldest one in the (aging research) book  As I believe Goldsmith points out this was first proposed by Weisman in the late 1800's. There is a major flaw in the logic of suggesting that aging is an adaptive mechanism to remove older members of the population. The logic is circular - If an organism wears out from damage it is unlikely to be able to compete with younger members of the species, so no program for senescence is necessary, the decay is part of the system. Also, older organisms with high genetic fitness would still be more desirable for a population than less fit younger ones.

I think the proper way to think of aging is as an arc, that is why I use the word trajectory fairly often. With all the molecular data we have to date it seems as if biological systems that age are set up to hit a certain peak of reproductive fitness at a particular age. What happens beyond that peak is of no concern to evolution, unless it impacts negatively on species fitness, and is just rolling down a hill. If Weisman had been right there would be a sudden onset of senescence after reproductive age - which there is not. Goldsmith appears to have confused the processes that set the arc's trajectory with the decay processes that define the downturn in the trajectory.

There is a possibility that program and damage theories could be linked, but to date there is no evidence that any aspect of aging is programmed. The one exception to this was brought up by Lazarus Long earlier, and that is unique in the animal kingdom to humans. Menopause represents a sudden change in the hormonal/metabolic program of a woman. See the earlier posts to the ideas behind why this might be true.
Best,
Ocsrazor

I was using that thread to file articles for future reference and use and this is why I leave whole articles and I think is invalid to insist on micromanaging the flow of information such that we are forcing those trying to create an open research atmosphere have the repeat the searches again and again for information that once found should be kept and accessible. That is the whole point of data-mining, it isn't just about the links to articles it is about the information contained in the threads and the works that people put in to building them. It is a serious error to presume that what is considered nonsense one day will always be considered so and worse it almost amounts to sabotaging another person's efforts.

[Lazarus Long]

Specifically I began a thread on the study of Progeria, also known as Werner's Syndrome and put up an number of full articles & links as well as an impasioned appeal to study this rare genetic based condition because I anticipated exactly what this recent study discovered. I guess somebody must have been offended by my linking of medicine and good will because the essay I wrote suggested that we would be doing a good deed for the children suffering from this generally neglected genetic condition as well as serving our own interests. [angry]

[kevin]

Link: http://www.eurekaler...r-sfg062603.php
Date: 06-26-03
Author: Kristen Woodward
Source: Fred Hutinson Cancer Research Center
Title: Scientists find genetic link between cancer and premature aging

---

Public release date: 26-Jun-2003
Contact: Kristen Woodward
kwoodwar@fhcrc.org
206-667-5095
Fred Hutchinson Cancer Research Center

Scientists find genetic link between cancer and premature aging

SEATTLE - Biologists have long known that the promise of eternal youth comes with a hefty price tag, a truth borne out by the immortality of most cancer cells.

The link between aging and cancer is now clearer thanks to a new study that connects a powerful cancer-causing protein to a gene associated with Werner syndrome, a disease that causes premature aging.

Carla Grandori, M.D., Ph.D., of Fred Hutchinson Cancer Research Center, and colleagues report in the July issue of Genes & Development that the cancer-promoting activity of Myc - a protein implicated in breast, prostate and many other tumors - depends in part on its ability to activate the WRN gene, whose absence leads to Werner's syndrome.

Based on their results, Grandori and co-investigators at Fred Hutchinson, the University of Washington School of Medicine and Columbia University speculate that a novel class of anti-cancer therapies might be developed based on drugs that interfere with the anti-aging properties of the WRN gene.

Werner syndrome is a rare genetic disorder that develops when the WRN gene is missing or defective. The disease causes the onset of premature aging shortly after puberty and results in the appearance of old age when patients are 30 to 40 years of age. The syndrome is thought to occur because mutations in WRN cause genetic instability, a condition in which chromosomes are dramatically rearranged. Because genetic instability is also a common feature of tumor cells, Werner patients often die prematurely of cancers.

But the cancers that result from loss of the WRN gene differ from the tumors that are triggered by Myc, which require an intact WRN gene, said Grandori, a staff scientist in Fred Hutchinson's Human Biology Division and lead author of the paper.

"No one had implicated the Werner syndrome gene as a general pro-tumor agent," she said. "Patients with Werner do develop cancers, but they are very rare cancers and tend to occur later in a patient's life. They don't develop Myc-related cancers, and our findings help to explain why."

Myc already had been known to cause cell immortality, a characteristic that enables tumors to grow indefinitely. Grandori and colleagues in Riccardo Dalla-Favera's laboratory at Columbia University discovered in 1999 that Myc switches on telomerase, an enzyme that extends the lifespan of cells.

"Although telomerase is important for immortalizing cells, it's not sufficient in all cell types," she said. "We asked, 'What other gene could be important for preventing senescence?' The Werner syndrome gene was an obvious candidate."

Using human cells grown in the laboratory, Grandori found that when Myc was overproduced, activity of the Werner syndrome gene was similarly induced and cells became immortalized.

In cells in which the Werner syndrome gene was missing, an overabundance of Myc caused the cells to rapidly age. Aging cells have a flat appearance, stop dividing and have a unique pattern of gene expression.

Grandori said the these results suggest that it may be possible to block Myc's tumor-promoting activity by inhibiting the WRN gene, which would cause the cells to begin the aging process and cease to grow. She speculates that such drugs would be unlikely to mimic the symptoms of Werner syndrome.

"If cancer cells have higher levels of WRN than normal cells, tumor cells are likely to be more susceptible than healthy cells to drugs that inhibit WRN, so that normal cells would be relatively unaffected by the treatment." she said. "This could be a new approach for treating many cancers, since Myc is associated with numerous tumor types."


###
This research was funded by grants from the National Institutes of Health and the Nippon Boehringer-Ingelheim Virtual Research Institute on Aging.

The Fred Hutchinson Cancer Research Center, home of two Nobel Prize laureates, is an independent, nonprofit research institution dedicated to the development and advancement of biomedical technology to eliminate cancer and other potentially fatal diseases. Fred Hutchinson receives more funding from the National Institutes of Health than any other independent U.S. research center. Recognized internationally for its pioneering work in bone-marrow transplantation, the center's four scientific divisions collaborate to form a unique environment for conducting basic and applied science. Fred Hutchinson, in collaboration with its clinical partners, the University of Washington Academic Medical Center and Children's Hospital and Regional Medical Center, is the only National Cancer Institute-designated comprehensive cancer center in the Pacific Northwest and is one of 39 nationwide. For more information, visit the center's Web site at http://www.fhcrc.org.

[kevin]

Link: http://www.eurekaler...BPSH-291196.php
Date: 11-29-96
Author: Karyn George
Source: Duke University
Title: Bacterial Protein Structure Hints At Mechanism Of A Class Of Premature Aging Diseases
Comment: An early indicator of the role that helicases and chromosomal integrity play in ageing

---

Public release date: 29-Nov-1996
Contact: Karyn Hede George
georg016@mc.duke.edu
919-660-1301
Duke University

Bacterial Protein Structure Hints At Mechanism Of A Class Of Premature Aging Diseases
DURHAM, N.C -- Using a bacterial model system, scientists at Duke University Medical Center have determined the first step in understanding how a new class of genetic flaws may translate into diseases.

Deepak Bastia and Steven White, professors of microbiology at Duke, have determined how a protein, called a replication termination protein (RTP), stops DNA replication in the bacterium Bacillus subtilis, a common experimental organism.

Rather than simply acting as a roadblock to replication, as had been previously thought, RTP is more like a one way door, allowing the DNA replication machinery to move in only one direction along the DNA strand, the researchers said. They said the work has implications for human disease because RTP interacts with a class of proteins known as helicases, which have been shown to be involved in several genetic diseases. Bastia is now starting work on identifying the comparable protein in humans.

The researchers' findings appear in the Nov. 29 issue of the journal Cell. The research was funded by the National Institutes of Health.

RTP has been known to exist for 20 years, but it wasn't until two years ago that its structure was revealed by Bastia and White. "This [recent] work relates structure to function and takes us one step further in understanding how RTP works," Bastia said.

When DNA replicates, it unzips, starting and ending at specific sites. The helicases are responsible for pulling apart the DNA strands, which are twisted in a helical pattern. "RTP ensures that when DNA replicates, it is brought to a neat and accurate finish, and the cell knows that it is time to divide into two," White said.

Recently, helicase malfunction has been found responsible for a class of genetic diseases including Werner's syndrome and Cockayne's syndrome, premature aging syndromes; Bloom's syndrome, a type of dwarfism; and some kinds of skin cancer. Understanding of these diseases on the molecular level is minimal. But since the helicase's job is to help replicate the chromosomes, any malfunction would be expected to have severe consequences.

"No one knows anything about arresting helicases in the human system," Bastia said. "There's zero information in the literature."

The events taking place between the genetic flaw and its expression as a disease are unknown. "It's not enough to know where a defect in the gene is." Bastia said. "You want to know how it causes the disease."

If the mechanism of a genetic malfunction can be mapped out, said Bastia, drug therapies will be easier to design as would gene therapies. The new research is the first step in that direction.

The Duke researchers have shown that the RTP, rather than simply acting as a road block to replication, actually interacts with the helicase protein.

"That's a major controversy in this field," White said. A competing theory, published in the Oct. 17, 1996, issue of the journal Nature is that RTP mechanically interferes with helicases in a non- specific way, but the Duke research shows that RTP actually interacts with the helicase on a molecular level. "There's a flexible region on the helicase that the RTP seems to interact with," said White.

To test how RTP works, the researchers had to create a mutant version of the protein that would not interact with the helicase but wouldn't be deformed beyond recognition.

"Our big worry was that we would have destroyed the structure," said White, who determined RTP's structure two years ago using X-ray crystallography. Engineering mutations at the molecular level, the scientists changed one amino acid in RTP to test their hypothesis that it interacts with a specific region on the helicase.

"Identifying the corresponding proteins from a human system and then finding a mutant protein will lead to understanding of the disease process involving helicase proteins," Bastia said. "And this understanding may eventually help to work out gene therapy techniques."

Collaborators on the project were Adhar C. Manna, Karnire S. Pai, Dirksen E. Bussiere and Christopher Davies.


###

[kevin]

Link: http://www.eurekaler...MBIA-261297.php
Date: 12-12-97
Author: Sarah Wright
Source: MIT
Title: MIT Biologists Identify Aging Mechanism

---

Public release date: 26-Dec-1997
Contact: Sarah H. Wright
shwright@mit.edu
617-258-5400
Massachusetts Institute of Technology

MIT Biologists Identify Aging Mechanism

CAMBRIDGE, Mass.--MIT biologists have identified a mechanism of aging in yeast cells that suggests researchers may one day be able to intervene in, and possibly inhibit, the aging process in certain human cells.

The mechanism of aging, it turns out, is elegant in its simplicity. During a yeast cell's life, whenever a particular, coiled piece of DNA pinches off from one of its chromosomes, that extrachromosomal ribosomal DNA (ERC) replicates until the cell becomes overwhelmed and dies. Aging in yeast cells is started by the formation of that first ERC.

"The best part is, it's obvious it's a clock," said Leonard Guarente, Professor of Biology, referring to the ERCs' role in yeast cell mortality. "Set the clock early and the alarm rings early."

An article to be published in the December 26 Cell culminates a year's published work on this topic (articles appeared in Cell, Science and now Cell, again). The piece, co-authored by David A. Sinclair, a postdoctoral fellow in biology at MIT, and Professor Guarente, also communicates the researchers' enthusiasm for the work, with an overtone of wonder at its broad implications and precise beauty.

"It is remarkable that this mechanism of aging in mother yeast cells is so simple at a molecular level," the biologists wrote. "It is conceivable that inhibitors of this (aging) process can be found and if so, such strategies might eventually prove useful in forestalling aging in yeast and, perhaps, in higher organisms."

The discovery of the simple role of ERCs in cell aging and death has a profound appeal well beyond the laboratory. Indeed, William Shakespeare, a man of powerful intuition and observation, would be pleased to learn how closely Hamlet's phrase denoting mortality -- the "mortal coil" -- portrays an actual molecular drama. A drawing of ERCs in action shows that an aging yeast mother cell is full -- fatally full -- of little mortal coils.

PREVIOUS WORK: THE FOUNDATION

The MIT biologists' current research builds on two related discoveries published earlier this year in the magazines Cell and Science magazines.

The article published in Cell in May measured normal aging in yeast by determining the number of daughter cells a mother cell could produce before dying. Mother and daughter yeast cells are differentiated by their size: mother cells are bigger.

That article, by nine authors including Drs. Guarente, Sinclair and Mr. Kevin Mills, a graduate student in biology, also demonstrated that yeast genes SIR2, SIR3, SIR4, and UTH4 determine the life span in yeast. When these genes were deleted from a yeast strain, life span was shortened. When they were overexpressed, the life span of the yeast strain was extended.

The research also showed that the gene products encoded by SIR2, SIR3 and SIR4 promote cell longevity by moving from one cell structure to another (from the telomeres to the nucleolus). This action and the fragmentation of the nucleolus would form the basis of more groundbreaking discoveries.

A second article, published in Science magazine in August, reported further refinement in the MIT biologists' study of aging. This research, reported by Dr. Sinclair and Professor Guarente, identified the crucial role played by another yeast gene, SGS1, in determining the life span of yeast cells.

The gene SGS1 has a DNA code that corresponds structurally to the human gene, WRN. Mutations in WRN result in Werner's Syndrome, a disease whose symptoms resemble a fast-forward aging process. The MIT biologists demonstrated that experimental mutation of SGS1 -- the yeast homolog for WRN -- produced symptoms of aging in yeast cells.

Again, the biologists noted how aged SGS1 yeast cells displayed fragmentation of the nucleolus.

"Our findings indicate a particular cellular structure, the nucleolus, may be the Achilles' heel as cells get old. We think this fragmentation of the nucleolus is a cause of aging," Professor Guarente commented at the time.

The next phase of research would include "answering the question, can we find a way to slow down the fragmentation of the nucleolus as a way to slow down aging?" Professor Guarente said.

NEW RESEARCH: THAT MORTAL COIL

"Strikingly, the nucleolus of old SGS1 cells is enlarged and fragmented, and the following findings indicate that these changes may represent a cause of aging," wrote the authors in an introduction to the December 26th article in Cell. "We thus sought to identify the molecular events embodied by the enlarged and fragmented nucleoli of old cells."

First, the researchers tackled nucleolar enlargement. This, they discovered, was caused by ERCs -- the supercoiled circular form of DNA -- accumulating abundantly in old yeast cells. They named the supercoiled circular molecules "ERCs" -- extrachromosomal rDNA circles -- and showed that accumulation of ERCs is a general phenomenon that occurs as cells age.

Next, the researchers noted that the ERCs accumulated in yeast mother cells but not in daughter cells and that mother cells were subject to aging (i.e. sterility) due to this asymmetrical accumulation. Replicating ERCs were also presumed to cause enlargement and fragmentation of the nucleolus in mother cells.

But old age is not death, and the researchers still wondered, How do ERCs kill cells?

They suggest that the sheer abundance of ERCs could gum up components of the mother cells' replication machinery, leading to an inability to replicate the DNA necessary for life.

A WONDROUS PARADOX

Armed with data suggesting that the accumulation of ERCs may be the aging clock itself, the researchers wondered, what set the fatal accumulation in motion? What, as Professor Guarente inquired above, could "set the clock early (so) the alarm rings early"?

Their experimental results suggest a paradox. The formation of ERCs may be a result of damage to rDNA; that is, ERCs may be the cell's attempt to repair itself. Yet, the very mechanism which saves the cell becomes its "mortal coil" as ERCs "accumulate exponentially in mother cells resulting in fragmented nucleoli, cessation of cell division, and cellular senescence," the authors wrote.

Intriguingly, a yeast cell need not itself be damaged to set the mortal clock in motion. ERCs, the researchers note, can be inherited, with the same effect.

Near the concluding section of the Cell article, the authors wrote, "Once an ERC is formed or inherited, the period of time until a lethal number of ERCs has accumulated ... may be the clock that determines the life span of the cell."

BROADER IMPLICATIONS

The implications of the MIT research include possibilities of inhibiting the process of ERC-formation in mother yeast cells and in cells of higher organisms where cell division is asymmetrical. These latter cells -- known as stem or progenitor cells in mammals -- are found in organs such as the skin, kidney, liver and blood.

The authors suggest, too, that yeast mother cells may be analogous to mammalian stem or progenitor cells, just as SGS1 was homologous to the human WRN gene. Thus, the next phases of aging research have been defined by the MIT biologists' groundbreaking work.

Next, "it will be important to determine whether ERCs or other circular DNAs accumulate in stem cells of aging mice and humans," the authors wrote.

David Sinclair is supported by the Helen Hay Whitney Foundation. The Guarente lab is supported by a National Institutes of Health grant.

[kevin]

Link: http://www.eurekaler...r-rig041603.php
Date: 04-16-03
Author: Geoff Spencer
Source: NIH
Title: Researchers identify gene for premature aging disorder
Comment: Mutation in Lamin-A gene, a protein responsible for integrity of the nuclear membrane, causes Progeria/Hutchinson-Gilford Syndrome

---

Public release date: 16-Apr-2003
Contact: Geoff Spencer
spencerg@mail.nih.gov
301-402-0911
NIH/National Human Genome Research Institute

Researchers identify gene for premature aging disorder
WASHINGTON, D.C., April 16, 2003 – A team led by the National Human Genome Research Institute today announced the discovery of the genetic basis of a disorder that causes the most dramatic form of premature aging, a finding that promises to shed new light on the rare disease, as well as on normal human aging.

In their study, to be released online next week in the journal Nature, researchers identified the genetic mutations responsible for Hutchinson-Gilford progeria syndrome (HGPS), commonly referred to as progeria. Derived from the Greek word for old age, "geras," progeria is estimated to affect 1 in 8 million newborns worldwide. There currently are no diagnostic tests or treatments for the progressive, fatal disorder.

Francis S. Collins, M.D., Ph.D., director of the National Human Genome Research Institute (NHGRI) and leader of the research team, said, "This genetic discovery represents the first piece in solving the tragic puzzle of progeria. Without such information, we in the medical community were at loss about where to focus our efforts to help these children and their families. Now, we finally know where to begin."

Dr. Collins added, "The implications of our work may extend far beyond progeria – to each and every human being. What we learn about the molecular basis of this model of premature aging may provide us with a better understanding of what occurs in the body as we all grow older."

In addition to NHGRI, the multi-institution research team included scientists from the Progeria Research Foundation, the New York State Institute for Basic Research in Developmental Disabilities in Staten Island, N.Y., the University of Michigan in Ann Arbor and Brown University in Providence, R.I.

W. Ted Brown, M.D., Ph.D., co-author of the study and chairman of the Department of Human Genetics at the Institute for Basic Research, said, "Many people consider progeria to be the most dramatic example of a genetic disease that clearly resembles accelerated aging. The children appear to have an aging rate that is five to 10 times what is normal." Dr. Brown is widely regarded as the world's leading clinical expert on progeria.

Children with progeria usually appear normal at birth. However, within a year, their growth rate slows and their appearance begins to change. Affected children typically become bald with aged-looking skin and pinched noses. They often suffer from symptoms typically seen in elderly people, especially severe cardiovascular disease. Death occurs on average at age 13, usually from heart attack or stroke.

Leslie Gordon, M.D., Ph.D., medical director of the Progeria Research Foundation (PRF) and executive director of the PRF Genetics Consortium, said, "Isolating this gene is just the beginning. It is our goal to find treatments and possibly a cure for this rare, life-threatening disease that robs children of their adulthood. The Progeria Research Foundation will continue to lead the fight against progeria."

In 2001, PRF co-hosted a workshop with various institutes and centers of the National Institutes of Health (NIH), including the National Institute on Aging and the Office of Rare Diseases. The workshop brought together leading scientists from around the world to identify promising areas of research in progeria. This partnership eventually led to funding for progeria research and the formation of the PRF Genetics Consortium, a group of 20 scientists whose common goal is to find the genetic cause of progeria and to develop ways of treating the disease. Six of those scientists are co-authors of the study to be published in Nature.

Dr. Collins commended the collaborative efforts, saying, "The Progeria Research Foundation's commitment and cooperation played a key role in the hunt for the disease gene. They brought the urgent need to find this gene to the attention of the biomedical research community."

Earlier this week, Dr. Collins, as leader of the Human Genome Project, announced the successful completion of the international project's effort to sequence the 3 billion letters that make up the human genetic instruction book. "Free and unrestricted access to the human genome sequence is greatly speeding the pace of disease gene discovery. Finding the gene for progeria would have been impossible without the tools provided by the Human Genome Project," said Dr. Collins, who still spends some of his time in a small research lab at the National Institutes of Health (NIH). "This was a particularly challenging project for the gene hunters, since there are no families in whom the disease has recurred, and geneticists generally depend on such families to track the responsible gene. This was a detective story with very few clues."

Taking advantage of an array of genomic technologies – from whole-genome scans to high-throughput sequencing of targeted DNA regions– researchers determined the most common cause of progeria is a single-letter "misspelling" in a gene on chromosome 1 that codes for lamin A, a protein that is a key component of the membrane surrounding the cell's nucleus. Specifically, the researchers found that 18 of 20 children with classic progeria harbored exactly the same misspelling in the lamin A (LMNA) gene, a substitution of just a single DNA base – a change from cytosine © to thymine (T) – among the gene's 25,000 base pairs. In addition, one of the remaining progeria patients had a different single base substitution – guanine (G) to adenine (A) – just two bases upstream. In every instance, the parents were found to be normal indicating that the misspelling was a new, or "de novo," mutation in the child.

At first glance, the point substitution in the LMNA gene would appear to have no effect on the production of lamin A protein. "Initially, we could hardly believe that such a small substitution was the culprit. How could these bland-looking mutations lead to such terrible consequences in the body?" said NHGRI's Maria Eriksson, Ph.D., a post-doctoral fellow in Dr. Collins' lab and the first author of the study.

However, when Dr. Eriksson conducted laboratory tests on cells from progeria patients, she found that the minute change in the LMNA gene's DNA sequence dramatically changed the way in which the sequence was spliced by the cell's protein-making machinery. The end result was the production of an abnormal lamin A protein that is missing a stretch of 50 amino acids near one of its ends.

To determine what effect abnormal lamin A has upon cells, the NHGRI-led team used fluorescent antibodies to track lamin A in skin cells taken from progeria patients known to have the common misspelling, as well as skin cells taken from unaffected people. The studies showed that about half of the cells from the progeria patients had misshapen nuclear membranes, compared with less than 1 percent of the cells from the unaffected controls.

"We suspect that this instability of the nuclear membrane may pose major problems for tissues subjected to intense physical stress – tissues such as those found in the cardiovascular and musculoskeletal systems, which are so severely affected in progeria," said Dr. Eriksson, noting that nuclear instability ultimately may lead to widespread death of cells.

Researchers hope to move their new findings into the clinic almost immediately with the development of a genetic test for progeria. Such a test will help doctors diagnose or rule out progeria in young children much earlier than their current method of looking at outward physical changes.

The new findings also may have implications for the treatment of progeria, with the newfound understanding of progeria's molecular roots pointing to possible therapeutic approaches. For example, researchers plan to explore the possibility that statins and/or other drugs known to inhibit a step in protein processing, known as farnesylation, might reduce the production of abnormal lamin A in progeria patients. Another avenue for identifying possible therapies involves screening large libraries of chemical molecules with the hope of finding a compound that can reverse the nuclear membrane irregularities seen in the cells of progeria patients.

"It is impossible to predict how soon our findings will translate into treatments for children suffering from progeria. We and other researchers across the nation will be working hard to find ways of helping them. Unfortunately, as we have witnessed with other genetic discoveries, the road from the lab to the clinic is not always swift or smooth," Dr. Collins said.

More also remains to be done to determine what role the LMNA gene may play in the normal aging process. "Aging clearly has a strong genetic component. Discovery of this key genetic mutation that causes progeria may lead to a much clearer understanding of what causes aging in us all. Eventually, this information may lead to improvements in health care for our aging population," said Dr. Brown.

Researchers plan to look at the LMNA genes of people who are exceptionally long-lived to see if there are any variants of the gene associated with longevity. Other studies might focus on determining whether repeated damage to the LMNA gene over the course of a lifetime may influence the rates at which people age.

"Our hypothesis is that LMNA may help us solve some of the great mysteries of aging," Dr. Collins said. "However, it will probably take more than one genetic key to unlock the secrets to a biological process as complex as aging. There are probably a host of other genes related to aging still waiting to be discovered."

Another interesting footnote to the recent findings is that different mutations in other regions of the LMNA gene previously have been shown to be responsible for a half-dozen other rare, genetic disorders. Those disorders are: Emery-Dreifuss muscular dystrophy type 2, limb girdle muscular dystrophy type 1B, Charcot-Marie-Tooth disorder type 2B1, the Dunnigan type of familial partial lipodystrophy, mandibuloacral dysplasia and a familial form of dilated cardiomyopathy.

Prior to coming to NIH to lead the Human Genome Project in 1993, Dr. Collins had established a reputation as a relentless gene hunter using an approach that he named "positional cloning." In contrast to previous methods for finding genes, positional cloning enabled scientists to identify disease genes without knowing in advance what the functional abnormality underlying the disease might be. Dr. Collins' lab, together with collaborators, applied the new approach in 1989 in their successful quest for the long-sought gene responsible for cystic fibrosis. Other major discoveries soon followed, including identification of the genes for neurofibromatosis, Huntington's disease, multiple endocrine neoplasia type 1, one type of adult acute leukemia and Alagille syndrome.


###
NHGRI is one of the 27 institutes and centers at the NIH, which is an agency of the Department of Health and Human Services. The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. Additional information about NHGRI can be found at its Web site: www.genome.gov.

[Cyto]

[>] How Does The Body Know It's Age?
I put that title just for the time being, change it at will.

It was still in the biomed & genetics section. I merged posts. This is when I was trying to organize things but we can figure that out later. [sfty]

Edited by CarboniX, 01 October 2003 - 06:43 AM.

[Lazarus Long]

Thanks Helix could you put in the link to it here please so we can review the stuff there?

Sorry if I sounded cross I was frustrated and exhausted near the end of a 22 hour work schedule at 2:3oam. It was just too anticlimatic for me after benig seriously interested in the current article. The catcher has come in handy: how come I couldn't find it? I looked all over the place.

[Lazarus Long]

Here is another good example of genetic regulation. Thisis a news blurb and interestingly it is also referencnig deCode Genetics again. I suspect we will see true regulators for weight coming form this remarkably soon. Maybe we should track down the actual scientific paper?

http://uk.news.yahoo.../325/e9spf.html

Icelanders find one gene makes you fat...or thin
Tuesday September 30, 10:43 AM
LONDON (Reuters) - Icelandic researchers say they have found a gene that in different versions determines whether people are predisposed to being obese or thin.

Scientists have long suspected a genetic link in determining how our bodies regulate weight. Now Icelandic biotechnology company deCODE genetics says it has isolated a specific gene which, in different forms, tends to make us either overweight or underweight.

The finding is the result of analysis of DNA from more than 1,000 Icelandic women.

"Obesity and thinness are two sides of the same coin," said deCODE Chief Executive Officer Kari Stefansson on Tuesday. "This is an important step towards developing new drugs that can treat obesity, perhaps by utilising the body's own mechanisms for promoting and maintaining thinness."

The Reykjavik-based company, which signed an obesity drug research deal worth up to 55 million pounds with Merck last year, will receive an unspecified milestone payment from the U.S. pharmaceuticals giant for the discovery.

Set up in 1996, deCODE is trawling Iceland's gene pool -- which has changed little since the Vikings arrived in the ninth and 10th centuries -- to tease out links between genes and common diseases.

[Cyto]

Looked in Science Direct.
Wiley InterScience.
Science.

Can't find the paper.

The site looks as if the last time they tended to it was in 2002.
deCODE Genetics Site
>> Look in Science & Research
>> Click Publications

[kevin]

Link: http://www.eurekaler...h-gep100603.php
Date: 10-06-03
Author: Aislinn Raedy
Source: American Society of Hematology
Title: Gene expression profiling may lead to customized treatments for pediatric leukemia patients

---

Public release date: 6-Oct-2003
Contact: Aislinn Raedy
araedy@hematology.org
202-776-0544
American Society of Hematology
Gene expression profiling may lead to customized treatments for pediatric leukemia patients

(WASHINGTON, DC, October 3, 2003) -- Gene expression profiling can help doctors accurately identify subtypes of pediatric acute lymphoblastic leukemia (ALL), according to the October 15, 2003, issue of Blood, the official journal of the American Society of Hematology. Diagnosing a subtype of ALL can allow physicians to customize a treatment program based on a patient's likelihood of responding to therapy.

Pediatric acute lymphoblastic leukemia has a number of subtypes, each with unique cellular and molecular characteristics. Since the subtype may also imply a less favorable prognosis, it is critical to diagnose each individual patient's subtype so that therapy can be tailored to reduce the chance of a relapse. ALL patients currently have a 70 to 80 percent chance of surviving the disease, but the odds of survival decrease following a relapse.

ALL subtypes are used to assign patients to risk groups. Risk group assignment is an important element of cancer care because it allows physicians to avoid overtreating patients who are at low risk of relapse, while ensuring optimal treatment for patients with a high risk of relapse. Patients are currently classified into risk groups based on factors such as age and gender, white blood cell count, the presence or absence of leukemia in cerebral spinal fluid, and genetic characteristics of the leukemic cells. These risk features were identified from epidemiological studies and have resulted in excellent overall long-term survival rates, but gene expression profiling may provide an even more precise profile of a patient's disease.

Researchers from St. Jude Children's Research Hospital in Memphis, Tenn., utilized DNA microarray technology to study the pattern of genes expressed in a leukemic cell. DNA microarrays, also called gene chips, contain copies of known gene samples from the human body. Researchers used the Affymetrix HG-U133A and B microarrays to identify the set of human genes expressed in samples of cells taken from 132 pediatric ALL patients.

Computer-aided data analysis demonstrated that the pediatric ALL cases cluster into seven major subtypes, including the six known prognostic subtypes (BCR-ABL, E2A-PBX1, Hyperdiploid >50, MLL, T-ALL, and TEL-AML1) and an "other" category. The researchers were successful in using the expression profiles provided by the microarrays to accurately diagnose and subclassify pediatric ALL, and they discovered that changes in a cell's expression profile vary markedly depending on the genetic lesions that underlie the initiation of the leukemic process.

"DNA expression profiling allows us to make extremely accurate diagnoses. If microarray technology can be implemented in a cost-effective manner, we may see a day when all leukemia patients undergo expression profiling and then have a unique treatment plan customized for them based on which genes are turned on and which are turned off in his or her leukemia cells," according to James R. Downing, M.D., of St. Jude Children's Research Hospital, the senior author of the study.

Microarray technology also can reveal the mutated genes that cause cancer to develop, the first step in designing treatments that target the cause of the disease, not just the symptoms. If physicians can target and repair the damaged DNA, they may be able to stop cancer from progressing.

According to hematologist George Daley, M.D., Ph.D., of Children's Hospital and Harvard Medical School, "Microarray studies of human leukemia have been at the forefront of efforts to exploit the human genome project to better diagnose and treat cancer, and have set the stage for similar insights into common solid tumors like breast and prostate cancer."

This work was supported in part by National Cancer Institute grants P01 CA71907-06 (JRD), CA-21765 (Cancer Center CORE grant to SJCRH), T32-CA70089, and by the American Lebanese and Syrian Associated Charities (ALSAC) of St. Jude Children's Research Hospital.

To receive a copy of the study or to arrange an interview with James R. Downing, M.D., please contact Aislinn Raedy at 202-776-0544 or araedy@hematology.org.

###

The American Society of Hematology is the world's largest professional society concerned with the causes and treatment of blood disorders. Its mission is to further the understanding, diagnosis, treatment, and prevention of disorders affecting blood, bone marrow, and the immunologic, hemostatic, and vascular systems, by promoting research, clinical care, education, training, and advocacy in hematology.

Blood, the official journal of the American Society of Hematology, is the most cited peer-reviewed publication in the field. Blood is issued to Society members and other subscribers twice per month, available in print and online at www.bloodjournal.org.

St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fund-raising organization. For more information, please visit www.stjude.org.





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[Lazarus Long]

This subject of this article is of vital importance because it represents the serious attempt to put what we are learning about the human genome into practical application. The company in question is one that we should watch but more importantly the methods they are developing will have profound impact over our lives in the years to come.

This is not just about testing genes for determining risk but understanding the interactive mechanism between the genetic "program"and how that program expresses itself biologically and how can we might manipulate the process to our advantage, or prevent the process from reaching its deterministic conclusion. If there is an "aging clock" then I suspect that from techniques developed here will achieve methods of intervening with the clock's rate to create the first true anti-agathics.


Geneticists hunt control patterns
Tuesday, 7 October, 2003
http://news.bbc.co.u...ure/3169686.stm


Scientists finished decoding human DNA this year

A major project will attempt to map out just how genes are controlled in the human body, scientists in the UK and Germany have told BBC News Online.
The Human Epigenome Project will look for patterns in our "life code" that are associated with gene regulation but are also implicated in causing disease.

Researchers at Epigenomics AG in Berlin and the Sanger Institute in Cambridge will take part in the five-year study. It was the Sanger centre which decoded one-third of the DNA found in humans. Along with their German colleagues, the UK institute staff will now search through the full sequence for sites of so-called methylation.

Levels of complexity

These are locations along the DNA molecule where the structure of one of its four constituent units - the base cytosine - has been modified by the addition of a methyl chemical group.

THE DNA MOLECULE


* The double-stranded DNA molecule is held together by chemical components called bases

* Adenine (A) bonds with thymine (T); cytosine© bonds with guanine (G)

* These letters form the "code of life"; there are about 2.9 billion base pairs in the human genome wound into 24 distinct bundles, or chromosomes

* Written in the DNA are 30,000 genes which human cells use as templates to make proteins; these sophisticated molecules build and maintain our bodies 

Changes to the DNA sequence - the order of cytosine ©, guanine (G), adenine (A) and thymine (T) - and its role in health and disease are increasingly well understood thanks to the completion of the Human Genome Project.

But DNA methylation is a further layer of control and is regarded by scientists as one of the most important regulators of gene activity. The precise pattern of methyl-tagged cytosines will determine whether or not certain genes are expressed in particular tissues.

As well as being important for normal development, methylation changes are detected in many cancers and some developmental disorders such as Beckwith-Wiedemann syndrome. Methylation is linked to ageing, too, as the patterns change over time.

It is also thought this crucial system is influenced by a person's upbringing and lifestyle. In effect, it is one of the means by which our environment influences our genetic make-up.


Timely finish

"The mapping of all DNA methylation sites promises a better understanding of the biological basis of disease and may allow diagnosis at a much earlier stage," commented Dr Kurt Berlin, the chief scientific officer at Epigenomics. The German company has been working on an EU-funded pilot, identifying 100,000 methylation sites on a segment of the DNA bundle known as chromosome six.

The full-scale Epigenomics/Sanger work will now extend the pilot to take in the rest of the human genome. The data obtained in the multi-million-pound project will be released in specific batches following its discovery and made available on the internet.

The Human Genome Project, which set out to read all 2.9 billion bases in human DNA, was completed earlier this year. The finish coincided with the 50th anniversary of the discovery of the structure of DNA by scientists at Cambridge University and Kings College London.

Researchers believe about 30,000 genes are written in the code. They will spend many years trying to work out precisely what the genes all do and how they interact to build and maintain the body's cells.


RELATED BBCi LINKS:
BBCi: Gene stories
http://www.bbc.co.uk/genes/
The Human Code Crackers
http://news.bbc.co.u...ome/default.stm

RELATED INTERNET LINKS:
DNA 1953-2003
http://www.dna50.org.uk/

Nature: 50 years of DNA
http://www.nature.com/nature/dna50/

Chief executive of Epigenomics Alex Olek
"I find it a very exciting project"
(BBC Audio interview)
http://news.bbc.co.u...nome06_olek.ram