The fourth meeting on the Molecular Genetics of Aging is being organized by Steven Austad, University of Texas Health Science Center; Judith Campisi, Lawrence Berkeley National Laboratory, Buck Institute for Age Research and David Sinclair, Harvard Medical School
Judith Campisi is working on one of the major SENS life extension projects to deal with too many old cells. (Apoptosens)
Topics and Co-Chairs:
Genetics I
Heidi Tissenbaum (U Mass Worcester MA USA)
Scott Pletcher (Baylor Houston TX USA)
Genomic Stability
Jan Vijg (Buck Institute Novato CA USA)
Elizabeth Blackburn (UC San Francisco CA USA)
Mitochondria / Metabolism
Peter Rabinovitch (U Washington Seattle WA USA)
Leonard Guarente (MIT Boston USA)
Cellular Senescence / Apoptosis / Stress
John Sedivy (Brown U Providence RI USA
Norman Sharpless (UNC Chapel Hill NC USA)
Stem Cells
Irina Conboy (UC Berkeley CA USA)
Karl Rudolph (Med Sch Hanover Germany)
Proliferative Homeostasis
Paul Hasty (UT Health Science Center, San Antonio, TX USA)
Rolf Bodmer (Burnham Institute San Diego CA USA)
Environment / Interventions
Richard Miller (U. Mich., Ann Arbor MI USA)
Steven Spindler (UC Riverside CA USA)
Genetics II
Anne Brunet (Stanford U CA USA)
Jan Hoeijmakers (Erasmus U Rotterdam Netherlands)
Showing posts with label stem cells. Show all posts
Showing posts with label stem cells. Show all posts
June 30, 2008
Molecular Genetics of Aging conference september 24-28, 2008
June 27, 2008
UCLA Sens anti-aging conference abstracts
There will be about thirty speakers at the Understanding aging conference in UCLA this weekend
Here are links to the abstracts of the presentations and some of the highlighted presentations.
Zheng Cui will discuss his Natural Cancer Resistance in Mice and in Humans: basis for a novel cancer therapy (GIFT therapy was covered here) and if successful would be a significant advance in reducing cancer deaths. [possibly a high cure rate and preventing many cancers by helping people fight off early stage cancer]
A new clinical trial is underway at Wake Forest University to test this novel cancer therapy, termed "Leukocyte Infusion Therapy" or LIFT. This clinical trial has met all regulatory requirements including approval by the Wake Forest University School of Medicine's Institutional Review Board (IRB) and been granted an IND (Investigational New Drug) status by the Food and Drug Administration (FDA).
B.N. Ames talks about delaying the Degenerative Diseases of Aging
I [B.N. Ames] propose that during evolution micronutrient shortages were very common, e.g. the 15 essential minerals, which are not distributed evenly on the earth. The consequences of this homeostatic response are, for example, DNA damage (future cancer), adaptive immune dysfunction (future severe infection), and mitochondrial decay (future cognitive dysfunction and accelerated aging). Much evidence supports this idea that micronutrient shortages accelerate aging.
S.F. Badylak of the McGowan Institute for Regenerative Medicine, Pittsburgh, PA will be talking about Regenerative Medicine and Aging
Regenerative medicine is typically based upon the strategic use of undifferentiated stem and progenitor cells, inductive bioscaffolds, and appropriate micro-environmental cues that signal the need for tissue reconstruction. In many respects, the desired result is the recapitulation of developmental biology but limited to a specific tissue or organ. There are many fundamental questions yet to be answered with regard to implementation of such strategies in an aging population. Do aging cells have the same potential for regeneration as young cells? Are biologic scaffolds composed of extracellular matrix from fetal tissues more "instructive" than biologic scaffolds harvested from adult extracellular matrix? How does the micro-environment of aged tissues and organs differ from that or neonatal tissues and organs? These and other questions will be discussed.
L.A. Briggs will discuss the struggle to keep telomeres long
The purpose of this presentation will be to review the current progress [to keep telomeres long], including the recent discovery of several small molecules that induce telomerase activity in normal human cells.
J. Campisi will discuss New tricks for dealing with old cells?
Some senescent cells can escape immune killing by secreting very high levels of matrix metalloproteinases (MMPs). These enzymes likely destroy the ligand-receptor interactions that are needed for killing by natural killer cells. Moreover, the killing of senescent cells can be greatly enhanced by MMP inhibitors, which therefore hold promise for improving the clearance of senescent cells from aged or diseased tissues. We also find that the senescence-associated secretion of inflammatory cytokines is dependent on continuous DNA damage signaling, particularly signaling initiated by the ATM protein kinase. Ablation of ATM kinase activity by RNA interference markedly reduces inflammatory cytokine secretion, suggesting that ATM inhibition might also hold promise for reducing local inflammation caused by senescent cells
C. Gravekamp is working on an improvement of cancer vaccination for older people
K.E. Healy is presenting Synthetic Environments to control Human Embryonic Stem Cell Self-Renewal and Fate Determination
Larocca is presenting Targeted Nanoparticle Probes for Identifying, Tracking and Isolating Embryonic Stem Cell Derived Progenitor Cells
C. Leeuwenburgh will be presenting Mitochondrial iron accumulation with age and functional consequences
D.A. Taylor will be presenting three-fold cell-based approaches to cardiovascular repair and answering the question Is Aging a Treatable Disease in the 21st Century?
FURTHER READING
Over twenty poster abstracts
The agenda of the conference with links to abstracts.
Pre-coverage of the conference
and coverage of Wired article on the conference
The new SENS projects AmyloSENS, ApoptoSENS, Glycosens, Oncosens and Replenisens
May 17, 2008
Artificial cell created from scratch
Simple artificial cell created from scratch
A team of Penn State researchers has developed a simple artificial cell with which to investigate the organization and function of two of the most basic cell components: the cell membrane and the cytoplasm--the gelatinous fluid that surrounds the structures in living cells. The work could lead to the creation of new drugs that take advantage of properties of cell organization to prevent the development of diseases.
The model cell uses as the cytoplasm a solution of two different polymers, PEG and dextran (Panel A). The image in Panel B is the image in Panel A highlighted with fluorescent dyes. The blue region is PEG, which is concentrated in the outer polymer solution; the green area is the portion of the membrane that contains PEG groups, which interact with the contents of the cell; and the red area is the portion of the membrane with fewer PEG groups, which interact with the contents of the cell to a lesser extent. After exposure to a concentrated solution of sugar, the cell converted to a budded form (Panel C). A dextran-rich mixture filled the bud, while a PEG-rich mixture remained inside the body of the cell. Panel D shows the image in Panel C highlighted with fluorescent dyes. The blue area is the PEG-rich region. This new structure exhibits polarity both in the membrane and in the aqueous interior of the model cell. (Credit: Christine Keating, Penn State)
The team's next step is to create a cascade in polarity. "By creating a model cytoplasm with different compositions, we demonstrated that we can control the behavior of cell membranes," said Keating. "Now we want to find out what will happen if, for example, we add an enzyme whose activity depends on the compositions of the cytoplasm and cell membrane."
Although Keating and her colleagues plan to continue adding components to their model cell, they don't expect to make a real cell. "We aren't trying to generate life here. Rather, we want to understand the physical principles that govern biological systems," said Keating. "For me the big picture is trying to understand how the staggering complexity observed in biological systems might have arisen from seemingly simple chemical and physical principles."
May 10, 2008
You say inVitro meat, yuck. But eat deep fried meat slurry, corn and chemicals. Called chicken nuggets
I had previously covered the PETA $1 million prize for invitro (test tube / factory meat from stem cells) meat. PETA prize for chicken meat that can pass a fried chicken taste test and be sold in ten states commercially
Many people have an initial reaction that invitro meat would be yucky and they do not want it. However, people already eat meat slurry in fairly large quantities.
Meat slurry is mechanically separated meat (MSM), also known as mechanically recovered/reclaimed meat (MRM), is a paste-like meat product produced by forcing beef, pork or chicken bones, with attached edible meat, under high pressure through a sieve or similar device to separate the bone from the edible meat tissue. Then this is mixed with water to make it more easily fed through tubes.
From Wikipedia: Meat slurry is part of chicken nuggets (like at McDonalds) The meat part is mainly reconstituted meat slurry. Then there is chicken skin. Most of a chicken nugget (56%) is corn.
From Wikipedia:
A meat slurry, reconstituted meat, or emulsified meat, is a liquefied meat product that contains fewer fats, pigments and less myoglobin than unprocessed dark meats. Meat slurry also eases the process of meat distribution and is more malleable than dark meats.
UPDATE: Why would invitro meat not be so bad ? I would eat both invitro meat or chicken nuggets in spite of how their production could be viewed negatively. Invitro meat will be the same as regular meat at the cellular level. Producing stem cells and differentiating them is leading to transplantable livers and other organs. Therefore, the meat that it produces for us to eat will be like the real thing. It should be 4-20 times more energy efficient to produce than beef from a cow. It will not be sold until it is more cost efficient to produce for a particular type of meat.
NOTE: I had fairly quickly put this article together and was sloppy in my cut and paste although I had links to all of my multiple references. So the parts with the specific descriptions of meat slurry is not and was not claimed to be original. What was original was pointing out the meat slurry, chicken nugget, and invitro meat yuck factor connection.
Meat slurry is not designed to sell for general consumption; rather, it is used as a meat supplement in food products for humans, such as chicken nuggets, and food for domestic animals. Poultry is the most common meat slurry; however, beef and pork are also used.
Some other Poultry science, turning dark meat into white meat
So people can say yuck - invitro meat.
But deep fry it and call them improved McNuggets and they eat billions.
4.8 Billion Chicken McNuggets are sold annually.
FURTHER INFORMATION
What is in a McDonald's chicken Nugget ?
McDonald’s Chicken McNugget is 56% corn.
NOTE: It was a yahoo answer below that I was particularly sloppy with which had the citation issues as the yahoo anwer was pieced together from .
From Yahoo answers:
Chicken nuggets are often made using a high proportion of chicken skin.This is because without the skin the consistency would not be sticky enough for the nuggets to hold together. Food labeling law dictates that skin used to make the nugget need not be distinguished from the muscle consumers normally think of when they hear the word "meat". The remainder of the nugget is most likely to be made up of mechanically separated meat, with some processing additives such as anti-foaming agents (usually polydimethylsiloxane). The meat of the nugget may also be composed of reconstituted meat slurry.
Other coverage on work towards invitro meat
Test tube meat work
April 09, 2008
Life extension Update, metabolic pathway drug modification and SENS
But more than the apparent result, what excites and interests Dillin is the way the drug achieves its result. A-Beta does its damage by causing cell proteins to misfold; Dillin suspects that the drug works not by specifically blocking A-Beta but rather by encouraging proteins to keep folding accurately and precisely. That is, he thinks the drug works by promoting an overall cellular well-being, otherwise known as youthfulness. Specifically, he thinks the drug works by "upregulating the PHA-4 pathway," which has been defined as a pathway regulating longevity. But he thinks it does more than that. He thinks it will enable him to define and deal experimentally with youthfulness.
The article mentions doubling lifespans to 250 years. However, to achieve that effect would require more than calorie restriction effects. It would also not apply to people who are already middle age or older if it is reducing metabolic aging in half.
Andrew Dillin's research papers
The SENS and MPrize funding combined are over $11 million
SENS is looking to launch several new research projects.
AmyloSENS: Extracellular junk is aggregates of stuff that do not have any function and should ideally have been cleared out of the body, but have proven resistant to destruction. Most of this junk is termed “amyloid” of one variety or another. You may have heard of one form of amyloid – Abeta, the stifling, web-like material that forms plaques in the brains of patients with Alzheimer's disease, and also (more slowly) in everyone else’s.
Elan Pharmaceuticals’ most recent candidate Alzheimer vaccine, bapineuzumab, has been the subject of recent excitement after the company launched a full-scale (“Phase III”) clinical trial at an unusually early point, leading to speculation that the as-yet-undisclosed preliminary results of its earlier trials may be exceptionally promising.
The Methuselah Foundation is presently in discussion with leading researchers in this field with a view to initiating work on a vaccine – similar to that developed by Elan for Alzheimer’s disease – to stimulate the aged body to clear the widespread amyloids (particular of transthyretin) responsible for senile systemic amyloidosis.
ApoptoSENS
There are three main classes of cells that sometimes acquire a metabolic state that is damaging to their neighbours. (Visceral fat cells, Senescent cells, Immune cells)
There are two main alternatives:
1. Inject something that makes the unwanted cells commit suicide but doesn't touch other cells.
2. Stimulate the immune system to kill the target cells.
Glycosens
The Methuselah Foundation is currently planning out a project to engineer enzymes capable of cleaving the ubiquitous glucosepane crosslinks, which may comprise as much as 98% of all the long-lived crosslinks in aged human tissue. This work is still in the early planning stages, but we hope to be able to begin full-time research before the end of 2008.
Oncosens
We don't actually need to fix chromosomal mutations at all in order to stop them from killing us: all we need to do is develop a really really good cure for cancer. The one that I favour (and which was the topic of the third SENS roundtable, a meeting I convened in Cambridge in 2002) is called WILT, for Whole-body Interdiction of Lengthening of Telomeres.
The Methuselah Foundation is planning to launch three projects in the OncoSENS strand during 2008.
The first project aims to characterise the enzyme responsible for ALT, which is still unknown. Recently, however, observations in two different organs have given good reason to consider a hitherto unsuspected gene. A relatively simple series of experiments could test this hypothesis.
The second project addresses a potential problem with the WILT strategy. It’s possible that telomerase activity per se – independent of telomere length – may have roles in maintaining the health of the stem cells themselves, or of their rarely-dividing neighbours in the so-called “stem cell niche”. We are arranging a project to address this question, in the blood of mice, with the world’s leading professor in the area.
Finally, the theory that non-cancer-causing mutations are unlikely to be harmful in a normal lifetime – protagonistic pleiotropy – is not yet widely accepted. We are therefore initiating a rigorous study into the effects of such mutations in mouse brains.
Replenisens
Cell depletion is the loss of cells without equivalent replacement. Cell depletion can be fixed in two main ways: by stimulating the division of existing cells, or by directly introducing new ones. There is a lot of active work with Stem cells, so the Methuselah Foundation does not currently intend to allocate its limited resources to projects in this area.
Regenerative medicine advance: 140 Cell Types From Human Embryonic Stem Cells
Research published this week in Regenerative Medicine, reports on a new technology that yields over 140 previously uncharacterized cell types, many on an industrial scale. This advance holds great promise for future research and may one day lead to many new cell-based therapies in the emerging field of regenerative medicine.
Previously there have been occasional reports that individual cell types have been generated from hES (human embryonic stem cells) cells, such cells have often been generated in small quantities, not useful on an industrial scale. In a paper titled The ACTCellerate Initiative: large-scale combinatorial cloning of novel human embryonic stem cell derivatives", a team led by Dr Michael D. West, now CEO, BioTime, Inc and Adjunct Professor, University of California, Berkeley, along with collaborators at Advanced Cell Technology, the Burnham Institute, Ontario Cancer Institute, and the University of California, San Francisco demonstrated that primitive precursors of the many body cell types have an unpredicted ability to be propagated from a single cell, leading to the clonal expansion of these embryonic progenitor cell types. A careful genome-wide analysis of gene expression showed evidence that the "Zip code" that the developing body uses to place cells in their proper location in the body is preserved in these cells, giving researchers a means to make cell types from a single location in the body.
Another important finding in this publication is that these highly purified cell types show that primitive embryonic cell types show the expression of genes generally associated with malignant cancer. However, when used in this highly purified form, no malignant tumors could be observed when the cells were injected into mice.
Dr Chris Mason (UCL), Associate Editor of Regenerative Medicine said, "This is an enormously exciting development for the regen sector. The research reported by Dr West and his team represents a quantum leap forward in embryomics, the mapping and characterization of the cells of early human development. Without any doubt, the ACTCellerate technology will greatly hasten the translation of human embryonic stem cell-based therapies into safe and effective products for routine clinical practice ".
"The demonstration that combinatorial cloning can lead to numerous and diverse purified cell types opens the door strategies to map the human embryome. This roadmap is critical to the clinical application of the emerging field of regenerative medicine", said Dr. West.
EXECUTIVE SUMMARYThe unique challenges of pluripotency
• Human embryonic stem (hES) cells show the capacity to differentiate into all of the hundreds of somatic cell lineages in the developing human.
• Human embryonic progenitor (hEP) cells are primitive precursors of terminally differentiated cells that are capable of propagation in vitro and display makers generally associated with the embryonic stages of development.
• Challenges to the field include the mapping of the ‘embryome’ for example to identify the unique molecular markers that allow the identification and isolation of hEP cells.
Multiplex generation & characterization of hEP cell clones
• The ACTCellerate protocol utilizes a two-step differentiation and propagation protocol to isolate clonal populations of scalable hEP cell lines. Of 1090 clones isolated in this report, 280 lines (25.7%) expanded to at least four roller bottles.
Clonal hEP cells do not display hES markers but instead show markers of diverse primitive embryonic progenitors
• Cell lines derived with the ACTCellerate protocol do not express markers of hES cells such as hTERT or OCT4.
• A total of 71% of the hEP cell lines show positive expression for MEOX1, MEOX2, or FOXF1, which in the mouse are reported to be expressed only in early stages of embryonic development.
• Non-negative matrix factorization suggested that the complexity of distinct cell types isolated was at least 140.
Immunocytochemical confirmation of hEP microarray gene-expression analysis
• Selected markers in putative ectodermal, mesodermal, endodermal and neural crest gene cell lines were confirmed by immunocytochemistry.
Clonal hEP lines express diverse cell surface antigens
• Flow cytometry confirmed that gene expression often predicts CD antigen expression on the cell surface and provides a means of manipulating hEP cell types.
hEP clones express unique secreted factors
• hEP cell clones expressed diverse secreted growth factors. Select factors confirmed by ELISA included AREG, FGF7, IGFBP5, TGFβ-1 and PDGF-BB.
hEP cells lack tumorigenicity
• hEP cell lines expressed a wide array of oncofetal genes including: SILV, PLAG1, AMIGO2, HCLS1, SPINK1, PRAME, INSM1, ENC1 and CEACAM1, as well as others.
• Clonal hEP cell lines did not generate malignant tumors in 4-6 months at doses of 10 million cells per mouse when injected subcutaneously and intramuscularly.
hEP cells include clones with a robust & mortal proliferative capacity
• hES cells express high levels of telomerase activity by telomeric repeat amplification protocol (TRAP) assay, and an immortal phenotype when maintained in the undifferentiated state.
• hEP cells were telomerase negative by TRAP assay, but often display a long proliferative lifespan in vitro useful in scaling the cells.
March 31, 2008
Gene Therapy Breakthrough- Three Micro RNA inhibition injections reduces cholesterol 30%, 2013 for human use
Two forms of RNA either boost or suppress protein production, and scientists have in recent years discovered this system is central to a range of illnesses, including cancers, viral infections, cardiovascular disease and neurological disorders.
Previous attempts to manipulate this process have failed because the drug molecules used were too large to get to the target cells. Now scientists at Santaris Pharma have developed smaller compounds that can cross cell membranes and intercept the microRNA molecules that usually put a brake on protein production.
LNA-mediated microRNA silencing in non-human primates.
MicroRNAs (miRNAs) are small regulatory RNAs that are important in development and disease and therefore represent a potential new class of targets for therapeutic intervention. Despite recent progress in silencing of miRNAs in rodents, the development of effective and safe approaches for sequence-specific antagonism of miRNAs in vivo remains a significant scientific and therapeutic challenge. Moreover, there are no reports of miRNA antagonism in primates. Here we show that the simple systemic delivery of a unconjugated, PBS-formulated locked-nucleic-acid-modified oligonucleotide (LNA-antimiR) effectively antagonizes the liver-expressed miR-122 in non-human primates. Acute administration by intravenous injections of 3 or 10 mg kg-1 LNA-antimiR to African green monkeys resulted in uptake of the LNA-antimiR in the cytoplasm of primate hepatocytes and formation of stable heteroduplexes between the LNA-antimiR and miR-122. This was accompanied by depletion of mature miR-122 and dose-dependent lowering of plasma cholesterol. Efficient silencing of miR-122 was achieved in primates by three doses of 10 mg kg-1 LNA-antimiR, leading to a long-lasting and reversible decrease in total plasma cholesterol without any evidence for LNA-associated toxicities or histopathological changes in the study animals. Our findings demonstrate the utility of systemically administered LNA-antimiRs in exploring miRNA function in rodents and primates, and support the potential of these compounds as a new class of therapeutics for disease-associated miRNAs.
Mice on a high fat diet were given three injections of a drug to block miRNA-122, a compound in the liver that controls cholesterol levels. Those given the highest dose had 30 per cent lower cholesterol levels than those given placebo injections, and the effects lasted three weeks after the last injection.
Laboratory tests also showed that blocking miRNA-122 also prevented the hepatitis C virus replicating. Human trails of a drug to treat hepatitis C will begin next year and scientists are using the method to develop a treatment to combat blood cancers.
Santaris predicts new therapies will be ready for use by patients within five years if trials go well.
Santaris Pharma is preparing to advance its first LNA-antimiR compound, targeting miR-122, into human clinical testing in the first half of 2008.
FURTHER READING
Safer and more precise methods of targeting gene therapy are being made with synthetic zinc fingers.
Researchers have figured out the real problem with a common gene therapy delivery system the adenovirus type 5. Adenovirus consists of three major proteins - fiber, penton and hexon. Previously researchers thought the fiber protein was the problem. New research indicates it is the hexon. Now by modifying the hexon they can make adenovirus delivered gene therapy safe.
“Now that we have learned the mechanism that an adenovirus uses we could modify that process by genetically engineering the virus, to improve uptake into several cell types, including stem cells,” says Dr. Napoli.
There has also been progress in using gene therapy to treat brain cancer.
Safe and effective gene therapy or drugs that safely target genetic effects could be used to safely boost muscle mass by four times. This could make people stronger and healthier. Better weight control with more muscle that burns excess fat. 2012-2016 seems to be the likely timeframe when these procedures start making a big societal impact. It could happen sooner and more could happen later, but that seems to be the time when more people will realize that a new age is upon the world.
February 13, 2008
New implantable device can extract stem cells from the bloodstream
Cell Traffix, using a microtube device coated with the protein P-selectin, has isolated and collected adult stem cells residing in human bone marrow to eight times greater purity than can be obtained through traditional centrifugation.
The device, a length of plastic tubing coated with proteins, could lead to better bone-marrow transplants and stem-cell therapies, and it also shows promise as a way to capture and reprogram cancer cells roaming the bloodstream. The system could capture and differentiate stem cells and other cells in the body and allow them to altered or replaced inside or outside the body. It is a path to killing cancer and removing aged cells with rejuvenated cells. There has also been promising work in reprogramming adult stem cells to revert to embryonic stem cells
Researchers used genetic alteration to turn back the clock on human skin cells and create cells that are nearly identical to human embryonic stem cells, which have the ability to become every cell type found in the human body. Reprogramming adult stem cells into embryonic stem cells could generate a potentially limitless source of immune-compatible cells for tissue engineering and transplantation medicine.
The behavior of stem cells, or any new tissue, in the body has a great deal to do with the holistic functioning of signaling networks and the cellular environment. The Cell Traffix device can enable alterations in the signaling to regular cells, cancer cells and stem cells.
Direct capture of blood-borne nucleated cells from circulation using P-selectin and non-coated control surfaces in implanted devices. Following incorporation into the femoral artery of anesthetized rats and 1-h blood perfusion, P-selectin coated tubes (A) showed a significantly greater average concentration of captured nucleated cells than non-coated control tubes (B) [184·6 ± 19·9 cells/mm2 for P-selectin tubes (40 μg/ml) vs. 4·7 ± 1·4 cells/mm2 for control surfaces (P < 0·01), bar = 50 μm]. (C) Total cell yields from 50 cm implanted tubes with cell adhesion molecule surfaces were significantly greater than the yield from non-specific binding in control tubes (**P < 0·01).
The new device mimics a small blood vessel: it's a plastic tube a few hundred micrometers in diameter that's coated with proteins called selectins. The purpose of selectins in the body seems to be to slow down a few types of cells so that they can receive other chemical signals. A white blood cell, for instance, might be instructed to leave the circulation and enter a wound, where it would protect against infection. "Selectins cause [some] cells to stick and slow down," says Michael King, a chemical engineer at the University of Rochester who's developing the cell-capture devices. Different types of selectins associate with different kinds of cells, including platelets, bone-marrow-derived stem cells, and immune cells such as white cells.
Nanowerk describes and ridicules a pure brute force nanotechnology robot approach to cellular repair. The new work by Cell Traffix shows that there could be other more clever paths to being able to achieve cellular rejuvenation.
Twenty-eight percent of the cells captured by King's implants were stem cells. "This is astounding given how rare they are in the bloodstream," says King. Implants would probably not be able to capture enough stem cells for transplant. But King believes that filtering a donor's blood through a long stretch of selectin-coated tubing outside the body, in a process similar to dialysis, would be very efficient. "This technique will clearly be useful outside the body" as a means of purifying bone-marrow-derived stem cells, says Daniel Hammer, chair of bioengineering at the University of Pennsylvania.
Mike King holding the cell capture device
Hammer believes that King's devices will also have broader applications as implants that serve to mobilize a person's own stem cells to regenerate damaged tissues. By slowing down cells with selectins and then exposing them to other kinds of signals, says Hammer, King's devices "could capture stem cells, concentrate them, and differentiate them, without ever having to take the cells out of the body." There might be a way to use selectins to extract neural stem cells, too. "This is a very broad-reaching discovery," says Hammer. Indeed, King says that he has already had some success using selectin coatings to reprogram cancer cells. Leukemia is a blood cancer, but King expects that the anticancer coating would work for solid tumors as well. Devices lined with these coatings might be implanted into cancer patients to prevent or slow metastasis. The company hopes to begin clinical testing of the anticancer coatings by early 2010.
FURTHER READING
Implanted CellTraffix Device Extracts Adult Stem Cells Directly from the Bloodstream, online in the British Journal of Haematology
Cancer killing invention also harvest stem cells
Other stem cell work: embryonic stem cells can be used to create functional immune system blood cells, a finding which is an important step in the utilisation of embryonic stem cells as an alternative source of cells for bone marrow transplantation.
January 18, 2008
Important progress to nanomedicine: Magnetically controlling cells and biochemical events
For the first time, researchers have demonstrated a means of controlling cell functions with a physical, rather than chemical, signal. Immune cells coated with nanoparticles take up calcium in the presence of a magnetic field. Each nanoparticle measures approximately 30 nanometers in diameter.
In this image, yellow cells are taking up calcium in response to a localized magnetic field. Cells that are farther away from the field are shown in purple and do not take up calcium. Credit: Donald Ingber, Harvard Medical School
Using a magnetic field to pull together tiny beads targeted to particular cell receptors, Harvard researchers made cells take up calcium, and then stop, then take it up again.
This is another important step to cellular and molecular control to enable nanomedicine
Ingber's group demonstrated its method for biomagnetic control using a type of immune-system cell that mediates allergic reactions.
Targeted nanoparticles with iron oxide cores were used to mimic antigens in vitro. Each is attached to a molecule that in turn can attach to a single receptor on an immune cell. When Ingber exposes cells bound with these particles to a weak magnetic field, the nanoparticles become magnetic and draw together, pulling the attached cell receptors into clusters. This causes the cells to take in calcium. (In the body, this would initiate a chain of events that leads the cells to release histamine.) When the magnetic field is turned off, the particles are no longer attracted to each other, the receptors move apart, and the influx of calcium stops.
"It's not the chemistry; it's the proximity" that activates such receptors, says Ingber.
The approach could have a far-reaching impact, as many important cell receptors are activated in a similar way and might be controlled using Ingber's method.
"In recent years, there has been a realization that physical events, not just chemical events, are important" to cell function, says Shu Chien, a bioengineer at the University of California, San Diego. Researchers have probed the effects of physical forces on cells by, for example, squishing them between plates or pulling probes across their surfaces. But none of these techniques work at as fine a level of control as Ingber's magnetic beads, which act on single biomolecules.
Many drugs, from anticancer antibodies to hormones, work by activating cell receptors. Once a hormone is in the blood, however, there's no turning it on or off. "This shows that you can turn on and off the signal, and that you can do it instantly," says Christopher Chen, a bioengineer at the University of Pennsylvania. "That's something that's hard to do, for example, with an antibody."
Ingber has many ideas for devices that might integrate his method of cellular control. Magnetic pacemakers could use cells instead of electrodes to send electrical pulses to the heart. Implantable drug factories might contain many groups of cells, each of which makes a different drug when activated by a magnetic signal. Biomagnetic control might lead to computers that can take advantage of cells' processing power. "Cells do complex things like image processing so much better than computers," says Ingber. Ingber, who began the project in response to a call by the Defense Advanced Research Projects Agency for new cell-machine interfaces, acknowledges that his work is in its early stages. In fifty years, however, he expects that there will be devices that "seamlessly interface between living cells and machines."
They have developed micromagnetic and nanomagnetic technologies to apply controlled mechanical stresses to specific cell surface receptors via surface-bound, ligand-coated, magnetic micro- and nano-beads.
Picture of a cell and expanded view of a cell receptor
FURTHER READING
Harvard Institute for Biologically Inspired Engineering.
Here the Ingber group discusses how new understanding of the fundamental role that mechanical forces play in tissue development might be leveraged to facilitate the development of new types of biomimetic materials for regenerative medicine, with a focus on the design of injectable materials that can target to injury sites, recruit stem cells and direct cellular self-assembly to regenerate functional tissues and organs in situ.
The group was funded by the NIH to try to grow heart valves, and parts of a pancreas and a tooth, from scratch in the lab. NIH funds Ingber Lab as part of a Harvard-Wide Consortium to Engineer Whole Organs.
January 07, 2008
UCLA reports on progress and promise to reversing paralysis
Spinal cord damage blocks the routes that the brain uses to send messages to the nerve cells that control walking. Until now, doctors believed that the only way for injured patients to walk again was to re-grow the long nerve highways that link the brain and base of the spinal cord. For the first time, a UCLA study shows that the central nervous system can reorganize and follow new pathways to restore the cellular communication required for movement.
The UCLA team’s next step will be to learn how to entice nerve cells in the spinal cord to grow and form new pathways that connect across or around the injury site, enabling the brain to direct these cells. If the researchers succeed, the findings could lead to the development of new strategies for restoring mobility following spinal cord injury.
“Our study has identified cells that we can target to try to restore communication between the brain and spinal cord,” explained Sofroniew. “If we can use existing nerve connections instead of attempting to rebuild the nervous system the way it existed before injury, our job of repairing spinal cord damage will become much easier.”
The discovery could lead to new therapies for the estimated 250,000 Americans who suffer from traumatic spinal cord injuries. An additional 10,000 cases occur each year, according to the Christopher and Dana Reeve Foundation, which helped fund the UCLA study
December 11, 2007
What is needed to achieve broad clinical success for tissue engineering
A worldwide body of 24 leaders in tissue engineering was queried systematically to determine the best paths toward that goal. Using a modified Hoshin process, we identified 14 critical activity categories and then stratified them by their immediate priority for the field. The result of the analysis illustrates a highly interdependent set of activities that are dominated by the need for an understanding of angiogenesis, stem cell science, and the utilization of molecular biology and systems biology tools to enable a deeper comprehension of tissue development and control.
1. ‘‘Understanding and controlling the cellular response: A fundamental challenge is to understand how cells— the building blocks of tissues—receive and respond to information from their local environment in establishing and maintaining tissues.
2. Formulating biomaterial scaffolds and the tissue matrix environment: The scaffolding that supports cells and gives tissues their form is increasingly appreciated as an important source of information that drives cell fate determination. A deeper understanding of the biology underlying this relationship will allow more effective tissue design and engineering.
3. Developing enabling tools: Complex, multiparametric inputs are required to assess the state of a tissue and the cells within it. This information will be supplied by improvements in high-throughput assays and instrumentation, imaging modalities, fabrication technologies, computational modeling, and bioinformatics. Additionally, tissue preservation technologies and bioreactors will facilitate the generation of tissues on demand.
4. Promoting scale-up, translation, and commercialization: Demonstrating the feasibility of designing an engineered tissue is not enough. Realizing the full benefits tissue engineering science requires increased reproducibility, robustness, and user-friendliness that will enable the broad distribution of products.’’
Critical priorities for the field:
- ‘‘Understanding the Cellular Machinery
- Identifying, Validating Biomarkers and Assays
- Advancing Imaging Technologies
- Defining Cell/Environment Interactions
- Establishing Computational Modeling Systems
- Assembling and Maintaining Complex Tissue
- Improving Tissue Preservation and Storage
- Facilitating Effective Applications Development and Commercialization’’
December 07, 2007
Stem cells made from skin cells treats sickle cell anemia in mice
U.S. and Japanese researchers last month reported they had reprogrammed human skin cells into behaving like embryonic stem cells, the body's master cells. They call the cells induced pluripotent stem cells, or iPS cells for short.
Hanna and colleagues working in Rudolf Jaenisch's lab at Whitehead Institute took skin cells from diseased mice and inserted four genes that reprogram the cells into becoming iPS cells.
Pluripotent or multipurpose cells, such as embryonic stem cells and the new cells, can morph into any type of cell in the human body.
The researchers then coaxed these mouse master cells into becoming blood-forming stem cells and substituted the faulty gene that causes sickle cell anemia with a working one.
When they transplanted these cells into the diseased mice, tests showed normal blood and kidney function, they report in Friday's issue of the journal Science.
The four genes needed to turn skin cells into master cells are delivered using a type of virus called a retrovirus.
"Once they enter the genome, there is the danger that they can silence some genes that are important or they can activate some dangerous genes that shouldn't be activated," Hanna said.
Another obstacle is that one of the four genes used is c-Myc, which is known to cause cancer.
Hanna and colleagues got around that by removing the c-Myc gene after it had done its job of converting the skin cells into iPS cells. "It is far from solving the problem," he said.
Scientists hope to use stem cells to treat a host of diseases like diabetes, Parkinson's disease and spinal injuries. And the new technique for making stem cells will make them easier to study.
November 20, 2007
Making embryonic stem cells without destroying embryos
Two separate teams of researchers say they have sidestepped the
cloning method and reprogrammed mature human cells into a primordial,
embryonic-like state. Those cells were then transformed into other tissue types, such as heart cells. The long-term hope is that such freshly-created tissue may, for example, be used to heal a heart-attack patient. Unlike cloning, "the wonderful thing about this approach is that it's easy."
There are several limitations to the current approach. For now, both teams had to use dangerous viruses to effectively transport the genes into the cell, which could have deadly consequences if it was immediately applied to humans. Dr. Yamanaka and others say they are testing other viruses in the hopes of finding a non-harmful one.
And before the reprogramming technique can be applied to human patients, it needs to be tested on large animal models to ensure that it's safe and effective.
Still, the latest results are a big step up from similar breakthroughs in mice, separately reported this summer by Dr. Yamanaka's group and two other research teams in the U.S. The Kyoto team reported that embryonic-like cells developed with the new technique could even help form a new mouse -- a gold-standard test for the viability of the created tissue.
UPDATE: "I believe that these new results, while they don't end that controversy, are the beginning of the end of the controversy," James Thomson Thomson, a cell biologist at the University of Wisconsin in Madison (on one of two teams that did the work), said.
One first step may be to grow tissue transplants to repair a damaged heart, replace the brain cells destroyed by Parkinson's disease, or perhaps even to grow another whole organ.
But the ultimate goal is even more ambitious. "From a heart cell we don't have to go back to an embryonic stem cell," Gearhart said in a telephone interview.
"We could go back to a cardiac progenitor cell. If we knew the right combination of things ... we could be instructing our own cells to get them to do what we want them to do."
November 12, 2007
Possible cloning of primate embryos
The scientists who carried out the latest primate work are believed to have tried to implant about 100 cloned embryos into the wombs of around 50 surrogate rhesus macaque mothers but have not yet succeeded with the birth of any cloned offspring.
However, one senior scientist involved in the study said that this may simply be down to bad luck – it took 277 attempts, for instance, to create Dolly the sheep, the first clone of an adult mammal.
The work was led by Shoukhrat Mitalipov, a Russian-born scientist at the Oregon National Primate Research Centre in Beaverton. Dr Mitalipov helped to pioneer a new way of handling primate eggs during the cloning process, which involved fusing each egg with a nucleus taken from a skin cell of an adult primate.
Dr Mitalipov said he was unable to comment on the study until it was published in the journal Nature. But he told colleagues at a scientific meeting this year that he had made two batches of stem cells from 20 cloned embryos and tests had shown they were true clones.
Professor Alan Trounson of Monash University in Australia said Dr Mitalipov's findings represented the long-awaited breakthrough. Despite many attempts, no one had been able to produce cloned primate embryos from adult cells, yet this had been done on dozens of other non-primate species. " This is 'proof of concept' for the primate. It has been thought by some [to be too] difficult in monkeys – and humans – but those of us who work [with] animals such as sheep and cattle thought that success rates would be much like that achieved in these species," Professor Trounson said.
"Mitalipov's data confirms this. They have the skills necessary and we can now move on to consider what might be able to be achieved in humans."
Professor Don Wolf, who led the laboratory at the Oregon National Primate Research Centre before his recent retirement, said the new procedure was based on a microscopic technique that does not use ultraviolet light and dyes, which appear to damage primate eggs.
"We're the first to do it, although it's a tainted subject because of the fraudulent research that came out of South Korea. One can never be sure but there may be some validity to what the South Koreans did. But this would now be the first documented therapeutic cloning in a primate," he added.
Two Stem cells advances: one for vascular treatment another for controlled release of cells
The stem cells were differentiated into blood vessels that were grafted onto the animals afflicted with ischemia. Ischemia is caused by a shortage of blood to a part of the body, stemming from the constriction of blood vessels. Of the 11 mice treated, four developed new vascular cells that fully revived the damaged limb, while four suffered from a relatively mild case of necrosis. Three lost their legs due to the cut-off of blood flow. 10 other mice given alternative treatment failed to recover.
Engineers at Rensselaer Polytechnic Institute have transformed a polymer found in common brown seaweed into a device that can support the growth and release of stem cells at the sight of a bodily injury or at the source of a disease.
“We have developed a scaffold for stem cell culture that can degrade in the body at a controlled rate,” said lead researcher Ravi Kane, professor of chemical and biological engineering. “With this level of control we can foster the growth of stem cells in the scaffold and direct how, when, and where we want them to be released in the body.”
Kane and his collaborators, which include the author of the paper and former Rensselaer graduate student Randolph Ashton, created the device from a material known as alginate. Alginate is a complex carbohydrate found naturally in brown seaweed. When mixed with calcium, alginate gels into a rigid, three-dimensional mesh.
The device could have wide-ranging potential for use in regenerative medicine, Kane explains. For example, the scaffolds could one day be used in the human body to release stem cells directly into injured tissue. Kane and his colleagues hope that the scaffold could eventually be used for medical therapies such as releasing healthy bone stem cells right at the site of a broken bone, or releasing neural stem cells in the brain where cells have been killed by diseases such as Alzheimer’s.
In order to control the degradation of the alginate scaffold, the researchers encapsulated varying amounts of alginate lyase into microscale beads, called microspheres. The microspheres containing the alginate lyase were then encapsulated into the larger alginate scaffolds along with the stem cells. As the microspheres degraded, the alginate lyase enzyme was released into the larger alginate scaffold and slowly began to eat away at its surface, releasing the healthy stem cells in a controlled fashion.
October 17, 2007
Progress to nerve and paralysis repair
Dr Paul Kingham and his team at the UK Centre for Tissue Regeneration (UKCTR) isolated the stem cells from the fat tissue of adult animals and differentiated them into nerve cells to be used for repair and regeneration of injured nerves. They are now about to start a trial extracting stem cells from fat tissue of volunteer adult patients, in order to compare in the laboratory human and animal stem cells.
Following that, they will develop an artificial nerve constructed from a biodegradable polymer to transplant the differentiated stem cells. The biomaterial will be rolled up into a tube-like structure and inserted between the two ends of the cut nerve so that the regrowing nerve fibre can go through it from one end to the other.
This 'bionic' nerve could also be used in people who have suffered trauma injuries to their limbs or organs, cancer patients whose tumour surgery has affected a nearby nerve trunk and people who have had organ transplants.
With a clinical trial on the biomaterial about to be completed, the researchers hope the treatment could be ready for use in four or five years.
"The frequency of nerve injury is one in every 1,000 of the population — or 50,000 cases in the UK — every year.
"The current repair method — a patient donating their own nerve graft to span the gap at the injury site — is far from optimal because of the poor functional outcome, the extra damage and the possibility of forming scars and tumours at the donor site. Tissue engineering using a combination of biomaterials and cell-based therapies, while at an early stage, promises a great improvement on that. Artificial nerve guides provide mechanical support, protect the re-growing nerve and contain growth factor and molecules favourable to regeneration. The patient will not be able to tell that they had ever 'lost' their limb and will be able carry on exactly as they did before."
October 15, 2007
Improved printing for organs and tissue
A jet of air can draw out a thread of living cells and sticky polymer that could provide a way to carefully position cells to regenerate tissue or organs (Image: Suwan Jayasinghe
Currently printers use a 60-micrometre needle, so the droplets are at least 100 µm in diameter. Those needles can also damage larger cells like neonatal cardiomyocites – baby heart cells – can be 100 µm across. Squeezing them through an inkjet needle can make them rupture and die.
Jayasinghe is developing an alternative approach, called Pressure Assisted Spinning. Three needles nested inside one another separately deliver cells, a viscous polymer and pressurised air. The cells and polymer mix are drawn out and mixed by the pressurised air, explains Jayasinghe.
Vladimir Mironov of the Medical University of Southern California says Jayasinghe's simple solution doesn't tackle the problems hindering all types of cell printing. "The precise placing of different cell types [along the thread] is not possible," he says. "And [manual] cell seeding on a scaffold is laborious and expensive."
As well as inkjet printing, some researchers are experimenting with electrospinning, Mironov points out, a well-understood technology first developed about 100 years ago for making textiles.
In this process, a cell solution flows through an electrically charged hollow needle a few centimetres above an electrically grounded target. The charged solution is drawn towards the target, a little like lightning being drawn towards the Earth, pulling it into a very fine fibre with cells along its length.
But electrospinning also cannot space cells controllably, and has other drawbacks, says Jayasinghe, pointing out that up to 30,000 volts of electricity is needed. The current is low, though, making the chance of serious injury minimal. It is still a hazard, he says, one not present using pressure assisted spinning.