New Magic Bullets Against Emerging and Chronic Infections?

Emerging infections -- both human engineered and naturally evolved -- present a difficult challenge for modern and future medicine. Recent scares from SARS and Bird Flu have sent journalists and health watchers into a frenzy, although fortunately neither outbreak proved as rapidly contagious and broadly lethal as anticipated -- so far.

A "magic bullet" that could provide resistance against a wide array of new viral, bacterial, and fungal infections would give medical practitioners and public health officials new confidence for a healthier human future.

Two potential "magic bullets" have been recently developed. The first is an artificial protein -- EP67 -- which appears to boost mammalian immune systems -- even when given alone without other drugs or vaccines.

Mice treated with EP67 within a twenty-four hour window of non-lethal infection were significantly protected from influenza-induced weight loss. Furthermore, EP67 delivered twenty-four hours after lethal infection completely blocked influenza-induced mortality (0% vs. 100% survival). Since protection based on innate immune induction is not restricted to any specific pathogen, EP67 may well prove equally efficacious against a wide variety of possible viral, bacterial, and fungal pathogens. Such a strategy could be used to stop the worldwide spread of emergent respiratory diseases, including but not limited to novel strains of influenza.

...In summary, this report shows that the C5a agonist peptide EP67 provides both prophylactic and therapeutic protection against influenza infection. Protection results from the rapid induction of a robust innate immune response that includes high local concentrations of anti-viral cytokines and the influx of several populations of innate immune effector cell types. These results have profound implications for influenza therapeutic development and, ultimately, for broad-spectrum emergency therapy against unidentified respiratory pathogens. _PLoS

Medical Express News Release on EP67

Another potential "magic bullet" approach to both new and old infectious diseases, is the T Cell vaccine.

For some infectious diseases, traditional vaccines just don't cut it. Microbes that hide inside human cells and cause chronic illness aren't stymied by the antibody response generated by the kind of vaccine available at the doctor's office. T-cell vaccines, which activate a different type of immune response, could, in theory, better prevent or control such chronic infections, but so far nobody has been successful at transitioning T-cell vaccines from the lab bench to the clinic.


A Cambridge, Massachusetts, biotech company called Genocea thinks its high-throughput method could change that. The company will begin its first clinical trial later this year, when its experimental herpes vaccine will be the first test of its claims.


All existing vaccines rouse the body into creating antibodies that attach to the surface of infecting microbes and flag them for destruction. But pathogens that live inside our cells, such as the viruses, bacteria, and other microbes that cause AIDS, malaria, herpes, and chlamydia, can evade this surveillance. "In order to deal with those types of pathogens, oftentimes we have to stimulate what we call cellular immunity. Unlike antibody immunity, which recognizes pathogens directly, cellular immunity has to recognize the infected cell and get rid of your own infected cells," says Darren Higgins, a biologist at Harvard Medical School who studies the interaction between hosts and pathogens and is a cofounder of Genocea.


... our understanding of how T cells control infection is still developing. The challenge is to identify the right protein—or antigen—from a pathogen that will grab a T cell's attention and signal that a human cell harbors an infectious agent. "If you can figure out what those protein pieces are, then you can use those proteins as a vaccine to sort of educate your immune system on what to respond to," says Higgins, who is now a consultant and scientific advisor for Genocea.


...Genocea plans to enter clinical trials with its genital herpes vaccine later this year. If successful, Genocea's herpes simplex 2 vaccine would be the first to combat the disease, which affects one out of every six people aged 15 to 49. Currently, patients can take antiviral drugs as a treatment, but there is no cure. Genocea's candidate vaccine would be used as a therapeutic treatment for patients who already have the disease.


Genocea's herpes vaccine program is moving faster than typical vaccine research, which can take 10 years to go from discovery to proof-of-concept and 20 years to reach the market, says Higgins. "Now you can screen very rapidly what is going to be the optimal vaccine component that allows you to get into clinical trials at a rapid rate." _TechnologyReview

These two distinct approaches to triggering immune system activity work on different parts of the immune system. EP67 protein induces an immediate immune response against acute threats. T Cell vaccines induce cellular immunity to destroy cells which are already infected, often chronically.

Human knowledge of the immune system was advanced significantly by the $billions spent on HIV / AIDS since the 1980s. Research tools and computational power have advanced along with this growing knowledge. Understanding the immune system better is one of the most important keys to effective treatment of a wide range of cancers, as well as to the development of effective anti-aging treatments.

Brian Wang looks at T Cell vaccines

A New Angle of Attack Against Alzheimer's Dementia

A study published this week in the Journal of Neuroscience shows that the compound epothilone D (EpoD) is effective in preventing further neurological damage and improving cognitive performance in a mouse model of Alzheimer's disease (AD). The results establish how the drug might be used in early-stage AD patients.

...EpoD acts by the same microtubule-stabilizing mechanism as the FDA-approved cancer drug paclitaxel (Taxol™). These drugs prevent cancer cell proliferation by over-stabilizing specialized microtubules involved in the separation of chromosomes during the process of cell division. However, the Penn researchers previously demonstrated that EpoD, unlike paclitaxel, readily enters the brain and so may be useful for treating AD and related disorders.

After three months of receiving EpoD, additional tau clumps did not form in the brains of the aged AD mice, and nerve-cell function was increased compared to the AD mice that did not receive drug. What’s more, the EpoD-treated mice showed improvements in learning and memory. Importantly, the doses of EpoD that resulted in these benefits were much lower than had previously been used in Phase II clinical testing of EpoD in cancer patients. The investigators observed no side-effects — including the suppression of the immune system and peripheral nerve damage -- in the transgenic mice that received EpoD. _UPennNews

Most approaches to treating Alzheimer's dementia aim to either affect the levels of neurotransmitters in the brain -- particularly acetylcholine -- or to decrease accumulation of amyloid beta protein.

The idea of over-stabilising neurotubules to prevent tau tangles from forming in early stage Alzheimer's is an intriguing approach, and dates to earlier studies attempting to discover the true etiological origins of Alzheimer's. More from a 2011 study published in The Journal of Neuroscience:

Alzheimer's disease (AD) pathology is characterized by senile plaques (SPs) and neurofibrillary tangles (NFTs) (Selkoe, 2001). SPs are extracellular deposits of amyloid-β (Aβ), a 3–4 kDa peptide derived from proteolytic cleavage of the amyloid precursor protein (APP) by β-site APP cleavage enzyme 1 (BACE) (Hussain et al., 1999; Sinha et al., 1999; Vassar et al., 1999; Yan et al., 1999) and the presenilin (PS)-containing γ-secretase complex (De Strooper et al., 1998; Wolfe et al., 1999). NFTs are intracellular accumulations of hyperphosphorylated tau (Lee et al., 2001). About 5% of AD cases are linked to pathogenic mutations in APP, PS1, or PS2 genes (Selkoe, 2001). Tau gene mutations are pathogenic for familial frontotemporal lobar degeneration characterized by tau pathology without SPs, indicating that tau abnormalities alone cause neurodegenerative disease (Lee et al., 2001). _Journal of Neuroscience 25 May 2011, 31(21): 7691-7699; doi: 10.1523/​JNEUROSCI.6637-10.2011

Note that researchers are still attempting to unravel the apparent multiple strings of causation involved in Alzheimer's Disease (AD) and similar neurodegenerative diseases of the brain.

The new research involving microtubule stabilisation, was performed in transgenic mice, meaning that results in human populations using such treatments may be quite different. The fact that both amyloid placques and tau tangles are seen in pathological brain specimens from AD patients suggests that more than one treatment approach may ultimately be required for many, if not most AD sufferers.

Cross-posted to Al Fin Longevity

Bonus: Rather far-out reading for extra credit -- http://www.dhushara.com/cosfcos/cosfcos2.html. The fascinating webpage at the link ties into the theme of brain microtubules, via the much debated idea of a microtubular quantum coding involvement in human consciousness. Most readers will want to skip this topic, but for the obsessive compulsives among the Al Fin readership, it may prove interesting. More from the online Journal of Cosmology

Rejuvenating 100 Year Old Cells: Steps to Regenerative Medicine

"Signs of aging were erased and the iPSCs obtained can produce functional cells, of any type, with an increased proliferation capacity and longevity," explains Jean-Marc Lemaitre who directs the Inserm AVENIR team....The age of cells is definitely not a reprogramming barrier. _SD

Cell Rejuvenation via IPSC
Scientists at the Functional Genomics Institute have taken cells donated by persons older than 100 years, and reprogrammed these senescent cells into pluripotent stem cells and embryonic stem cells. These stem cells can then be differentiated into specialised cells for cell, tissue, and organ replacement therapy -- once the details are worked out.

The researchers have successfully rejuvenated cells from elderly donors, some over 100 years old, thus demonstrating the reversibility of the cellular aging process.


To achieve this, they used an adapted strategy that consisted of reprogramming cells using a specific "cocktail" of six genetic factors, while erasing signs of aging. The researchers proved that the iPSC cells thus obtained then had the capacity to reform all types of human cells. They have the physiological characteristics of "young" cells, both from the perspective of their proliferative capacity and their cellular metabolisms.


Researchers first multiplied skin cells (fibroblasts) from a 74 year-old donor to obtain the senescence characterized by the end of cellular proliferation. They then completed the in vitro reprogramming of the cells. In this study, Jean-Marc Lemaitre and his team firstly confirmed that this was not possible using the batch of four genetic factors (OCT4, SOX2, C MYC and KLF4) traditionally used. They then added two additional factors (NANOG and LIN28) that made it possible to overcome this barrier.


Using this new "cocktail" of six factors, the senescent cells, programmed into functional iPSC cells, re-acquired the characteristics of embryonic pluripotent stem cells.
In particular, they recovered their capacity for self-renewal and their former differentiation potential, and do not preserve any traces of previous aging. To check the "rejuvenated" characteristics of these cells, the researchers tested the reverse process. The rejuvenated iPSC cells were again differentiated to adult cells and compared to the original old cells, as well as to those obtained using human embryonic pluripotetent stem cells (hESC).


...The results obtained led the research team to test the cocktail on even older cells taken from donors of 92, 94 and 96, and even up to 101 years old. "Our strategy worked on cells taken from donors in their 100s. The age of cells is definitely not a reprogramming barrier." He concluded. "This research paves the way for the therapeutic use of iPS, insofar as an ideal source of adult cells is provided, which are tolerated by the immune system and can repair organs or tissues in elderly patients." adds the researcher.


...Inserm's AVENIR "Genomic plasticity and aging" team, directed by Jean-Marc Lemaitre, Inserm researcher at the Functional Genomics Institute (Inserm/CNRS/Université de Montpellier 1 and 2) performed the research. The results were published in Genes & Development on November 1, 2011 _SD

The first use of this new regenerative technology is likely to be cell replacement therapy. But as the methods for growing replacement tissues and organs in the lab are perfected, the methods should be suitable for producing cells to use in growing replacement tissues and organs for purposes of disease treatment and for treating senescence.

Cross-posted to Al Fin Longevity

HIV and AIDS: A Question of Causation

A recent controversy has sprung up around the decision of the journal Medical Hypothesis to publish a paper by Peter Duesberg, a famous critic of the dominant medical belief that HIV causes AIDS. Several websites are dedicated to refuting the "HIV causes AIDS" hypothesis, including Heal Toronto. Millions of reasonably intelligent people have become highly skeptical of HIV as the cause of AIDS.

The problem goes back to the basic issue of causation -- specifically disease causation. Koch's postulates for establishing microbial disease causation include:

1. Isolate the organism from every case
2. Propagate in pure culture in vitro
3. Reproduce disease by injecting the organism into a suitable recipient
4. Re-isolate the organism
__microbiologybytes

These postulates have served quite well over the years, but for some microbial diseases they have proved insufficiently powerful to establish causation. Variations in microbe virulence and in host susceptibility can complicate the establishment of causation.

A more subtle set of postulates for establishing genetic virulence in  more ambiguous situations, have been dubbed the "Molecular Koch's Hypotheses"

1. Identify gene (or gene product) responsible for virulence determinant
2. Show gene present in strains of bacteria that cause the disease
3. Not present in avirulent strains
4. Disrupting the gene reduces virulence
5. Introduction of cloned gene into avirulent strain confers virulence.
6. The gene is expressed in vivo
7. Specific immune response to gene protects
__microbiologybytes

In the case of HIV / AIDS, the classical Koch's Postulates cannot be tested ethically, since intentionally injecting a human with HIV might easily lead to charges of attempted murder against the researcher.  Of course, not even Duesberg himself is likely to be so reckless as to inject himself or others with HIV intentionally.   Which may be one way of measuring the limits of skepticism for this particular hypothesis.  Is the skeptic willing to inject himself with HIV?

At one time, Peter Duesberg was better known as a leading cell biologist and discoverer of the first true human oncogene, src, in 1970.  A long-time tenured professor at UCB and a member of the NAS, Duesberg's vocal skepticism of the HIV to AIDS hypothesis has, since his 1996 book "Inventing the AIDS Virus", placed him well out of the mainstream of biomedical thought.

It is not the intent of Al Fin Epidemiiologists to refute Duesberg's various lines of arguments in a blog post.  Rather, it is the intent of this posting to take a short peek into the phenomenon of human belief itself.   Duesberg's various lines of attack against the HIV to AIDS theory have been sufficient to establish strong doubts in the minds of large numbers of intelligent thinkers. 

Al Fin Epidemiologists do not accept Duesberg's arguments as convincing, but then Al Fin Epidemiologists are trained to go to root issues when determining the likelihood of an argument -- particularly an argument dealing with disease causation.   For Al Fin Epidemiologists -- unlike most people -- the question is not one of belief.  It is a question of likelihood, and the most likely routes to efficacious disease therapies and cures.  These are things that can be tested -- or falisified -- as Karl Popper would put it.

Humans are prone to "beliefs", which may or may not be well supported by testable facts or observations.  Humans are easily seduced by "reason and rationality" into forsaking empirical testing of apparent "facts".   How much time is wasted in the media, in congress and parliament, in the social sciences, and in dorm rooms and homes -- on arguments that are not formulated to produce testable hypotheses? 

Instead of bullishly "believing" or "disbelieving", humans should always be asking, "How can I test that assertion?"  If assertions, assumptions, and lines of argument do not lend themselves to testing, they are essentially a waste of a practical person's time.

That is how Al Fin Epidemiologists view Duesberg's arguments over the "HIV to AIDS" hypothesis.  Worse than Duesberg's arguments, are the "meta-arguments" that spring up over Duesberg's original arguments.  These meta-arguments then spawn their own "meta-meta-arguments" in a recursive explosion of wasted hours, days, weeks, months, and years.

What can be tested?

If HIV infection leads to low CD4 cell count, and if low CD4 cell count is associated with much higher incidences of PCP pneumonia, Kaposi's sarcoma, CMV, and a host of other low-immunity associated and opportunistic infections and malignancies, these associations lead directly to testable hypotheses.

If a rebound to higher CD4 cell counts after retroviral treatments is associated with remission from opportunistic diseases, further falsifiable hypotheses can be generated.

In fact, the pertinent level of testable argument, scientifically, lies far away from most of Duesberg's arguments.  That is the main problem that Al Fin Epidemiologists have with Duesberg's arguments -- not his skepticism.  Al Fin applauds skepticism wherever it is productive of meaningful falsifiable hypotheses.

Humans in advanced, High IQ societies are not being taught to use their rationality, their judgment, their discriminatory powers of mind.  This leads to lifelong adult-children, incompetent on many fronts, and ineffectual in determining basic probabilities, likelihoods, and wise choices of everyday life.

Biotech and Nanotech: Novel Cancer Killers

Until recently, physicians have had to rely on "sledge hammer" treatments for fighting cancer: surgery, radiation, chemotherapy. All three mainstream approaches to cancer therapy can kill the patient, or have devastating effects on the person's quality of life above and beyond any impact from the cancer. Both doctors and patients would like access to finely targeted therapies that kill only the cancer, and leave the patient whole and healthy. Both biotech and nanotech (as well as the two combined) offer hope for such "magic bullet" therapies.

Specialists at the Curie Institute in Paris have devised a method of "baiting" cancer cells into killing themselves, using special DNA decoys.

North Carolina State University researchers are using modified plant viruses coated with targeting molecules to selectively target and destroy cancer cells.

UC Santa Cruz researchers are coating hollow gold nano-spheres with short-chain targeting molecules that bind to cancer cells. Infrared light beamed onto the tumour is trapped by the gold particles, and the cancer cells are cooked.

Tel Aviv University researchers are building nano-submarines out of phospholipids, filling them with siRNA particles that shut down the target cell's cell division machinery, and coat them with specific targeting molecules.

German researchers are injecting nano-magnetic particles of iron directly into tumours, then using an extermal oscillating magnetic field to induce a killing heat inside the cancer.

You can see how the convergence of nanotech and biotech is aiding researchers in their highly specific targeting of tumour cells, and other cells of interest (over-active immune cells in autoimmune disorders). Some of these treatments require the application of external energy (infrared light, magnetic fields, heat, etc), and other approaches insert the killing impetus inside the nanoparticle itself. Most of the methods use bio-targeting molecules to guide the nanoparticle to the cells of interest.

This is only the beginning. As long as the entire economic infrastructure of the western world is not destroyed by the neofascists currently reigning in Washington, resources will continue to find their way to productive researchers. The pace of discovery may slow, as more resources are diverted to non-productive government programs as well as to politically connected crony-friends of the reich. It is quite possible that even after cleaning out the rat's nest through future elections, recovery from the current spree of corrupt dysfunction may take many years, or decades.

Autologous Stem Cells Hold Most Promise in MS

Medical scientists are learning how to use autologous stem cells -- a person's own stem cells -- to treat serious illnesses such as multiple sclerosis (MS). A recent study at Northwestern University demonstrates an ingenious approach to the use of autologous stem cells:

In clinical trials, a team of scientists led by Richard Burt of Northwestern University in Chicago essentially rebuilt the immune system of 21 adults – 11 women and 10 men – who had failed to respond to standard drug treatments.

First they removed defective white blood cells that, rather than protecting the body, attacks the fatty sheath, called myelin, that protects the nervous system.

The immune systems were then replenished with so-called haemopoeitic stem cells – extracted from the patient's bone marrow – capable of giving rise to any form of mature blood cell.

....After an average follow-up period of three years, 17 of the 21 patients improved by at least one point on a standard disability scale, and none had a final score lower than before the stem cell transplant. _Cosmos

The ability to not only stabilise, but to actually reverse symptoms of advanced MS using autologous cells, is encouraging. Autologous cell therapies are preferred over cell transplants from donors or ESCs, due to the virtual absence of immune system rejection. That is why the new methods of inducing pluripotent stem cells from adult cells such as skin cells, will almost certainly be the preferred method of future medical rejuvenative and regenerative cell and (grown) organ replacement therapies.

Lancet article

Pig Organs for Transplantation? An Increasingly Muslim Europe Says No!

Under UK and EU rules, his team has been banned from mating and producing offspring from the transgenic pigs. Research in developing transgenic pigs is now likely to move to the US where the regulatory system is more relaxed.

Europe is increasingly controlled by labile Muslim sensibilities. Although Muslim males often behave in pig-like ways toward women, the Islamic culture possesses a "pig phobia" that often verges into violent intolerance. No wonder research into pig organ transplantation has to move to the US. At least until the US Muslim population begins to attain the type of inordinate influence the European Muslim population wields over EU nation polities.

What are the prospects for pig organ tranplants to humans?

The first organs suitable for transplanting, most likely kidneys, are expected to be ready within three years and, if tests are successful, their use could be widespread by 2018...The humanisation process of the organs is expected to be achieved by breeding genes into the pigs, probably by injecting them directly into the parent boar’s testicles, that provoke a greatly reduced response in the patient’s immune system.

Patients who received pig organs would have to take immune suppressant drugs for the rest of their lives, but no more than those who received organ transplants from other people...Pigs are regarded as ideal for animal-to-human transplants, xenotransplantation, and other research because of the similarity in the physiological make-up and because they get many of the same diseases, such as diabetes. _Times

The main use of these pigs is for study as animal models of human diseases. But if the immune profile of pig organs can be made compatible enough with humans for transplantation, that would be an added bonus to this line of research.

Can you imagine transplanting a pig heart into a bigoted Muslim imam or mullah? Like most third world peoples, most Muslims are extremely superstitious. For a Muslim male, the only thing worse than receiving a pig heart transplant would be receiving porcine testicular transplants. Imagine the subsequent behaviour of such a Muslim male!

Laughing More

A long list of benefits goes to those who learn to laugh well and laugh often. Perhaps that is why more people are beginning to use laughter as a form of recreation, amusement, and regeneration. Around the world, you can find laughter clubs, and centers for laughter yoga.

...laughter yoga (also known as hasya yoga) can provide many health benefits:

* Help to reduce stress
* Enhance the immune system
* Strengthen cardiovascular functions
* Oxygenate the body by boosting the respiratory system
* Improve circulation
* Tone muscles
* Help with digestion and constipation

“Kids laugh about 400 times a day, and adults only about 15,” notes Barb Fisher, a certified laughter yoga leader...As developed by laughter yoga creator Madan Kataria, a family physician from India,

....these laughing exercises can include many varieties, such as:

* Hearty laughter: Laughter by raising both the arms in the sky with the head tilted a little backwards.
* Greeting laughter: Joining both the hands and shaking hands with at least four or five people in the group.
* Appreciation laughter: Join your pointing finger with the thumb to make a small circle while making gestures as if you are appreciating your group members and laughing simultaneously.

...“The biggest effect that I’ve gotten from laughter yoga is what it’s done for me mentally, and that it has lightened up my day and my week,” says Deborah Slosberg. “I also think it has improved my breathing.”

“It gives me a relaxed feeling, and yet I actually feel like I worked out,” says Ann Twork. “You get back some of the child in you.”
__SciDaily

Laughter has been used as meditation for centuries, and as modern medical therapy for decades. In my experience, laughter serves as a re-balancing of the brain and body tension settings.

All of us know of people who seem without humour, without any sense of lightness. You may find persons like that at work, but you certainly are impacted by politicians, journalists, and activists of all stripes who are without the depth and perspective that comes from being able to see the funnier side of life.

This is one part of your life where you are almost completely on your own, unless you were born into a large family rich with humour, or married well in levity and truth. You can find help, if you need it, from the clubs and yoga centers near you. Can't find one? Start one yourself.

The best laughter I have had is the kind that wakes me up from dreams. But there is also benefit to be had from designed laughter.

The next time someone comes along trying to convince you of the truth and importance of a cause--any cause--look for the humour that may be there. The more intent and zealous the cause, the harder you may have to look. That's fine. The payoff will be worth it by the look on the zealot's face when you burst into the deepest belly laugh of your life.