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

WHO Says Super-Clap Wants You!

The World Health Organisation (WHO) recently sounded an alert on the spread of drug resistant gonorrhea in Japan, Australia, and Europe. More on the spread of the superbug across Europe:

"Superbug" strains of gonorrhea which are becoming untreatable accounted for almost one in 10 cases of the sexually transmitted disease in Europe in 2010, more than double the rate of the year before, health officials said on Monday.

The drug-resistant strains are also spreading fast across the continent, officials warned. They were found in 17 European countries in 2010, seven more than in the previous year. _ChiTrib

The US CDC recently held a Grand Rounds on the topic of the growing threat of multi-drug resistant gonorrhea (see video below).



Lost in all the PC-tainted publicity, are the details of where the drug resistant strains are coming from, and the nature of the populations which are affected.

If multi-drug resistant have started popping up in the past few years in Japan, Australia, and Europe, where were these microbes found before that? In Sub-Saharan Africa.

This study illustrates the high frequency of resistant gonococci in Africa and shows that tetracycline-resistant N. gonorrhoeae have become highly endemic in different geographic areas of the continent. The use of effective drugs is essential to reduce gonorrhea transmission. Surveillance of temporal changes in antimicrobial resistance in gonococcal strain populations should be part of sexually transmitted diseases control programs. _STD Jan 1997

Over the years, the microbes developed resistance to more and more antibiotics, so that now some strains of super-clap are resistant to virtually all commonly available antibiotics.

We know that STDs (including HIV) are running particularly rampant in African American populations, in Sub-Saharan (SS) Africa, and in all populations of the SS African diaspora. It only took a few years for HIV to spread from Africa to Haiti and to gay communities across the developed world.

We are told that super-gonorrhea is spreading rapidly throughout Europe. But so are African immigrants. Perhaps the news stories should divulge the nature of the populations in Europe which are particularly affected? That would be much more helpful to the public than current news stories, which neglect to inform the public of such crucial information.

People of SS African descent suffer from a wide variety of problems, including low average intelligence, high rates of violence, high rates of poverty, high rates of illegitimacy, and high rates of a wide range of infectious and degenerative diseases. The last thing that this community needs is to be "protected and shielded" by PC journalists and politicians, to the point of not understanding the serious threats its people are facing.

Gonorrhea is often asymptomatic, and often the symptoms are ignored without seeking treatment. When the disease is treated, it is often undertreated -- either due to medical error, lack of adequate drug supply, or due to the patient's own neglect in skipping doses or discontinuing the treatment too soon.

Complications of inadequately treated gonorrhea include neonatal blindness, often fatal ruptured tubal pregnancy, long term painful pelvic inflammation, scarring of pelvic tissues leading to infertility, and more.

The problem of bacterial drug resistance is not limited to STDs such as gonorrhea. Multi-drug resistant TB is an even greater threat than gonorrhea, in terms of potential loss of life.

While no populations are immune to such diseases, particular populations are in more danger than others. Prison populations, for example, can be more exposed to a wide range of infectious diseases, depending upon the conditions of the prisons. Infectious disease spread by sexual contact, airborne spread, and contact with fomites, can all be more common in many prison populations -- particularly in the third world.

There are many ingenious research plans for dealing with multi-drug resistant microbes. But it takes a long time for ideas to progress through the many stages of research into common clinical usage. The process of treatment research and development is also very expensive. When research pioneers are trying to break through one or more common paradigms of standard medical treatment, the delays can stretch even longer.

Be careful out there.

Flashblood: Accelerating Africa's Sad Trajectory

From Mombasa to Zanzibar, the blood of heroin addicts is circulating, carrying pleasure, disease, and death in its current. Referred to as "flashblood", the practise involves heroin addicts sharing not just needles, but their blood as well. The amount of blood transferred is about 5 ml, or a teaspoon, which is more than enough to transfer HIV from one person to another.

In most East African countries like Tanzania and Kenya, only 3 to 8 percent of adults are infected with the AIDS virus, far fewer than in southern Africa, where the rates reach 15 to 25 percent.

But among those who inject heroin, the rates are far higher. In Tanzania, about 42 percent of addicts are infected. The rate is even higher — 64 percent — among female addicts, Dr. McCurdy said, and since most support themselves through prostitution, they are in two high-risk groups, and their customers are at risk of catching the disease.

Most of the addicts she has interviewed who practice flashblood, Dr. McCurdy said, are women. For them, sharing blood is more of an act of kindness than an attempt to get high: a woman who has made enough money to buy a sachet of heroin will share blood to help a friend avoid withdrawal. The friend is often a fellow sex worker who has become too old or sick to find customers.

...And, there have been scattered reports of flashblood-type practices in other countries with large numbers of heroin addicts, including Pakistan, but they also have not been confirmed by researchers.

...After piercing a vein, an addict will typically draw some blood into the syringe, push it back out and repeat that three or four times to make sure all the heroin has been flushed into their blood. Those offering flashblood will usually hand over the syringe after only one in-out cycle.

The heroin sold in East Africa, she added, is often quite strong because it has come from relatively pure shipments on their way to Europe from Afghanistan or Asia.

Until recently, heroin use was uncommon on the continent because most Africans are too poor for traffickers to bother with. But in the last decade, smugglers have begun using port cities like Dar es Salaam and Mombasa and airport cities like Nairobi and Johannesburg as way stations on their routes: law-enforcement officials can often be bribed, and couriers from countries with no history of drug smuggling may escape searches by European border officers. The couriers may be paid in drugs, which they resell.

With more local users, more heroin is being sold in Africa. In the last decade, law-enforcement and drug treatment agencies said, heroin use has increased, especially in Kenya and Tanzania, South Africa and Nigeria. Brown heroin that must be heated and inhaled — “chasing the dragon” — has given way to water-soluble white heroin that can be injected. Prices have fallen by as much as 90 percent. _NYT

The dual epidemic of heroin and HIV is a tragedy for East Africa, which has experienced lower rates of AIDS up until now. Blood sharing increases the chance of drug resistant HIV in the population -- largely negating the billions of dollars in well-intended medical aid channeled to Africa over the past decade, in terms of future impact.

Much of the heroin is flowing into Africa's East Coast is hidden within the burgeoning conventional trade with China. The heroin is strong and uncut, giving the blood recipient a stronger rush than would be the case for the deeply cut heroin in North American or European cities.

For a population of low average IQ, you will not find many mind-altering drugs which have an overall beneficial effect. Heroin removes a person's motivation to achieve anything beyond acquiring the next dose of drug. Niceties of hygiene are seen as inconsequential in comparison to staving off withdrawal, and achieving the next rush. Communities of drug addicts become evolutionary incubators for colonies of pathological organisms, perfecting their virulence in preparation for a greater assault on the outside world.



Photo Credit: World News

There Is No Cure for What Ails the Undeveloped World

This is a world map highlighting the "developing world nations." Often referred to as the "third world" or the "undeveloped world", but more accurately seen as the "unraveling world." But why is the poor world unraveling? Why does the undeveloped world not improve with the trillions of dollars worth of aid that has been showered on its nations and people?

This map looks like a mirror image of the undeveloped world. It highlights penetration by the internet. It is the connected world.

This map looks at average population IQ by country. There is a clear correlation between chronic poverty and low population mean IQ. There is also a good correlation between internet "connectedness" and mean IQ.

This map combines the mean population IQ with a measure of national GDP. The correlation between national production and population IQ is made more obvious using such a combination graph.

This map shows the parts of the world that receive remittances from migrants who work outside the country and region. It is a reflection of the "brain drain" of the impoverished world, and the compensatory flow of wealth back to the home countries.

This map is a graphic portrayal of HIV rates. HIV rates have stabilised in the western world, but continue to rise in the third world.

World tuberculosis rates tend to be high in areas of limited or low quality medical care. As the demographic makeup of European countries changes to reflect the rapid growth of third world populations, Europe will not be able to fend off many diseases which were previously quite rare.

There is no cure for low population IQ, once basic nutritional and early childhood needs have been met. There is no cure for chronic bad government, violent and self-defeating behaviours, and bad infrastructure -- which directly derive from low population IQs. There is no cure for the diseases of inbreeding common to Arab lands -- including Gaza, the picture boy of suicidal government and culture.

Marvelous schemes have been devised to pull the third world up by its bootstraps, but unless these schemes address the deeper innate problems of the undeveloped world, they will come to nothing. Far from being a cure for chronic third world backwardness, rapid urbanisation will only focus the blights of the third world into a concentrated area.

Europe cannot afford to support the third world any longer -- it is becoming the third world. China is moving into the third world, but the people may not be as happy about that development as the elites who take the bribes.

The maps are all in play, all will change over time. As parts of the first world come to more closely resemble the third world in demographic makeup, they will increasingly take on more other characteristics of the third world.

China, Japan, South Korea, Taiwan -- all had times of poverty. But when given the opportunity to pull themselves up, the people of East Asia rose to the challenge. Of course, some of these countries are caught in the same demographic implosion as large parts of Europe and Russia. There is a point of no return for a shrinking population -- particularly if it is being replaced by a less capable substitute population.

The trend will not go in the other direction without the same type of evolutionary forces which caused some groups to grow out of the chronic third world condition in the first place.

Artificial intelligence and nano-fab cornucopias will only shift the trend to dysgenics more quickly -- as the human brain becomes more of a vestigial organ. The singularity as envisioned by many of its devotees, is simply a high tech trap.

Humans of the advanced world must have challenges in order to stretch their abilities to the limit. Challenges AND opportunities. The welfare state is the opposite of the sort of environment that encourages growth.

It is an existential problem, in a world of shrinking mental capacities.

Galapagos?

Vaccine Hope: Antibodies Neutralise HIV's Prick

Image SourceThe envelope of HIV has pricks, or spikes made up of proteins gp120 and gp41. These proteins are highly variable, and therefore difficult for vaccines to pin down. But two particular antibodies (PG9 and PG16) researched by Scripps and IAVI (International Aids Vaccine Initiative) seem to target sections of the HIV prick which are less variable -- and would thus neutralise a much wider range of HIV strains around the world.

NEW YORK, NY, LA JOLLA and SAN FRANCISCO, CA, SEATTLE, WA, September 3, 2009—Researchers at and associated with the International AIDS Vaccine Initiative (IAVI), at The Scripps Research Institute, and at the biotechnology companies Theraclone Sciences and Monogram Biosciences have discovered two powerful new antibodies to HIV that reveal what may be an Achilles heel on the virus. They published their work in Science this week.

...The two new antibodies target a region of the viral spike used by HIV to infect cells. The viral spike glycoproteins, termed gp120 and gp41, are highly variable and have evolved to thwart immune attack. But biochemical studies suggest that PG9 and PG16 target regions of gp120 that do not change, which probably accounts for their breadth of neutralization. Now researchers at the IAVI-organized Neutralizing Antibody Consortium (NAC), a scientific network focused on designing vaccines capable of eliciting broadly neutralizing antibodies, will turn their attention to studying the molecular structure of PG9 and PG16 and that of the region they target on the HIV spike. _IAVI_via_MachinesLikeUs

The approach to an HIV vaccine is necessarily more difficult than for most other viruses. This is not only because HIV's viran envelope is highly variable, but also has to do with the way HIV attacks the immune system. Traditional approaches to activating the immune system can actually make the disease syndrome worse, leading to the infection of many more immune cells.

That is why scientists grasp at any conceivable approach that may either block or blunt the effect of HIV on the immune system. In this case, it looks as if an effective "blunting" maneuver may have been discovered.

HIV Replication: Five Minute Animated Tutorial

These biological animations provide insights to biomedical students that would otherwise be beyond reach. More realistic mental pictures of biomedical phenomena allow more accurate mental projection of other possibilities.

Hat tip Biosingularity blog.

Computers Hack Resistant AIDS Virus--HIV Naked Before Researchers

Computers are finding many uses in modern scientific research. Newer, more powerful computers are being programmed to simulate complex proteins and other large molecules and complex systems. One of the proteins being simulated is the HIV protease, a molecule vital to HIV replication inside the cell. Protease inhibitors are commonly used to treat HIV infections, but some HIV strains have grown resistant to protease inhibitors. In order to understand this resistance, researchers have used computer simulations to mimic the particular HIV proteases that are resistant--so that they can find a weakness to target.

For more than a year, researchers watched patiently as a few computer-simulated HIV protease molecules squirmed into more than 15,000 slightly different shapes. In real time, this contortion takes only a fraction of a second. In the end, however, this suspended animation paid off, as the simulations uncovered a potential new drug target to fight drug-resistant AIDS.

Howard Hughes Medical Institute (HHMI) scientists made the discovery while studying how one rare strain of HIV can evade a commonly prescribed class of drugs used to treat the virus that causes AIDS. The strain of HIV contained mutations that are often seen after failure of treatment with protease inhibitors, drugs that block the action of the enzyme protease and prevent the virus from making mature, infective copies of itself. When protease inhibitors fail -- as they often do with a fast-mutating virus like HIV -- new drug targets become vital.

"Recognizing these variations in conformation -- the three-dimensional arrangement of the amino acids that make up a protein -- is the first step in identifying a new drug target," said Alex Perryman, first author of the study published early online in the journal Biopolymers on February 28, 2006.

....Perryman used a computer simulation program called AMBER that performs several different types of calculations. The x-ray crystal structure of the molecule is used as the input, and the various motions and shapes sampled are governed by Newtonian physics, the electric forces among atoms, the complementarity or clash of the different shapes that the enzyme takes, and penalties or bonuses for creating or relieving geometric strain.

The scientists depict the protease enzyme in a brightly colored cartoon, with features that resemble a fat cat face. From the front or the back, the identical halves of the enzyme have an ear and cheek protrusion on each side. (See illustration.) Frayed whiskers even appear to sprout from the bottom. The similarity to a face ends at the top of the molecule, where two flaps open to reveal a cavity. That is where enzymes and other proteins are cleaved into the parts necessary to assemble infectious virus particles. Structural studies of this cavity helped scientists find the original protease inhibitors. Other scientists are trying to design drugs to bind to the whiskers and or to lock down the flaps by binding to their top.

Perryman's first results, which were published in the April 1, 2004, issue of Protein Science, showed that the mechanism of drug resistance seemed to involve the motion of the flaps. More specifically, the double-mutant virus displayed larger flap motions, especially at the tips. These larger movements seem to make it more difficult for the current drugs to function, since they must force the flaps to close and remain closed in order to prevent the enzyme from working. It probably takes more energy for the drugs to close the more mobile flaps of the mutant.

Perryman and his colleagues also observed that the flaps opened in a seesaw motion on each side, pinching the "cheek and "ear" together. That observation suggested to them that a small molecule might be able to wedge between the ear and cheek, blocking the flap opening.

"Some drugs act by binding to the active site of a target molecule, such as the site that an enzyme normally uses to catalyze reactions," McCammon said. "But increasingly, scientists are finding that other binding sites can be important. For HIV/AIDS, an important class of drugs called non-nucleotide inhibitors for reverse transcriptase typically bind at such alternate sites."

Once Perryman had a hypothesis to test in a second round of simulations -- the proposed mechanics of the protease enzyme's nanomachinery--he used artificial restraints in the computer program to block the flaps from opening by expanding the gap between "ear" and "cheek." A new type of drug that binds there and controls flap motion could enhance the ability of the current protease inhibitors to bind to the active site, or it could offer a new way of inhibiting protease activity from afar by itself, Perryman suggested.

This type of computer simulation can certainly be used to locate a wide range of molecular targets. Read the entire report, including other potential target molecules being simulated, here.

Conventional von Neumann computers are actually pretty stupid. But they are very fast calculators, and can model some complex systems. Computers are getting faster all the time, and more sophisticated designs incorporating massive parallelism and neural net architectures can do some impressive things. Expect a lot more in the future.

Helping CD4+ Cells Survive: Stealth Vectors, Antisense RNA, HIV/AIDS

HIV/AIDS is an increasingly severe worldwide problem. If the infected person can keep his CD4+ count high enough, he will probably not get AIDs. Anti-retroviral drugs have helped millions of HIV infected persons stave off AIDS, where the drugs are available, but a better method of restoring the CD4+ cell population is needed--one that does not require taking so many expensive pills on a daily basis.

Enzo Biochem has developed a "gene construct" consisting of three anti-sense genes, which are introduced into blood stem cells that are destined to become CD4+ T cells. These new CD4+ T cells will be resistant to the HIV retrovirus because the antisense genes they contain will neutralize the HIV gene products that are necessary for the virus to infect the cell. The more CD4+ T cells that survive, the less likely the person is to develop full blown AIDS.

Here is the report from Enzo Biochem (NYSE:ENZ):

In the upcoming trial, which is expected to get underway shortly, Enzo’s StealthVector® HGTV43™ gene construct will be used to transfer three antisense genes designed to interfere with the growth of HIV-1 into blood stem cells. These cells are expected to replicate and differentiate within the body of the HIV-1 infected individual to produce CD4+ T-cells, the main target of infection by HIV-1. The novel aspect of the current study is to increase the percentage of CD4+ cells that contain the anti-HIV-1 antisense genes with a protocol designed to partially reduce the patient’s blood stem cells before infusion of the engineered cells. The trial is intended to determine whether this procedure will create a supply of HIV-1 resistant CD4+ cells large enough to materially defer the disease progression of these HIV-1 infected individuals into AIDS

The Phase I study that took place at UCSF demonstrated the safety of the procedure and showed that the engineered stem cells were able to survive long term in vivo and to produce a low number of CD4+ cell progeny containing functioning antisense genes. Although there was no increase in the CD4+ cell count or reduction in the viral load, the yield of engineered cells has remained approximately constant over a number of years, in the case of one individual for as long as five years, supporting the conclusion that stable engraftment of anti-HIV-1 antisense RNA-producing blood stem cells occurred and the antisense genes continued to function.

....The HGTV43™ vector was developed by Enzo to include a proprietary delivery system designed to overcome a major challenge in gene medicine, namely the efficient and safe delivery of the medicine to the appropriate target. The benefits of Enzo’s “Stealth” vector technology are that it achieves efficient delivery of the genes into the patient’s cells, and that it is “silent” and unlikely to trigger an immune response. In addition, during the development of the vector two critical safety features were incorporated to minimize the possibility of inadvertently turning on deleterious genes in the subject.

“The Phase I trial demonstrated the safety of the HGTV43™ gene construct in 5 subjects and the ability of the engineered cells to survive and continue to function in vivo.

Read the full Enzo release here.
Hat tip medgadget.

Anti-sense RNA gene constructs are just one form of non-coding RNA. HIV/AIDS is such a complex infection, that it has been difficult for scientists to find the best way to attack it. Approaches to developing working vaccines have not been productive so far, but there is more than one way to skin this cat. Molecular biology has just begun to flex its muscles. Microbes, even HIV, do not stand a chance, in the long run--if.

If what? If western civilisation can continue to support its vast scientific research infrastructure. Given all the ongoing threats, that is not guaranteed.