Category Archives: Strange but True
Kelley Monaghan (12:00 Micro) found an article from Science Daily about a genetic sequence from a Neanderthal that is shared by modern humans. What makes this sequence particularly interesting is that it is a viral sequence that became incorporated into the genome as a provirus, at some point in human evolution where humans and Neanderthals shared a common ancestor. Here is Kelley’s summary:
Researchers at both Oxford University and Plymouth University recently discovered that in modern DNA there is an ancient virus that dates back to the Neanderthals. They came up with the theory that roughly half a million years ago this virus originated in our human ancestors. This was proven when researchers compared a cancer patient’s genetic data from modern day to the genetic data of fossils from both human ancestors the Neanderthals and Denisovans. Scientist plan to look into the relationship between modern diseases and ancient viruses could even help further our knowledge of the diseases such as cancer and HIV, and make us one step closer to finding the cure.
Endogenous retroviruses are simply viruses from our DNA sequence that can be passed down from one generation to the next generation, and they make up eight percent of our DNA. Scientists clump endogenous retroviruses into “junk” DNA, which has no known function yet and makes up 90% of our DNA. Medical Research Council (MRC) member Dr Gkikas Magiorkinis of Oxford University’s Department of Zoology say that, “’I wouldn’t write it off as “junk” just because we don’t know what it does yet,” concerning the recent discoveries. He believes this because under some circumstances disease has been caused from the combination of two “junk” viruses. This isn’t a new concept; we have seen this before in animals. For example, in mice endogenous retroviruses when activated by bacteria can lead to cancer. Dr Gkikas and his colleagues at Oxford University’s Department of Zoology have been studying the possible link between these ancient viruses to cancer and HIV. The link may be from the ancient viruses being apart of the HML2 family for viruses. Dr Gkikas and his colleagues are testing to see in humans today if these ancient viruses are active or the cause of diseases. To conduct these tests they are going to use 300 patients’ DNA sequences in order to see how common these ancient viruses are in the modern day human population. Dr Rober Belshaw, who is a former Oxford University staff member and currently at Plymouth University, said, “We would expect viruses with no negative effects to have spread throughout most of the modern population, as there would be no evolutionary pressure against it. If we find that these viruses are less common than expected, this may indicate that the viruses have been inactivated by chance or that they increase mortality, for example through increased cancer risk.”
Without the modern day technology, none of this research would have ever been able to happen. And, hopefully there will be upcoming technological breakthroughs that will be able to further fuel this research. Researchers are planning to see these technological advances as soon as 2014! They are hoping to have some solid proof for the connection between ancient viruses and modern human diseases, and what role the ancient viruses are playing concerning out modern day diseases within the next five years.
Long time readers of BIO230 know of my fascination with all things feces. One interesting idea is to use a fecal transplant from a healthy individual to someone with gastrointestinal disease as a potential treatment. There has been some excellent preliminary data that this is a useful approach, in particular for treatment of things like chronic Clostridium difficile infection. The premise is that an infusion of “normal” microorganisms will out compete and eliminate the pathogens in the digestive tract, resulting in recovery without the use of things like antibiotics. Indeed, the ability of C. difficile to form endospores makes that organism particularly resistant to antibiotic therapy, which is why some patients have problems clearing the infections even with long term antibiotic therapy.
The problems with fecal transplants have been several fold so far, and most have been related to collection and delivery. First, the organisms to be infused have to be to some degree tailored to the patient. It is better to acquire the normal microorganisms from a donor who would likely share a similar microbial makeup to the patient, and so a family member would be best. Quite frankly, I am pretty sure that I would not want a poop donation from a total stranger. Second, there is an “ick” factor associated with the process that requires either a feeding tube to bypass the stomach or else delivery via colonoscopy to put the donor organisms into the correct location. Passage of the donated material through the stomach would likely greatly reduce the viability of the microorganisms and diminish the effectiveness of the treatment.
A news update on Gizmodo reporting a CBSNews story details an innovation in fecal transplant technology, and summarizes research done by scientists at the University of Calgary. (Editorial note: I would take off points if I graded the CBSNews report, due to their egregious failure to underline or italicize the names of microorganisms!) The researchers treated 27 patients of persistent, antibiotic resistant C. difficile infections by administering donor microorganisms. The novelty of this approach was that the donor microorganisms (taken from a relative at home) were brought into the lab to be cleaned of food and other non-bacterial fecal material, and packaged into triple gel capsules before administering orally to the patients. The gel capsule allowed the donated microorganisms to get past the stomach, so that the capsules could dissolve in the intestines. One patient, a retired nurse’s aide who reported two years of debilitating gastrointestinal disease due to C. difficile, has been cured by the donor bacteria pills.
Currently, the treatments are essentially tailored by specific donors for each patient. Other gastroenterologists foresee the potential for “universal” donors who might be able to contribute organisms that might help many different, unrelated patients. Since the donated fecal material can be frozen and stored to produce “poop banks”. Alternatively, people might go for the Do It Yourself approach in order to avoid needing to deal with health insurance companies.
In our current BIO230 discussion about viruses, we introduced the link between certain types of cancers and infection by a variety of different viruses. The first to be characterized by Francis Rous was a cancer of chickens, which had been infected with a virus that now bears his name, Rous Sarcoma Virus. The mechanisms by which viruses can induce cancer are rather complex, but the presence of an infectious agent as the causative agent allows the possibility of preventing the cancer by preventing the infection. Indeed, this is the premise behind the vaccine Gardasil which offers protection against infection by Human Papilloma Virus–a virus highly correlated with cancers in both genders. Of course, many cancers have no association with an infectious agent, which led me to be very surprised by this news alert pointed to me by Summer 2013 Micro student Dominique S. This was surprising because there was no indication that any infectious agent was involved with the cancer, so the mechanism of how a vaccine might protect was unclear.
The news alert references a primary research article by scientists at the Cleveland Clinic. The scientists used a model in mice to study the metastasis of tumors. A cancer cell line grown in tissue culture was injected into healthy mice, and the mice were observed to develop mammary tumors that resembled human breast tumors. The researchers noted that the tumors strip only expressed a protein called α-lactalbumin, a protein normally found only in breast tissue during milk production. Since the tumors cells in a non-lactating mouse would be the only cells to be making α-lactalbumin, the felt that this protein would make an attractive anti-cancer target. Consequently, they immunized mice with α-lactalbumin antigen, so that the mouse’s own immune system would start to produce an immune response against the protein, and hopefully against the tumor cells should they be present. This is essentially an induced autoimmune response (the body attacks an antigen that belongs to its own cells, in this case in lactating breast tissue), with the hope that the immune response would essentially be specific for the tumors. What they found was that the mice produced a strong T cell response against the tumor antigen, and it offered significant protective effect.
The work is currently progressing into clinical trials, and the Cleveland Clinic hopes to enroll human subjects into a pilot study in the near future. Phase 1 trials will be with women who have survived breast cancer using standard treatments but are at risk for recurrence, to determine the necessary vaccine dose to promote an effective immune response. Later trials will be with healthy, but at risk women, to see if the vaccine offers protection in humans as it seems to in mice. Some significant issues can still arise. First, the immune response of the mouse is not the same as the immune response of the human, and what works well in one animal may not work at all in the other. Second, the approach promotes an autoimmune response in the host. While α-lactalbumin expression in healthy women is only during active lactation, this likely means that it would be highly inadvisable for anyone receiving this vaccine to become pregnant.
Via Gawker.com and the LA Times, here’s a news alert that all college students should be mindful of. Researchers at the London School of Hygiene and Tropical Medicine have published in the medical journal PLOS One a new defense against malaria transmission. Malaria is a disease which affects a large proportion of the world’s population, with an estimated 220 million cases (nearly 1 in 20 people) worldwide in 2010. It is caused by the several species of the protozoan genus Plasmodium, and transmission requires specific species of mosquitoes that are essential for the life cycle of Plasmodium. There are treatments for malaria that can help infected patients to clear the parasite, but there is currently no vaccine. Main methods for control for the transmission of malaria have traditionally focused on controlling the reproduction of mosquitoes.
The experiments conducted by the researchers were simple; new adult female mosquitoes were fed human blood which was either infected or uninfected with Plasmodium. Following verification of infection, mosquitoes were introduced to socks (20 Den panty sock, HEMA, The Netherlands) that had been worn for 20 hours beforehand
…by a male volunteer of whom the relative attractiveness to An. gambiae s.s. compared to 47 other men is known…
Control socks, of course, were fresh right out of the package. The researchers constructed a mesh matrix, and measured the rate at which the mosquitoes landed on the matrix (landing rate).
As can be clearly noted from their data figure, infected mosquitoes were 4 times as likely to be attracted to the human odor than uninfected mosquitoes. The authors conclude that the presence of Plasmodium is altering the behavior of the mosquitoes, which may increase the rate of transmission as the population of infected vectors (the mosquitoes) rises. They suggest that current mathematical models for malaria transmission may be underestimating the rate at which the protozoan spreads through populations, as generally uninfected mosquitoes are used in behavioral studies and do not take into account the effects of the parasites themselves on vector-host interactions. Effective malaria control programs need to accurately model all aspects of parasite/vector/host interactions.
From the point of view of the pathogen (Plasmodium,) this is a perfect strategy. Plasmodium species depend upon the mosquito vector for the sexual portion of their life cycle, and this requires approximately 2 to 3 weeks to occur. As this occurs, it is advantageous for the organism not to be transmitted to a new host during a blood meal. However, after sexual maturation has occurred and the new sporozoites migrate to the salivary glands of the mosquito, modification of behavior will allow the subsequent transmission back into a new host during as the mosquito feeds. Long time fans of BIO230 will recall how another Apicomplexan protozoan, Toxoplasma gondii, has been found to potentially modify its host’s behavior, leading to the inappropriately named “Crazy Cat Lady Syndrome.”
An article in the latest issue of Infection and Immunity caught my attention: “Candida albicans-Staphylococcus aureus Polymicrobial Peritonitis Modulates Host Innate Immunity” describes work by researchers at the Louisiana State University Health Science Center. Many models of infectious disease use virulence studies in animals such as mice. A typical experiment may infect an animal with a defined number of pathogenic organisms, and changes in health of the animal are measured–this is the basic premise of Koch’s Postulates, where the etiologic agent of a disease can be experimentally determined. Some diseases of humans may not be well mimicked in animal models, and this presents a problem when trying to study significant human diseases.
The work summarized here examined the disease produced by two separate pathogens, the Gram positive bacterium Staphylococcus aureus, and the fungus Candida albicans. Infection of mice with either one of these pathogens was non lethal at the infectious doses used in their experiments. However, when an animal was co-infected with both the bacterium and the fungus at the same time and at the same individual dose, a 40% mortality rate was observed, with significant infiltration of the organisms into the peritoneum and other target organs. At the same time, a number of important immune system signalling hormones were also elevated in mice who were co-infected with both pathogens, leading to a much higher inflammatory response in those animals. Mice treated at the same time with the inflammation inhibitor indomethacin did not die. Further injection of mice with a second inflammatory medidator prostaglandin E2 at the same time as administering indomethacin overrode the protective effects of indomethacin, and significant mortality of mice was again observed. The authors conclude that combination of pathogens have very important effects on the innate immune response, and that the lethality of the disease is exacerbated by the powerful inflammatory response.
Nosocomial infections are a critical issue in US health care, with billions of dollars annually being adding to the total costs of our health care. The graphic to the left from our textbook illustrates the relative contributions of various classes of pathogens; the sections of the pie labeled “Gram-positive bacteria” and “Yeast” are comprised primarily of the two species in this report, S. aureus and C. albicans. Many of the organisms responsible for causing nosocomial infections do so due to the a perfect storm of conditions in health care–a population very susceptible individuals, healthy carriers moving between patients, use of antibiotics leading to resistance, medical procedures which can bypass normal routes of entry for these pathogens. The first inclination upon developing a nosocomial infection is to combat it with antibiotics, and in fact many surgical procedures may involve the prophylactic use of antibiotics to help avoid this outcome. But the use of antibiotics themselves can lead to problems in the form of rampant antibiotic resistance and loss of efficacy of those drugs. This research shows that an alternative approach that tweaks the host’s immune response might also be effective.
Constance Heidel (3 PM Micro) found an article about nanosponges via the science blog Live Science. This technology has the possibility of adsorbing things like toxins, bacteria, and viruses from the body using artificial microscopic devices (nanosponges) directly from the bloodstream. Here is Constance’s take on this topic:
She blinded me with science!
There was a motion picture released in 1966 called “Fantastic Voyage” that is considered one of the best science-fiction films ever made. While the movie may not be visually stunning (compared to today’s CGI-driven films), it is a truly in a league of its own in terms of conceptual brilliance.
Plot: A failed assassination attempt leaves a scientist in a coma. In order to save him, a task force is assembled upon The Proteus, a submarine. Then the crew and submarine are reduced to microscopic size and injected into the scientist’s bloodstream in order to operate on the surgically inaccessible clot in his brain using a laser. This team travels throughout his bloodstream, marveling at the wonders of the human body at a microbiological level. They must reach the brain within 60 minutes or else the effect will wear off and they will return to full-size. To further complicate things, the voyage is being compromised by a crew member who is a saboteur and is prepared to risk everything to stop the mission.
While the concept of shrinking a crew and submarine down to a microscopic level is definitely better left to science-fiction books and films, there are concepts and themes in the movie that were way beyond its time and are relevant today. Analogously to this film, scientists continue to wage biochemical wars within the human body in order to diagnose, treat and cure. Alas, there is a new battle looming on the horizon!
Dammit Jim, I’m a doctor not a scientist!
Don’t worry about it, Bones. The researchers at the University of California, San Diego have it all under control. They have invented a nanosponge which is capable of safely removing a broad range of toxins from our blood stream. Most antidotes or treatments against venoms, bacteria or bioweapons are targeted to counteract a specific molecular structure, like a lock and key mechanism. These nanosponges are more like a like a skeleton key. They work by absorbing pore-forming toxins, regardless of the toxins’ molecular structure. So it doesn’t matter if it is a virus, bacteria or evil spirits… these nanosponges are coming in there to eradicate them.
Liangfang Zhang, a nanoengineering professor at the UCSD Jacobs School of Engineering stated, “Instead of creating specific treatments for individual toxins, we are developing a platform that can neutralize toxins caused by a wide range of pathogens.”
Nanosponges: Troops against toxins
The word “sponge” doesn’t exactly conjure up images worthy of villains as epic as Darth Vader, but trust me… these aren’t your average loofahs. These microscopic sponges are sheathed in a suit of armor made of red blood cells. It is this design that allows the nanosponges to act as decoys and destroy.
By using a centrifuge, Zhang’s team is able to separate red blood cells from a sample of blood. The cells are then put into a solution that causes them to lyse. This releases the hemoglobin and leaves the skin of the RBCs behind. At this point, the globular nanoparticles (which are made of a biocompatible polymer core) are mixed with the skins until they’re fully cloaked with the red blood cell membrane. This cloaking allows the nanosponges to be undetected to the immune system and serve as a decoy to absorb the toxins away from their cellular targets. Unlike a red blood cell, the nanosponge’s center is made of lactic acid. This organic material acts like a scaffold to keep the membrane from falling apart once the toxins are trapped.
Each nanosponge is approximately 85 nanometers in diameter and they are 3,000 times smaller than that of a red blood cell. Scientists only need the membrane from one red blood cell to synthesize thousands of nanosponges. This is the stuff science fiction films are made of: “In a single dose, an army of nanosponges will be deployed to conquer your bloodstream. They will evade your immune system, outnumber your red blood cells, intercept toxins and deliver them to your liver in order to save your life!” The coolest part is, this is science NON-fiction!
To see a nanosponge in action, check out this video:
The war wages on…
The efficacy of this treatment was demonstrated through a study in mice. A lethal dose of MRSA was given to the mice, which normally causes acute death. The control group didn’t receive any treatment and all of the mice died as expected. When nanosponges were injected two minutes before the toxin was administered, an overwhelming number of mice survived – 89 percent. When the nanosponges were administered two minutes after the lethal dose was administered, an impressive amount – 44 percent – survived. Surviving mice were studied further and it was shown that the nanosponges accumulated primarily in the liver and were safely metabolized without any damage. Studies also showed that the nanosponges also have a half-life of about 40 hours. These results were published in Nature Nanotechnology.
The most virulent toxins in MRSA were used in the experiments with great success. It can be deduced that toxins with lower virulence factors would have an even higher success rate. These nanosponges are capable of removing a broad class of dangerous substances from the bloodstream including toxins produced by E. coli, S. aureus, venom from snakes, bees, sea anemones and more. With more and more strains of bacteria becoming resistant to antibiotics, nanosponges could work with or in lieu of most antibiotic treatments that are being prescribed today.
The goal of these experiments is to lead to approved therapies on human patients as soon as possible. Before that can happen, the researchers’ must pursue clinical trials. Follow this “fantastic voyage” on Twitter @UCSD_Nanomed for the latest on this promising technology!