Ahead of this week’s Morningside Center conference on repurposing drugs, we wanted to highlight a recent paper in NPJ Precision Oncology by dermatologist Jack Arbiser. It may represent a new chapter in the story of the beta-blocker propranolol.
Several years ago, doctors in France accidentally discovered that propranolol is effective against hemangiomas: bright red birthmarks made of extra blood vessels, which appear in infancy. Hemangiomas often don’t need treatment and regress naturally, but some can lead Read more
Briefly, they found that increased appetite and insulin resistance can be transferred from one mouse to another via intestinal bacteria. The results were published online by Science magazine.
Previous research indicated intestinal bacteria could modify absorption of calories, but Gewirtz and his colleagues showed that they influence appetite and metabolism (in mice)
“It has been assumed that the obesity epidemic in the developed world is driven by an increasingly sedentary lifestyle and the abundance of low-cost high-calorie foods,” Gewirtz says. “However, our results suggest that excess caloric consumption is not only a result of undisciplined eating but that intestinal bacteria contribute to changes in appetite and metabolism.”
A related report in Nature illustrates how “next generation” gene sequencing is driving large advances in our understanding of all the things the bacteria in our intestines do to us.
Gewirtz’s laboratory’s discovery grew out of their study of mice with an altered immune system. The mice were engineered to lack a gene, Toll-like receptor 5 (TLR5), which helps cells sense the presence of bacteria.
Dr. Carlos del Rio possesses a keen view of how the novel H1N1 virus emerged last spring. Del Rio was in Mexico as the virus established itself south of the border. Its rapid, far-reaching spread marked the first influenza pandemic of the 21st century.
During Emoryâ€™s fifth annual predictive health symposium, “Human Health: Molecules to Mankind,” del Rio discussed his experiences in Mexico, what weâ€™ve learned, and what novel H1N1 has to do with predictive health.Â View a video of his presentation and five lessons learned.Â
Only a day after the virus was identified, on April 23, Mexican authorities closed schools, called off sporting events, and canceled religious gatherings. Known as â€œsocial distancing,â€ these actions led to a decrease in cases, an important lesson, says del Rio. The public knew what to do, they were cooperative, and whatâ€™s more, they applied a lot of peer pressure when it came to hand washing and sneezing hygiene.
Another lesson learned: preparation paid off. Anticipating a pandemic, The World Health OrganizationÂ had earlier mandated that countries draw up influenza pandemic plans. â€œThose plans were incredibly helpful in getting people to work together, communicate, and know what to do,â€ says del Rio.Â Interestingly, the plans in Mexico and the United States were aimed at a virus projected to originate from an avian source from southeastern Asia. â€œIt was not developed for a swine virus coming from inside the country,â€ explained del Rio.
Novel H1N1, even though itâ€™s thought of as a swine virus is in fact only about 47% swine–30% from North American swine and 17% from Eurasian swine. The virus also contains human and avian strains. Thatâ€™s important, says del Rio, because the characteristics of its genes determine how symptoms, susceptibility, and immunity manifest themselves.
â€œWhat weâ€™re seeing nowadays is the new strain has crowded out the seasonal influenza virus,â€ he says. Thus far, most of the deaths from novel H1N1 have been in children, young adults, and pregnant women. â€œThe people who are dying are a very different group than in previous flu seasons,â€ says del Rio.Â
Carlos del Rio, MD
Del Rio says a lot was learned early on about the novel virus thanks to frequent and transparent international communication. This flu pandemic is really the first to occur in this era of 24-hour newscasts and the Internet. So thereâ€™s a challenge for health workers: how do you continue to communicateÂ in an effective way. â€œOne thing you say one day may be contradicted the next day because you have new information. How do you make people understand that you werenâ€™t lying to them before, but you have updated information and that information is continuously changing.”
In trying to predict whatâ€™s in store for the current flu pandemic, researchers are looking back at past pandemics. Last century, there were three major flu pandemics. The largest and most important was the 1918 pandemic.
â€œA couple of things that happened back then are very important: one was there was a second wave that was actually much more severe and much more lethal than the first one.â€ says del Rio. â€œAnd over the summer, the virus actually changed. It started very much like it did this time. It started in the spring and then we had a little blip, and then we had a big blip in the second wave, and then almost a third wave. So, clearly influenza happens in waves, and weâ€™re seeing the same thing happening this time around.â€
Emory University is hosting an 800-panel display of The AIDS Memorial Quilt in recognition of World AIDS Day. â€œQuilt on the Quad,â€ on the Emory quadrangle, is the largest collegiate display and the second largest in the world today. An opening ceremony featured a talk by Sandra Thurman, president and CEO of the International AIDS Trust, based at Emoryâ€™s Rollins School of Public Health. Members of the Emory community read the names of each individual memorialized by a quilt panel on the quad.
An estimated 60 million people have acquired HIV, and 25 million people have died from AIDS. Emory scientists and physicians have been leaders in research to develop effective drugs and vaccines against HIV and AIDS. The Emory Center for AIDS Research is an official National Institutes of Health CFAR site. More than 120 faculty throughout Emory are working on some aspect of HIV/AIDS prevention or treatment.
More than 94 percent of HIV patients in the U.S. on life saving antiviral therapy take a drug developed at Emory. And many of the scientists within the Emory Vaccine Center are focused on finding an effective vaccine against HIV. A vaccine developed at the Vaccine Center and Yerkes National Primate Research Center is being tested nationally in a phase II clinical trial.
The Hope Clinic of the Emory Vaccine Center is conducting several clinical trials of HIV vaccine candidates through the HIV Vaccine Trials Network (HVTN) sponsored by the NIH. The HVTN 505 vaccine trial, which is currently enrolling at the Hope Clinic and 13 other cities around the country, is a test-of-concept efficacy trial for an NIH vaccine (DNA + Adnovirus â€“ gag/pol/nef/EnvABC).
Mark Mulligan, MD, executive director of Emoryâ€™s Hope Clinic, emphasizes that on World AIDS Day there would be no better way to honor those who have already died or are already infected than to produce a vaccine that will protect their families and friends.
â€œThe recent analysis of the RV144 Thai trial surprisingly taught us that an envelope glycoprotein vaccine regimen can protect (albeit modestly, thus far)! This is an amazing result that has re-ignited the field, and is capturing the attention of the community. We must do all we can to leverage this result for success,â€ Mulligan says. â€œAlbert Sabin said that no scientist can rest while a vaccine that might help humanity sits on the shelf. To me, this underscores the importance of successfully executing the HVTN 505 trial.â€
Jorg Goronzy, MD, PhD and Cornelia Weyand, MD, PhD
Weyand and Goronzy show that with age, T cells begin to turn on genes that are usually turned on only in â€œnatural killerâ€ cells. NK cells play a major role in rejecting tumors and killing cells infected by viruses. They are white blood cells like T cells but they have a different set of receptors on their surfaces controlling their activities.
Many of these receptors act to hold the NK cells back; so when they appear on the T cells, their activation is dampened too, thus contributing to the slowing down of the immune system in elderly people.
The authors report that NK cell genes get turned on because they lose the â€œmethylationâ€ on their DNA. Methylation is a pattern of tiny modifications on DNA, emphasizing whatâ€™s important (or forbidden) in a given cell, sort of like a highlighterâ€™s yellow pen on top of text.
Apparently, in elderly people (aged 70-85), the methylation is more â€œspottyâ€ than in younger people (aged 20-30). It seems that after the DNA is copied several times, the highlighting gets fuzzy and the T cells start to look like their cousins, natural killer cells.
An outbreak of measles in the state of Washington last year sickened 19 children. Of those who fell ill, 18 had something in commonâ€”they were not vaccinated.
Saad Omer aims to increase vaccine compliance to prevent childhood diseases.
For Emory Rollins School of Public Health researcher Saad Omer, the Washington outbreak is a perfect example of the effect on an entire community when individuals are unimmunized. His research aims to shed light on ways to encourage increased vaccine compliance for adults and their children.
Omer says vaccine-preventable diseases such as measles, influenza, and pertussis often start among persons who forego vaccinations, spread rapidly within unvaccinated populations, and also spread to other subpopulations.
In a recent New England Journal of Medicinearticle, Omer and his colleagues reviewed evidence from several states showing that vaccine refusal due to nonmedical reasons puts children in communities with high rates of refusal at higher risk for infectious diseases such as measles and whooping cough.
Even children whose parents do not refuse vaccination are put at risk because “herd immunity” normally protects children who are too young to be vaccinated, who can’t be vaccinated for medical reasons, or whose immune systems do not respond sufficiently to vaccination.
Research findings indicate that everyone who lives in a community with a high proportion of unvaccinated individuals has an elevated risk of developing a vaccine-preventable disease.
Read more about Omerâ€™s research on vaccine refusals in the fall 2009 issue of Public Health magazine.
Omer also discusses the importance of vaccinating against the H1N1 virus in an Oct. 16 article in The New York Times.
Emory Vaccine Center researcher Cynthia Derdeyn and her colleagues have a new paper in PLOS Pathogens that is a reality check for researchers designing possible HIV vaccines. The results come from a collaboration with the Rwanda Zambia HIV Research Group. (Although the patients in this paper are from Zambia only.)
Red and green depict the parts of the HIV envelope protein that mutated in two patients (185F and 205F) in response to pressure from their immune systems.
Recently there has been some excitement over the discovery of robust neutralizing antibodies in patients.
The bottom line, according to Derdeyn’s team: even if a vaccine succeeds in stimulating antibodies that can neutralize HIV, the virus is still going to mutate furiously and may escape those antibodies. To resist HIV, someone’s immune system may need to have several types of antibodies ready to go, their results suggest.
A companion paper in the same issue of PLOS Pathogens from South African scientists has similarly bracing results.
Clinical trials are underway at Emory and Children’s Healthcare of Atlanta testing an investigational H1N1 flu vaccine along with the seasonal flu vaccine. Emory will enroll about 100 children, ages six months to 18 years, and up to 650 children nationally will participate in the study.
The study will look at the safety of and measure the body’s immune response to the H1N1 flu vaccine. In addition, it will help determine how and when the vaccine should be given with the seasonal flu vaccine to make it most effective.
Another important factor is learning if there are any potential problems by giving the vaccines together, such as whether one vaccine will undermine the protective power of the other.
The answer is important because experts are predicting that both strains of flu will circulate this fall and winter.
Keyserling says that because children and young adults are considered among the most vulnerable populations for new and emerging strains of influenza, such as the current H1N1 pandemic, it is critically important that testing for a vaccine is quick and efficient.
Lampreys are primitive creatures â€“ basically, tubes with teeth. Their primitive nature makes them a fascinating entry-point for studying the evolution of the immune system.
At Emory, Max Cooper and his colleagues have been studying lampreysâ€™ versions of white blood cells. In a recent Nature paper, they show that lampreys have two kinds of cells that look very much like B and T cells in mammals, birds and fish.
Non-immunologists may shrug at this revelation. Â But consider: lampreys have a completely different set of tools for fighting infections. They have proteins in their blood that glob on to invaders, but they donâ€™t look anything like the antibodies found in mammals, birds and fish.
Lampreys in a laboratory tank. Courtesy of Masa Hirano.
Similarly, lampreys have cells that look like T Ray Ban outlet cells, in terms of some of the genes that are turned on. However, they donâ€™t have MHC genes, which are important in human transplant medicine because they determine how and when T cells get excited and reject transplanted organs.
Lampreys are thought to be an early offshoot on the evolutionary tree, before sharks and fish, and way before critters that crawl on land. This suggests that the categories (B or T) came first even though the characteristic features of the cells (antibodies/responding to MHC) are different.
â€œLampreys have the same types of cells, but they just use different building blocks to put them together,â€ Cooper says.
He says he is now collaborating with Thomas Boehm in Freiburg, Germany to better understand the evolution of the thymus. Again, lampreys donâ€™t have a thymus, but they may have an area next to their gills where the T-like cells develop.
In a Darwin-anniversary essay, Travis tells the story of how the evolution of the immune system was a centerpiece of the 2005 Kitzmiller v. Dover trial, when a Pennsylviania school districtâ€™s requirement to teach intelligent design was successfully challenged.
When our bodies encounter a bacteria or a virus, the immune system sends some cells out to fight the invader and keeps others in reserve, in order to respond faster and stronger the next time around. Vaccination depends on this phenomenon, called immunological memory.
Several recent papers â€” from Emory and elsewhere â€“ provide insight into this process, and highlight this area of research as especially active lately.
In addition, Wnt signaling, which plays critical roles in embryonic development and cancer, influences memory T cell formation as well, according to a July paper in Nature Medicine.
To summarize â€” pushing on several different â€œbuttonsâ€ produces the same thing: more memory T cells. How are the wires behind the buttons connected? Work by Ahmed and others may eventually help enhance vaccine efficacy or fight cancer with the immune system.
Rapamycin, the focus of the Ahmed/Larsen paper, was also recentlyfound to slow aging in mice. However, with previous anti-aging research findings, translating results into the human realm has been a considerable challenge.