Though antiretroviral “cocktails” can target an active infection, they cannot get at the virus when it retreats inside the host’s T cells, where it may lie dormant for decades, waiting for an opportunity to burst forth in a fresh round of infection. What HIV hunters need is a good bird dog.

Now, Stanford chemist Paul Wender and his coworkers have found a way to synthesize better bird dogs, agents that can be tailored to flush HIV out into the open where the immune system and antiretroviral therapies can destroy it. Wender is senior author of a paper about the research in the May 2 issue of Science.

“We’re not sure how far this will go, but certainly, from a theoretical point of view, it has promise of taking therapy to the next level???that is, addressing issues related to eradication of the disease, of the virus, at least,” said Wender, the Francis W. Bergstrom Professor.

Wender and his co-workers Jung-Min Kee and Jeff Warrington have developed a way to synthesize prostratin and DPP, two compounds that occur naturally in plants, in the laboratory. Prostratin, found in the Mamala plant (Homalanthus nutans) that grows in the Samoan rainforest, has shown promise in previous studies as an activator of dormant HIV. DPP, a molecular relative of prostratin found in resin spurge (Euphorbia resinifera), which grows in arid regions, also has shown potential.

Research has been hampered, though, because the compounds are difficult to obtain, particularly in the quantities needed for practical lab work on their mode of action and therapeutic potential. The yield from both plants is low and highly variable; the availability of the plants is limited; and isolating the compound is difficult. Heavy harvesting of the wild plants, especially in Samoa, also could cause ecological damage.

But synthetic prostratin and DPP, which now can be readily made in the lab, changes that equation.

“We have now minimized, if not eliminated, the issue of availability of prostratin and DPP,” Wender said. “But equally, if not more importantly, we have opened access to other compounds that might be similar in structure but superior in function.”

Previous work done in mice by researchers at the University of California-Los Angeles indicates that prostratin, used in combination with interleukin-7, an immune system stimulator made in bone marrow, managed to flush out and eliminate approximately 80 percent of the dormant virus. But with HIV, 80-percent efficiency is not enough. Anything less than 100 percent means the virus is still lurking in the T-cells and will spring back to action as soon as an opportunity presents itself.

“Nature has produced these compounds for various reasons in the plants from which they’re derived, but certainly not to treat human maladies,” Wender said. “They’re not optimized for human therapy.”

But with synthetic prostratin and DPP available, researchers can take the basic compounds and tinker with the structure and related function. “We could find out how to improve them by reverse engineering: figuring out what is important and what isn’t important,” Wender said. “We could begin to design and synthesize molecules that would never be found in nature but might actually be therapeutically more beneficial than what has been found thus far.”

In the Science paper, Wender and his team detail how both compounds can be synthesized, but also show the initial phase of designing and making new derivative compounds.

Although prostratin has long been used by traditional Samoan healers without their patients experiencing acute side effects, it is possible that undesirable effects could show up in an immune-impaired patient taking prostratin or DPP. But Wender noted that engineering the compounds in a lab would permit scientists to circumvent these problems. “Usually these kinds of side effects are a result of a drug hitting multiple targets. So it hits one target, which is beneficial, but then it hits some other target, too,” he said. “But by modifying the structures, you could select for the beneficial activity over the non-beneficial activity.”

“It’s a little bit like draw poker,” Wender said. “The important point is that we’re not forced to use the hand we get. We’ll get a hand and we’ll return a few cards if we don’t like it, because we can keep on tuning this until we get it right, so that a royal flush, hopefully, can be realized.”

Wender’s team developed their method of synthesizing prostratin and DPP by using a renewable resource, croton oil, made from the seeds of a small tree (Croton tiglium) cultivated in Asia. They derived phorbol from the croton oil and then converted it into the structure of prostratin.

The conversion process required some engineering finesse; they had to overcome a hurdle when, by removing an oxygen atom, they triggered a series of anticipated but seemingly undesired changes.

“To the credit of my coworkers, Jung-Min Kee and Jeff Warrington, they employed a strategy that sometimes is missed,” Wender said. “Rather than fighting the flow, they went with it.” They found a way to redirect the chemical complications into a solution to the problem that proved even better than the route they had initially sought to follow.

“Eventually they produced a shorter, more economical way of connecting our starting material, phorbol, to our target, prostratin,” Wender said. The process Kee and Warrington came up with requires only five steps, which is of tremendous importance in making it economically feasible. As Wender pointed out, “steps cost money and human time.”

Wender emphasized that the work of his team is the most recent chapter in efforts of a truly global community, starting with the Samoan healers, who willingly shared their knowledge with Paul Cox, an ethnobotanist who saw them prescribing a tea made from Mamala bark for patients with hepatitis-like symptoms. Cox, in turn, sent samples to the National Institutes of Health, in hopes that the bark might have antiviral properties useful in fighting some cancers. Researchers at NIH then analyzed the bark and isolated prostratin.

Prostratin belongs to a class of compounds called tiglianes, many of which promote tumor growth, so it had no initially perceived use in fighting cancer. But NIH researchers found that prostratin was not a tumor promoter and checked to see if perhaps it could help combat HIV, which is when its remarkable ability to flush out the dormant virus was discovered. Significantly, prostratin has also been found to block uptake of the purged virus, offering yet another potentially therapeutic benefit.

“The whole effort is a testimonial to a global community working to deal with what I think is a global, and top priority, problem,” Wender said.

The research was funded by the National Institutes of Health. At the time of the study, Kee was a doctoral candidate in chemistry and Warrington was a postdoctoral scholar at Stanford. Kee is now a postdoctoral scholar at Rockefeller University, and Warrington is working in the biotech industry.

The Joint United Nations Programme on HIV/AIDS estimates that 33.2 million people were living with HIV and 2.1 million people lost their lives to AIDS in 2007. Current antiviral therapies require lifelong treatment, and patients must consistently take doses of medication on a precise schedule, which creates compliance challenges for many of them. The antiviral drugs often become ineffective as the virus develops resistance and are exceptionally costly, the last a major problem in less-developed regions of the globe.

[Louis Bergeron @ Stanford University]

The Socratic dialogue is a particular way of developing children’s, as well as adults’, thinking skills through cooperative dialogue where significant human ideas and values are discussed. By participating in Socratic seminars regularly every other week, preschool children and older students develop their thinking skills. The seminars address literature and art work, with questions such as these: is Pippi Longstocking a good friend, is Jack stupid or smart when he sells his mother’s cow for some beans, or are we born good or evil? In the beginning the students have difficulty expressing their thoughts, but with time their ability to express themselves and to examine ideas critically and logically develops.

The study included seven groups of children, five to sixteen years old. The groups were filmed during three years of philosophizing in the classroom and the films were analyzed. The interaction in the classroom was positively influenced, according to Ann S Pihlgren. The teacher dominated less, more students spoke and the students gradually took over the responsibilities of the teacher to promote exploration in the dialogue. The ability to use the Socratic seminar is learned by students and teachers through practice and by testing the rules of the seminar. The students construct a supportive group culture through their silent interaction, where gestures, glances, and body language are used to show not only support or sympathy for each other, but also cooperation with each other when someone attempts to disturb or to provoke the dialogue. The teacher role changes to one of support, ensuring that the analysis is fruitful and that the dialogue is respectful.

Socratic methods have developed independently in various countries. They all describe a set of methodological steps to attain similar objectives. An opening question is answered by all participants and followed by cooperative, critical analysis. Finally, the new ideas are connected to the everyday life experience of the participants.

It seems as if this ritualized structure and the nurturing culture of the seminar provide a safe circle, helping the participants to try new, bold ideas that they might otherwise not have tested, Ann S. Pihlgren says. By cooperating when examining the ideas they also seem to learn a way to address problems on their own without teacher intervention.

To work with methods connected to the ancient philosopher Socrates may seem out-of-date in a modern school, but that is absolutely not the case, Ann S. Pihlgren states.

The Socratic seminars have been seen as a complement to traditional classroom teaching for hundreds of years. But it is not easy to learn how to stage them to get positive effects. It is especially hard for teachers, who often fall back to their traditional, controlling “teacher” roles. The dissertation offers excellent tools for teachers who want to develop students’ thinking and to foster cooperative group dialogue.

The name of the dissertation: Socrates in the Classroom. Rationales and Effects of Philosophizing with Children. The dissertation can be downloaded as a pdf here.

[Jonas Ablad @ Swedish Research Council]

Professor Downing found that constructed ponds and lakes on farmland in the United States bury carbon at a much higher rate than expected; as much as 20-50 times the rate at which trees trap carbon. In addition, ponds were found to take up carbon at a higher rate than larger lakes.

“Aquatic ecosystems play a disproportionately large role in the global carbon budget,” Downing said. “Despite being overlooked in the past, it’s small bodies of water that are important because they take up carbon at a high rate and there are more of them than previously thought. The combined effect is that farm ponds could be burying as much carbon as the world’s oceans, each year.”

Ponds capture carbon in two main ways:

The research estimated there are 304 million natural lakes and ponds in the world, covering an area of 4.2 million square kilometers, twice the area previously thought. As many as 90 percent of these water bodies are one hectare (two acres) or less in area.

Downing’s research team published its most recent findings in the Feb. 15 issue of the journal Global Biogeochemical Cycles in a paper titled, “Sediment organic carbon burial in agriculturally eutrophic impoundments over the last century.” The team included members from Europe, the United States and Canada. The work was sponsored by the National Center for Ecological Analysis and Synthesis and the Iowa Department of Natural Resources.

Downing has presented invited seminars on this research to the International Society of Limnology, the American Society of Limnology and Oceanography, and at several major research institutions in North America and Europe. Most recently, he was invited to discuss his research by the Pond Conservation, a charity in the United Kingdom dedicated to creating and protecting ponds and the wildlife they support. He will spoke today at University College London. An upcoming presentation is scheduled for the annual meeting of the European Pond Conservation Network in Valencia, Spain.

Jeremy Biggs, Pond Conservation director of policy and research, said the research has exciting implications. “It may be that ponds will be the modern equivalent of the swamps that formed coal in the past. But before we all rush into making ponds to trap carbon we need to do some basic research here in the UK. If the rate of carbon uptake in ponds in Europe is the same as that found in the USA study, we may well have discovered an important new natural way of trapping carbon,” he said.

Downing’s ongoing research, partnering with the United States Geological Survey, and his contributions to the Iowa Lakes Survey will investigate the role of small Iowa lakes in the absorption of atmospheric carbon dioxide and other important gases such as methane.

[John Downing @ Iowa State University]

Denise Jackson had such success with her first book that she was inspired to write another. via WBIR-TV