Sanaria Wins $3M Grant for Development of Malaria Vaccine

by

Sanaria has won a three-year, $3 million phase 2 Small Business Research Innovation grant from the National Institutes of Health to further develop its malaria vaccine.

The money will support research by scientists at the Rockville company and its partner, Columbia University, according to Sanaria information. The new grant continues earlier NIH-supported efforts at Sanaria and Columbia to develop genetically modified strains of the human malaria parasite Plasmodium falciparum that do not cause disease, but stimulate protective immunity when administered as a live, whole parasite malaria vaccine.

“There is considerable excitement about whole parasite malaria vaccines, and research towards developing genetically modified strains for such vaccines is at the cutting edge of this field,” said Christian Loucq, director of the Malaria Vaccine Initiative with PATH-Program for Appropriate Technology in Health, in a statement.

The parasites have been weakened by exposure to radiation and confer high-level protection against malaria when introduced by the bite of infected mosquitoes, according to Sanaria. These parasites invade host tissues, but cannot complete differentiation and do not replicate or cause disease.

“Sanaria is uniquely positioned at this time to expand the pipeline of candidate sporozoite vaccines to include vaccines based on precisely gene-altered parasites that are highly potent in inducing protective immunity against malaria and are unable to cause disease,” said Stephen L. Hoffman, Sanaria’s founder and chief scientist, in the statement.

In Agartala, India, Malaria Claims More Soldiers Than Bullets Do

by

Agartala, Indi — Malaria poses a bigger threat than insurgents and smugglers to Border Security Force (BSF) men posted along India’s northeastern border with Bangladesh, with many dying of the disease every year, say security officials.

“On an average, five to six BSF personnel died of malaria every year on the Tripura border alone. No one was killed by insurgents during the past three years,” said a senior BSF officer.

Comprising eight states, northeast India is a malaria prone zone, with the vector-borne disease claiming an estimated 500 civilian lives annually. Most parts of the borders with Bangladesh and Myanmar are mountainous, densely forested and unfenced. According to the officer, more than 2,360 BSF troopers posted along the 856-km-long Tripura-Bangladesh border were hit by malaria last year. The number of such cases since 2008 was a staggering 11,580.

via NDTV.

Malaria Control with Transgenic Mosquitoes

by

Malaria has been eliminated from a large part of the world. By the mid-twentieth century both North America and Europe were free of the disease, although both had suffered greatly during the prior century [1,2]. While a variety of means were used to achieve this eradication, the most important are thought to be reducing the number of breeding sites for malaria vectors and improving residential areas to separate humans from mosquitoes.

Other parts of the world have not been so fortunate. In sub-Saharan Africa, it is now estimated that there are more than 360 million clinical cases and one million deaths due to malaria each year [3,4]. Furthermore, despite ambitious goals such as those of the Roll Back Malaria Initiative to halve malaria deaths by 2010, mortality from the disease has actually risen halfway through the program [5]. Clearly the tools we have to control malaria, or the ways in which we are using them, are not working.

The failure of existing methods for malaria control has sparked interest in several new approaches. These include better and cheaper antimalarial drugs [6], renewed efforts to find a vaccine [7], and the development of genetically modified mosquitoes (GMMs) designed either to reduce population sizes or to replace existing populations with vectors unable to transmit the disease. In this review we describe some of the efforts currently underway to create GMMs and assess some of the obstacles they face.

Background

Malaria in humans results from infection by any of five species of Plasmodium: P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi. These are transmitted to humans by approximately 50 species of mosquitoes, all belonging to the genus Anopheles. In sub-Saharan Africa, the vast majority of deaths are caused by P. falciparum transmitted by An. gambiae and the closely related An. arabiensis. These species are difficult to work with in the laboratory, so other model systems of malaria are often used in laboratory studies.

Most species of mosquitoes do not transmit malaria, and even among species that do, many individuals seem incapable of transmitting the disease, i.e., are refractory. Accordingly, there is reason to hope that the genes that permit malarial infections in mosquitoes can be identified and then replaced or altered in terms of their function. In this way, it is hoped that mosquito populations will become refractory to the parasite, eventually leading to malaria transmission being halted.

A variety of methods for engineering refractory mosquitoes are currently being studied and show promise for malaria control. The laboratory of Marcelo Jacobs-Lorena at Johns Hopkins University has successfully engineered mosquitoes that confer resistance to rodent malaria [8]. Their approach was to first identify receptor sites for proteins that the parasite requires to pass through the gut after ingestion. They next produced small proteins that saturate the receptor sites and hence block amplification and transmission of the parasite (Figure 1). Future research in this area should focus on optimizing refractory genes to effectively confer resistance to human malaria.

Figure 1 - Left: Mosquitoes become infected with the malaria parasite upon taking an infected human blood-meal. This produces an oocyst in the mosquito's gut wall (light red). When the oocyst ruptures, it releases sporozoites that pass through the gut (dark red) and into the hemocoel (white). The sporozoites are then amplified and migrate through the mosquito's body to the salivary glands, ready to infect a new human. Right: The laboratory of Marcelo Jacobs-Lorena at Johns Hopkins University has identified receptor sites for proteins that are necessary for the malaria parasite to pass through the gut wall after the oocyst ruptures. The same receptors are involved with the passage of sporozoites into the salivary glands. The laboratory has produced small proteins that preferentially occupy these sites (blue), blocking transmission of sporozoites through the gut wall and into the salivary glands. The appropriate gene constructs have been introduced into An. stephensi mosquitoes, thus rendering them refractory to P. berghei (a model system for human malaria). (doi:10.1371/journal.pmed.1000020.g001)

 

 

Other methods for generating refractoriness involve using antibodies that kill parasites within the mosquito [9] and discovering genes that govern refractoriness in natural populations [10]. A great deal is being discovered about the immune system of mosquitoes [11], leading many researchers in this field to believe that an effective gene construct to reduce the ability of mosquitoes to transmit malaria is not far away.

FIVE KEY PAPERS IN THE FIELD

Marshall, 2008 [18] This article focuses on TEs as a drive system and models the impact of dissociation between the drive system and refractory gene. It references much of the important work to this time on TEs.

Chen et al., 2007 [20] This article describes the biology and potential uses of a synthetic Medea element observed to spread through laboratory Drosophila populations.

James, 2005 [19] A general overview of the criteria required by gene drive systems intended to drive refractory genes into mosquito populations.

Alphey et al., 2002 [27] A discussion of the benefits, risks, and research priorities associated with using transgenic insects to control vector-borne diseases.

Ito et al., 2002 [8] An historic paper that describes one of the first candidate antiparasitic genes that works in a disease vector model system in the laboratory.

Drive Systems

More problematic is the means of driving a refractory construct quickly and efficiently through the vector mosquito population so that the population of susceptible mosquitoes will be replaced. Transposable elements (TEs) were one of the first gene drive systems to gain widespread attention for population replacement [12]. These elements are able to spread quickly through a population due to their ability to replicate within a host genome and hence to be inherited more frequently in the offspring’s genome. This increase in inheritance enables TEs to spread even in the presence of a fitness cost to the host [13]. It has also led to their widespread prevalence among many taxa, to the extent that various families of TEs represent 47% of the Aedes aegypti mosquito genome [14].

One source of encouragement for the use of TEs in population replacement is the observation that the P element spread through most of the global Drosophila melanogaster population within the span of a few decades following a natural acquisition from D. willistoni [15]. It is hoped that such an invasion could be repeated in a mosquito species using a TE that is attached to a refractory gene conferring resistance to malaria. Ideally, such an invasion would be repeated in each of the major mosquito species that transmits malaria.

Despite initial excitement, TEs have become less favored as a means of population replacement in recent years. The first major hurdle has been the failure to introduce a highly active TE into An. gambiae—the main vector of malaria in sub-Saharan Africa. TEs tend to repress their activity over time to avoid corrupting the host genome. Many TEs, including the P element, accumulate mutations leading to their inactivation. This may make the discovery of a highly active TE more challenging than originally anticipated.

Additionally, preliminary data suggest other reasons that TEs may be ill-suited to driving foreign DNA into populations. A study on the Himar1 mariner element suggests that TE activity declines substantially with increasing size [16]. Given current refractory gene sizes (e.g., [17]), the mariner element is estimated to have its replication rate reduced by at least 95% when burdened by a refractory construct [16]. Its drive would have to be very strong in order to suffer such a decline in replication.

This is compounded by the fact that TEs are particularly vulnerable to losing internal sequences during replication. Mathematical modeling suggests that, if the refractory gene is lost from the TE at a modest rate, the malaria-susceptible TE will return to again dominate the population [18]. Therefore, even if active TEs can be identified, their ability to drive refractory genes into a population is questionable.

Disenchantment with TEs as a means of population replacement has coincided with interest in several other gene drive systems. Some of the most promising drive mechanisms currently being investigated include Medea elements, homing endonuclease genes (HEGs), engineered underdominance constructs, and the intracellular bacterium Wolbachia. Other systems that are being investigated include engineered underdominance constructs and meiotic drive [19].

The favorability of one gene drive system over another will depend on its ability to quickly and efficiently spread a refractory gene. However, this on its own is not enough. The ideal gene drive system will also address ecological, epidemiological, and social concerns that such a system engenders and minimize the likelihood of any risks. In our opinion, the most promising system at present is Medea.

Medea has attracted much attention as a tool for population replacement in recent years, following the observation that an engineered Medea element is able to rapidly spread through D. melanogaster populations in the laboratory [20]. The design of this synthetic element is based on a naturally occurring selfish genetic element first discovered in a species of flour beetle, Tribolium castaneum. Medea is able to rapidly spread through a population in the presence of a fitness cost by distorting the offspring ratio in its favor. It does this by causing the death of all offspring of heterozygous females that do not inherit the allele, thus giving rise to its name—an acronym for maternal-effect dominant embryonic arrest, with reference to the mythological Greek figure who murdered her own children.

The synthetic Medea element developed by Chen et al. [20] works by the hypothesis that Medea encodes both a maternally expressed toxin and a zygotically expressed antidote. The toxin causes the death of all progeny lacking the Medea allele, and the antidote rescues Medea-bearing progeny from an otherwise imminent dealth (Figure 2). In this way, the proportion of Medea-bearing individuals is increased with each generation; and it is hoped that an attached refractory gene conferring resistance to malaria could come along for the ride.

Figure 2 - Parental Crosses Representing the Reproductive Advantage of the Medea Allele Females carrying the Medea allele produce a maternally expressed toxin (red outer circle) that is deleterious to their offspring. Offspring who carry the Medea allele are rescued by a zygotically expressed antidote (green inner circle) expressed by the same allele. Offspring of heterozygous females who do not inherit the Medea allele are killed by the toxin because they lack the antidote (yellow represents lack of the toxin/antidote). This distorts the offspring ratio in favor of the Medea allele. (doi:10.1371/journal.pmed.1000020.g002)

Medea does not suffer from many of the ailments inflicted upon TEs—an active Medea element has been engineered, its spread is not retarded by the insertion of foreign DNA, and a solution has been proposed to minimize the rate of dissociation of refractory genes [20]. Additionally, in the event that a refractory gene should be recalled following an environmental release with unwanted consequences, it has been proposed that another strain of Medea could be introduced to replace the first, thus removing the refractory gene from the population.

One attractive feature of Medea is that its rate of spread is strongly dependent on its release ratio [21]. While Medea will spread very quickly following a large intentional release, it is very likely to go extinct following a small accidental release [22]. This is particularly important since it is impossible to guarantee that there will be no escapes while outdoor cage trials assess the potential outcomes of an environmental release [23]. Medea therefore presents a desirable balance between invasiveness and containment. At present, there is an active effort to construct Medea systems for mosquitoes, but as yet no such systems have been made.

HEGs are another system for which there are active development efforts. These genes are able to spread through a population by expressing an endonuclease that creates a double-stranded break at a highly specific site lacking the HEG. Homologous DNA repair then copies the HEG to the cut chromosome, thus increasing its representation over subsequent generations [24].

Next Steps in Research

The first requirement of any transgenic mosquito project will be the discovery of genes that confer resistance to human vector-borne diseases. The proof of principle has been shown for rodent and chicken malaria, and it remains to optimize genes to confer resistance to human malaria. Several refractory genes will be necessary for a successful intervention both to improve the efficacy of refractoriness, and to reduce the probability that resistance to antipathogen genes will emerge in the Plasmodium population.

Possibly more challenging will be the optimization of gene drive systems to deliver these refractory genes into mosquito populations. Medea has been shown to drive population replacement in Drosophila; and future research should work towards repeating this in mosquitoes. If this can be achieved, Medea will be a very promising candidate for population replacement; however, potential hazards for Medea and other gene drive systems must be identified and responded to, such as their ability to spread through reproductively isolated populations, and their persistence following an accidental release. Mathematical modeling can assist in assessing the severity of these concerns.

A broad study is required of the ecology of mosquito vectors through which the refractory genes are intended to be driven. Comprehensive ecological studies have been carried out in selected regions (e.g., [25]); however, these must be extended to other regions of Africa to gain a broader picture of species distributions and rates of gene flow. Malaria is a complex disease, and the biology of its vectors is also complex. In most parts of Africa, there is more than one species of Anopheles that transmits malaria. If hybridization among species is judged to be insufficient, then the feasibility of altering several species of malaria vectors will need to be considered.

We have focused our review on the effort to produce GMMs for malaria control; however, developing GMMs for dengue control will likely be achieved much earlier. Dengue virus, transmitted by the vector Ae. aegypti, is likely the second-most important vector-borne disease system after malaria. It is also much simpler than malaria—Ae. aegypti is easier to rear and experiment with than An. gambiae, and dengue does not have a complicated life cycle like Plasmodium. Much of the current work on GMMs is being conducted with dengue virus, and many of the problems confronting vector replacement will probably be worked out first with this system.

Finally, a large number of ethical concerns must be addressed and resolved satisfactorily before GMMs can be introduced. These include questions about the meaning of informed consent in communities that are largely illiterate, unfamiliar with genetic modification, and sometimes uneducated on the role of mosquitoes in disease transmission. These consent issues are confounded by the possibility of unknown and potentially serious side effects of a release, for example, an increase in the transmission of non-target diseases. Furthermore, acceptance by one community, or even country, is likely to affect many of its neighbors, whether they agree with the decision to release or not. Such a release may occur accidentally from an outdoor cage trial; however, an intentional release cannot be conducted prior to evaluation in cage trials.

Despite this, mosquito-borne diseases kill in excess of a million people every year, mostly children under five years old. GMMs offer some hope of reducing this burden of disease, and hence their risks, both known and unknown, must be weighed against the certain toll of inaction. In addition to some helpful initial studies [22,26,27], there is a clear need for much more analysis of the human research participant issues posed by these new methods.

GLOSSARY

Refractory gene: Gene conferring inability to transmit malaria.

Transposable elements: Genomic components that express a transposase enzyme catalyzing their replication in the genome. This enables them to spread through a population despite a fitness cost.

Fitness costs: Reduction in fitness associated with carrying foreign DNA.

Himar1 mariner element: A transposable element of the Mariner class. It contains its own transposase gene and moves by a cut-and-paste mechanism.

Internal sequences: Region of DNA between the characteristic end sequences of a transposable element.

Homing endonuclease gene: A selfish gene that spreads through a population by expressing an endonuclease that creates a double-stranded break in a DNA sequence and then copies itself to this site.

Medea element: A selfish genetic element that is able to spread through a population through its ability to cause the death of all offspring of heterozygous females that do not inherit the allele.

Wolbachia: A maternally inherited intracellular bacterium that can disrupt reproduction with noninfected sperm. This may be used to drive refractory genes into vector populations.

Engineered underdominance constructs: A form of underdominance in which there are two transgenic constructs, each of which possess a lethal gene and a suppressor gene that down-regulates the expression of the lethal gene on the other construct.

Meiotic drive: Any mechanism by which a heterozygous locus segregates at a greater-than-Mendelian frequency, often by destroying or disabling the homologous chromosome.

Dissociation of refractory genes: Loss of refractory gene DNA from a gene drive construct such that the refractory gene no longer functions.

Release ratio: The ratio of transgenic mosquitoes to natives ones at the time of a release.

Conclusion

Malaria control with transgenic mosquitoes will be challenging; however, recent advances suggest that it may be a possibility in the foreseeable future. Progress towards discovering refractory genes for rodent malaria and gene drive systems for Drosophila provide hope that similar advances may be made for human malaria in mosquito vector species.

That said, the African malaria burden has proved exceptionally difficult to diminish by all means tried thus far; and it is unlikely that transgenic mosquitoes will provide an all-in-one solution. Transgenic mosquitoes should be considered within the context of an integrated vector management strategy which should also include insecticide-treated bed-nets, indoor residual spraying with insecticides, and treatment of infected individuals with antimalarial drugs. Integrated strategies will be a necessity for any successful African malaria control program [28]; and transgenic mosquitoes should be considered as a potential ingredient in the future goal of continent-wide disease control.

Acknowledgments

We thank Marcelo Jacobs-Lorena, who kindly provided an illustration that became the model for Figure 1, Gregory Lanzaro, who provided a photo of An. gambiae, and Benny Gee, who made the figures.

References

  1. Humphreys M (2001) Malaria: Poverty, race and public health in the United States. Baltimore: Johns Hopkins University Press. 208 p.
  2. Bruce-Chwat LJ, de Zulueta J (1980) The rise and fall of malaria in Europe: A historico-epidemiological study. Oxford, New York: Oxford University Press. 256 p.
  3. Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI (2005) The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature 434: 214–217. Find this article online
  4. Hay SI, Guerra CA, Tatum AJ, Atkinson PM, Snow RW (2005) Urbanization, malaria transmission and disease burden in Africa. Nat Rev Microbiol 3: 81–90. Find this article online
  5. Yamey G (2004) Roll Back Malaria: A failing global health campaign. BMJ 328: 1086–1087. Find this article online
  6. Ridley RG (2002) Medical need, scientific opportunity and the drive for antimalarial drugs. Nature 415: 686–693. Find this article online
  7. Todryk SM, Hill AVS (2007) Malaria vaccines: The stage we are at. Nat Rev Microbiol 5: 487–490. Find this article online
  8. Ito J, Ghosh A, Moreira LA, Wimmer EA, Jacobs-Lorena M (2002) Transgenic anopheline mosquitoes impaired in transmission of a malaria parasite. Nature 417: 452–455. Find this article online
  9. de Lara Capurro M, Coleman J, Beerntsen BT, Myles KM, Olson KE, et al. (2000) Virus-expressed, recombinant single-chain antibody blocks sporozoite infection of salivary glands in Plasmodium gallinaceum-infected Aedes aegypti. Am J Trop Med Hyg 62: 427–433. Find this article online
  10. Riehle MM, Markianos K, Niare O, Xu J, Li J, et al. (2006) Natural malaria infection in Anopheles gambiae is regulated by a single genomic control region. Science 312: 577–579. Find this article online
  11. Waterhouse RM, Kriventseva EV, Meister S, Xi Z, Alvarez KS, et al. (2007) Evolutionary dynamics of immune-related genes and pathways in disease-vector mosquitoes. Science 316: 1738–1743. Find this article online
  12. Ribeiro JM, Kidwell MG (1994) Transposable elements as population drive mechanisms: Specification of critical parameter values. J Med Entomol 31: 10–16. Find this article online
  13. Charlesworth B, Sniegowski P, Stephan W (1994) The evolutionary dynamics of repetitive DNA in eukaryotes. Nature 371: 215–220. Find this article online
  14. Nene V, Wortman JR, Lawson D, Haas B, Kodira C, et al. (2007) Genome sequence of Aedes aegypti, a major arbovirus vector. Science 316: 1718–1723. Find this article online
  15. (1989) P elements in Drosophila melanogaster. In: Berg DE, How MM, editors. Mobile DNA. Washington (D. C.): ASM Press. pp. 439–484.
  16. Lampe DJ, Grant TE, Robertson HM (1998) Factors affecting the transposition of the Himar1 mariner transposon in vitro. Genetics 149: 179–187. Find this article online
  17. Marrelli MT, Li C, Rasgon JL, Jacobs-Lorena M (2007) Transgenic malaria-resistant mosquitoes have a fitness advantage when feeding on Plasmodium-infected blood. Proc Natl Acad Sci U S A 104: 5580–5583. Find this article online
  18. Marshall JM (2008) The impact of dissociation on transposon-mediated disease control strategies. Genetics 178: 1673–1682. Find this article online
  19. James AA (2005) Gene drive systems in mosquitoes: Rules of the road. Trends Parasitol 21: 64–67. Find this article online
  20. Chen CH, Huang H, Ward CM, Su JT, Schaeffer LV, et al. (2007) A synthetic maternal-effect selfish genetic element drives population replacement in Drosophila. Science 316: 597–600. Find this article online
  21. Wade MJ, Beeman RW (1994) The population dynamics of maternal-effect selfish genes. Genetics 138: 1309–1314. Find this article online
  22. Marshall JM (2009) The effect of gene drive on containment of transgenic mosquitoes. J Theor Biol. In press.
  23. Benedict M, D’Abbs P, Dobson S, Gottlieb M, Harrington L, et al. (2008) Guidance for contained field trials of vector mosquitoes engineered to contain a gene drive system: Recommendations of a scientific working group. Vector Borne Zoonotic Dis 8: 127–166. Find this article online
  24. Rong YS, Golic KG (2003) The homologous chromosome is an effective template for the repair of mitotic DNA double-strand breaks in Drosophila. Genetics 165: 1831–1842. Find this article online
  25. Taylor C, Touré YT, Carnahan J, Norris DE, Dolo G, et al. (2001) Gene flow among populations of the Malaria vector Anopholes gambiae in Mali, West Africa. Genetics 157: 743–750. Find this article online
  26. Lavery JV, Harrington LC, Scott TW (2008) Ethical, social and cultural considerations for site selection for research with genetically modified mosquitoes. Am J Trop Med Hyg 79: 312–318. Find this article online
  27. Alphey L, Beard CB, Billingsley P, Coetze M, Crisanti A, et al. (2002) Malaria control with genetically manipulated insect vectors. Science 298: 119–121. Find this article online
  28. Beier JC (2008) Malaria control in the highlands of Burundi: An important success story. Am J Trop Med Hyg 79: 1–2. Find this article online

More information: Full text – Malaria Control with Transgenic Mosquitoes (PDF)

 

Priorities in Malaria Research

by

Malaria remains a challenging prospect for researchers and health workers, but there is encouraging news to report. Malaria research, after many years on the back burner, has risen dramatically up the priority list of donors and policy makers. Much of the credit for this turnaround must go to the Multilateral Initiative on Malaria (MIM; http://www.mim.su.se). MIM’s achievements in the malaria world may indeed be a model for raising the profile of other neglected health issues. [Read more…]

Use of Integrated Malaria Management Reduces Malaria in Kenya

by

During an entomological survey in preparation for malaria control interventions in Mwea division, the number of malaria cases at the Kimbimbi sub-district hospital was in a steady decline. The underlying factors for this reduction were unknown and needed to be identified before any malaria intervention tools were deployed in the area. We therefore set out to investigate the potential factors that could have contributed to the decline of malaria cases in the hospital by analyzing the malaria control knowledge, attitudes and practices (KAP) that the residents in Mwea applied in an integrated fashion, also known as integrated malaria management (IMM). [Read more…]

Malaria FAQ

by

Photo by Matthew Naythons, MD

Malaria is a serious and sometimes fatal disease caused by a parasite that infects a certain type of mosquito which feeds on humans. People who get malaria are typically very sick with high fevers, shaking chills, and flu-like illness. Four kinds of malaria parasites can infect humans: Plasmodium falciparum, P. vivax, P. ovale, and P. malariae. Infection with P. falciparum, if not promptly treated, may lead to death. Although malaria can be a deadly disease, illness and death from malaria can usually be prevented. [Read more…]

Interview with Peter Agre, Johns Hopkins Malaria Research Institute Director

by

Peter Agre is director of the Johns Hopkins Malaria Research Institute, which celebrates its 10th birthday this year. Before turning his focus to malaria, Agre won the Nobel Prize in Chemistry in 2003 for his discovery of aquaporins, water channels in cell membranes. Agre spends a third of his year in regions of the world where malaria is endemic, mostly in Zimbabwe and rural Zambia, but he has never had the disease.

Rachel Saslow of the Washington Post recently spoke with Agre, 62, about malaria, his scheme to meet actor George Clooney and how he got a D in high school chemistry.

Read the interview, via: The Washington Post.

Seaweed May Hold Secrets to Fighting Malaria

by

Julia Kubanek, an associate professor at the Georgia Institute of Technology, holds samples of a tropical seaweed whose surface chemicals are being studied for their potential antimalarial properties. Photo by Gary Meek, Courtesy Georgia Tech.

A group of chemical compounds used by a species of tropical seaweed to ward off fungus attacks may have promising antimalarial properties for humans. The compounds are part of a unique chemical signaling system that seaweeds use to battle enemies – and that may provide a wealth of potential new pharmaceutical compounds.

Using a novel analytical process, researchers at the Georgia Institute of Technology found that the complex antifungal molecules are not distributed evenly across the seaweed surfaces, but instead appear to be concentrated at specific locations – possibly where an injury increases the risk of fungal infection.

A Georgia Tech scientist will report on the class of compounds, known as bromophycolides, at the annual meeting of the American Association for the Advancement of Science (AAAS) Feb. 21, 2011 in Washington, D.C. The research, supported by the National Institutes of Health, is part of a long-term study of chemical signaling among organisms that are part of coral reef communities.

“The language of chemistry in the natural world has been around for billions of years, and it is crucial for the survival of these species,” said Julia Kubanek, an associate professor in Georgia Tech’s School of Biology and School of Chemistry and Biochemistry. “We can co-opt these chemical processes for human benefit in the form of new treatments for diseases that affect us.”

More than a million people die each year from malaria, which is caused by the parasite Plasmodium falciparum. The parasite has developed resistance to many antimalarial drugs and has begun to show resistance to artemisinin – today’s most important antimalarial drug. The stakes are high because half of the world’s population is at risk for the disease.

“These molecules are promising leads for the treatment of malaria, and they operate through an interesting mechanism that we are studying,” Kubanek explained. “There are only a couple of drugs left that are effective against malaria in all areas of the world, so we are hopeful that these molecules will continue to show promise as we develop them further as pharmaceutical leads.”

In laboratory studies led by Georgia Tech student Paige Stout from Kubanek’s lab – and in collaboration with California scientists – the lead molecule has shown promising activity against malaria, and the next step will be to test it in a mouse model of the disease. As with other potential drug compounds, however, the likelihood that this molecule will have just the right chemistry to be useful in humans is relatively small.

Other Georgia Tech researchers have begun research on synthesizing the compound in the laboratory. Beyond producing quantities sufficient for testing, laboratory synthesis may be able to modify the compound to improve its activity – or to lessen any side effects. Ultimately, yeast or another microorganism may be able to be modified genetically to grow large amounts of bromophycolide.

The researchers found the antifungal compounds associated with light-colored patches on the surface of the Callophycus serratus seaweed using a new analytical technique known as desorption electrospray ionization mass spectrometry (DESI-MS). The technique was developed in the laboratory of Facundo Fernandez, an associate professor in Georgia Tech’s School of Chemistry and Biochemistry. DESI-MS allowed researchers for the first time to study the unique chemical activity taking place on the surfaces of the seaweeds.

As part of the project, Georgia Tech scientists have been cataloging and analyzing natural compounds from more than 800 species found in the waters surrounding the Fiji Islands. They were interested in Callophycus serratus because it seemed particularly adept at fighting off microbial infections.

Using the DESI-MS technique, researchers Leonard Nyadong and Asiri Galhena analyzed samples of the seaweed and found groups of potent antifungal compounds. In laboratory testing, graduate student Amy Lane found that these bromophycolide compounds effectively inhibited the growth of Lindra thalassiae, a common marine fungus.

“The alga is marshalling its defenses and displaying them in a way that blocks the entry points for microbes that might invade and cause disease,” Kubanek said. “Seaweeds don’t have immune responses like humans do. But instead, they have some chemical compounds in their tissues to protect them.”

Though all the seaweed they studied was from a single species, the researchers were surprised to find two distinct groups of antifungal chemicals. From one seaweed subpopulation, dubbed the “bushy” type for its appearance, 23 different antifungal compounds were identified. In a second group of seaweed, the researchers found 10 different antifungal compounds — all different from the ones seen in the first group.

In the DESI-MS technique, a charged stream of polar solvent is directed at the surface of a sample under study at ambient pressure and temperature. The spray desorbs molecules, which are then ionized and delivered to the mass spectrometer for analysis.

“Our collaborative team of researchers from the Department of Biomedical Engineering and the College of Sciences has worked within the Bioimaging Mass Spectrometry Center at Georgia Tech to better understand the mechanisms of chemical defenses in marine organisms,” said Fernandez. “This is an example of cross-cutting interdisciplinary research that characterizes our institute.”

Kubanek is hopeful that other useful compounds will emerge from the study of signaling compounds in the coral reef community.

“In the natural world, we have seaweed that is making these molecules and we have fungi that are trying to colonize, infect and perhaps use the seaweed as a substrate for its own growth,” Kubanek said. “The seaweed uses these molecules to try to prevent the fungus from doing this, so there is an interaction between the seaweed and the fungus. These molecules function like words in a language, communicating between the seaweed and the fungus.”

Source: Newswise