Researchers Use Genetic Engineering to Wipe Out Malaria-Carrying Mosquitoes in Lab

In September,  Nature Biotechnology published a paper by researchers describing their efforts to use CRISPR-Cas9 in a laboratory setting to prevent reproduction in a population of mosquitoes that transmit malaria to human beings,

In the human malaria vector Anopheles gambiae, the gene doublesex (Agdsx) encodes two alternatively spliced transcripts, dsx-female (AgdsxF) and dsx-male (AgdsxM), that control differentiation of the two sexes. The female transcript, unlike the male, contains an exon (exon 5) whose sequence is highly conserved in all Anopheles mosquitoes so far analyzed. We found that CRISPR–Cas9-targeted disruption of the intron 4–exon 5 boundary aimed at blocking the formation of functional AgdsxF did not affect male development or fertility, whereas females homozygous for the disrupted allele showed an intersex phenotype and complete sterility. A CRISPR–Cas9 gene drive construct targeting this same sequence spread rapidly in caged mosquitoes, reaching 100% prevalence within 7–11 generations while progressively reducing egg production to the point of total population collapse. Owing to functional constraint of the target sequence, no selection of alleles resistant to the gene drive occurred in these laboratory experiments. Cas9-resistant variants arose in each generation at the target site but did not block the spread of the drive

Researchers Discover How Malaria Evades Immune System

Researchers at the Howard Hughes Medical Institute have discovered how malaria parasites evade the human immune system on their way to infecting people. Their discovery was published in Nature in late 2005.

Essentially, the parasite has a number of cloaking mechanisms, and keeps most of them in reserve. As it encounters resistance from the human immune system the parasite is capable of tailoring its cloaking to the immune system. The parasite has dozens of genes designed to get past the immune system, and what the researchers found was that as one gene was activated, that also trigger the suppression of the others. In this way, the malaria parasite is able to try one method after another to infect the host, and reduce the risk that the host might quickly develop an immunity against most or all of the parasite’s cloaking methods.

As HHMI researcher Alan Cowman put it in a press release announcing the discovery,

It’s like a leopard being able to change its spots. New forms come up, and the immune system beats them down again. Because of this a lot of people think you need five years of constant exposure to malaria in its different disguises to gain immunity.

Unfortunately too many people, especially children, die long before they can develop immunities to the malaria parasite’s numerous tricks. Even among people who develop immunity, that immunity can be quickly lost if the individual is not consistently exposed to malaria parasites.

This sort of research could one day lead to a treatment for malaria that might, for example, defeat this mechanism and allow for those exposed to malaria to quickly develop immune responses to all of its cloaking mechanisms.

Sources:

How malaria dupes immune system. BBC, December 29, 2005.

Scientists Lift Malaria’s Cloak of Invisibility. Press Release, Howard Hughes Medical Institute, December 28, 2005.

India Uses Low-Tech Method of Malaria Control: Fish that Eat Mosquitoes

An Indian malaria researcher recently reported on the success of initial pilot projects to use fish that eat mosquito larvae to control malaria.

This is a traditional method that was commonly used before the introduction of DDT in the 1950s and is once again being looked at as part of the solution to malaria.

The idea is to stock ponds, rivers and wells with fish like guppies that feed on the mosquito larvae. Dr. VP Sharma of the COuncil for Medical Research said that while the technique could not be used everywhere, in places where it was appropriate to use it had virtually eliminated a subspecies of malaria-carrying mosquito in some districts where mosquito-eating fish were introduced.

According to the BBC, Sharma credited the fish introduction program for India’s falling malaria rate which declined by about 200,000 cases per year after the program’s introduction. Sharma did add that, “It will take another five years before the real impact would be known” from the numerous fish introduction programs that the World Bank is underwriting.

Source:

Fish eat away at malaria in India. Richard Black, BBC, January 5, 2004.

Article Critical of World Health Organization’s Anti-Malaria Approach

Amir Attaran, who has been highly critical of donor organization’s approach to malaria control, published an opinion article in The Lancet in January arguing that “institutional inadequacies” in the World Health Organization’s anti-malaria efforts impede the organization’s ability to save lives from the disease.

Specifically, Attaran argues that by favoring expensive traditional malaria therapies over newer, more effective — but more expensive –treatments such as artemisinin combination therapies, the WHO is guilty of the equivalent of “medical malpractice.”

Attaran notes that WHO itself concedes that the drugs it using in Africa are growing increasingly ineffective,

WHO now writes of “global malaria control . . . being threatened on an unprecedented scale” by continued use of outdated drugs such as chloroquine, which is ineffective in most parts of Africa, and sulfadoxine-pyrimethamine, which is becoming so. For example, in East Africa, surveillance and clinical trial data show that up to 64% of patients given chloroquine and 45% given sulfadoxine-pyrimethamine will fail treatment, and those figures are climbing.

When treatment failure becomes so frequent, malaria deaths rise greatly, especially in children. In West Africa (Senegal), results of a 12-year community-based study showed that the onset of chloroquine resistance at least doubled childhood malaria death risk, and in some sites, increased it up to 11-fold in the youngest children. In East and southern Africa, the proportion of children dying from malaria doubled as chloroquine and later sulfadoxine-pyrimethamine resistance took hold from the 1980s to the 1990s, even as deaths from other causes declined. Elsewhere in Africa, chloroquine resistance increased the proportion of admissions to hospital and deaths from malaria by two-fold to four-fold.

Moreover, Attaran argues,

The superiority of ACT is now so established that of the five treatments WHO recommends for drug resistant P falciparum malaria, four are ACTs (the other is a “short-term solution” for countries that cannot use ACT immediately).3 ACT is now the preferred policy for WHO and the Roll Back Malaria campaign as a whole:

“Recently WHO has formulated policy that elevates combination drug therapy to preferred first therapy for all malaria infections in areas where P falciparum is the predominant infecting species of malaria. Combination therapy (CT) with formulations containing an artemisinin compound (ACT) is the policy standard . . .”22

However, WHO violates its own policy standard regularly. Most African countries reluctantly cling to chloroquine, sulfadoxine-pyrimethamine, or the insignificantly better combination of chloroquine and sulfadoxine-pyrimethamine, because ACT is ten times more expensive and, therefore, unaffordable to them.2,23 When those same countries seek financial aid from the Global Fund for AIDS, Tuberculosis, and Malaria (GFATM) to purchase ACT, they are forcefully pressured out of it by governments such as the USA, whose aid officials say that ACT is too expensive and “not ready for prime time”.24 WHO acquiesces to this pressure to cut costs, and despite a policy that names ACT as the gold standard of treatment, WHO signs its approval when GFATM funds cheap but ineffective chloroquine or sulfadoxine-pyrimethamine to treat P falciparum malaria.

. . .

These are very obvious errors of scientific and medical judgment; and although WHO might be expected to spearhead a corrective intervention, the evidence suggests that it instead exacerbated the errors. In Kenya, Ethiopia, and Uganda, WHO’s country representatives reviewed the funding proposals in which inappropriate drugs were sought–and signed their approval. Those signatures follow a declaration that WHO “has participated throughout the . . . process” of developing the proposal to GFATM, and that it “reviewed the final proposal and [is] happy to support it”.31-33

These decisions are indefensible. For WHO and GFATM to provide chloroquine and sulfadoxine-pyrimethamine treatments in the countries we cite as examples at least wastes precious international aid money, and at most, kills patients who have malaria. If one takes the measured increase in childhood malaria mortality that follows P falciparum drug resistance (two-fold to 11-fold) and extrapolates it to populations in which GFATM is funding chloroquine or sulfadoxine-pyrimethamine despite resistance (more than 100 million people in the four countries we name), then at least tens of thousands of children die every year as a direct result. Those patients who survive will often become much sicker and require retreatment, at some further expense of time and money. We do not exaggerate to state that, based on the outcomes, there is no ethical or legal difference that separates them from conduct otherwise condemned as medical malpractice (compare the case in which a doctor or pharmacist who, like these institutions, knowingly furnished treatments that failed perhaps 80% of the time, while withholding the alternatives as “too expensive”).

WHO responded with a letter to Lancet saying that it does encourage use of ACT, but that its high cost has hampered efforts to distribute it in Africa,

Although progress is encouraging, there are still major challenges to the adoption of ACTs, especially sustainable financing. Although with growing demand a price decrease can be expected in the coming years, the cost of growing the raw ingredient, Artemisia annua, means that ACTs will remain relatively expensive. Governments need to trust that sustainable funding from the Global Fund and other sources will be available before they can make the commitment–of up to US$2 per head per year–of switching to ACTs. WHO and its partners are developing a new mechanism to facilitate access to quality medicines and other products for malaria control. WHO will continue to work with the public and private sectors, and major institutions such as the Global Fund, to make ACTs more widely available through lowered costs, increased access, and technical cooperation.

The bigger problem is that so little money is devoted worldwide to fighting malaria.

Sources:

WHO, the Global Fund, and medical malpractice in malaria treatment. Amir Attaran, et al, The Lancet 2004; 363: 237-40.

Response to accusations of medical malpractice by WHO and the Global Fund. Fatoumata Nafo-Traoré, The Lancet 2004; 363.

Combination Therapy with Artemisinin Effective at Fighting Malaria

A review of existing studies of anti-malarial compound artemisinin recently concluded that adding the Chinese folk remedy for malaria to existing anti-malarial drugs increased the effectiveness of those drugs in fighting malaria.

The International Artemisinin Study Group looked at 16 clinical trials involving 6,000 patients who were administered artemisinin along with other anti-malarial drugs. Artemisinin is an extract from sweet wormwood has been used for centuries in Asia to treat malaria.

Their review found that adding artemisinin to existing compounds doubled the rate of parasite clearance (the level of parasites removed from the blood) with no additional side effects. Additionally, patients taking artemisinin combination therapies were less likely to suffer a relapse of the disease after ending treatment.

In an article in Lancet describing the results of the survey, the International Artemisinin Study Group wrote,

If used widely, this inexpensive, fixed-dose artemisinin-based combination antimalarial could make important contributions to ‘rolling back malaria’.

Sources:

Drug cocktail ‘may beat malaria’. The BBC, January 2, 2004.

Drug combinations for malaria: time to ACT?. The Lancet, January 3, 2004.

Combination therapy, the best way to tackle malaria: Lancet. January 2, 2004.

Bill Gates Donates $168 Million for Malaria Research

In September, Microsoft Chairman Bill Gates announced a $168 million donation to fund malaria research. Currently only about $100 million is spent annually to research malaria, so Gates’ donation will have a significant impact on efforts to find treatments for the disease.

In announcing the donation, Gates said it was time for the world to get serious about dealing with malaria,

Malaria is robbing Africa of its people and potential. Beyond the extraordinary human toll, malaria is one of the greatest barriers to Africa’s economic growth, draining national health budgets and deepening poverty.

About 90 percent of malaria cases occur in Africa, where the disease kills more than 900,000 people annually — mostly children.

$100 million of Gates’ grant will be devoted to vaccine research, $40 million to develop drugs to combat drug-resistant strains of malaria, and $28 million to research ways to use existing drugs to lower infections in infants.

Sources:

Gates boosts war on malaria. The BBC, September 21, 2003.

Bill Gates Donates $168 Million to Fight Malaria. Wambui Chege, Reuters, September 23, 2003.

Bill Gates donates $168 M for malaria research. Associated Press, September 22, 2003.

Africa’s Malaria Death Toll Still “Outrageously High”. Afshin Molavi, National Geographic News, June 12, 2003.