Team:TrinityCollegeDublin/Malaria
An Overview and History
The Malaria-causing parasite, Plasmodium, has been at war with mankind for as long as about 10,000 years ago when human settlements and agricultural advances were starting to develop. References have been made to the disease’s recurrent symptoms in Ancient Chinese scripts, by Hippocrates and by the Romans. In fact, the term malaria originates from Medieval Italian: mala aria or "bad air". Prior to this, the disease was called ague or marsh fever due to its association with swamps and marshland, places that contain stagnant water where mosquitoes can breed.
Transmitted typically by the bite of the female Anopheles mosquito, the parasite is lodged into the liver via the bloodstream. The symptoms show ten to fifteen days after being bitten and, over the course of time, may be recurrent if not treated. The life cycle of Malaria can be shown in the following simplified diagram:
Malaria is currently prevalent in a broad band around the equator, in regions of South America, many parts of Asia, and majority of Africa; 85–90% of malaria fatalities occur in Sub-Saharan Africa.
An estimated 3.3 billion people are at risk of malaria. Of these, 1.2 billion are said to be at high risk. In high-risk regions, more than one malaria case occurs per 1000 people. Even though malaria was one of the first infectious diseases to be treated with a pharmaceutical drug, scientists are still looking develop quicker and more effective cures.
Economists believe that malaria is responsible for a “growth penalty” of up to 1.3% per year in some African countries. Malaria also impedes children’s schooling and social development through both nonattendance and perpetual neurological and other damage linked with severe episodes of the disease. The mere presence of malaria in a country also hinders individual and national prosperity due to its effect on social and economic decisions. - Economic costs of malaria, World Health Organization (last accessed October 2, 2010)
In the context of malaria, synthetic biology has been used to create a reliable source of artemisinin. In 2005, Amyris was awarded a five-year grant from the Bill & Melinda Gates Foundation to create artemisinic acid (a precursor to artemisinin) in yeast using the synthetic biology platform in partnership with PATH and UC Berkeley. Their objective was to improve artemisinin production and reduce Artemisinin-based combination Therapies' (ACT) prices. In 2008, Amyris licensed the yeast strains to pharmaceutical company Sanofi-Aventis; and in 2013, Sanofi started using large-scale production to produce the semi-synthetic artemisinin for ACT treatments. Kay Monroe, who is currently executive director of Zagaya, reported on the situation:
Having also interviewed Chris Paddon, who was project leader for the semi-synthetic artemisinin project at Amyris, we got to know of the importance artemisinin has on the fight against malaria:
He also commented on the significance of trying to get E.coli to produce precursors of artemisinin as it has previously been unsuccessful due to limited technology/information available at the time:
Current statistics on Malaria control and prevention: The current package of core interventions – namely, vector control, chemoprevention, diagnostic testing and treatment – has proved to be highly cost-effective and needs to be further expanded in order to save more lives. During the past 10 years, vector control interventions increased substantially in Africa.
In 2013, 392 million ACT courses were acquired by the public and private sectors in endemic countries – up from just 11 million in 2005. In 2014, approximately 214 million long-lasting insecticidal nets (LLINs) were delivered to endemic countries, a main escalation from the 70 million bed nets that were delivered in 2012. Due to such measures being taken, the malaria mortality rate was reduced globally by 47%. In the under-five age group, mortality rates have declined by 53% globally, and by 58% in Africa. Initially, 55 countries were on track to reduce their malaria case incidence rates by 75%, in line with World Health Assembly and Roll Back Malaria targets for 2015. 64 countries were on track to meet the Millennium Development Goal target of reversing the incidence of malaria (between 2000 and 2015). The malaria-specific Millennium Development Goal has already been met. This has been very effective at preventing Malaria in a lot of areas. However, the fact remains that Malaria is still endemic in many African countries mainly because no drastic measures have been taken to combat it, such as intense pesticide control or a drug that cures Malaria instead of treating it.
Kay Monroe stressed on this fact:
Plasmodium falciparum resistance to artemisinin was first established on the Cambodia-Thailand border in 2008 and is now existent in five countries: Cambodia, Myanmar, the Lao People’s Democratic Republic, Thailand and Vietnam. Artemisinin resistance spreading to other countries could generate a major public health emergency. The WHO has recurrently advised countries to rid their pharmaceutical markets of artemisinin monotherapies, which could possibly encourage artemisinin resistance and thus, threaten the effectiveness of ACTs.
Kathleen Monroe states of her experience:
We also interviewed Ingrid Chen, who is academic coordinator at Malaria Elimination Initiative, Global Health Group, at UCSF Global Health Sciences, and had her take on the subject. Even though she also emphasized on the importance of getting the drugs to people in the right dosage and quality at an affordable price, she commented on the fact that artemisinin remains a strong contender in the war against Malaria:
Ingrid Chen gave a vivid picture of what it was like to face Malaria in person and how most dispensaries treated the disease in Africa for a long time:
International and domestic funding for malaria control and elimination totaled US$ 2.7 billion in 2013. Although this represents a threefold increase since 2005, it is still significantly below the US$ 5.1 billion that is required to achieve global targets for malaria control and elimination.
According to the WHO report for the future of Malaria control, to guarantee long-term efficacy of the core interventions, countries are commended to: strengthen efforts to prevent and manage drug and insecticide resistance as well as diverse vector behaviour; to remove all ineffective antimalarial medicines from markets; to further develop community-based diagnostic testing and treatment; and to impose pre- and post-shipment quality testing of vector control products. It also appeals for eradication of falciparum malaria from the Greater Mekong sub region, where multi-drug resistance has arisen.
Symptoms and lifecycle of Plasmodium:
- Symptoms typically include:
- Fever
- Fatigue
- Vomiting
- Headaches
- And in more severe cases:
- Yellow skin
- Seizures
- Coma or death
Transmitted typically by the bite of the female Anopheles mosquito, the parasite is lodged into the liver via the bloodstream. The symptoms show ten to fifteen days after being bitten and, over the course of time, may be recurrent if not treated. The life cycle of Malaria can be shown in the following simplified diagram:
Epidemiology
Malaria is currently prevalent in a broad band around the equator, in regions of South America, many parts of Asia, and majority of Africa; 85–90% of malaria fatalities occur in Sub-Saharan Africa.
An estimated 3.3 billion people are at risk of malaria. Of these, 1.2 billion are said to be at high risk. In high-risk regions, more than one malaria case occurs per 1000 people. Even though malaria was one of the first infectious diseases to be treated with a pharmaceutical drug, scientists are still looking develop quicker and more effective cures.
A disease of poverty
Malaria is involved in a nasty feedback loop with poverty. It is not only the result of poverty but is also a contributor to poverty. The WHO notes thatMalaria has significant measurable direct and indirect costs, and has recently been shown to be a major constraint to economic development. Annual economic growth in countries with high malaria transmission has historically been lower than in countries without malaria.
Economists believe that malaria is responsible for a “growth penalty” of up to 1.3% per year in some African countries. Malaria also impedes children’s schooling and social development through both nonattendance and perpetual neurological and other damage linked with severe episodes of the disease. The mere presence of malaria in a country also hinders individual and national prosperity due to its effect on social and economic decisions. - Economic costs of malaria, World Health Organization (last accessed October 2, 2010)
Treatment of Malaria, Artemisinin and Synthetic Biology
The first operative treatment for malaria came from the cinchona tree bark that has the compound quinine. However, the parasite developed resistance to the drug and later, artemisinin, which was discovered by Chinese scientist, Tu Youyou and company, in the 1970s from the herb Artemisia annua, became the commended treatment for P. falciparum malaria. It was often given in combination with other antimalarial drugs.In the context of malaria, synthetic biology has been used to create a reliable source of artemisinin. In 2005, Amyris was awarded a five-year grant from the Bill & Melinda Gates Foundation to create artemisinic acid (a precursor to artemisinin) in yeast using the synthetic biology platform in partnership with PATH and UC Berkeley. Their objective was to improve artemisinin production and reduce Artemisinin-based combination Therapies' (ACT) prices. In 2008, Amyris licensed the yeast strains to pharmaceutical company Sanofi-Aventis; and in 2013, Sanofi started using large-scale production to produce the semi-synthetic artemisinin for ACT treatments. Kay Monroe, who is currently executive director of Zagaya, reported on the situation:
Sanofi is a good partner and have done a fabulous job of implementing photosynthetic chemistry but exclusivity is not what we signed up for. This is what Zagaya has been pushing hard against. So if we can get fermented product to somebody else, those people can use whatever technology, like cheaper standard chemistry, to make artemisinin from the precursor. The chemistry conversion is therefore, not exclusive. Amyris is making sure the exclusivity is going to go away as it’s been working closely with Sanofi.” “…Sanofi is a European company so it’s easier for them to make SSA even if it’s expensive but we felt this can be done faster and cheaper especially in factories in India and China, …50% of what Sanofi charges.
Having also interviewed Chris Paddon, who was project leader for the semi-synthetic artemisinin project at Amyris, we got to know of the importance artemisinin has on the fight against malaria:
Artemisinin is the only available, effective, relatively cheap, antimalarial. Given in combination with other antimalarials for 3 days. At the moment there is nothing close that can take its place. Hopefully there will be further developments in the fermentation and the chemistry and the supply chain in the next decade.
He also commented on the significance of trying to get E.coli to produce precursors of artemisinin as it has previously been unsuccessful due to limited technology/information available at the time:
Artemisinin is a medicine for the developing world so we had to develop a highly efficient process. We took the knowledge that had been gained of Artemisia… and assembled all of this knowledge into E.coli but that proved to be untenable so we moved it into yeast.
E.coli grows faster and if you can get the dehydrogenases to get working you may be able to produce artemisinic acid in ways that yeast cannot. So any results that you guys generate will be useful.
Current statistics on Malaria control and prevention: The current package of core interventions – namely, vector control, chemoprevention, diagnostic testing and treatment – has proved to be highly cost-effective and needs to be further expanded in order to save more lives. During the past 10 years, vector control interventions increased substantially in Africa.
In 2013, 392 million ACT courses were acquired by the public and private sectors in endemic countries – up from just 11 million in 2005. In 2014, approximately 214 million long-lasting insecticidal nets (LLINs) were delivered to endemic countries, a main escalation from the 70 million bed nets that were delivered in 2012. Due to such measures being taken, the malaria mortality rate was reduced globally by 47%. In the under-five age group, mortality rates have declined by 53% globally, and by 58% in Africa. Initially, 55 countries were on track to reduce their malaria case incidence rates by 75%, in line with World Health Assembly and Roll Back Malaria targets for 2015. 64 countries were on track to meet the Millennium Development Goal target of reversing the incidence of malaria (between 2000 and 2015). The malaria-specific Millennium Development Goal has already been met. This has been very effective at preventing Malaria in a lot of areas. However, the fact remains that Malaria is still endemic in many African countries mainly because no drastic measures have been taken to combat it, such as intense pesticide control or a drug that cures Malaria instead of treating it.
Kay Monroe stressed on this fact:
You’re only in a net at night when you sleep and mosquitoes don’t only bite at night. This medication doesn’t eliminate reinfection so there are a lot of other things that needs to be done. We eliminated malaria in the US by drug treatment and by spraying a whole lot of DDT- we killed all the mosquitoes consistently. Governments, thus have to be involved, there has to be infrastructure and money. Poor countries are not going to spend money on this when they barely have enough for food or where there are governments being run by different radical groups every 6 months. As far as I’m concerned all mosquitoes carrying malaria need to die. They are the most adaptive species of insects I’ve seen. That’s my opinion and I’m an animal scientist. I don’t want to get rid of any animal species but mosquitoes, I mean what good are they doing? Oh yeah, fish eat them but so what? We only want to eliminate the ones with the malaria parasite.I’m fairly opinionated about this because at the end of the day Malaria doesn’t need to exist. When you see the kids suffering and dying of Malaria, you think ‘what is the point of this? It just needs to go.
Resistance to Artemisinin
Plasmodium falciparum resistance to artemisinin was first established on the Cambodia-Thailand border in 2008 and is now existent in five countries: Cambodia, Myanmar, the Lao People’s Democratic Republic, Thailand and Vietnam. Artemisinin resistance spreading to other countries could generate a major public health emergency. The WHO has recurrently advised countries to rid their pharmaceutical markets of artemisinin monotherapies, which could possibly encourage artemisinin resistance and thus, threaten the effectiveness of ACTs.
Kathleen Monroe states of her experience:
Getting drugs to people in Africa is an issue. We are trying to work with the supply chain. We know that when people come to clinics, they take their drugs home and give it to their kids and don’t give the full dose and so they get it again and come back again.
We also interviewed Ingrid Chen, who is academic coordinator at Malaria Elimination Initiative, Global Health Group, at UCSF Global Health Sciences, and had her take on the subject. Even though she also emphasized on the importance of getting the drugs to people in the right dosage and quality at an affordable price, she commented on the fact that artemisinin remains a strong contender in the war against Malaria:
The phenotype for artemisinin resistance is pretty soft. It’s not like chloroquine like in several parts of Africa where people get sicker and sicker. Artemisinin history has shown that it’s an awesome drug- it’s so effective and so fast. It works against young gametocytes which are in the transmission stages. A lot of drugs don’t do thatThis means that Artemisinin and ACTs will remain the main drugs to combat malaria in the coming years but of course, with the ever advancing technologies and developments there is greater hope for the future.
Conclusions on the current situation
Ingrid Chen gave a vivid picture of what it was like to face Malaria in person and how most dispensaries treated the disease in Africa for a long time:
Before the Gates money permeated Africa, I went to an island in Lake Victoria in Kenya. We found this abandoned building infested with bats and faeces and we cleaned it all up. Everybody from the island heard about it and went there. A lot of the people had malaria and typhoid. We got drugs in big bottles and we would write basic instructions on papers on how to take them. We also walked around the island and gave them education on nutrition and sanitation, Malaria and HIV. I thought Africa really needed money. It was really devastating. It was beyond what I could do with my own hands and energy. We also went to a hospital in Kendu. People were so emaciated. There was no treatment for them and they were just lying there waiting to die. They were waiting for us to give them injections. They would get bed sores and were really skeletal. It seemed really, really painful. It’s therefore, very inspiring what Gates has now done; They launched that project because the crops were different every year and the supply was insufficient and it’s changing things out there for the better by a lot.
International and domestic funding for malaria control and elimination totaled US$ 2.7 billion in 2013. Although this represents a threefold increase since 2005, it is still significantly below the US$ 5.1 billion that is required to achieve global targets for malaria control and elimination.
According to the WHO report for the future of Malaria control, to guarantee long-term efficacy of the core interventions, countries are commended to: strengthen efforts to prevent and manage drug and insecticide resistance as well as diverse vector behaviour; to remove all ineffective antimalarial medicines from markets; to further develop community-based diagnostic testing and treatment; and to impose pre- and post-shipment quality testing of vector control products. It also appeals for eradication of falciparum malaria from the Greater Mekong sub region, where multi-drug resistance has arisen.