Hi, my name is Joseph Derisi and I am an associate professor in the department of biochemistry,
biophysics, and a Howard Hughes Investigator at the University of California, San Francisco.
The subject of my lecture today is malaria.
And it is my goal to give you a background, and general overview of the disease,
and the parasites that cause this deadly affliction.
So first, let's talk about the disease.
The disease malaria is a devastating condition, it is caused by one of four parasitic protozoa.
It's characterized by a periodic fever,
and/or a febrile incident. This is usually followed by chills, sweats, aches, and other devastating conditions.
It is also characterized by enlargement of the spleen, and in the worst form,
so called cerebral malaria, can result in seizures, comma, severe anemia,
and ultimately organ failure and death.
It is true that children are the most affected by this disease and most likely to die.
The toll of human malaria is incredible.
There is somewhere between 1 and 2 million deaths due to this disease per year.
And that is in addition to 4 million to 9 million disease incidents per year.
So let me put that in perspective for you.
One million deaths per year equates to someone dying of this disease
every 30 seconds, of every minute, every day of the year.
And so, it can not be understated how incredibly this disease is on humanity.
So, why is malaria such a problem?
Why are we still dealing with this today,
when the cause of this disease has been known for over 100 years?
Well, it is simple. Today, malaria enjoys world-wide drug resistance.
That is the limited medications that we have to treat the disease,
are useless in many parts of the world.
And I'll have more to say about this in a little bit.
There is currently no vaccine for this disease with any operation impact.
And, to acquire some limited immunity to the disease,
requires that people be repeatedly infected, on a very frequent basis.
Therefore, to have any immunity to the disease requires continual pressure by the parasite.
No vaccine that has been created today achieves the same level of protection as natural infection.
And that is a problem.
So, this is where in the world the risk of transmission of malaria is the most severe.
Colored in dark green, are those areas of the most transmission of the disease.
And as you can see, here in sub-Saharan Africa, the problem is the worst.
Now, this is not to say that the problem isn't bad in South America, Central America, and South-east Asia,
it is. But by far and away, the largest burden to malaria is sub-Sahara Africa.
And the disease malaria is transmitted by the Anopheles mosquito.
There are over 60 species of the Anopheles mosquito,
that are capable of transmitting the disease.
This is why it is so difficult to control.
You might think that one way to control the disease
would simply be to eradicate the mosquitoes that carry it.
This is what has worked in many first world countries that have the organization,
the money, and the governmental structure to support such an effort.
And in fact, during the 1950s through the 1970s,
there was a world-wide global eradication effort led by WHO,
the World Health Organization.
And here is a post card from the United States
commemorating the initiation of the world-wide eradication effort.
But, since I'm giving you this lecture,
you know that this eradication effort was doomed to failure.
Why did it fail? It failed for a variety of different reasons that are illustrated here.
First of all, as I mentioned before,
there is drug resistance to the medications we use to treat the sick.
Furthermore, a lot of the eradication effort bypassed Africa
where the worst problems with malaria were occurring.
Furthermore, there was a lack of sustainable funding for this effort.
And, along with that, a lack of sustainable community participation in the eradication effort.
This was compounded and complicated by the fact
that there was massive population movements throughout the world,
in areas endemic with malaria,
and war, which never helps anything.
Furthermore, insects became resistant to many of the insecticides used
to try to eradicate the vectors themselves.
So what about the parasites themselves?
What is it we are trying to treat?
Well, as I mentioned before, the disease malaria is caused by any one of four protozoa parasites.
And their names are right here.
The worst, and by far the most deadly one, is Plasmodium falciparum.
Followed by Plasmodium vivax, Plasmodium malariae, Plasmodium ovale.
Plasmodium falciparum, as I mentioned,
is the most deadly of the four, and has the largest distribution worldwide.
Now, if you were to take some blood from an infected individual, smear it on a glass slide,
and stain with dye that binds DNA, you would see something like this.
Now, as you may know, red blood cells, or erythrocytes,
do not contain nuclei, and thus do not contain DNA.
But the parasites do.
So, if we did stain with a dye that bound DNA,
you would see healthy red blood cells, such as this one and this one.
But you would also see red blood cells with dark objects on the inside,
such as here and here.
These are Plasmodial parasites. In fact this is Plasmodium falciparum.
And this is the most frequent way an infection by Plasmodium is diagnosed.
The so called blood smear.
So let us talk more about the life cycle of these parasites,
and how they go about creating this horrible disease.
The life cycle is shown in cartoon form here.
Now, this is oversimplified for the purpose of this lecture,
but I just want to hit on the main points of the developmental cycle.
So it begins with the bite of the mosquito,
as I mentioned the Anopheles mosquito carries the Plasmodium parasites.
The Anopheles mosquito then releases sporozoites into the blood stream.
These sporozoites travel through the blood stream to the liver,
where they then invade hepatocytes.
It is here that the parasites replicate,
and develop over the course of a little more than a week.
After this period of replication,
the so called merozoites burst forth from the hepatocyte,
and begin a continual cycle of infecting red blood cells.
The so-called asexual stage of the parasite.
It is here that the parasites will invade red blood cells,
and consume the hemoglobin inside as a food source.
This is where all the clinical manifestations of the disease occur,
and this is where most drugs attempt to eradicate the parasite.
Now, with some infrequent rate, by a mechanism that is frankly poorly understood,
a small number of parasites will develop into a sexual form called gametocytes.
It is these gametocytes that are then picked up by a new anopheles mosquito
when taking up a blood meal,
and the entire cycle starts again.
And so, if one can treat the disease either here,
or block transmission here,
or block passing on the disease to new mosquitoes here,
one can effectively control this disease.
Now, let's take a little more close look at each stage here.
So I'd like to show you a movie first.
So in this movie by Vandenberg and colleagues,
which you will see is the proboscis of a mosquito that is the needle-like, tube-like structure
that the mosquito uses to suck the blood of its victim,
piercing the skin of a mouse,
and what you will observe are the infective form of the malaria parasites,
the sporozoites, being released from the tip of the proboscis into the saliva.
So let me start the movie and guide you through it.
So first, what you will see,
is the proboscis moving around trying to find a good blood supply.
Then, a second mosquito comes on the scene,
and you will see the proboscis over here.
See these small white particles, that seem to be moving around?
These are the sporozoites, and they exhibit what is called gliding motility.
As they try to find the blood stream,
and ultimately seek out the liver and invade hepatocytes.
We will let that movie run for a second so you can see the sporozoites circle around.
And then finally, the proboscis of this mosquito will withdraw.
O.K. So, back to the life cycle.
You have seen sporozoites enter the blood stream,
from here they go to the liver, replicate,
and then burst forth in a multitude of numbers to infect erythrocytes,
in essentially a perpetual asexual cycle.
And it is here, that again, all the clinical manifestations of the disease occur.
So, let's focus on that blood stage, asexual cycle of the parasite.
This is it shown in more detail.
As I mentioned before, this is the form that bursts forth from the liver, the so called merozoites.
It is these small forms of the parasite that will bind to a new erythrocyte and invade it.
Now, after invasion the parasite is called a ring stage,
and that is because it resembles a small diamond ring on the inside of the erythrocyte.
Then, the main metabolic phase of the parasite follows,
this is the so-called trophozoite phase,
and after this, the parasite undergoes multiple rounds of replication,
to ultimately form what is called a schizont.
A schizont will then mature and burst again,
and merozoites are released,
and this entire cycle repeats itself essentially every 48 hours in Plasmodium falciparum.
So, let's focus a little bit more on this stage, and this stage with yet another movie.
In this movie, by Glushakova and colleagues,
what you will see is an infected erythrocyte shown here,
burst spilling forth merozoites.
This erythrocyte that is uninfected over here,
will become infected by a new merozoite that attaches to it,
and then enters through the membrane.
So, as I start this movie, you will see this dark spot in the middle,
this a crystal of so-called hemozoin, this is the by product of hemoglobin digestion,
that has been collected in the food vacuole of the parasite.
So let's start the movie.
The erythrocyte bursts, and now you can se the merozoites.
Now look closely here.
There goes a merozoite into the cell. Did you see that?
It actually happens quite fast.
Now, the real time of this movie is shown in the upper left corner.
Let's see it again.
The erythrocyte bursts, and watch here.
There it is.
The merozoite enters the blood cell.
So in a matter of about less than 120 seconds,
cells burst, merozoites find new homes,
invade, and yet the process starts again.
And as you can see, if one parasite enters a cell, and many more come out,
upwards from anywhere 12 to 24,
you can imagine that this exponential increase in parasites is devastating to the human host.
And you can also imagine how complications like severe anemia can occur.
OK. Let's go back to the life cycle.
As I mentioned before,
the asexual erythrocytic cell cycle, of the Plasmodium parasites,
is where all the clinical manifestations of the disease occur.
So, if we are seeking to control malaria,
at the level of treating patients, people sick with the disease,
this is the stage which drugs must be designed to work against, to have efficacy.
So let me give you a quick review of the historical nature of drugs used against malaria.
Now, I'm not going to cover all of the drugs,
but some of the milestone drugs in malaria development.
So, we can begin in the 1600s with quinine.
This is the most famous of all malaria drugs,
and it comes from the bark of a particular tree found in South America.
It was brought to the new world by the Jesuits,
and for the last 400 years, it has been the mainstay of malaria treatment.
Now that being said, there are instances of quinine resistance throughout the world.
Now, during the 1940s, actually, during World War 2,
there became a need for additional malaria drugs,
because quinine supplies,
were not available to allied forces because they came under the imperial Japanese control
Chloroquine, was a German drug, that was rediscovered by Walter Reed, of the US Army,
during an effort to find new anti-malarial medications.
I should mention that many of the wars throughout history
have been shaped by malaria, and the disease that it causes.
And so there is great interest to the US Army, who puts troops in harms way,
in places where malarial transmission is endemic, to find new treatments.
Chloroquine is one of the wonder drugs of its time.
It was very cheap to make, very bio-available, and extremely potent against Plasmodium falciparum.
This was the drug of choice for a long time.
But unfortunately, due to misuse, and frankly, overuse throughout the world,
it became useless in South America and Southeast Asia,
and then resistance spread worldwide.
Which is why, in the 1970s during the Vietnam war, Walter Reed, the US Army, once again embarked on large screening programs.
Out of which came the new drug mefloquine.
Also known as lariam.
Mefloquine has been the mainstay for the use against drug-resistant parasites for some time.
Although now, there are parasites, again spread worldwide,
that have shown mefloquine resistance.
This is also a drug that is not as cheap or easy to use as chloroquine,
and so it is not ideal.
Out of the very same screening efforts that brought us mefloquine,
also came halofantrine.
This is a drug that was being investigated during the 1980s for use,
it was shown to bypass resistance to chloroquine and mefloquine resistant parasites.
Yet, halofantrine also has its issues. Primarily, cardio toxicity in certain individuals.
And so, it cannot be considered as a drug for ultimate widespread use.
Now, we are here in the 1990s, and the drug of choice for researchers to investigate is artemisinin.
Artemisinin is a compound that was originally discovered in a Chinese herbal remedy,
as part of a screening program on the part of the Chinese army,
and was later validated by Walter Reed in the US Army and others.
Now, as you can see from this timeline,
over the last 400 years, and these are not all the malaria drugs,
but over the last 400 years, there has been very few compounds developed for malaria.
And that is because malaria is endemic in the poorest parts of the world.
And there is not a very large profit incentive for major pharmaceuticals to develop.
This is beginning to change,
now with the advent of greater philanthropy for malaria research and therapeutic development.
Yet, I want to impress upon you,
that very few drugs are developed,
every year or even every decade
for anti-malarial use. And, I should also mention that the days of mono-therapy are over.
It is not possible for us to rely on a single drug,
to help eradicate this scourge. And from the lessons of HIV and other infectious disease,
we have learned that to bypass resistance,
or to lower the probability that resistance will occur in new parasites,
we must used drugs in combinations.
And so, artemesinin is being used in combination.
This is a formulation called Coartem,
which is a mixture of artemesinin and lumifantrane, another drug,
That can be used in combination
to help lower the probability that parasites will become resistant to this drug.
Now, these compounds are not easy to make and not cheap to make,
which is why there is limited availability of Coartem
throughout the developing world right now.
But if we are ever to hope to control malaria,
we need to treat people that are sick, and we need combination therapies.
So, a large emphasis of research in the malaria community,
and in my lab, is to help try to develop new, cheap,
bio-available, non-toxic anti-malarial therapeutics.
So the other way to control malaria of course,
is to block the route of transmission.
Or at least reduce the risk of transmission. Which you can see here is a mother and her child,
sleeping under an insecticide treated bed net.
And this is a very effective way to prevent transmission.
And of course, the bed nets need to be maintained,
and the insecticide needs to be re-applied to the bed net, with a certain periodicity.
Therefore, this cannot be the only method of choice for control of the vector.
Sense leaving the responsibility of the implementation of such a public health policy to the individual,
is most likely not going to be successful or sustainable over the long run.
Now one of the primary weapons against the insect,
the vector that transmits malaria, the Anopheles mosquito, of course is insecticides.
And the most infamous insecticide of all is DDT.
DDT, or dichloro-diphenyl-trichloroethane,
is of course one of the most infamous insecticides ever applied.
And this is because, used inappropriately or irresponsibly,
for agricultural crops spraying,
can result in leakage of this compound into the environment and the ecology.
Causing detrimental effects to many species of birds in particular.
However, DDT is very cheap, very safe for humans,
and can be applied indoors, inside residents and dwellings,
where mosquitoes might land after taking a blood-meal.
And used in this conservative fashion, can prove to be a very effective weapon,
against the vector. However, because of worldwide bans against the use of DDT,
there has been decreasing use of this compound,
and the effects of decreasing use of DDT are shown here.
So in blue, are indoor residual house sprayings in South America,
as you can see, as a function of time,
going into the 1970s here, the number of dwellings sprayed decreases.
And in the red bars, shows relative number of malaria cases per year.
And so what you see is a very clear anti-correlation
between the use of DDT and the increased prevalence of the malaria parasite in South America.
And this holds true for other parts of the world as well.
And so, as a result, there are new recommendations on the part of the World Health Organization.
Basically, in 2006, the W.H.O. has said effective implementation
of indoor residual spraying with DDT, or other recommended insecticides,
should be a central part of national malaria control strategies,
where the intervention is appropriate.
And so, without the use of insecticides, we think, basically,
that the battle against malaria will be very difficult indeed.
If not totally intractable.
So to summarize, controlling malaria requires certain things.
We need a new generation of anti-malarial drugs that can be used in combination.
Again, the days of mono-therapy, single drugs, are over.
But we need combinations of cheap, effective, non-toxic, easy to make drugs.
This must be supplemented by an organized healthcare delivery system.
The infrastructure in countries that have endemic malaria
must be subsidized to be able to distribute such effective medications.
If we don't treat sick people, we do not break the chain of transmission.
Furthermore, we need sustainable vector control.
Either through insecticide treated bed nets, indoor residual spraying,
or, ecological means, such as draining swamps and so on.
This could hopefully one day be supplemented by vaccine development.
As I said before, there is no vaccine in existence today
with an operational impact against Plasmodium falciparum, or the other three Plasmodia
that cause malaria.
Yet, we can hold out hope, hopefully,
that a vaccine will be developed to help eradicate this scourge.
Without these elements, the battle against malaria will continue.
And that is going to be a big problem.
So, hopefully you have enjoyed this presentation,
and background about malaria, the disease, and it's parasites.