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Toxoplasma gondii is a single-celled parasite that causes a disease called Toxoplasmosis.
Infected cats can give the disease to humans when they shed cysts containing the parasite.
Toxoplasma infects many, many people worldwide.
The estimates range from 10 percent in certain populations to up to 70 percent of individuals in others.
While the infection stays dormant in most people, it can spread and become life-threatening
in people with weakened immune systems.
Toxoplasma is quite good at getting into places it shouldn’t be, like your eyes or your
brain, and once it’s there it focuses on eating and replicating as much as it can—
in the process, destroying those very important organs.
But Toxoplasma is also able to change into a dormant state and resist the immune system
for years.
There are all these open questions around how the parasite is able to evade the immune
system, how the parasite is able to survive for such a long period of time undetected,
and then how it is eventually able to reactivate from that state and cause disease in people
who become immunocompromised.
One key question is exactly how Toxoplasma controls its transformation from its fast-growing state
to its resistant, slow-growing form.
This process is called differentiation.
The form of Toxoplasma that first invades human cells is called a tachyzoite.
Tachyzoites are replicating very quickly, they’re infecting host cells, replicating
for a couple of days and then exploding that host cell and finding new ones
to invade.
But once inside a cell, the parasite can then differentiate into a second form called
a bradyzoite.
And what’s tricky about bradyzoites is that they actually encyst.
So they form a very resistant wall around themselves inside of your cells.
And they stop growing as quickly, which means that they don’t actually get targeted by
many of the therapeutics we would normally use.
Scientists have been trying to figure out what molecular mechanisms Toxoplasma uses
to control differentiation.
For some time it seemed that a number of proteins called transcription factors allowed the parasite
to activate genes needed to make the transformation.
The field had arrived at this consensus that because of the complexity of that differentiation,
it was likely dependent on several transcription factors working in unison, all contributing
minor effects to the overall transition.
But Lourido and Waldman suspected that there had to be a single main control switch for
this process, called a master regulator.
If you think about differentiation, it’s this massive change in life cycle.
You want to decide to differentiate and you want to commit.
And to do that you need to have a tighter set of transcriptional control for that process.
It’s kind of hard to do if you have that many players.
The researchers developed a strain of Toxoplasma that would signal when it was differentiating
by glowing green.
What I did for a lot of my early years of my PhD was get a reporter strain established
in Toxoplasma—something that would read out whether these parasites were trying to
differentiate or not.
Then they used the gene editing platform CRISPR-Cas9 to knock out a set of about 200 genes
that could act as transcription factors.
They looked to see if any gene seemed necessary for the parasite to differentiate.
And there was only one gene that, when lost, completely prevented the parasite from differentiating
into bradyzoites.
Almost nothing in these libraries has any effect on differentiation at all
except for this one gene that we found.
We’ve named it BFD-1, for Bradyzoite Formation Deficient 1.
We could show not only that it was important, that in breaking it we broke that circuit,
that transition from the acute state to the chronic state, but also that
upon upregulating it, we could artificially induce that switch.
And in my mind this is sort of where biology meets engineering.
Our ability to actually control that transition through the synthetic expression of that particular
factor really shows us that we’ve gotten it.
We’ve gotten the key bridge between those two different states of the parasite.
The master regulator of differentiation offers a new target
for treating chronic Toxoplasmosis infections.
Finding what we call the master regulator of this process was both surprising
and exciting, and I think it’ll help us really understand in a clinical scenario
how we can interfere with that process.
The findings highlight the importance of basic biology research in finding new ways
of attacking problems to treat disease.
I think basic biology is incredibly important to advance human health long term.
To combat something in a rational way, you really need to understand
how what it is you’re fighting works.
If you’re trying to understand how to stop a process or how to reverse chronic infection,
you need to understand how they got there in the first place.
So by doing this kind of basic biological research, we can identify what those
targets are, and by understanding the mechanism, you can really understand how to
try to interfere with or reverse that mechanism.