How Vaults Could Revolutionize Cancer Treatment and Gene Therapy

Today, Julia B, a student at Detroit Country Day School, dives into the fascinating world of vaults, a mysterious cellular organelle that has scientists scratching their heads. Julia shares her extensive research journey that spans topics from Alzheimer's genetics to water quality. She highlights the accidental discovery of vaults back in 1986, which are intriguing due to their simple structure and the puzzling absence in certain organisms. Despite their simplicity, the function of vaults remain unclear, yet they show promise in medicine, particularly in cancer therapy and gene therapy. Julia discusses how vaults could revolutionize treatment by acting as nanocontainers for delivering therapeutic proteins and DNA, potentially leading to more effective and comfortable healthcare solutions.

Episode Transcript

(00:03):
Hello, My name is Julia Bergiaand I'm a junior at Detroit Country
Day School.
Over the past three years,I've dedicated a lot of my time to
science and scientific research.
I've done projects on thegenetics behind Alzheimer's, changes
in water quality variableswith precipitation, and optimizing
nutrition standards forcompetitive rowers.
Although these topics may seemincredibly disconnected at first,

(00:24):
I've begun to see thateventually all branches of science
end up fitting together likepuzzle pieces, at least when you
zoom out far enough.
But every once in a while youfinish a puzzle and end up with a
piece left over.
And that's the situationscientists have found themselves
in after discovering acellular organelle called the Volt.
In 1986, Leonard Rohm and hiscolleagues were trying to isolate
cellular vesicles in a lab atUCLA when they found something contaminating

(00:47):
their samples.
It looked a little somethinglike this.
The contaminant was a particleabout three times the size of a ribosome
made of proteins and rna.
This particle turned out to bea newly discovered cellular organelle,
which Roam's team named theVolt because its shape resembled
the vaulted ceilings on cathedrals.
Rome and his team quicklyshifted their focus to vaults and

(01:08):
began to do more research.
They found that vaults arehighly conserved in eukaryotes, which
means that they're found inmost eukaryotic organisms, with very
few differences betweenspecies in terms of their structure,
function or genetic code.
However, they are notablyabsent in fungi, plants and organisms
like yeast and flies.
In addition to being highlyconserved, it also turns out that

(01:28):
vaults have very simple structures.
They're made up of only threedifferent proteins and one very short
type of RNA.
The outer shell is made of 78copies of a major vault protein,
or MVP, which attach to oneanother in a circular pattern to
form the outer shell of the vault.
MVP is highlighted in red onthis picture and you can see how
the different strands interactwith each other to form a shell.

(01:50):
The inside of the vault ismade out of three components.
The first is vault RNA or VRNAat the top and bottom of the structure,
which interacts withtelomerase associated protein 1 or
TEP1.
Vault poly ADP ribosepolymerase, or VPARP is a circular
protein that binds to theinside of the NVP proteins, stabilizing

(02:10):
the structure which finalizesthe shape of the organelle.
The Volt's top and bottomhalves can come apart at acidic pHs
or at high temperatures,releasing releasing the internal
contents of the vault.
Despite knowing a lot aboutits structure.
Scientists are still unsure ofwhat the function of the vault is.
Multiple studies have beendone about the role of vaults in
multidrug resistance and intumor development.

(02:31):
Scientists have found thathigh MVP expression is typically
correlated with aggressivecancer tumors and poorer outcomes,
which indicates that MVP mightplay a role in drug resistance.
MVP also regulates cellularpathways concerning cell survival,
growth and apoptosis or celldeath, all of which are incredibly
relevant to the study andtreatment of cancer.

(02:51):
However, a key study done byMariecki Masink and her group of
researchers suggests thatvolts and the major Volt protein
may not play as significant arole in multidrug resistance as some
scientists may think.
In the monumental 2002 study,a group of researchers removed the
gene coding for the major Voltprotein MVP from a group of mice.
Not only were the micecompletely fine, but they also didn't

(03:14):
exhibit a higher or lowerresistance to cytostatic agents or
the drugs that the scientiststested them with.
This study indicates thatvolts are not necessary for eukaryotic
life, nor do they play asignificant role in drug resistance.
This discovery has stumpedscientists for more than 20 years
and is still being cited byresearch teams to this day.
However, just becausescientists can't seem to figure out

(03:35):
what vaults do doesn't meanthey can't try to put them to good
use.
In 2001, Rome, the vault guy,decided to try implementing an MVP
gene from rats into moth cells.
Moths are insects, so theydon't produce vaults or any of their
components naturally.
But after receiving the MVPgene, they were able to produce the
major Volt protein despite thefact that they themselves did not
produce volts.

(03:56):
Even more interesting was thefact that the moth's NVP proteins
assembled into normalfunctional vaults, each even without
VRNA, VPARP, or the TAP1 genes.
This monumental discovery gavescientists a way to create simple
synthetic Volts and sparkedcountless research projects about
how vaults can be used in medicine.
Because they're made ofproteins, vaults act as perfect nanocontainers

(04:18):
for a variety of molecules,including drugs and enzymes.
Roam is currently researchinghow vaults can be used in cancer
therapy to deliver CCL21 to cells.
CCL21 is a signaling proteinthat starts an anti tumor response
in cells, helping our bodiesfight cancer.
This therapy usually requiresrepeated injections of CCL21 into
cells, which is inefficientand definitely uncomfortable.

(04:40):
Rome is raising money to starta project that tests whether vaults
can be used to enclose CCL 21.
He thinks that vaults might beable to carry this protein into a
patient's body and slowlyrelease it into their cells, Eliminating
the need for injections andmaking the treatment much smoother
and more comfortable.
Vaults also have the potentialto solve one of the biggest problems
in gene therapy.
The development of thesetherapies has been one of the most

(05:03):
influential discoveries ofmodern medicine.
Through this treatment,scientists use viruses to transport
pieces of DNA or RNA intocells, which can then be used to
make proteins, Helping peoplewith genetic mutations manage their
symptoms.
However, using viruses astransport vehicles presents some
issues, Mostly because ourbodies have gotten pretty good at
defending ourselves againstthem and can't always tell the good

(05:24):
viruses from the bad viruses.
David Curiel, a gene therapyresearcher at Washington University,
thinks that putting theseviruses inside volts may solve the
problem.
Because volts are naturallymade in our bodies, they're unlikely
to trigger immune responsesthe same way that viruses do.
By hiding viruses from ourimmune system in volts, researchers
might be able to safelydeposit life saving genetic material

(05:46):
directly into our cellswithout triggering an immune response.
So vaults could berevolutionary in the field of medicine.
But that's not all they'rebeing limited to.
Vaults are also being testedin the context of environmental science.
Some experiments were donewith synthetic volts to test whether
they can control the releaseof enzymes that can help break down
groundwater pollutants.
A research team led by AngeliLoth showed that using vaults as

(06:08):
transports actually helpsstabilize these enzymes, Allowing
them to work faster and moreefficiently in cleaning up our groundwater.
I've done a bit of my ownresearch testing water quality variables
in a river near my house.
So to hear that a cellularorganelle that was accidentally discovered
almost 40 years ago is nowbeing used to improve water quality
was incredibly interesting.
In conclusion, vaults abilityto act as biological nanocontainers

(06:31):
Means that they can be appliedto a wide range of scientific problems,
Both biological and not.
Vaults are still a scientificmystery, but they have the potential
to be an incredible success story.
Sometimes that last remainingpuzzle piece can be the key to a
whole new world of possibilities.