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So, say you were getting sick.
Like, I hope that you’re thriving right now, but let’s just imagine that you got sick,
and you went to the doctor for some medicine.
You’d hope that the medicine your doctor gave you was developed carefully
and responsibly by scientists studying the specific disease you have.
And you’d be right.
Mostly. Probably.
Certainly, by the time a drug gets to clinical trials, the process is really robust.
But sometimes, at the just-starting-out level, researchers developing new
treatments aren’t actually testing them on the illnesses they aim to treat.
Completely by accident, they are studying the wrong cells in Petri dishes
that have become contaminated.
And when other researchers cite that flawed work not knowing it is flawed,
it becomes entrenched.
And this is happening all the time.
How could so many researchers make such a basic mistake?
Well let’s explore the answer to that and how they can fix it.
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Human cell lines are groups of human cells that are modified to grow
indefinitely and survive outside of a human body.
Think of like every stock video of a researcher
peering intently at a Petri dish of pink stuff.
There’s probably one on the screen right now.
This is what scientists call cell culture or tissue culture.
The first human cell line was created in 1951,
from cervical cancer cells taken from 31-year-old Henrietta Lacks.
These cells were taken without her consent, and while further discussion of that
is outside the scope of this video, it is also already an excellent book
that we will link to down in the description.
Now typically, cells only survive for a few days after they’ve been sampled.
But the cells from Ms. Lacks’ tumor behaved differently.
The cells retrieved from a biopsy were super hardy,
and very easy to grow, making them ideal for researchers to test on.
The doctors found that by mixing them with blood plasma,
they could keep the cell line going and going, and going,
meaning they had a virtually infinite supply of new cells for experiments.
Despite being created over 70 years ago, the HeLa cell line is still used today,
and it’s been central to many massive medical breakthroughs.
Polio vaccines, IVF, our understanding of cancers, drugs for herpes…
just to name a few.
The knowledge gained from deriving HeLa cells
allowed scientists to develop more cell lines.
With those, they could closely study and test treatments on other diseases,
understand gene functions, create artificial tissues, and more.
In modern labs, cell lines are a very important tool,
because they provide an unparalleled way for us to
test things like medicines on real, complex biological systems.
And having multiple kinds of cell lines,
derived from multiple kinds of tissues, means researchers can
choose the one that’s most relevant to what they’re interested in.
Cell lines may or may not be models of a specific disease,
but they're derived from a specific tissue, so they still work like a tissue.
At least, enough to help understand how that tissue works.
So if you're studying insulin secretion for diabetes research,
you probably want pancreatic cells, for example.
Using cell lines also means that you don’t have to start your research
in humans or animals right off the bat.
Since the cells are alive and doing cell things, you can test how they’ll respond in
your experiments quickly and easily without involving any, like, living organisms.
That might, for example, get you as far as a drug candidate
that you can then test in animals and, if all goes well, on humans later on.
And it’s not just drug development.
Every detailed little “how does molecule A work with molecule B” experiment
that molecular biologists do probably needs cell lines at some point,
so they’re a huge part of how we understand everything in biology
that’s smaller than a bacterium.
Cell lines are even cost-effective compared to other techniques,
which is always a plus when you’re trying to
make your research budget go as far as possible.
Researchers can make their own cell lines,
or they can buy them from other private companies or non-profit cell banks.
So cell lines are ridiculously useful.
It is not too bold to say that biological research
as we know it in the 21st century would not exist without them.
But there is a problem.
One that makes cell line research really difficult for other scientists to reproduce,
slowing advances in the field.
Contamination.
There are two types of cell culture contamination.
The first is by chemical contaminants;
things like detergents, toxins, or the occasional bit of debris.
The second is biological.
When they’re inside our body, cells usually have a whole immune system
to protect them from things like bacteria, mold, and viruses.
But isolated in a little dish, infection can take hold of a cell line culture,
damaging them and ruining the whole experiment.
Though it is a pretty common hurdle, good,
sterile lab technique can usually keep this issue at bay.
However, the biggest, most problematic biological contaminant in cell lines is cells.
Not the ones that researchers are trying to grow,
but other cells from other cell lines that quietly outcompete
and replace the cells researchers think they are growing.
This is not a new problem.
Scientists first noticed this happening in the 1950s.
Researchers began to note that many cell lines labeled as all kinds of species,
from hamsters to ducks, were not.
Instead, they were all either human or mouse cells.
And it did not stop then.
HeLa is actually a big culprit for taking over other cell lines,
but it’s far from the only cell line that likes to
set up shop where it’s not supposed to.
When a contaminating cell finds its way into a cell line,
by hitching a ride on a glove, from airborne particles, or otherwise, if it grows faster
than the intended cell culture, it can outcompete and eventually replace it.
That’s just because of how things grow.
If Cell 1 needs less time to divide than Cell 2, its numbers are going to double
and double again and again faster than Cell 2, and pretty soon,
it crowds out the competition.
And this isn’t the sort of thing that’s easily spotted under a microscope.
Animal cells are typically all kinds of blobby, so there’s
not really an instant visual give-away that your petri dish has been invaded.
Before you know it, you’re testing your diabetes treatment
on a cervical cancer cell line.
Those are different kinds of cells, with different specializations.
Cervical cells were never going to make insulin,
though cancer cells admittedly do do what they want.
Even so, you’re barking up the wrong tree.
This is not a rare, isolated issue.
It’s global, and it’s persistent.
Research has been conducted to try and piece together just how widespread
this issue is, and how much research from years gone by is
probably completely invalidated by contamination.
Some researchers estimate that as many as
18 to 36% of cell lines are contaminated.
That is hundreds of millions of dollars worth of research affected.
Research from 2002 found that the WSU-CLL cell line,
which is meant to be a cell line for chronic lymphocytic leukemia,
was actually REH, a cell line derived from acute lymphoblastic leukemia.
This means that WSU-CLL is mislabeled,
and doesn’t reflect what the name says it is.
So researchers who think they’re studying one type of leukemia
are actually getting a different one.
That might seem like a small difference, but small differences matter in science.
Different cancers are driven at the molecular level by different genes,
so if you want to find those genes and understand how they work,
you need the right cancer model.
Of course, once this oversight was identified,
every scientist everywhere threw out their WSU-CLL cells
and moved to an actual model of chronic lymphocytic leukemia.
Except no they didn’t.
Some organizations, like The International Cell Line Authentication Committee,
or ICLAC, are on the case, promoting awareness to fight this issue.
ICLAC followed up on this with a case study,
and found that of 27 articles using WSU-CLL, 24 referred to it incorrectly,
seemingly unaware that the cell line was contaminated.
And those 24 articles were cited a total of 848 times.
And those studies were cited by other studies in the literature, and so on,
meaning studies using the wrong cell line have become basically accepted as fact.
Same for studies using the other 535 contaminated
cell lines already identified by ICLAC.
Opinions among scientists vary about exactly how flawed this makes those papers,
but most will at least raise an eyebrow.
And researchers are rarely required to prove that their cells
are the ones they think they are.
Only some journals, like Nature, ask authors to
confirm they’ve checked the identity of their cell lines.
And that doesn’t really do much for the papers already out there being cited.
The findings coming from these potentially flawed studies have real world impacts.
Clinical trials proceed from evidence gathered from the cell line studies.
A lot of early clinical trials end in failure,
so it makes sense to build them on the best possible foundations.
Otherwise, you risk sending whole labs of scientists and doctors
on wild goose chases for months on end,
not to mention the patients who put their health on the line
to volunteer in these studies.
A great example of this is INT 407,
a cell line originally derived from intestinal tissue.
This cell line is used by many researchers who look at Crohn’s disease
to test treatments and make observations,
since Crohn’s affects the intestines, so it makes sense to use an intestinal model.
Except it’s not intestinal cells anymore.
That cell line has been taken over by HeLa: the cervical cancer cell line.
Vendors for INT 407 specifically state that this cell line
is now indistinguishable from HeLa.
It’s no secret.
Now that’s not to say that researchers haven’t made great progress
when it comes to Crohn’s disease, because they have,
and we couldn’t find any clinical trials that specifically
said they failed because someone used the wrong cells.
But a 2021 meta-analysis also didn’t find any papers referring to INT 407
as cervical cancer, and hundreds referring to them as intestinal.
And maybe it’s just me, but that doesn’t seem like
the way we should be studying intestines!
So now you see this problem and you see that it is a big problem.
Where do we go from here?
Is all cell line research useless and doomed?
No. Of course not.
This problem is frustrating, but there are best practice guidelines
that can help researchers verify the integrity of their data.
The first vital precaution is making sure researchers
get into good habits when handling cells.
That means handling just one cell line at a time,
labeling each cell culture with the name of the cell line and relevant info,
like the date it was last used, and making sure all equipment is sterile.
No double dipping with different samples into the same liquids,
discarding used pipettes properly, cleaning workbenches with
70% alcohol before and after using them, that kind of thing.
But even with all the caution in the world, contamination can still happen.
And since it’s not typically easy to spot, we need to get more technological.
We need to get more CSI.
That’s where DNA analysis, like STR sequencing, comes in.
STR, or Short Tandem Repeat, sequencing decodes specific highly-variable
regions of DNA called, you guessed it, short tandem repeats.
These are strings of repeated DNA bases.
They make up around 3% of the human genome.
These regions are so variable that they actually differ between individuals.
So scientists can use the number of repeats like a kind of fingerprint.
Once the sample has been sequenced,
particular repeats can be compared to a database of cell line DNA.
If the number of repeats in your sample matches
those listed against your intended cell line’s database entry, perfect!
That means that the cells in your cell line genetically
match with the cell type you intended to work with.
All is well.
At least for now. Contamination can happen fast,
especially in a lab that handles multiple cell lines,
so regular retests are recommended.
And this might not work for some older cell lines,
since a lot of the original samples weren’t kept.
Still, it’s a good way to make sure that you’re
doing the research you think you’re doing.
Despite how easy it is to test, though, many labs and authors elect not to.
Perhaps due to lack of funds, lack of time, or just lack of will,
since many journals won’t verify whether they’ve checked anyway.
But the cool thing about science is when there is a problem,
you can fix it with more science.
Admittedly, organizations like ICLAC are asking researchers to be
a little more proactive; just because no one’s making you check your cells,
doesn’t mean you don’t have to.
But it’s also pretty cool that the more we learn about cells,
the more we learn about how to use them to do science responsibly,
like knowing there’s a stretch of DNA that can
tell you if you’re doing the right experiment.
That helps us keep science reproducible,
which is key to making sure that the knowledge that we have is
correct and also to making sure that anyone, anywhere, can participate.
And if we can do that with cell cultures, which have provided
such massive wins for the medical and biological fields, we all stand to gain.
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[♪ OUTRO]