Translator: Kathleen Trautwein Reviewer: Robert Tucker
As a kid, anytime someone would ask me what I want be when I grow up,
I would always respond with the same thing:
a biologist ...
and the President of the United States.
(Laughter)
To be honest, this was mostly because I share a birthday
with Charles Darwin and Abraham Lincoln.
(Laughter)
But in my six-year-old mind,
that was a perfectly logical way to pick a career.
And somehow it came true.
I am a biologist -
still working on that second one.
(Laughter)
But as a scientist,
I get to study some of the smallest, simplest units of life
and ask the most complicated questions.
And it's this methodical system of asking questions and testing answers
that really attracted me to basic research in the first place,
and has led me to become a stem cell biologist.
And now around the time
that my childhood self had settled on a career
was the first time that stem cells were being grown in a lab.
Nearly 20 years ago.
And this was met by a strong response
from the media and the public in general.
Dr. James Thomson
of the University of Wisconsin, Madison,
had figured out how to grow human embryonic stem cells in the lab.
And there were two opposing reactions to this news.
On the one hand,
medical professionals,
and patients suffering from degenerative diseases,
were excited at the prospect of what this meant for them.
But on the other hand, a debate ensued.
Just a couple of years before this,
there had been a ban on federal funds
for any research in which embryos were destroyed.
But, private companies could still pursue this work.
So, Geron, a biotechnology company founded in 1990,
funded Dr. Thomson
in his work to produce embryonic stem cells
from the excess embryos
that come about during in vitro fertilization.
These excess embryos are normally frozen
and stored at fertility clinics.
So, for a long time, the debate circled around this issue.
The two questions that were always asked were:
1) should we consider these frozen embryos a life,
and 2) if they are going to be discarded eventually anyway,
wouldn't it be better to use them for medical research?
Studying the simple units of life had led,
not only to exciting scientific questions,
but also to a challenging ethical one.
But what if we didn't need embryos to study stem cells?
What if there's a scientific solution to this ethical problem?
We'd be able to move forward
with work that could help us treat degenerative disease
without the ethical concerns.
And, about 10 years ago, that was no longer a "what if" question.
On the same day in 2006,
Dr. James Thomson and Dr. Shinya Yamanaka
published work
in two of the highest impact scientific journals,
announcing they could make stem cells from skin.
This work has been so impactful
that Dr. Yamanaka,
who did this originally with mouse skin as a proof of concept,
was awarded the Nobel Prize in Medicine in 2012.
Now the field of stem cells had two major tasks ahead of it.
In terms of the science, they needed to show
that these skin-derived stem cells were just as potent as the embryonic ones.
And in terms of the ethics,
we are still working on shaking off
this controversial reputation that's developed,
which is no easy task
after two decades of scrutiny and misinformation.
This technological advancement in stem cell research
is allowing scientists to study and potentially treat degenerative disease
all without the use of embryos.
And when Thomson and Yamanaka set out
to figure out how to make stem cells from skin,
they had to turn to their embryonic research
and ask the question:
What even makes something a stem cell?
And there's really just two things that make a stem cell special.
The first is that it has to be able to reproduce itself indefinitely
by dividing over and over again.
Our normal cells can't do this.
They can only multiply a certain number of times,
which is why we can't live forever.
The second characteristic is that stem cells are actually unspecialized.
They are kind of like a college freshman that hasn't picked a major yet,
(Laughter)
but, with the proper guidance and cues from its surroundings,
that stem cell can become any type of tissue in the body.
And we have ways in the lab
to take those stem cells and make beating heart cells,
active pancreas cells, or even active neurons.
[Corrects an error in delivery of talk.]
And it's clear why an embryonic cell
would need to be able to divide over and over again
and produce all of the parts of an organism.
But it is not so clear
how you can take an ordinary skin cell and make it act like an embryonic cell.
To understand this, it's helpful to think about
what these two things have in common.
And that is: the skin cell and the stem cell
both contain a full copy of our DNA at the center of the cell.
And our DNA acts as this giant instruction booklet
that our cells can go read, and transcribe portions of,
to figure out what they are supposed to be doing.
The trick is: cells only read the parts that are relevant to their function.
So, a muscle cell in your heart is going to transcribe
what it needs to know to contract,
whereas a cell in your pancreas
is going to read what it needs to know to secrete insulin,
and so on.
What Thomson and Yamanaka figured out
is that you can actually force a skin cell
to transcribe the parts that a stem cell normally does.
They do this using just four proteins,
which are appropriately called transcription factors.
What these do is get into the skin cell
and tell it to turn on genes
and produce proteins
that will allow it to divide over and over again
and produce any type of tissue in the body.
This process is now called reprogramming.
We have defined procedures in the lab
to take these reprogrammed cells and make whatever cell type we'd like.
And what my adviser, Dr. Dennis Clegg at UCSB,
was interested in
is how we could use these reprogrammed cells
to study blindness.
Dr. Clegg has been studying blinding diseases for many years.
He started with a disease called age-related macular degeneration.
This disease is the leading cause of blindness
amongst the elderly in the developed world.
At the time Dr. Clegg started this project,
scientists were using embryonic cells.
So, he and his team,
with a grant from the California Institute for Regenerative Medicine,
figured out how to turn those embryonic cells
into the type of cell in your eye that's destroyed by this disease.
From that work, he and a team
at the California Project to Cure Blindness
are currently in a phase I clinical trial
where they are actually transplanting those cells
into the eyes of patients with macular degeneration.
And unlike most stem cell clinical trials
which rely on embryonic sources,
there are in fact trials in Japan
that are using these skin-derived reprogrammed cells
in patients with macular degeneration.
And unlike the embryonic sources,
these cells are from the patient themselves,
which reduces the risk of an immune response.
Just like [in] an organ transplant,
[embryonic] cells introduce foreign material into the body.
What the reprogrammed cells do is reduce the risk of an immune rejection
and also expand how we think about personalized or precision medicine.
It's due to the advanced surgical techniques
that exist in the eye,
as well as good end-point parameters for measuring rescue of vision,
that cell therapies in the eye are really leading the rest of the field.
Unlike macular degeneration,
there are other blinding diseases that start when a patient is young,
like retinitis pigmentosa.
This is the most common form of inherited blindness.
It affects about 1 in 3,000 people.
These patients have vision when they're children,
but it starts with a loss of night vision,
followed by a gradual loss of peripheral vision,
and eventually can lead to total blindness.
On a personal level,
these patients have to cope with the fact that their sight will slowly evade them,
they will likely need to learn Braille,
train a Seeing Eye dog, or walk with a cane,
and lose some of their independence.
Currently, this diagnosis is a grim one, with little that the doctor can do,
leaving the patient with little hope.
But where we can look for hope is with reprogrammed cells.
This disease is caused by a mutation -
Oh, hello -
or simply a typo in the patient's DNA
that's causing the cells in their eyes to degenerate.
In fact, there are many different mutations
across dozens of different genes,
and any one of those can be enough to cause retinitis pigmentosa.
But until recently, we really were not sure
how some of these typos
were causing degeneration of the eye specifically.
And that's largely what my project is focused on.
During my second year of graduate school,
when I joined Dr. Clegg's lab,
they were focused on macular degeneration.
I can clearly remember the day I came into lab to find a paper on my desk
about an entirely different disease,
retinitis pigmentosa,
complete with a little note in the corner that said, "See me!", signed Dr. Clegg.
I walked across the hall to his office,
which on UCSB's campus is complete with a panoramic ocean view,
bookcases floor to ceiling,
filing cabinets stuffed with decades of Xerox research papers,
taxidermy animals everywhere you look,
(Laughter)
including a human brain preserved in a pretzel jar.
But upon entering, what I can remember most
is how excited Dr. Clegg was
about this brand new type of project he had for me.
Clegg has worked closely with Dr. Thomson over the years,
and Thomson's lab had produced reprogrammed cells
from a patient with retinitis pigmentosa.
This is where the potential of these cells really comes into view.
Imagine you're that patient,
maybe about 14 years old,
given the diagnosis of a degenerative disease
with no treatment plan.
But your doctor tells you,
if you are willing to give a skin sample,
scientists can make stem cells and functioning eye cells
to learn about and study your disease in the lab.
So, shortly after my meeting in the "taxidermy office,"
Thomson's lab sent us a frozen package full of vials of cells,
and each one of these little vials
contains millions of reprogrammed stem cells.
And there were some that had this mutation,
but then there were others for which the mutation had been corrected,
using a brand new gene-editing technology at the time, called CRISPR.
So for the past couple of years,
Dr. Clegg and I have been working on a disease model
where we take these mutated and corrected stem cells,
make fully functioning eye cells,
and then try to find the differences between the two.
Not only can we make one cell type at a time,
but we can actually produce entire small eyes in the lab,
shown here as a cross-section
complete with the DNA in blue,
light-sensing cells in red,
and a protein we know causes the disease in green.
We're doing this not just for the cells that I received,
but also for other mutations that can cause retinitis pigmentosa,
and other blinding diseases entirely.
These two incredible technological advancements,
skin-derived reprogrammed stem cells
and gene editing using CRISPR,
are allowing us and other scientists
to answer molecular and cellular questions about this disease
that the field has been struggling to resolve.
Let's be clear,
it will be a lot of work
before these technologies are widely used in patients.
My dream is for the future treatment of degenerative disease
to be a simple and straightforward process.
You could imagine a doctor takes a skin sample,
or maybe something less invasive like a cheek swab from a patient,
sends those off to a scientist
who can make as many stem cells as you'd like,
corrects any mutations,
and then bring the cells that the patient needs.
But, in order for this treatment to be a reality,
we need to make sure
we can make all of these different cell types efficiently,
that we can precisely edit the mutations,
and that we can safely transplant the cells
back into the patients.
And while this is in a somewhat distant future,
this technology gives me hope,
and, more importantly, it gives the patients hope
that future generations won't have to suffer
from the same diseases that they currently face.
And there's value in hope.
There's value in going to a doctor's office
and being given options rather than a grim diagnosis.
With the invention of reprogrammed cells,
we're learning that the ethical considerations of stem cell research
should no longer be a concern.
I invite you to embrace this technology fully,
so we can further our potential to improve lives and treat disease.
Thank you.
(Applause)