Translator: Gabriella Patricola Reviewer: Shlomo Adam
I grew up with a healthy twin brother, Scott David Shannon.
We loved our mum and our grandparents.
We had many childhood friends to climb trees, go swimming,
and play 'hide and go seek' with.
We enjoyed school but we enjoyed vacations more.
As twins we were close.
We were sometimes sworn allies and other times serious competitors.
As we began to change from children into teenagers,
we drifted apart.
In fact, Scott was drifting from everyone, becoming focused on his motorcycle
and on listening to rock music.
At age 16 I remember watching him zone out during trigonometry class.
Now that may seem like normal male adolescent behavior,
but not for Scott,
as he and I were both trying for 100% on the state math exams.
So I was puzzled, 'Why isn't he paying attention?'
Later, I remember him begging Mum to allow him to quit high school
and he shied away from even close neighbourhood friends.
I didn't realise it at that time,
but I was watching my twin brother begin to descend into madness.
Mum allowed us, allowed Scott, to quit high school.
I was still in high school,
but she moved us to a neighbourhood town, enrolled Scott in a community college
and bought him a car.
And most times things felt quite normal,
but Scott did spend a lot of time in his room
claiming to be receiving special voice messages,
and this was well before iPhones.
In fact, there was no phone in his room at all.
I remember, over eating pieces of our 17th birthday cake together,
that Scott started saying very strange things,
like, 'You are not my sister. You are the daughter of the devil'.
We tried to talk Scott out of these bizarre beliefs and others like it,
but mostly we dismissed his irrational speech
and hoped it would go away.
Instead, things turned from bad to worse one night
when he shoved my mum up against the wall, started calling her names
and began to choke her.
Mum said, 'Call the police', so I did.
The police came, handcuffed my brother, arrested him and threw him in jail.
At the station,
in front of my mum, he told the police,
'She is not my mother. My mother is Yoko Ono'.
At this moment in time I didn't recognise my twin brother
as the same person I knew and played with as a child.
It was only after his arrest
that Scott was diagnosed with schizophrenia.
Schizophrenia was a label I had not encountered.
Schizophrenia was a label that would change my life.
I didn't know that one percent of the entire world's population
suffers from schizophrenia.
I didn't know that auditory hallucinations and delusions were common features
of the disease.
I did not know that there weren't medications
that could treat schizophrenia satisfactorily.
Nor did I know that my twin brother
would have to spend time in a state mental institution
where he would feel poisoned by the first antipsychotics he received.
It took me months to years to realise just how sick Scott was
and that he wasn't going to get better any time soon
and that something major had to be done to bring Scott back to his former self.
I was convinced that having schizophrenia was not Scott's fault,
was not my mum's fault,
but his illness had a biological basis just like diabetes does.
So my journey to understand this illness,
my search for answers and my quest for a cure began.
That was 30 years ago.
What clues did I have that guided me in my quest?
I had three, from my own experience with my twin's illness,
hardly objective, but real to me.
So these three clues, what were they?
Number one: Scott and I shared the same womb,
so it was unlikely that Scott's schizophrenia
was due to an early embryonic event.
Number two: Scott was a normal kid, very bright, in fact, a boy genius.
So, his brain was developing just fine during childhood.
Number three: something major had to have happened to Scott
during adolescence,
whereas I appeared to be spared from this terrible event.
The obvious difference?
He was a male and I was a female.
So this led to my curiosity around sex differences in schizophrenia.
And I learned that males and females experience schizophrenia differently.
Males tend to get schizophrenia earlier on in life,
be more treatment-resistant and have more severe symptoms.
Women with schizophrenia have worse symptoms
at times when oestrogen levels are low.
This led me and others to consider and postulate
that somehow oestrogen was protective against schizophrenia.
At this point in my story I must teach you two very important things
about how sex hormones act in the human body and the human brain.
Number one:
testosterone, that we tend to think of as the male hormone,
gets converted quickly and directly into oestrogren once it hits the brain.
Number two: sex hormone action is not only controlled
by the levels of hormones circulating in your blood,
but on the location, the amount and the type of the oestrogen receptor
that's in your brain.
Now, these receptors are proteins
that are necessary to detect the hormonal signal,
capture it and transmit a meaningful message to the cell.
Since Scott's schizophrenia was impacting his ability to think clearly
I hypothesised that these oestrogen receptors
may be found in areas of the brain responsible for reasoning and language.
However, I ran into huge road blocks in the field,
where eminent neuroscientists were saying,
'There are no oestrogen receptors in the cerebral cortex'.
It took me ten years to develop the sensitive molecular tools
to provide convincing evidence that the oestrogen receptors
were in the brain areas responsible for rational thought.
Now, during these experiments, I found, surprisingly,
that the male brain and the female brain have equal levels of oestrogen receptor.
So, males listening today,
while you may not feel very in touch with your 'inner female',
your brain neurons sure are!
(Laughter)
So, in terms of the damaging event in schizophrenia,
I hypothesised that both males and females with schizophrenia
may be less responsive to oestrogen
because they have lower than normal oestrogen receptors
in their cerebral cortex.
However I found that oestrogen receptors were equal
in schizophrenia sufferers and in healthy controls.
At this point, most scientists would have thrown in the towel
on the oestrogen hypothesis,
but I wasn't ready to give up, so I was forced to rethink my strategy.
During my long effort to prove
that oestrogen receptor was alive and well in the cerebral cortex,
I discovered there wasn't just one oestrogen receptor,
but there were a dozen different flavors of oestrogen receptors
in the cerebral cortex.
This again was greeted with skepticism by the scientists
who wanted a nice tight package, 'one gene, one receptor'.
Anything more than that was considered artifact.
So my findings were originally dismissed.
However we now know that this type of variation is common,
and is in fact the rule for human genes.
In the case of oestrogen receptors this was important,
because it allowed for a lot of diversity in how each person's brain
could respond uniquely to the same hormonal signal.
So getting back to my quest to figure out how is the oestrogen receptor altered,
or how is the brain response to oestrogen changed in the people with schizophrenia,
I asked, 'Is the type of oestrogen receptor different?'
And, bingo!
I found that in the brains of people with schizophrenia,
they were more likely to express a mutated or altered form
of the oestrogen receptor.
I was 39 years old,
I was working at the National Institute of Health in America,
I was a postdoctoral fellow, and this is my Eureka moment.
I finally figured out how the oestrogen receptor was broken,
what a molecular basis for an abnormal response
to oestrogen could be.
Once you have the critical information on how the oestrogen receptor is broken
you can now determine ways to fix it.
Meanwhile, my brother was going on and off various antipsychotics,
and at certain points he did feel better.
One day he said, 'Cindy, can I come help you in the Lab'?
And I knew he had the motivation and the smarts,
but I also knew he lacked the education,
so I suggested that he goes and studies general chemistry first.
I was really proud of him for finishing his first semester of general chemistry
with above-average grades,
but then social anxiety took over.
He couldn't focus on the material or sit for exams,
so he never finished his second semester of general chemistry.
I was getting really frustrated and impatient
that the research was taking so long
and I really wanted to help Scott,
and people like him were denied their opportunity in life,
due to having schizophrenia.
I couldn't offer my brother his dream job, but then I was offered mine,
altough it came with challenges.
I had to move from Washington DC all the way to here, Sydney, Australia.
It also came with tremendous opportunity
and that was to work with my husband, Dr. Thomas Weickert.
He's a cognitive neuroscientist trained in clinical trials,
and making this move allowed us to collaborate and work together
and to finally translate those oestrogen receptor discoveries I made at the bench
into a novel treatment for people with schizophrenia.
Tom and I agreed that we want to stimulate the oestrogen receptor.
We also agreed that we want to try to improve cognition
in males and females with schizophrenia
because this is one of the most treatment- resistant aspects of the disease.
Tom and I also agreed that we didn't want to make a brand new compound.
Because we were lousy organic chemists,
we didn't have a billion dollars hanging around,
and we didn't want to wait a couple of more decades.
We wanted a medicine that we could use in the here and now.
So Tom and I chose SERM, a selective oestrogen receptor modulator.
This drug is already in use for osteoporosis,
thus we repurposed the available drug that was already known to be safe
and we used it in schizophrenia.
Tom and I wrote our first federal grant and our clinical trial was born.
Meanwhile, back in my childhood home, my brother was slipping from me.
It was harder to make our regular calls work
and he had to e-mail me with his worries and requests,
which just it isn't the same.
Scott's health got worse,
and he developed diabetes and put on weight.
I was the one he relied on,
and I was getting harder and harder to reach.
So I did make it home in between scientific meetings for a few weeks,
to visit my family,
and I told Scott about the trial
and we discussed how wonderful it was going to be
when we licked this damn disease,
and he voiced he wouldn't be afraid to travel
and see the world with me.
And I imagined him being able to pursue his interest in math and engineering.
During this break, my family celebrated Thanksgiving,
where we eat roast turkey, stuffing, and pumpkin pie.
It's our family's tradition to go around the table before we eat
and say what we are thankful for.
My brother said, 'I'm thankful for my family, my home, my dog' -
we did have a great hound dog, Mookie - 'and my car'.
When it was my turn, I said, 'I'm thankful for you, Scott,
because you've given meaning to my life'.
Indeed, he gave me something to live for, to find the cure for schizophrenia.
Scott won't have the chance to travel the world with me,
or to get that higher degree, or even try the SERM,
because he died,
on Thanksgiving night.
It makes me extremely sad that I can't help my brother.
But I chose to fight this damn disease, to continue to fight.
And today, today I'm more hopefull than ever
that we can beat my brother's illness.
The clinical trial took three and a half years to complete,
with over 80 people enrolled in Sydney and Adelaide.
I'm pleased to report the positive, preliminary data
where with six weeks of SERM therapy,
we found an improvement in memory and attention.
Perhaps, with these renewed cognitive skills,
people will be able to resume studies, gain more meaningful employment
and have more confidence in daily life.
It feels so amazing to be here at this place, in this time.
Am I really in the Opera House? Pinch me!
To be here at this place, in this time, and sharing with you
that finally we have a ray of hope that the molecular pathology
that we've been digging up for the past 20 years
can be turned into rational drug development
for males and females with schizophrenia,
that we can succeed where many large drug companies have not,
this gives tremendous momentum to our team
and I believe we can and we will cure schizophrenia now.
And I do hope for your support in this mission.
I'd like to remember my twin brother, Scott David Shannon,
for the man that he was
and the lives that he touched with his kindness and bravery.
(Applause)