All language subtitles for 1-WPS Office2

For our opening address, I
have the great pleasure of

introducing our keynote
speaker, Dr.Randy Schekman.

Randy, welcome to the future.

Yes. Good morning from Berkeley.

Good morning.

Let me say a few words about
our keynote speaker today.

Randy Schekman is a professor
in the Department of Molecular

and Cell Biology at the
University of California, Berkeley,

and an investigator of the
Howard Hughes Medical Institute.

He studied DNA replication as a
graduate student at Stanford University,

and his current interest
is in cellular membranes.

In 2013, Randy Schekman was
awarded the Nobel Prize in Physiology

or Medicine for their discoveries of
the machinery regulating vesicle traffic,

a major transport system in our cells.

In addition to the
Nobel, his other awards

include the Gairdner
International Award,

as well as the the Albert Lasker
Award in Basic Medical Research.

Dr. Segment and his team are still
conducting research into the mechanisms

of the of traffic in the secondary
pathway of eukaryotic cells.

He served as editor
or editor in chief for the

annual reviews of Cell
and developmental biology.

I beg your pardon and the Proceedings
of the National Academies of Science,

and was founding editor and editor in
chief of the open access journal eLife.

Since 2018, Dr Schekman has
served as the scientific director

of Aligning Science
across Parkinson's Disease,

a major philanthropic
effort organized by

the along with the
Michael J. Fox Foundation

to identify molecular and
cellular mechanisms in the

initiation and progression
of Parkinson's disease.

If you have any questions
for Dr. Shechtman, I would ask

you, please, to post them here
in the Q&A box on this page.

All questions will be forwarded to
him after the conference and responses

will be published later this year
in the official conference report.

So without further ado, I
have the great pleasure of

introducing a keynote speaker
for today to see the future 2021.

Dr. Randy Schekman.

Thank you very much, Tony, and
welcome to my friends in the audience.

I'm going to divide my
talk into three subject areas.

The first will be a broad
overview of the of the area

of my research as it relates
to the current pandemic.

The coronavirus pandemic there is a
connection related to cellular membranes.

I'll again devote some time to
the issue of scientific publication.

Some of my concerns about how

scholars choose which
journals to publish it,

and the control that's exerted
by some of the largely commercial

enterprises in which many
investigators wish to publish their work.

And finally, I'm going to turn to another
topic, one that Tony just introduced,

and that is my personal and
professional interest in Parkinson's

disease and a very large
international collaborative program,

that I initiated at behest
of the Sergei Brin Family

Foundation in collaboration with
the Michael J. Fox Foundation,

to bring teams of investigators
together to try to get to the molecular

and cellular basis of this scourge
of mankind. Parkinson's disease.

Well, let's begin with a topic
of current interest to all of us.

This is a picture, a
cartoon view of the

outside in a slice of the
inside of the coronavirus.

Coronavirus looks very much
like a carrier that's found it

in all cells that have a nucleus,
a carrier called a vesicle.

But it's been designed by
evolution to convey this molecule, an

RNA molecule which is in the
interior of the virus for infection.

The outer surface of the
virus particle is a membrane.

You'll see a bit more about what
a biological membrane consists of.

It's a membrane that has lipids on its
surface, so it's kind of a greasy shell.

And most importantly, proteins, one
of which is called the spike protein,

that allows the virus
to engage a cell and

then enter the cell by
engulfing and process,

that allows the RNA to be
released into the interior of

a cell for its replication to
make more virus particles.

Now let's do just a very
brief primer on biological

membranes and how they
relate to the corona virus.

This is an image taken in an electron
microscope of a thin slice through a cell,

that reveals the perimeter or cell
surface membrane consisting of

two layers or a bilayer of lipid
molecules called phospholipids,

into which various protein molecules.

I indicated by Green
are inserted so that

part of the protein faces
the outside of the cell.

And another part of the protein
faces the inside of the cell.

This is a depiction that we now generally
appreciate about biological membranes.

They all consist of this kind
of fluid phospholipid bilayer

that's a kind of a has
the viscosity of a light oil,

and then membrane proteins
that impart unique personalities to

membranes and generate
particular functional qualities to a cell.

This, for instance, might be a
receptor, such as the receptor that I'll

tell you about that's responsible
for the uptake of the corona virus.

Now, this is a cartoon of a
typical cell, a eukaryotic cell.

This is a nucleus that contains
all of the chromosomes,

the 23 chromosomes that
constitute the human genome.

It's enclosed within a
membrane and envelope.

And in the outside the cytoplasmic
area, there are a number of organelles,

some of which may be part of the energy
producing machine called the mitochondria,

and others of which may be an
organ cell, such as the lysosome,

which is responsible
for degrading

macromolecules that are
no longer wanted by the cell,

and surrounding it all is another
membrane that is again a lipid bilayer.

This is in contrast to what
a bacterial cell looks like.

It's much smaller.

It doesn't have a nucleus
proper, but it has DNA.

It must allow the cell to
grow and divide, but it is

much less compartmentalized
than a eukaryotic cell.

We are eukaryotes.

Most of the organisms that we see
with our naked eye are eukaryotes.

Now this is a sketch
of the process that

cells use to manufacture
proteins for export.

This has been the subject of my
research research over many years.

Eukaryotic cells are
organized into compartments.

I mentioned the nucleus surrounding
the new nucleus is a network

of membranes referred to as
the endoplasmic reticulum or e-r.

And in many cells, these membranes
are studied with these green particles.

The color preferred
for this description the

green of particles, which
are called ribosomes.

Ribosomes are like the little
sewing machines in a cell that stitch

amino acids one next to two
another to make a polypeptide chain.

This may be, for
instance, a cell that such as

the cell in your in your
pancreas that makes insulin.

Insulin, then would start being
made by a ribosome such as this

threaded into this salmon
colored interior of this membrane,

and then in a series of steps,
is conveyed from one step

to the next to finally be
exported outside of the cell.

So of the twenty three thousand
genes in the human genome,

almost 30 percent of them encode
proteins that engage this process

and are delivered either to the cell
surface to intracellular membrane

organelles like the lysosome or
remain within this within this network.

It's a very elaborate process
that has been, as I said, the subject

of my work at MIT, many other
cell biologist over many years.

Now, how does this relate to coronavirus?

So here's a another image of the
virus, such as you saw in my first slide.

It's again, it's a little membrane
that carries a nucleic acid

inside, and then it has the
spike protein on its exterior.

This spike protein has a specific
affinity binding to one of our

own proteins on cells that has
a completely different function.

A protein that's called ACE2.

This protein serves a
normal purpose in our

body and the respiratory
canals of our body.

But the virus has evolved
to hijack this receptor and to

allow the virus to bind and
to be internalized into the cell.

Now what happens once it's in
the cell is really quite remarkable,

and it engages the very network of
membranes that I've just described.

Here, for instance, is another slice
through a coronavirus infected cell.

Here are the virus particles.

These are actual virus
particles binding on

the cell surface to that
ACE2 receptor molecule.

And they may then be swallowed
up internalized into these

structures when they are
compartmentalized in these structures.

The spike protein adheres to
the inner surface of this membrane,

in which the virus has been
engulfed and the membranes

surrounding the virus merges
with this organelle membrane,

to in a process that's
called membrane fusion.

And when that happens,
the interior of the virus, the

nucleic acid of the virus,
is spilled into the cytoplasm.

The rest of the cell and in the
cytoplasm, the RNA that constitutes

the genome of this virus is replicated
and more viruses are produced.

Now, the great triumph in
this first phase of the pandemic,

has been to realize the possibility
of taking an RNA molecule

called a messenger RNA
molecule that copies the information.

In part of the spike protein and
this RNA molecule, Imani can be

packaged into an artificial membrane
called a lipo, a lipid nanoparticle.

And these then are the
vaccines that many of you have

received from either
BioNTech or Pfizer or Moderna.

These RNA containing lipo lipid
like particles can be taken up by

the same process that I've just
described injected into the cell.

The RNAs can escape
into the cytoplasm, and

that RNA then will make a
piece of the spike protein.

It will not create a new infectious virus.

It will only make a part of
that spike protein that part

of the spike protein is
exported outside of the cell.

And that's what your
immune system recognizes

as foreign and generates
an immune response.

So this is a subversion of the
virus process that has been used by

biotechnology to engineer it quite
remarkably, successful vaccine.

Now, that's it for just a
very broad view of the

kind of cell biology that
we do in my laboratory.

I want to turn my attention
for a little while into

what scientists must
do to publicize their work,

and that is to publish in journals that
other scholars, colleagues can see.

You may be aware that during the

pandemic, a lot of the
literature on SARS-CoV-2,

the coronavirus and COVID 19 has
been published openly in commercial

or noncommercial journals
and made available for all to see,

irrespective of your location in
an academic institution or not.

This has been a bright light
on a process that is often held

behind a closed door that
most of you are not accessible to,

and this is a, I think, a big challenge.

Most of the research
that's conducted on

diseases such as COVID
is with government funds,

and the work that gets published
as a result of this taxpayers fund is in

then published in journals that are
not available to the general public.

They are only
available in the form of

subscriptions, often very
expensive subscriptions.

So I want to tell you how some of us
have been trying to change the culture

of scientific publication, and this
relates to the challenge that we face.

Now, here's one of the biggest problems
that we faced over the past 20 years.

Some of you may be aware that

beginning about a
dozen about 10 years ago,

reports started to emerge that very
important papers that were published

in the most high profile journals
journals like Nature Science,

could actually not be
replicated in the very

controlled conditions of a
pharmaceutical company.

This company, a major biotech company
in the United States called Amgen,

conducted its own study by an
Australian investigator who found that.

Over 80 percent of the key
experiments in papers on cancer

biology that Amgen wished to
use in order to discover new drugs,

that may be chemotherapeutic
agents over 80 percent, almost

90 percent of the key experiments
could not be reproduced.

Now, a biotech company lives and
dies on the accuracy and reproducibility

of what they produce, and if
they can't reproduce something,

it is of no commercial value.

So this was quite shocking.

This gentleman, Ed Begley, was the
key author on this, and he reported a

number of really quite frightening
examples of this failure of replication.

So what to do about this?

After all, the United States at
that time already was investing $30

billion a year in biomedical research
and institutions across the country.

Congress was, of
course, alarmed that much

of this investment
might have been wasted.

What to do about this?

Well, at the time, I was just
beginning a new open access journal.

Now, open access
is different than the

model of commercial
licensing and subscriptions,

and open access model
journal is where the

author of the work pays
for the publication costs.

These in a journal that is adequately
supported by philanthropic funds

such as We Were at Eli are
modest in comparison to the real cost,

considering the profit margin in some
of the very popular commercial journals.

So we decided as an
editorial policy to engage

with a group called the
Center for Open Science

to conduct our own study on the

reproducibility of key
papers in cancer biology.

This was an editorial that we published
at the outset of our investigation.

What we did and so this is the

journal that I initiated.
It's called eLife.

It was very generously supported
by three very important funders

of science the Howard Hughes
Medical Institute in the US,

the Max Planck Society in Germany,
Germany and the Wellcome Trust in the UK.

These three
organizations felt their

presence felt that it was
time for active scholars,

to take control of the literature
and to change the nature

of how scientific publications
are assessed and published.

So what we did in our investigation
of key papers that were published in

Cancer Biology was to conduct a
study in two stages in the first stage.

But certain research groups were
commissioned to design experiments,

that would test the
reproducibility of key experiments

in the papers that had
already been published.

We asked these groups
of contract organizations

to write what it's called
a registered report.

This is a report where
they simply describe in detail

exactly how they intend to
attempt to repeat the studies.

There are no studies
yet conducted it,

just a report of how
they plan to go about it.

These registered reports
were reviewed by the normal

procedures we had and
the Editorial Board of eLife.

And if finally approve, these registered
reports were published in our journal,

and then the contract groups
were then commissioned to

conduct the actual
investigation, the replication study.

So here are the parameters of this.

Ultimately, this took
quite quite a long time.

Ultimately, about half of the
studies that we initially investigated

were published of replication
studies, and the outcome was mixed.

A report in Science magazine
found that of the first five

papers that went through
this rigorous two stage process,

only two of the five really
could adequately be replicated.

The other three, we didn't
necessarily feel were fraudulent

or where the data was manipulated
in the original publication.

It's just that we required
that the protocols,

the detailed experimental
protocols that were used in the initial

publications be replicated precisely
as written by our contract groups.

We were not allowed to consult
with the original authors to see if

there were some variations that
they hadn't described in their papers,

and that may explain some
of the problem with these

three that did not did not
succeed by our standards.

But just to summarize that part of the
part of the investigation that he likes,

it left us with a feeling
that replication studies are

very difficult to do it
properly is very expensive,

very time consuming and would
be a burden on most investigators.

It's just a cautionary note that
one must be very careful in being

completely open and transparent
in the original publication of the work,

and all of the protocols
that are a part of

that study must be
described in great detail.

Now I'm going to turn to another
theme related to scientific publication,

and that is the challenge
that an investigator

such as myself faces
when we want to publish.

And what are these very so-called
high profile journals, nature or science?

And the problem that many
of us feel that has been a key.

So part of the failure of the
system is the peer review process.

So let me describe for those of
you who may not know what's what

happens in a peer review process,
a paper is submitted to any journal,

a member of the editorial
board of that journal, then decides

whether that paper is appropriate
for that particular journal,

and he or she then assigns
that paper to two or more

outside experts who are
knowledgeable in the subject area.

They then assess the work in
detail. They write individual reports.

The individual reports are then
considered by the member of the editorial

board, and if a final decision is made
about the about the fate of the work.

Now let me give you an
example of a paper, a rather

notorious paper that had a
very severe impact on our life.

Now, nearly 20 years
later, roughly 20 years ago, a

paper was published in the
journal called The Lancet,

a very important clinical journal
that's published by the major

publisher of scientific literature
in the world called Elsevier.

This journal Lancet is a
British journal of long note.

About 20 years ago,
they received a report

from one Andrew
Wakefield in in the U.K.,

and part of the message of this of his
study was that there may be a connection,

between immunization
and the development

of autism in young
children who are immunized.

Of course, this was a
frightening, frightening prospect.

Now I know from behind the
scenes what happened in the review of

that paper it was subjected to
the normal peer review process.

The outside reviewers
felt that the paper was

inadequate, that the data
wasn't up to the conclusion.

The internal members of the board
who were employees of Lancet felt.

Likewise, the paper
was about to be rejected.

But because the message was so important
was somehow really couldn't be held back.

The publisher decided
to publish this this paper,

now many of you heard
of the consequence of this.

The paper was eventually
found to be fraudulent.

Some of the data was manipulated.

Wakefield was.

The paper was after 12 years
finally retracted by the journal.

Wakefield was kicked out
of his home institution, but he

continues to agitate with
anti-vaccine groups around the world,

all because of this one
publication fraudulent

publication that failed
the peer review system.

This is a concern that we all have now.

Another problem is that
these journals, such as I

mentioned, science and
nature, are so powerful,

and they operate to make
themselves exclusive by accepting

only a very small number of
the papers that are submitted.

And the problem is
that this leads to bad

behavior on the part of
scientists, sometimes papers.

Our data is manipulated to make
it look better or conclusions are

overdrawn that cannot be just
justified by the by the experiments.

And here are a couple of
comments that are published in this

very nature is the nature and
science magazines themselves.

An immunologist at MIT to pluck
peer review of scientific papers in

top journals is bogged down by
unnecessary demands or extra lab work,

or by a team, including
Peter Walter at UCSF.

The stress associated with the
public and publishing experimental

results can drain much of
the joy from practicing science.

Another feature that journals
such as Nature used to use to

promote themselves is a number
called the journal Impact Factor.

This number was created over
four decades ago by something called

the Institute for Science
Scientific Information in the US.

It was a number that's used to
compute basically how popular a journal is

the number of citations to papers
in that journal over a two year period

divided by the number of papers published.

And so here you see this
number being advertised by

nature to promote itself to
people who wish to subscribe.

The number seemingly highly
accurate, in fact, is completely

inaccurate and a misrepresentation
of the importance of science.

It is an attempt to quantify
popularity or timeliness, and it

is not a measure of scholarship.
It never was intended for that.

And yet it has been used by most journals
over many years to hype themselves.

Now, even nature recognize the
damage done by the use of this number.

And the former editor in chief
Philip Campbell wrote an editorial

five years ago calling for a
reform of the journal Impact Factor.

His comments were very, very measured.

But I think highly
effective metrics are

intrinsically reductive and
as such can be dangerous.

Relying on them as a
yardstick of performance,

rather than as a pointer
to underlying achievements

and challenges usually
leads to pathological behavior.

The journal impact factor is just such a
metric, and I can assure you that is true.

And unfortunately, although nature
has issued the use of this number,

it continues to be used by
scientific societies and journals to

advertise their journals and to
promote them for popular attention.

Now, one of the pathological
consequences of this is in countries,

that where the
intellectual infrastructure is

not up to the challenge
of reviewing the literature

by use of experts to evaluate the
quality and importance of work in China.

As of a few years ago,
many of the institutions,

including one called the
Chinese Academy of Science,

issued a bulletin such as You
See Here, which I've had translated.

It's a bulletin that basically offers
a bounty a cash reward to Chinese

scholars who happen to win the
lottery and publish in cell nature science.

This is the equivalent
in China of thirty three

thousand U.S. dollars
personal spending money,

just for the privilege of having
published in these journals, irrespective

of the content of the paper and
journals of perceived lower rank,

including the Proceedings
of the National Academy of

Sciences, are worth much less
bounty for these investigators.

This is a this is a
distortion in the nature

of scholarship, and
it must be stopped.

It really is. It leads to
pathological behavior.

Now, many of us are feeling
strongly about this issue gathered

together in San Francisco
now about a dozen years ago.

So to write a declaration called
the Declaration of Research

Assessment, you can find us online
if you Google Dora San Francisco.

And although there are many
recommendations in this declaration, in this

declaration, the big message is
that scholars, academic institutions,

department chairs, university
administrators granting agencies and

publishers should move away from
the use of these misleading numbers,

particularly impact factor.

They should assess
outputs on their own merits.

For instance, maybe reading the
paper to evaluate its importance.

And there are always new tools
that may be available to do this.

There are now many more
people who have this, people

and individual institutions
who have signed on to this.

So it is a growing
movement that continues.

But nonetheless, in the face of
this opposition, there are still journals

that insist on measuring themselves
by this mis measure of scholarship.

The impact factor?

Now, my own institution, the
University of California, has conducted a

long term battle with the major
publishers Springer Nature and Elsevier,

to force these commercial
organizations to offer their

recent the research that we
scholars in the U.S. system,

publish in their journals that ought to
offer it free and open access format.

I'm very proud of the librarians
of our system for several years.

We simply canceled our contract with
Elsevier. Throughout the UC system.

Scholars no longer had access to the
many publications of elsewhere because

Ellesmere was simply unwilling to
cut into their enormous profit margin,

and allow our scholars,
constituting roughly 10

percent of the scholarly
output in the United States,

to have their papers viewed
in an open access format.

Fortunately, this past year, a
satisfactory contract has been rereleased,

which will allow
the university and

individual investigators
to share the expense,

and to give the opportunity for this
work to be published open access.

So it is a battle.

The Wellcome Trust in Britain has taken
a very strong position on open access.

Welcome Trust investigators
throughout funded investigative

throughout Britain are
now obliged to publish,

in the highest so-called gold
standard open access publications.

And this is a move that has taken
root largely in Europe through an

organization called Coalition S with a
publication policy plan called Plan S,

which calls for all funding agencies
around the world to change and

to require that their investigators,
as the Wellcome Trust does,

to publish an open access journal.

So I think the tide is
turning in favor of this

more greater openness
in scientific scholarship.

There are many
suggestions that I would like to

consider to journals, the
journal Lancet, for instance,

took 12 years to publish a retraction
of this dangerous Wakefield paper.

I think journals like
Lancet, like Nature, like

Science, really need
to own their mistakes.

They need to be more open and
provide space to authors wish to

challenge the work that's been
published in their page pages.

These very selective
journals are rather reluctant to

do so because they don't
like to admit their mistakes.

The review process needs to be more open.

There needs to be more
collegial collaboration in a decision

about whether a paper is
worth worthy of publication.

The comments of the
reviewers should be

made publicly available
in an open access forum,

so that readers can see
what went on behind the

behind the scenes in the
decision to publish the work.

There are also problems
with how misconduct

is investigated that I don't
have time to talk about.

Many now have post require
that articles that have been

submitted for publication
be posted in open archives,

and this has been true
during the pandemic.

A huge number of papers
have been posted even before

they've been peer reviewed
and are available for all to see.

And of course, most importantly,
stop advertising this misleading

number and use other evaluations
for the measure of scholarship.

Now I'd like to turn in the final
portion of my talk to something

of great interest around the world
and a personal concern to me,

neurodegenerative disease is on the rise.

We will eventually control the
pandemic, but as of this year,

there still is little or no progress in
arresting the inexorable development

of such debilitating diseases
as Alzheimer's and Parkinson's.

They are rising in the
incidence as the population

ages and both diseases
relate to these cells,

the nerve cells in our
brain, how they sustain

themselves and how with
damage of some unknown origin,

they progressively die and
lead to loss of cognitive function,

or loss of control of
movement characteristics

of either Alzheimer's
or Parkinson's disease.

So the problem is enormously complex,
it can be viewed as a huge puzzle.

Much more complex
than this image of the

human brain deconstructed
into pieces of a puzzle.

The human brain has roughly
10 to 12 billion nerve cells.

Each nerve cell can make up to 10000
connections to adjoining nerve cells,

which leads to
perhaps over a trillion

possible synaptic
connections in the entire brain.

So this is a supercomputer at an
enormous scale, all a process of evolution

that's allowed us to be constructed
as thinking, feeling human beings.

And when a piece of this puzzle is
removed, that can cause great damage.

Now, reconstructing this puzzle is
the challenge of trying to understand the

molecular and cellular basis of a of
these terrible progressive diseases,

such as Alzheimer's and Parkinson's.

My slide is not advancing.

OK.

Oops!

Here is just a little bit
of data that suggests

where we stand in relation
to Parkinson's disease.

It is rising in incidence quite
dramatically, even more rapidly than the

increase in the prevalence of
Alzheimer's disease in the next 10 years,

it will be close to 20 million.

Some fraction of the disease is
attributable to genetic influences.

There are now some 20 genes
and perhaps as many as 100 different

genetic loci that are found
in familial forms the disease,

where the disease
appears, at least in part to be

inherited, passed along
from parents to the child.

There are, of course,
other possible origins

having to do with industrial
pollutants or smoking,

or just the people living longer,
and these things inevitably happening.

Nonetheless, whatever, whatever the
origin of the disease, it is progressing

around the world that, like the
pandemic, observes no boundaries.

In the next 10 years, it's
estimated that over half of

the new cases of Parkinson's
disease will emerge in China.

So what we need is a
massive increase in investment

in trying to understand
the basis of the disease.

The disease was first
recognized now 200 years ago, and

yet in that two centuries,
very little has been achieved.

That changes the arc, the
progression of the disease.

There are palliative
treatments, but they are.

There are no cures.

Now let me take a deep
dove into the brain and then

into individual nerve
cells to tell you a little bit,

about what we know about the most
common aspect of Parkinson's disease.

Parkinson's disease.

At least a major portion of it
is attributable to the death of

cells in the mid brain that make
the neurotransmitter dopamine.

Dopamine is packaged
into little vesicles,

like I described in
the first part of my talk.

And it is these vesicles
discharge dopamine

to the space between
two nerve cells,

and the dopamine crosses the
gap and activates the receptor on the

other cell to turn that cell on and
to continue to convey information.

Now, most but not all, of the
dopamine in the brain is made

in a region of the mid brain
called the substantia nigra.

Those cells, some tens
of thousands of them

also produce a pigment
melanin that we know of it.

It's a skin pygmy pigmentation.

But it also happens to be a product
of the metabolism of dopamine

and can be detected by a simple
stain on sections of a human brain.

In this case, the brain of someone
who died for other reasons.

The section was stained so
as to reveal this melanin and

and you can see this as a
band in the mid brain region.

Now, a patient who died of Parkinson's
may have lost most of these cells.

When a patient first presents,
sometimes in as young as in their 20s.

More often, patients present in their 70s.

They present often with a
tremor or a movement disorder.

By the time the patient
presents with the symptoms, it's

estimated that maybe half of
these cells have already died.

And as the disease progresses and
becomes more severe, more and more

of these cells die by for reasons
that we don't entirely understand.

And here is a slice of the
patient brain who succumb

to Parkinson's, showing
much of the standing gone now.

About 100 years ago, a British
clinician named Louis examined

in the microscope the region
of the brain from a patient,

who has come from
succumb to Parkinson's

disease and noticed
that the substantia nigra

included many cells dopamine
producing cells that also had

inclusions inside the cell
that looked more dark staining.

We now know that these
inclusions are a collection of various

proteins and filaments and
membranes aggregated proteins.

One key protein in the Lewy body
is a protein called alpha synuclein.

This protein is itself one
of the genes that, when

mutated, causes a
familial form of the disease.

There are some patients who
have a mutation in this gene that

renders the alpha synuclein
product more prone to aggregation,

to be included in these Lewy bodies.

Or there are patients who have
three copies of this gene by a gene

duplication event that results
in a higher level of that protein,

which also makes it more prone to
aggregation and be able to see now.

In a postmortem, these inconclusive
they're called Lewy bodies.

Unfortunately, there
is no way to visualize

Lewy bodies in the
brain of a living patient.

We desperately need a
noninvasive stain that would allow

us to detect these structures
to mark their progression,

during the march of this terrible disease.

Now, subsequently, after
the initial work of Louis,

a German clinician by the name of
Dr. Brock looked at many postmortem brain

sections of patients who died of
Parkinson's disease at various stages,

and observed these Lewy
bodies appear in the brain

stem and as the disease
progresses, he believes.

Of course, this is by
reconstruction, not by

actual inspection, as
the patient him or herself.

Advances he observes that Lewy
bodies in later stages referred to

as Broch Stages three and four
appear to be elsewhere in the brain,

possibly by some kind of spread between
the cells, the nerve cells of the brain.

Eventually, they may appear
throughout the brain in the cortex.

They may cause other,
more advanced aspects

of the disease emotional
and cognitive disturbance.

It's estimated that about
30 percent of patients

who suffer from Parkinson's
progressed to dementia,

a dementia that's different in pathology
from that seen in Alzheimer's disease.

But nonetheless, just
it can be just as severe.

And so these Lewy bodies
then appear to be a marker

of the disease, though
that remains to be proven.

Now it's possible to reproduce
in the laboratory the build

up of these aggregated
proteins, including alpha synuclein.

This is an image of a thin
slice seeing a nerve cell that's

been incubated in the
laboratory for a couple of weeks,

under conditions where a fibrous
form of Elvis synuclein seeds,

the accumulation of the structure
which has been given a false color here,

is seen in an image
with a special microscopic

technique called
fluorescence microscopy,

where you can see a discrete particle not
not one that's enclosed within membranes,

but includes, but does include

membranes and filaments
and other proteins.

So given that we
can replicate the

production and build
up of these Lewy bodies,

it may be possible to use
cells grown in the laboratory

to investigate their
influence on cell physiology,

not having to rely on on an
animal or on the human patient.

These can be human
cells grown in the laboratory.

Now, let me tell you,
near the end of what we

know about two other
aspects genetic aspects

that come from different genes that
have been identified in some families

that have a familial form
of Parkinson's disease.

I told you about the first
one that's alpha synuclein that

affects the viability of cells
that are secreting dopamine.

But there are many
other genes, and

each one has a different
story associated with

I'm going to tell you about one
now that affects the ability of cells,

to control the health
of a very important

organelles in the cell
called the mitochondria.

So this is a electron microscope
image of the mitochondria.

It's the powerhouse of the cell.

It's the organelles that makes the
energy currency of the cell called ATP.

And it is highly elaborate
in its mechanism.

We don't have time to discuss this,
but the mitochondria and unlike other

organelles in a cell, even has its
own DNA molecule, its own genome.

That genome has to be housed
protected within the mitochondria

if it escapes from the
mitochondria and for any reason,

the Cell C's DNA in the cytoplasm.

And that sets in train a series of
steps that leads the cells to kill itself.

Because DNA in the cytoplasm is an
indication that something has gone very

wrong and the cell needed to kill
itself before other damage can occur.

So this is a cartoon of the structure
of the envelope of the mitochondria.

The details of this are
not necessarily important.

This is a fluorescence image of a cell.

This is the nucleus of the cell,
and the mitochondria form a kind of

a particular network different
from the air that I described earlier.

But each individual
mitochondria can be highlighted

and shown to contain its own
chromosome DNA molecule,

quite distinct from that found
in the nucleus of the cell.

Now, when a cell senses that
some damage has occurred and

the mitochondria can no longer
contain DNA or oxygen free,

free radicals of oxygen that are
generated during the production of ATP,

the cell has evolved a means of capturing
and destroying damaged mitochondria

and other damaged organelles,
and this is depicted in this slide.

It's a process that involves the
formation of a membrane that surrounds

the damaged organelles, a membrane
that then merges with the lysosome.

Remember, I told you the lysosome
is a is kind of the stomach of the cell.

It has the gist of enzymes that will
chew up anything that is delivered to it.

And so after some time,
these damaged mitochondria,

including their DNA
and their membranes,

are just completely destroyed down
to the nucleotides and amino acids and

sugars and these individual
components and can be reused in the cells.

This is a very important process called
autophagy or selectively for mitochondria.

It's called mitophagy.

Now, why am I telling you this?

It's important because two genes
that have been discovered in recent

years in familial forms of Parkinson's
affect the machinery in the cell,

that is required to recognize when a
mitochondria has become damaged

and to cause it to become engulfed
and degraded in the lysosome.

These jeans are called
pink one and parkyn, it

doesn't matter what these
jeans do for the time being.

Let me just tell you that
it's part of what is has a

general term called a
quality control mechanism.

The quality control mechanism
consists of a sensor that recognizes

if the mitochondrion has lost
some important aspect of its integrity,

and once recognized the damaged
mitochondria and is given a little protein

or fragment of a protein tag, a tag
of a protein that's called ubiquitin.

So it's a little tag.

It's basically a special code
that says this is now damaged

material and it should be engulfed
and destroyed in the lysosome.

So tags are given then to damaged,
but not to healthy mitochondria.

These tags are recognized.

They then become allow
the organelles to become

enveloped and destroyed
in the in the lysosome.

Now, so that's two genes
of some fraction of patients.

So a genetic disease of Parkinson's.

And there are now ongoing
efforts to try to control this process.

Oh, let me actually go back to this.

I forgot to give the punch line,
of course, patients who lack

pink one or parkin now fail to
mark damaged mitochondria.

These damaged mitochondria
then persist in the cell,

and the cells eventually
accumulate so much damaged

material that they die of
other natural processes.

So ordinarily, this would
be taken care of would

be part of the housekeeping
function of a cell.

The cell could survive because the
damaged mitochondria are disposed of.

But when you fail to recognize
these damaged mitochondria

that ultimately results
in the death of the cell,

and as a result, these
patients who have

these mutations lose
progressively many cells.

But most importantly,
they lose those cells in

the brain that make the
neurotransmitter dopamine.

Now, let me to
conclude turn to another

gene that is understood
it now a molecular level.

It's a different gene that
turns up in many patients

who have Parkinson's
disease with familial form.

It's a gene called Il R K
two or look to for short and

some very interesting recent
experiments have illuminated,

how Lark two may control the
viability the survival of doping neurons.

Lark two is an enzyme that modifies
another protein, and this other protein

is required in various avenues of
membrane traffic within the cells.

It's a kind of a molecular tag
this other protein that allows a

protein to move within a vesicle
from one compartment to the next.

And so it's a normal part
of normal cell function.

Now, patients who have the most
common mutations in the last two

gene produce this enzyme that
has even more activity than normal.

It's a kind of an unusual situation.

Mutations most often
cause a protein to

be less active and
enzyme to be less active.

But in this case, these mutations
actually make the enzyme the last two

enzyme more active, and it more
actively modifies its target protein.

And as a result, that
target protein loses its

normal function
because it's over modified.

One of the functions of
this normal protein is to

allow cells in the brain to
make a little appendage,

a little membrane appendage on
the surface of the cell called a psyllium.

Many cells have a psyllium
that serves as a kind of

an antenna as an antenna
on the surface of the cell,

that is open for the receipt
of signals from other cells.

One of the signaling
pathways that operates between

cells as a funny name, it's
called the hedgehog pathway.

And when the target
of LARC two is over

modified, those cells
fail to make the psyllium.

They thus fail to have an antenna
that would allow this hedgehog

signaling pathway that actually
comes from the dopamine neurons itself.

This pathway fails to deliver this signal.

The response is not received.

The dopamine cells then suffer
because this signaling pathway is required

for the target cell to make a growth
factor that sustains dopamine neurons.

A growth factor called GDNF is
manufactured by these target cells and will

only do so when this signaling pathway
elicits a response from the ceiling.

But when the psyllium
gone, this process is arrested

in the absence of GDNF in
these Parkinson's patients.

The dopamine neurons fail
to be nourished, and they die.

So this is a model of
yet another independent

means by which
dopamine neurons may fail.

Now, let me tell you about
my involvement in this process.

Several years ago, after a
long period of suffering, my

wife, who had Parkinson's
disease, died now four years ago,

and at the time I
was approached by a

representative of the Sergey
Brin Family Foundation

to consider organizing an
international collaborative research effort

to understand the molecular and
cellular basis of Parkinson's disease.

We were given an enormous
philanthropic donation, and we

decided to team up with the
Michael J. Fox Foundation,

which is the major philanthropic
organization that looks to

patients around the country
and certainly around the world.

That the donor in this
case felt that in spite of all

of the important clinical
work that was going on,

we still, after all this time
didn't really have a clear

picture of the molecular and
cellular basis of the disease,

unlike the few examples
that I've just given you.

Most forms of Parkinson's cannot
be explained as I've just done so.

Together with the team, we have
decided to create a funding initiative.

And we've done so now.

Over the course of two
years, we've identified

teams of investigators,
not individual investigators.

We feel that people really
on a problem like Parkinson's.

We feel that people really
need to get together to work

collaboratively to try to
tackle this, this terrible disease.

So here are the pillars of our effort.

We've decided to
focus on four themes the

genetics and associated
biology of the disease.

We know that there are, as I said, 20
different genes and probably more loci.

We think there's a great deal to
be learned of the sort that I've just

described about the individual
genes and how they affect the viability,

the survival of dopaminergic neurons.

So this continues to be a major theme.

We also estimate that there is
an impact of the immune system,

both the immune cells of the brain
and the body's immune responses

that may initiate or perhaps exacerbate
the progression of damaged neurons.

There's evidence that lesions in
the brain associated with Alzheimer's

and Parkinson's may be inflamed
by an innate immune process.

And we really don't understand
that and need to work on that.

So that's another area.

A third area is just the circuitry.

The dopaminergic neuron.

The neuron that makes
dopamine is the most common

one of the most complex
nerve cells in the brain.

It's enormously extended.

It makes many different connections
to different regions of the brain,

and we have yet to understand
the circuitry of all the cells that

interact with the dopamine secreting
neuron just in the normal situation.

And we we feel that knowing
that will help us further

understand Parkinson's that
leads to the death of these cells.

And finally, the most
mysterious kind of series of

syndrome precede the eventual
development of the disease.

It's called the prodromal
period that can appear

20 years before the onset
of the movement disorder.

There are certain.

Simple characteristics of patients who
eventually progressed to Parkinson's,

sometimes they very often they report
having a poorly developed sense of smell.

Often they have
problems with constipation.

Obviously, these are not key indicators
of just Parkinson's, they are more common.

But patients who
present eventually with

Parkinson's often have
these symptoms years earlier,

and one that is a more
clear indication of progression

of disease as a syndrome
called R.E.M. sleep disorders.

Patients who have REM
sleep disorder lose their ability to

discriminate their nightmares
or dreams from wakeful thoughts.

They often live out nightmares in
their sleep, flailing around in bed,

sometimes throwing
themselves off of the bed onto the

floor or harming themselves
or harming their partner.

It's a quite frightening syndrome
that's poorly understood,

and what is most
distressing about it is that

within five or 10 years,
80 percent of people

who present with REM sleep
disorder do progressed to Parkinson's.

So we're really keen to have a cohort
of patients who have such symptoms

that could then be used to try to
investigate where the disease originates.

And finally, finally,
let me tell you where

we stand in the course
of identifying teams.

We started last year with
a selection of 15 teams.

We selected these teams
because they contain.

They have assembled four
or five principal investigators

in laboratories, either at
one in one or two institutions.

These investigators, we
we we preferred investigators

who'd already had some
experience in collaboration.

It's very important to understand
how you can interact with

other scientists, it's not
normal, most scientists act alone,

but many collaborate, and we favored
people who had already demonstrated

a facility to engage in the give
and take of a collaborative effort.

We look for those teams
that showed that kind of

interaction that showed a
willingness to share new results

even before publication to
post their work on an archive,

as it's ready to be
published and then to publish

in open access journals,
as I described earlier.

We selected 15 teams consisting
of about 100 different individual

investigators in 60 different
institutions and 11 countries.

We've just concluded another
competition for slightly different

topics within the four that
we that I've just mentioned,

and we've identified
another 16 or so teams,

that find 15 teams that will
join so that we now have thirty

six teams of around one
and fifty different investigators.

These people have been integrated
into an online network and are expected

not merely to share their results
with other members of their team,

but also to communicate
on a regular basis with

other teams with who
have overlapping interests.

So we've created this network.

We were going to do this even
before the pandemic, but it's

worked out perfectly well to
do so during the pandemic.

We will have our first in-person
meeting of the principal investigators

next year, but thus far this
network has become very active.

Groups are expected
to present their work

in an online forum in
front of other individuals,

and they are expected to talk about
new data and not just publish data.

So we're very hopeful
that through this

kind of living network
organism of interactions,

we will bring to bear
one hundred and fifty

six of the finest
laboratories around the world

to challenge the devastation
of this disease, and the plan is

to carry on for 10 years and
to assess our progress thus far.

We've committed of
almost a half a billion

dollars to the teams
that we've assembled.

And there's more where that came from.

So we're very hopeful.

We feel this is going to be more effective
than just funding individual scientists.

So I'd be happy to
discuss this with you if

you have questions
after the presentation.

Thank you for your attention.

Randy, thank you very much
for that. Absolutely fascinating.

And as a non-scientist, clear
and informative presentation,

I'm sure all of us here
wish you and your team

and your colleagues
every success in that park,

to know that I can't
think of a family

where it doesn't, it isn't
infected in some way.

And this is the global conference.

So it's going to be seen by researchers
are all around the world with your...

I'm going to we haven't got
time for questions, and they're all

going to be lots of questions
which will forward answer you.

But I'm going to have
moderator's privilege

just for a second and
ask you one question,

and that is with your if it's possible
with your with your crystal ball,

how long do you think it's going to
be before we have the diagnostic tools,

in place to be able
to identify Parkinson's

symptoms and and treat it early?

Yeah. Right.

Well, even if we could find
a diagnostic molecule, the

progression of disease, there's
still no effective treatment.

So, you know, with cancer and

heart disease, it's
best to catch it early.

But with Parkinson's
or Alzheimer's, you

know, there's so far no
meaningful intervention.

So, but still, it is
important to have a marker.

See what the problem with one
of the problems with Parkinson's

is that the disease appears
with different symptoms,

and then it progresses in different
ways, depending on the patient.

And so a clinician, a neurologist,
is faced with a dilemma how to

advise patients and their families
what to expect in the years ahead.

I found this the most frustrating
aspect of the disease myself.

In dealing with my wife, I had access
to some of the world's best neurologists.

She had developed dementia, a form of
dementia called diffuse Lewy body disease,

because it was based just on her

behavior, not on a
biopsy of her brain tissue.

And I asked every
time, What what

can I look forward to?
Where is this going?

And they would all have answers,
but they were always wrong.

They were always wrong.

We had developments that
that no one could have predicted.

And eventually she died in the middle
of the night, likely of a heart attack.

So no one had told me
that this was one of the

consequences, not that
I could have prepared.

So this is, of course,
tragic and enormously

frustrating for patients
and their families.

But I can understand your
passion for wanting to contribute.

Also activates will do so.

Let me let me tell you
one thing that we are

doing if not to intervene
therapeutically yet,

but at least have a basis
to help patients prepare.

We fund an organization called PMI.

It's Parkinson's Progression
Monitoring Index,

and this is a clinical group
that is assembled now.

Thousands of patients with
different genetic or non-drug forms,

including these prodromal patients
who have REM sleep disorder.

and they are collecting these patients
have committed to providing not only DNA,

but tissue blood samples, urine, spinal
taps and all this material is collected,

stored and made available to
investigators to qualified investigators.

And as a result of
this collection, there is

now one promising
preclinical diagnostic,

which is not yet commercially available,

and that relates to this protein
synuclein that I mentioned.

This protein can be detected
in the Spinal Tap fluid.

The protein itself doesn't appear to
change in its abundance during the

progression of the disease, but the
form of the protein appears to change.

The form that appears to
increase is the form that is more

aggregation prone, which is what
constitutes the core of Lewy body.

This needs to be turned into a routine
clinical assay that can be done in a lab,

a lab that's not equipped with
necessarily with an electron microscope.

Anyway, that's that's a hopeful
development that will allow

patients at least to have some
knowledge and perhaps to prepare.

The most important
thing is to proceed with

these molecular clues that
we have from the genes.

And there are a number of biotech
companies that have very promising

approaches to target synuclein
and its aggregation character.

There's a drug that's being tested
now in phase one clinical trials on

human patients that reduces the
aggregation prone character of of synuclein.

And so maybe that will help mitigate
the progression of the disease.

There are there are two
different drug development

efforts underway to target
this gene, called LARC two.

I told you that mutations in that gene
actually make the enzyme more active.

And so you can look for
inhibitors that dampen that activity,

or you can look for
drugs that affect its

ability to target to
change the target protein,

that we think may be involved
in the production of cilia.

So, there are leads
that come from the

genes, but that that's
only the tip of the iceberg.

You know, there are still many other
genes that cause the disease, and

there are many patients who have
no parents genetic indication at all.

That sounds like it's
going to give you and your

first scientists busy for
many, many years to come.

Yeah.

So better all signs.

But but it's a great challenge. Great.

Randi, thank you very much again
for this inspiring, inspiring thing.

Keynote and thank you again for
addressing the key to the future audience.

As I mentioned earlier, we're
going to be collecting questions.

There'll be lots of questions
which will forward to you,

and those responses will be
published in the U.S.A. future

official report would be
published after the conference.

Again, thank you for
your time and good luck.

And please join us
in a few moment, few

minutes for the next
presentation and say the future.