Original subtitles

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.