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For our opening address, I
have the great pleasure of
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introducing our keynote
speaker, Dr.Randy Schekman.
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Randy, welcome to the future.
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Yes. Good morning from Berkeley.
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Good morning.
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Let me say a few words about
our keynote speaker today.
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Randy Schekman is a professor
in the Department of Molecular
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and Cell Biology at the
University of California, Berkeley,
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and an investigator of the
Howard Hughes Medical Institute.
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He studied DNA replication as a
graduate student at Stanford University,
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and his current interest
is in cellular membranes.
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In 2013, Randy Schekman was
awarded the Nobel Prize in Physiology
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or Medicine for their discoveries of
the machinery regulating vesicle traffic,
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a major transport system in our cells.
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In addition to the
Nobel, his other awards
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include the Gairdner
International Award,
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as well as the the Albert Lasker
Award in Basic Medical Research.
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Dr. Segment and his team are still
conducting research into the mechanisms
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of the of traffic in the secondary
pathway of eukaryotic cells.
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He served as editor
or editor in chief for the
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annual reviews of Cell
and developmental biology.
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I beg your pardon and the Proceedings
of the National Academies of Science,
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and was founding editor and editor in
chief of the open access journal eLife.
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Since 2018, Dr Schekman has
served as the scientific director
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of Aligning Science
across Parkinson's Disease,
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a major philanthropic
effort organized by
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the along with the
Michael J. Fox Foundation
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to identify molecular and
cellular mechanisms in the
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initiation and progression
of Parkinson's disease.
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If you have any questions
for Dr. Shechtman, I would ask
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you, please, to post them here
in the Q&A box on this page.
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All questions will be forwarded to
him after the conference and responses
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will be published later this year
in the official conference report.
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So without further ado, I
have the great pleasure of
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introducing a keynote speaker
for today to see the future 2021.
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Dr. Randy Schekman.
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Thank you very much, Tony, and
welcome to my friends in the audience.
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I'm going to divide my
talk into three subject areas.
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The first will be a broad
overview of the of the area
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of my research as it relates
to the current pandemic.
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The coronavirus pandemic there is a
connection related to cellular membranes.
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I'll again devote some time to
the issue of scientific publication.
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Some of my concerns about how
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scholars choose which
journals to publish it,
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and the control that's exerted
by some of the largely commercial
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enterprises in which many
investigators wish to publish their work.
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And finally, I'm going to turn to another
topic, one that Tony just introduced,
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and that is my personal and
professional interest in Parkinson's
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disease and a very large
international collaborative program,
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that I initiated at behest
of the Sergei Brin Family
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Foundation in collaboration with
the Michael J. Fox Foundation,
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to bring teams of investigators
together to try to get to the molecular
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and cellular basis of this scourge
of mankind. Parkinson's disease.
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Well, let's begin with a topic
of current interest to all of us.
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This is a picture, a
cartoon view of the
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outside in a slice of the
inside of the coronavirus.
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Coronavirus looks very much
like a carrier that's found it
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in all cells that have a nucleus,
a carrier called a vesicle.
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But it's been designed by
evolution to convey this molecule, an
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RNA molecule which is in the
interior of the virus for infection.
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The outer surface of the
virus particle is a membrane.
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You'll see a bit more about what
a biological membrane consists of.
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It's a membrane that has lipids on its
surface, so it's kind of a greasy shell.
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And most importantly, proteins, one
of which is called the spike protein,
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that allows the virus
to engage a cell and
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then enter the cell by
engulfing and process,
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that allows the RNA to be
released into the interior of
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a cell for its replication to
make more virus particles.
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Now let's do just a very
brief primer on biological
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membranes and how they
relate to the corona virus.
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This is an image taken in an electron
microscope of a thin slice through a cell,
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that reveals the perimeter or cell
surface membrane consisting of
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two layers or a bilayer of lipid
molecules called phospholipids,
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into which various protein molecules.
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I indicated by Green
are inserted so that
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part of the protein faces
the outside of the cell.
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And another part of the protein
faces the inside of the cell.
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This is a depiction that we now generally
appreciate about biological membranes.
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They all consist of this kind
of fluid phospholipid bilayer
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that's a kind of a has
the viscosity of a light oil,
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and then membrane proteins
that impart unique personalities to
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membranes and generate
particular functional qualities to a cell.
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This, for instance, might be a
receptor, such as the receptor that I'll
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tell you about that's responsible
for the uptake of the corona virus.
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Now, this is a cartoon of a
typical cell, a eukaryotic cell.
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This is a nucleus that contains
all of the chromosomes,
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the 23 chromosomes that
constitute the human genome.
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It's enclosed within a
membrane and envelope.
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And in the outside the cytoplasmic
area, there are a number of organelles,
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some of which may be part of the energy
producing machine called the mitochondria,
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and others of which may be an
organ cell, such as the lysosome,
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which is responsible
for degrading
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macromolecules that are
no longer wanted by the cell,
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and surrounding it all is another
membrane that is again a lipid bilayer.
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This is in contrast to what
a bacterial cell looks like.
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It's much smaller.
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It doesn't have a nucleus
proper, but it has DNA.
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It must allow the cell to
grow and divide, but it is
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much less compartmentalized
than a eukaryotic cell.
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We are eukaryotes.
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Most of the organisms that we see
with our naked eye are eukaryotes.
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Now this is a sketch
of the process that
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cells use to manufacture
proteins for export.
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This has been the subject of my
research research over many years.
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Eukaryotic cells are
organized into compartments.
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I mentioned the nucleus surrounding
the new nucleus is a network
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of membranes referred to as
the endoplasmic reticulum or e-r.
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And in many cells, these membranes
are studied with these green particles.
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The color preferred
for this description the
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green of particles, which
are called ribosomes.
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Ribosomes are like the little
sewing machines in a cell that stitch
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amino acids one next to two
another to make a polypeptide chain.
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This may be, for
instance, a cell that such as
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the cell in your in your
pancreas that makes insulin.
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Insulin, then would start being
made by a ribosome such as this
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threaded into this salmon
colored interior of this membrane,
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and then in a series of steps,
is conveyed from one step
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to the next to finally be
exported outside of the cell.
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So of the twenty three thousand
genes in the human genome,
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almost 30 percent of them encode
proteins that engage this process
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and are delivered either to the cell
surface to intracellular membrane
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organelles like the lysosome or
remain within this within this network.
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It's a very elaborate process
that has been, as I said, the subject
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of my work at MIT, many other
cell biologist over many years.
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Now, how does this relate to coronavirus?
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So here's a another image of the
virus, such as you saw in my first slide.
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It's again, it's a little membrane
that carries a nucleic acid
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inside, and then it has the
spike protein on its exterior.
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This spike protein has a specific
affinity binding to one of our
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own proteins on cells that has
a completely different function.
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A protein that's called ACE2.
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This protein serves a
normal purpose in our
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body and the respiratory
canals of our body.
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But the virus has evolved
to hijack this receptor and to
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allow the virus to bind and
to be internalized into the cell.
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Now what happens once it's in
the cell is really quite remarkable,
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and it engages the very network of
membranes that I've just described.
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Here, for instance, is another slice
through a coronavirus infected cell.
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Here are the virus particles.
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These are actual virus
particles binding on
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the cell surface to that
ACE2 receptor molecule.
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And they may then be swallowed
up internalized into these
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structures when they are
compartmentalized in these structures.
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The spike protein adheres to
the inner surface of this membrane,
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in which the virus has been
engulfed and the membranes
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surrounding the virus merges
with this organelle membrane,
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to in a process that's
called membrane fusion.
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And when that happens,
the interior of the virus, the
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nucleic acid of the virus,
is spilled into the cytoplasm.
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The rest of the cell and in the
cytoplasm, the RNA that constitutes
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the genome of this virus is replicated
and more viruses are produced.
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Now, the great triumph in
this first phase of the pandemic,
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has been to realize the possibility
of taking an RNA molecule
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called a messenger RNA
molecule that copies the information.
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In part of the spike protein and
this RNA molecule, Imani can be
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packaged into an artificial membrane
called a lipo, a lipid nanoparticle.
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And these then are the
vaccines that many of you have
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received from either
BioNTech or Pfizer or Moderna.
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These RNA containing lipo lipid
like particles can be taken up by
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the same process that I've just
described injected into the cell.
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The RNAs can escape
into the cytoplasm, and
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that RNA then will make a
piece of the spike protein.
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It will not create a new infectious virus.
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It will only make a part of
that spike protein that part
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of the spike protein is
exported outside of the cell.
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And that's what your
immune system recognizes
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as foreign and generates
an immune response.
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So this is a subversion of the
virus process that has been used by
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biotechnology to engineer it quite
remarkably, successful vaccine.
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Now, that's it for just a
very broad view of the
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kind of cell biology that
we do in my laboratory.
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I want to turn my attention
for a little while into
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what scientists must
do to publicize their work,
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and that is to publish in journals that
other scholars, colleagues can see.
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You may be aware that during the
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pandemic, a lot of the
literature on SARS-CoV-2,
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the coronavirus and COVID 19 has
been published openly in commercial
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or noncommercial journals
and made available for all to see,
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irrespective of your location in
an academic institution or not.
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This has been a bright light
on a process that is often held
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behind a closed door that
most of you are not accessible to,
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and this is a, I think, a big challenge.
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Most of the research
that's conducted on
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diseases such as COVID
is with government funds,
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and the work that gets published
as a result of this taxpayers fund is in
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then published in journals that are
not available to the general public.
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They are only
available in the form of
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subscriptions, often very
expensive subscriptions.
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So I want to tell you how some of us
have been trying to change the culture
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of scientific publication, and this
relates to the challenge that we face.
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Now, here's one of the biggest problems
that we faced over the past 20 years.
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Some of you may be aware that
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beginning about a
dozen about 10 years ago,
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reports started to emerge that very
important papers that were published
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in the most high profile journals
journals like Nature Science,
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could actually not be
replicated in the very
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controlled conditions of a
pharmaceutical company.
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This company, a major biotech company
in the United States called Amgen,
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conducted its own study by an
Australian investigator who found that.
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Over 80 percent of the key
experiments in papers on cancer
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biology that Amgen wished to
use in order to discover new drugs,
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that may be chemotherapeutic
agents over 80 percent, almost
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90 percent of the key experiments
could not be reproduced.
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Now, a biotech company lives and
dies on the accuracy and reproducibility
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of what they produce, and if
they can't reproduce something,
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it is of no commercial value.
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So this was quite shocking.
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This gentleman, Ed Begley, was the
key author on this, and he reported a
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number of really quite frightening
examples of this failure of replication.
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So what to do about this?
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After all, the United States at
that time already was investing $30
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billion a year in biomedical research
and institutions across the country.
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Congress was, of
course, alarmed that much
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of this investment
might have been wasted.
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What to do about this?
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Well, at the time, I was just
beginning a new open access journal.
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Now, open access
is different than the
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model of commercial
licensing and subscriptions,
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and open access model
journal is where the
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author of the work pays
for the publication costs.
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These in a journal that is adequately
supported by philanthropic funds
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such as We Were at Eli are
modest in comparison to the real cost,
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considering the profit margin in some
of the very popular commercial journals.
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So we decided as an
editorial policy to engage
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with a group called the
Center for Open Science
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to conduct our own study on the
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reproducibility of key
papers in cancer biology.
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This was an editorial that we published
at the outset of our investigation.
228
00:16:12,436 --> 00:16:14,192
What we did and so this is the
229
00:16:14,204 --> 00:16:16,915
journal that I initiated.
It's called eLife.
230
00:16:16,955 --> 00:16:21,072
It was very generously supported
by three very important funders
231
00:16:21,084 --> 00:16:24,769
of science the Howard Hughes
Medical Institute in the US,
232
00:16:24,809 --> 00:16:28,835
the Max Planck Society in Germany,
Germany and the Wellcome Trust in the UK.
233
00:16:28,875 --> 00:16:31,265
These three
organizations felt their
234
00:16:31,277 --> 00:16:34,653
presence felt that it was
time for active scholars,
235
00:16:34,693 --> 00:16:38,681
to take control of the literature
and to change the nature
236
00:16:38,693 --> 00:16:42,693
of how scientific publications
are assessed and published.
237
00:16:45,291 --> 00:16:49,307
So what we did in our investigation
of key papers that were published in
238
00:16:49,319 --> 00:16:53,291
Cancer Biology was to conduct a
study in two stages in the first stage.
239
00:16:53,945 --> 00:17:01,945
But certain research groups were
commissioned to design experiments,
240
00:17:04,109 --> 00:17:06,694
that would test the
reproducibility of key experiments
241
00:17:06,706 --> 00:17:08,925
in the papers that had
already been published.
242
00:17:08,965 --> 00:17:12,555
We asked these groups
of contract organizations
243
00:17:12,567 --> 00:17:16,094
to write what it's called
a registered report.
244
00:17:16,134 --> 00:17:19,708
This is a report where
they simply describe in detail
245
00:17:19,720 --> 00:17:23,572
exactly how they intend to
attempt to repeat the studies.
246
00:17:23,612 --> 00:17:25,528
There are no studies
yet conducted it,
247
00:17:25,540 --> 00:17:27,864
just a report of how
they plan to go about it.
248
00:17:27,904 --> 00:17:31,577
These registered reports
were reviewed by the normal
249
00:17:31,589 --> 00:17:35,204
procedures we had and
the Editorial Board of eLife.
250
00:17:35,244 --> 00:17:39,499
And if finally approve, these registered
reports were published in our journal,
251
00:17:39,539 --> 00:17:42,384
and then the contract groups
were then commissioned to
252
00:17:42,396 --> 00:17:45,356
conduct the actual
investigation, the replication study.
253
00:17:45,396 --> 00:17:48,666
So here are the parameters of this.
254
00:17:48,706 --> 00:17:51,710
Ultimately, this took
quite quite a long time.
255
00:17:51,750 --> 00:17:55,827
Ultimately, about half of the
studies that we initially investigated
256
00:17:55,839 --> 00:17:59,750
were published of replication
studies, and the outcome was mixed.
257
00:18:01,591 --> 00:18:05,195
A report in Science magazine
found that of the first five
258
00:18:05,207 --> 00:18:08,822
papers that went through
this rigorous two stage process,
259
00:18:08,862 --> 00:18:14,049
only two of the five really
could adequately be replicated.
260
00:18:14,089 --> 00:18:17,918
The other three, we didn't
necessarily feel were fraudulent
261
00:18:17,930 --> 00:18:21,963
or where the data was manipulated
in the original publication.
262
00:18:22,003 --> 00:18:26,442
It's just that we required
that the protocols,
263
00:18:26,482 --> 00:18:30,296
the detailed experimental
protocols that were used in the initial
264
00:18:30,308 --> 00:18:34,482
publications be replicated precisely
as written by our contract groups.
265
00:18:36,120 --> 00:18:39,343
We were not allowed to consult
with the original authors to see if
266
00:18:39,355 --> 00:18:42,783
there were some variations that
they hadn't described in their papers,
267
00:18:42,823 --> 00:18:45,818
and that may explain some
of the problem with these
268
00:18:45,830 --> 00:18:48,894
three that did not did not
succeed by our standards.
269
00:18:48,934 --> 00:18:55,271
But just to summarize that part of the
part of the investigation that he likes,
270
00:18:55,311 --> 00:18:59,411
it left us with a feeling
that replication studies are
271
00:18:59,423 --> 00:19:03,311
very difficult to do it
properly is very expensive,
272
00:19:03,629 --> 00:19:09,134
very time consuming and would
be a burden on most investigators.
273
00:19:09,174 --> 00:19:12,991
It's just a cautionary note that
one must be very careful in being
274
00:19:13,003 --> 00:19:17,174
completely open and transparent
in the original publication of the work,
275
00:19:18,558 --> 00:19:21,975
and all of the protocols
that are a part of
276
00:19:21,987 --> 00:19:25,572
that study must be
described in great detail.
277
00:19:25,612 --> 00:19:30,096
Now I'm going to turn to another
theme related to scientific publication,
278
00:19:30,136 --> 00:19:33,733
and that is the challenge
that an investigator
279
00:19:33,745 --> 00:19:37,277
such as myself faces
when we want to publish.
280
00:19:37,317 --> 00:19:41,766
And what are these very so-called
high profile journals, nature or science?
281
00:19:41,806 --> 00:19:46,038
And the problem that many
of us feel that has been a key.
282
00:19:46,078 --> 00:19:51,006
So part of the failure of the
system is the peer review process.
283
00:19:51,046 --> 00:19:54,858
So let me describe for those of
you who may not know what's what
284
00:19:54,870 --> 00:19:59,046
happens in a peer review process,
a paper is submitted to any journal,
285
00:20:00,124 --> 00:20:02,923
a member of the editorial
board of that journal, then decides
286
00:20:02,935 --> 00:20:05,792
whether that paper is appropriate
for that particular journal,
287
00:20:05,832 --> 00:20:09,606
and he or she then assigns
that paper to two or more
288
00:20:09,618 --> 00:20:13,832
outside experts who are
knowledgeable in the subject area.
289
00:20:14,101 --> 00:20:18,887
They then assess the work in
detail. They write individual reports.
290
00:20:18,927 --> 00:20:22,836
The individual reports are then
considered by the member of the editorial
291
00:20:22,848 --> 00:20:26,927
board, and if a final decision is made
about the about the fate of the work.
292
00:20:28,549 --> 00:20:32,285
Now let me give you an
example of a paper, a rather
293
00:20:32,297 --> 00:20:36,549
notorious paper that had a
very severe impact on our life.
294
00:20:37,637 --> 00:20:41,362
Now, nearly 20 years
later, roughly 20 years ago, a
295
00:20:41,374 --> 00:20:45,254
paper was published in the
journal called The Lancet,
296
00:20:45,294 --> 00:20:48,370
a very important clinical journal
that's published by the major
297
00:20:48,382 --> 00:20:51,518
publisher of scientific literature
in the world called Elsevier.
298
00:20:51,558 --> 00:20:56,351
This journal Lancet is a
British journal of long note.
299
00:20:56,391 --> 00:20:59,567
About 20 years ago,
they received a report
300
00:20:59,579 --> 00:21:02,693
from one Andrew
Wakefield in in the U.K.,
301
00:21:02,733 --> 00:21:08,816
and part of the message of this of his
study was that there may be a connection,
302
00:21:08,856 --> 00:21:11,796
between immunization
and the development
303
00:21:11,808 --> 00:21:15,192
of autism in young
children who are immunized.
304
00:21:15,232 --> 00:21:19,880
Of course, this was a
frightening, frightening prospect.
305
00:21:19,920 --> 00:21:23,452
Now I know from behind the
scenes what happened in the review of
306
00:21:23,464 --> 00:21:26,898
that paper it was subjected to
the normal peer review process.
307
00:21:26,938 --> 00:21:29,505
The outside reviewers
felt that the paper was
308
00:21:29,517 --> 00:21:32,600
inadequate, that the data
wasn't up to the conclusion.
309
00:21:32,640 --> 00:21:37,406
The internal members of the board
who were employees of Lancet felt.
310
00:21:37,446 --> 00:21:40,056
Likewise, the paper
was about to be rejected.
311
00:21:40,096 --> 00:21:46,196
But because the message was so important
was somehow really couldn't be held back.
312
00:21:46,236 --> 00:21:49,253
The publisher decided
to publish this this paper,
313
00:21:49,265 --> 00:21:52,294
now many of you heard
of the consequence of this.
314
00:21:52,334 --> 00:21:54,378
The paper was eventually
found to be fraudulent.
315
00:21:54,418 --> 00:21:56,259
Some of the data was manipulated.
316
00:21:56,299 --> 00:21:57,696
Wakefield was.
317
00:21:57,736 --> 00:22:02,495
The paper was after 12 years
finally retracted by the journal.
318
00:22:02,535 --> 00:22:06,292
Wakefield was kicked out
of his home institution, but he
319
00:22:06,304 --> 00:22:10,535
continues to agitate with
anti-vaccine groups around the world,
320
00:22:13,624 --> 00:22:17,570
all because of this one
publication fraudulent
321
00:22:17,582 --> 00:22:21,624
publication that failed
the peer review system.
322
00:22:22,053 --> 00:22:24,692
This is a concern that we all have now.
323
00:22:26,389 --> 00:22:29,155
Another problem is that
these journals, such as I
324
00:22:29,167 --> 00:22:31,833
mentioned, science and
nature, are so powerful,
325
00:22:31,873 --> 00:22:35,861
and they operate to make
themselves exclusive by accepting
326
00:22:35,873 --> 00:22:39,873
only a very small number of
the papers that are submitted.
327
00:22:40,438 --> 00:22:43,495
And the problem is
that this leads to bad
328
00:22:43,507 --> 00:22:47,452
behavior on the part of
scientists, sometimes papers.
329
00:22:47,492 --> 00:22:51,450
Our data is manipulated to make
it look better or conclusions are
330
00:22:51,462 --> 00:22:55,492
overdrawn that cannot be just
justified by the by the experiments.
331
00:22:58,438 --> 00:23:01,157
And here are a couple of
comments that are published in this
332
00:23:01,169 --> 00:23:03,856
very nature is the nature and
science magazines themselves.
333
00:23:03,896 --> 00:23:07,826
An immunologist at MIT to pluck
peer review of scientific papers in
334
00:23:07,838 --> 00:23:11,896
top journals is bogged down by
unnecessary demands or extra lab work,
335
00:23:12,974 --> 00:23:17,215
or by a team, including
Peter Walter at UCSF.
336
00:23:17,255 --> 00:23:20,962
The stress associated with the
public and publishing experimental
337
00:23:20,974 --> 00:23:24,298
results can drain much of
the joy from practicing science.
338
00:23:24,338 --> 00:23:28,166
Another feature that journals
such as Nature used to use to
339
00:23:28,178 --> 00:23:32,338
promote themselves is a number
called the journal Impact Factor.
340
00:23:34,111 --> 00:23:38,289
This number was created over
four decades ago by something called
341
00:23:38,301 --> 00:23:42,111
the Institute for Science
Scientific Information in the US.
342
00:23:42,226 --> 00:23:46,241
It was a number that's used to
compute basically how popular a journal is
343
00:23:46,253 --> 00:23:50,226
the number of citations to papers
in that journal over a two year period
344
00:23:54,146 --> 00:23:56,707
divided by the number of papers published.
345
00:23:56,747 --> 00:24:00,517
And so here you see this
number being advertised by
346
00:24:00,529 --> 00:24:04,747
nature to promote itself to
people who wish to subscribe.
347
00:24:05,263 --> 00:24:09,124
The number seemingly highly
accurate, in fact, is completely
348
00:24:09,136 --> 00:24:13,263
inaccurate and a misrepresentation
of the importance of science.
349
00:24:14,667 --> 00:24:18,561
It is an attempt to quantify
popularity or timeliness, and it
350
00:24:18,573 --> 00:24:22,667
is not a measure of scholarship.
It never was intended for that.
351
00:24:23,395 --> 00:24:28,487
And yet it has been used by most journals
over many years to hype themselves.
352
00:24:28,527 --> 00:24:33,002
Now, even nature recognize the
damage done by the use of this number.
353
00:24:33,042 --> 00:24:37,030
And the former editor in chief
Philip Campbell wrote an editorial
354
00:24:37,042 --> 00:24:41,042
five years ago calling for a
reform of the journal Impact Factor.
355
00:24:42,697 --> 00:24:45,621
His comments were very, very measured.
356
00:24:45,661 --> 00:24:48,524
But I think highly
effective metrics are
357
00:24:48,536 --> 00:24:52,323
intrinsically reductive and
as such can be dangerous.
358
00:24:52,363 --> 00:24:55,780
Relying on them as a
yardstick of performance,
359
00:24:55,820 --> 00:24:59,291
rather than as a pointer
to underlying achievements
360
00:24:59,303 --> 00:25:02,987
and challenges usually
leads to pathological behavior.
361
00:25:03,027 --> 00:25:09,081
The journal impact factor is just such a
metric, and I can assure you that is true.
362
00:25:09,121 --> 00:25:13,227
And unfortunately, although nature
has issued the use of this number,
363
00:25:13,267 --> 00:25:17,134
it continues to be used by
scientific societies and journals to
364
00:25:17,146 --> 00:25:21,267
advertise their journals and to
promote them for popular attention.
365
00:25:23,267 --> 00:25:30,593
Now, one of the pathological
consequences of this is in countries,
366
00:25:30,633 --> 00:25:34,143
that where the
intellectual infrastructure is
367
00:25:34,155 --> 00:25:38,136
not up to the challenge
of reviewing the literature
368
00:25:38,176 --> 00:25:44,754
by use of experts to evaluate the
quality and importance of work in China.
369
00:25:44,794 --> 00:25:48,065
As of a few years ago,
many of the institutions,
370
00:25:48,077 --> 00:25:51,627
including one called the
Chinese Academy of Science,
371
00:25:51,667 --> 00:25:55,332
issued a bulletin such as You
See Here, which I've had translated.
372
00:25:55,372 --> 00:25:59,278
It's a bulletin that basically offers
a bounty a cash reward to Chinese
373
00:25:59,290 --> 00:26:03,372
scholars who happen to win the
lottery and publish in cell nature science.
374
00:26:07,364 --> 00:26:10,918
This is the equivalent
in China of thirty three
375
00:26:10,930 --> 00:26:14,422
thousand U.S. dollars
personal spending money,
376
00:26:14,462 --> 00:26:18,535
just for the privilege of having
published in these journals, irrespective
377
00:26:18,547 --> 00:26:22,141
of the content of the paper and
journals of perceived lower rank,
378
00:26:22,181 --> 00:26:25,157
including the Proceedings
of the National Academy of
379
00:26:25,169 --> 00:26:28,664
Sciences, are worth much less
bounty for these investigators.
380
00:26:28,704 --> 00:26:32,167
This is a this is a
distortion in the nature
381
00:26:32,179 --> 00:26:35,267
of scholarship, and
it must be stopped.
382
00:26:35,307 --> 00:26:39,684
It really is. It leads to
pathological behavior.
383
00:26:39,724 --> 00:26:43,983
Now, many of us are feeling
strongly about this issue gathered
384
00:26:43,995 --> 00:26:47,724
together in San Francisco
now about a dozen years ago.
385
00:26:48,532 --> 00:26:52,274
So to write a declaration called
the Declaration of Research
386
00:26:52,286 --> 00:26:56,532
Assessment, you can find us online
if you Google Dora San Francisco.
387
00:26:58,615 --> 00:27:02,687
And although there are many
recommendations in this declaration, in this
388
00:27:02,699 --> 00:27:06,615
declaration, the big message is
that scholars, academic institutions,
389
00:27:10,572 --> 00:27:14,472
department chairs, university
administrators granting agencies and
390
00:27:14,484 --> 00:27:18,572
publishers should move away from
the use of these misleading numbers,
391
00:27:19,354 --> 00:27:21,034
particularly impact factor.
392
00:27:21,074 --> 00:27:23,964
They should assess
outputs on their own merits.
393
00:27:24,004 --> 00:27:28,640
For instance, maybe reading the
paper to evaluate its importance.
394
00:27:28,680 --> 00:27:32,745
And there are always new tools
that may be available to do this.
395
00:27:32,785 --> 00:27:36,224
There are now many more
people who have this, people
396
00:27:36,236 --> 00:27:39,882
and individual institutions
who have signed on to this.
397
00:27:39,922 --> 00:27:43,028
So it is a growing
movement that continues.
398
00:27:43,068 --> 00:27:47,111
But nonetheless, in the face of
this opposition, there are still journals
399
00:27:47,123 --> 00:27:51,068
that insist on measuring themselves
by this mis measure of scholarship.
400
00:27:51,695 --> 00:27:54,175
The impact factor?
401
00:27:54,215 --> 00:27:58,147
Now, my own institution, the
University of California, has conducted a
402
00:27:58,159 --> 00:28:02,215
long term battle with the major
publishers Springer Nature and Elsevier,
403
00:28:05,513 --> 00:28:09,430
to force these commercial
organizations to offer their
404
00:28:09,442 --> 00:28:13,513
recent the research that we
scholars in the U.S. system,
405
00:28:14,511 --> 00:28:19,375
publish in their journals that ought to
offer it free and open access format.
406
00:28:20,955 --> 00:28:25,349
I'm very proud of the librarians
of our system for several years.
407
00:28:25,389 --> 00:28:29,900
We simply canceled our contract with
Elsevier. Throughout the UC system.
408
00:28:29,940 --> 00:28:34,009
Scholars no longer had access to the
many publications of elsewhere because
409
00:28:34,021 --> 00:28:37,940
Ellesmere was simply unwilling to
cut into their enormous profit margin,
410
00:28:39,711 --> 00:28:42,514
and allow our scholars,
constituting roughly 10
411
00:28:42,526 --> 00:28:45,692
percent of the scholarly
output in the United States,
412
00:28:45,732 --> 00:28:49,864
to have their papers viewed
in an open access format.
413
00:28:49,904 --> 00:28:56,747
Fortunately, this past year, a
satisfactory contract has been rereleased,
414
00:28:56,787 --> 00:28:59,154
which will allow
the university and
415
00:28:59,166 --> 00:29:02,272
individual investigators
to share the expense,
416
00:29:02,312 --> 00:29:08,051
and to give the opportunity for this
work to be published open access.
417
00:29:08,091 --> 00:29:09,662
So it is a battle.
418
00:29:09,702 --> 00:29:15,289
The Wellcome Trust in Britain has taken
a very strong position on open access.
419
00:29:15,329 --> 00:29:18,791
Welcome Trust investigators
throughout funded investigative
420
00:29:18,803 --> 00:29:21,525
throughout Britain are
now obliged to publish,
421
00:29:21,565 --> 00:29:25,880
in the highest so-called gold
standard open access publications.
422
00:29:25,920 --> 00:29:29,634
And this is a move that has taken
root largely in Europe through an
423
00:29:29,646 --> 00:29:33,920
organization called Coalition S with a
publication policy plan called Plan S,
424
00:29:36,946 --> 00:29:41,024
which calls for all funding agencies
around the world to change and
425
00:29:41,036 --> 00:29:44,946
to require that their investigators,
as the Wellcome Trust does,
426
00:29:45,776 --> 00:29:47,084
to publish an open access journal.
427
00:29:47,124 --> 00:29:50,417
So I think the tide is
turning in favor of this
428
00:29:50,429 --> 00:29:53,802
more greater openness
in scientific scholarship.
429
00:29:55,620 --> 00:29:59,178
There are many
suggestions that I would like to
430
00:29:59,190 --> 00:30:03,354
consider to journals, the
journal Lancet, for instance,
431
00:30:03,394 --> 00:30:09,510
took 12 years to publish a retraction
of this dangerous Wakefield paper.
432
00:30:09,550 --> 00:30:12,520
I think journals like
Lancet, like Nature, like
433
00:30:12,532 --> 00:30:15,266
Science, really need
to own their mistakes.
434
00:30:15,306 --> 00:30:19,326
They need to be more open and
provide space to authors wish to
435
00:30:19,338 --> 00:30:23,306
challenge the work that's been
published in their page pages.
436
00:30:23,931 --> 00:30:26,826
These very selective
journals are rather reluctant to
437
00:30:26,838 --> 00:30:29,799
do so because they don't
like to admit their mistakes.
438
00:30:29,839 --> 00:30:33,261
The review process needs to be more open.
439
00:30:33,301 --> 00:30:37,529
There needs to be more
collegial collaboration in a decision
440
00:30:37,541 --> 00:30:41,295
about whether a paper is
worth worthy of publication.
441
00:30:41,335 --> 00:30:43,812
The comments of the
reviewers should be
442
00:30:43,824 --> 00:30:46,873
made publicly available
in an open access forum,
443
00:30:46,913 --> 00:30:49,660
so that readers can see
what went on behind the
444
00:30:49,672 --> 00:30:52,834
behind the scenes in the
decision to publish the work.
445
00:30:54,980 --> 00:30:57,978
There are also problems
with how misconduct
446
00:30:57,990 --> 00:31:01,685
is investigated that I don't
have time to talk about.
447
00:31:01,725 --> 00:31:05,396
Many now have post require
that articles that have been
448
00:31:05,408 --> 00:31:08,959
submitted for publication
be posted in open archives,
449
00:31:08,999 --> 00:31:10,914
and this has been true
during the pandemic.
450
00:31:10,954 --> 00:31:14,048
A huge number of papers
have been posted even before
451
00:31:14,060 --> 00:31:17,634
they've been peer reviewed
and are available for all to see.
452
00:31:17,674 --> 00:31:21,693
And of course, most importantly,
stop advertising this misleading
453
00:31:21,705 --> 00:31:25,674
number and use other evaluations
for the measure of scholarship.
454
00:31:27,552 --> 00:31:31,571
Now I'd like to turn in the final
portion of my talk to something
455
00:31:31,583 --> 00:31:35,552
of great interest around the world
and a personal concern to me,
456
00:31:39,490 --> 00:31:44,577
neurodegenerative disease is on the rise.
457
00:31:44,617 --> 00:31:49,317
We will eventually control the
pandemic, but as of this year,
458
00:31:49,357 --> 00:31:55,609
there still is little or no progress in
arresting the inexorable development
459
00:31:55,649 --> 00:32:00,308
of such debilitating diseases
as Alzheimer's and Parkinson's.
460
00:32:00,348 --> 00:32:04,339
They are rising in the
incidence as the population
461
00:32:04,351 --> 00:32:07,961
ages and both diseases
relate to these cells,
462
00:32:08,001 --> 00:32:11,675
the nerve cells in our
brain, how they sustain
463
00:32:11,687 --> 00:32:16,001
themselves and how with
damage of some unknown origin,
464
00:32:17,208 --> 00:32:21,760
they progressively die and
lead to loss of cognitive function,
465
00:32:21,800 --> 00:32:24,576
or loss of control of
movement characteristics
466
00:32:24,588 --> 00:32:27,317
of either Alzheimer's
or Parkinson's disease.
467
00:32:28,889 --> 00:32:34,626
So the problem is enormously complex,
it can be viewed as a huge puzzle.
468
00:32:34,666 --> 00:32:37,163
Much more complex
than this image of the
469
00:32:37,175 --> 00:32:40,296
human brain deconstructed
into pieces of a puzzle.
470
00:32:40,336 --> 00:32:48,240
The human brain has roughly
10 to 12 billion nerve cells.
471
00:32:48,280 --> 00:32:56,221
Each nerve cell can make up to 10000
connections to adjoining nerve cells,
472
00:32:56,261 --> 00:32:59,716
which leads to
perhaps over a trillion
473
00:32:59,728 --> 00:33:04,261
possible synaptic
connections in the entire brain.
474
00:33:04,934 --> 00:33:09,058
So this is a supercomputer at an
enormous scale, all a process of evolution
475
00:33:09,070 --> 00:33:12,934
that's allowed us to be constructed
as thinking, feeling human beings.
476
00:33:18,707 --> 00:33:23,367
And when a piece of this puzzle is
removed, that can cause great damage.
477
00:33:23,407 --> 00:33:27,474
Now, reconstructing this puzzle is
the challenge of trying to understand the
478
00:33:27,486 --> 00:33:31,407
molecular and cellular basis of a of
these terrible progressive diseases,
479
00:33:35,857 --> 00:33:38,535
such as Alzheimer's and Parkinson's.
480
00:33:43,825 --> 00:33:45,640
My slide is not advancing.
481
00:33:48,836 --> 00:33:50,664
OK.
482
00:33:50,704 --> 00:33:51,814
Oops!
483
00:33:53,624 --> 00:33:57,159
Here is just a little bit
of data that suggests
484
00:33:57,171 --> 00:34:00,939
where we stand in relation
to Parkinson's disease.
485
00:34:00,979 --> 00:34:04,995
It is rising in incidence quite
dramatically, even more rapidly than the
486
00:34:05,007 --> 00:34:08,979
increase in the prevalence of
Alzheimer's disease in the next 10 years,
487
00:34:10,204 --> 00:34:13,229
it will be close to 20 million.
488
00:34:13,269 --> 00:34:17,761
Some fraction of the disease is
attributable to genetic influences.
489
00:34:17,801 --> 00:34:21,983
There are now some 20 genes
and perhaps as many as 100 different
490
00:34:21,995 --> 00:34:25,801
genetic loci that are found
in familial forms the disease,
491
00:34:28,345 --> 00:34:31,821
where the disease
appears, at least in part to be
492
00:34:31,833 --> 00:34:35,390
inherited, passed along
from parents to the child.
493
00:34:35,430 --> 00:34:39,129
There are, of course,
other possible origins
494
00:34:39,141 --> 00:34:43,430
having to do with industrial
pollutants or smoking,
495
00:34:44,148 --> 00:34:49,212
or just the people living longer,
and these things inevitably happening.
496
00:34:49,252 --> 00:34:53,548
Nonetheless, whatever, whatever the
origin of the disease, it is progressing
497
00:34:53,560 --> 00:34:57,252
around the world that, like the
pandemic, observes no boundaries.
498
00:34:57,393 --> 00:35:00,845
In the next 10 years, it's
estimated that over half of
499
00:35:00,857 --> 00:35:04,572
the new cases of Parkinson's
disease will emerge in China.
500
00:35:04,612 --> 00:35:08,678
So what we need is a
massive increase in investment
501
00:35:08,690 --> 00:35:12,612
in trying to understand
the basis of the disease.
502
00:35:15,329 --> 00:35:19,247
The disease was first
recognized now 200 years ago, and
503
00:35:19,259 --> 00:35:23,329
yet in that two centuries,
very little has been achieved.
504
00:35:25,773 --> 00:35:28,622
That changes the arc, the
progression of the disease.
505
00:35:28,662 --> 00:35:31,680
There are palliative
treatments, but they are.
506
00:35:31,720 --> 00:35:33,379
There are no cures.
507
00:35:33,419 --> 00:35:35,981
Now let me take a deep
dove into the brain and then
508
00:35:35,993 --> 00:35:38,666
into individual nerve
cells to tell you a little bit,
509
00:35:38,706 --> 00:35:43,777
about what we know about the most
common aspect of Parkinson's disease.
510
00:35:43,817 --> 00:35:46,264
Parkinson's disease.
511
00:35:46,304 --> 00:35:50,261
At least a major portion of it
is attributable to the death of
512
00:35:50,273 --> 00:35:54,304
cells in the mid brain that make
the neurotransmitter dopamine.
513
00:35:57,052 --> 00:35:59,520
Dopamine is packaged
into little vesicles,
514
00:35:59,532 --> 00:36:02,242
like I described in
the first part of my talk.
515
00:36:02,282 --> 00:36:06,563
And it is these vesicles
discharge dopamine
516
00:36:06,575 --> 00:36:10,282
to the space between
two nerve cells,
517
00:36:10,397 --> 00:36:14,269
and the dopamine crosses the
gap and activates the receptor on the
518
00:36:14,281 --> 00:36:18,397
other cell to turn that cell on and
to continue to convey information.
519
00:36:18,584 --> 00:36:22,640
Now, most but not all, of the
dopamine in the brain is made
520
00:36:22,652 --> 00:36:26,584
in a region of the mid brain
called the substantia nigra.
521
00:36:27,195 --> 00:36:30,289
Those cells, some tens
of thousands of them
522
00:36:30,301 --> 00:36:33,902
also produce a pigment
melanin that we know of it.
523
00:36:33,942 --> 00:36:35,693
It's a skin pygmy pigmentation.
524
00:36:35,733 --> 00:36:39,661
But it also happens to be a product
of the metabolism of dopamine
525
00:36:39,673 --> 00:36:43,733
and can be detected by a simple
stain on sections of a human brain.
526
00:36:44,526 --> 00:36:48,125
In this case, the brain of someone
who died for other reasons.
527
00:36:48,165 --> 00:36:51,251
The section was stained so
as to reveal this melanin and
528
00:36:51,263 --> 00:36:54,307
and you can see this as a
band in the mid brain region.
529
00:36:54,347 --> 00:37:01,229
Now, a patient who died of Parkinson's
may have lost most of these cells.
530
00:37:01,269 --> 00:37:06,636
When a patient first presents,
sometimes in as young as in their 20s.
531
00:37:06,676 --> 00:37:10,819
More often, patients present in their 70s.
532
00:37:10,859 --> 00:37:14,995
They present often with a
tremor or a movement disorder.
533
00:37:15,035 --> 00:37:18,503
By the time the patient
presents with the symptoms, it's
534
00:37:18,515 --> 00:37:22,178
estimated that maybe half of
these cells have already died.
535
00:37:22,218 --> 00:37:26,120
And as the disease progresses and
becomes more severe, more and more
536
00:37:26,132 --> 00:37:30,046
of these cells die by for reasons
that we don't entirely understand.
537
00:37:30,086 --> 00:37:33,576
And here is a slice of the
patient brain who succumb
538
00:37:33,588 --> 00:37:37,222
to Parkinson's, showing
much of the standing gone now.
539
00:37:37,262 --> 00:37:41,383
About 100 years ago, a British
clinician named Louis examined
540
00:37:41,395 --> 00:37:45,262
in the microscope the region
of the brain from a patient,
541
00:37:47,696 --> 00:37:50,161
who has come from
succumb to Parkinson's
542
00:37:50,173 --> 00:37:52,952
disease and noticed
that the substantia nigra
543
00:37:52,992 --> 00:37:56,591
included many cells dopamine
producing cells that also had
544
00:37:56,603 --> 00:38:00,213
inclusions inside the cell
that looked more dark staining.
545
00:38:00,253 --> 00:38:04,374
We now know that these
inclusions are a collection of various
546
00:38:04,386 --> 00:38:08,253
proteins and filaments and
membranes aggregated proteins.
547
00:38:10,502 --> 00:38:17,438
One key protein in the Lewy body
is a protein called alpha synuclein.
548
00:38:17,478 --> 00:38:21,587
This protein is itself one
of the genes that, when
549
00:38:21,599 --> 00:38:25,478
mutated, causes a
familial form of the disease.
550
00:38:25,876 --> 00:38:29,708
There are some patients who
have a mutation in this gene that
551
00:38:29,720 --> 00:38:33,625
renders the alpha synuclein
product more prone to aggregation,
552
00:38:33,665 --> 00:38:35,929
to be included in these Lewy bodies.
553
00:38:35,969 --> 00:38:39,987
Or there are patients who have
three copies of this gene by a gene
554
00:38:39,999 --> 00:38:43,969
duplication event that results
in a higher level of that protein,
555
00:38:44,203 --> 00:38:49,330
which also makes it more prone to
aggregation and be able to see now.
556
00:38:49,370 --> 00:38:53,045
In a postmortem, these inconclusive
they're called Lewy bodies.
557
00:38:53,085 --> 00:38:56,075
Unfortunately, there
is no way to visualize
558
00:38:56,087 --> 00:38:59,226
Lewy bodies in the
brain of a living patient.
559
00:38:59,266 --> 00:39:02,991
We desperately need a
noninvasive stain that would allow
560
00:39:03,003 --> 00:39:06,740
us to detect these structures
to mark their progression,
561
00:39:06,780 --> 00:39:09,564
during the march of this terrible disease.
562
00:39:09,604 --> 00:39:14,780
Now, subsequently, after
the initial work of Louis,
563
00:39:14,820 --> 00:39:18,916
a German clinician by the name of
Dr. Brock looked at many postmortem brain
564
00:39:18,928 --> 00:39:22,820
sections of patients who died of
Parkinson's disease at various stages,
565
00:39:26,313 --> 00:39:30,381
and observed these Lewy
bodies appear in the brain
566
00:39:30,393 --> 00:39:34,313
stem and as the disease
progresses, he believes.
567
00:39:34,914 --> 00:39:37,793
Of course, this is by
reconstruction, not by
568
00:39:37,805 --> 00:39:41,017
actual inspection, as
the patient him or herself.
569
00:39:41,057 --> 00:39:44,985
Advances he observes that Lewy
bodies in later stages referred to
570
00:39:44,997 --> 00:39:49,057
as Broch Stages three and four
appear to be elsewhere in the brain,
571
00:39:52,005 --> 00:39:57,947
possibly by some kind of spread between
the cells, the nerve cells of the brain.
572
00:39:57,987 --> 00:40:02,770
Eventually, they may appear
throughout the brain in the cortex.
573
00:40:02,810 --> 00:40:05,843
They may cause other,
more advanced aspects
574
00:40:05,855 --> 00:40:09,454
of the disease emotional
and cognitive disturbance.
575
00:40:09,494 --> 00:40:12,600
It's estimated that about
30 percent of patients
576
00:40:12,612 --> 00:40:15,921
who suffer from Parkinson's
progressed to dementia,
577
00:40:15,961 --> 00:40:20,649
a dementia that's different in pathology
from that seen in Alzheimer's disease.
578
00:40:20,689 --> 00:40:24,071
But nonetheless, just
it can be just as severe.
579
00:40:24,111 --> 00:40:27,152
And so these Lewy bodies
then appear to be a marker
580
00:40:27,164 --> 00:40:30,099
of the disease, though
that remains to be proven.
581
00:40:32,349 --> 00:40:36,091
Now it's possible to reproduce
in the laboratory the build
582
00:40:36,103 --> 00:40:39,921
up of these aggregated
proteins, including alpha synuclein.
583
00:40:39,961 --> 00:40:43,561
This is an image of a thin
slice seeing a nerve cell that's
584
00:40:43,573 --> 00:40:46,945
been incubated in the
laboratory for a couple of weeks,
585
00:40:46,985 --> 00:40:52,728
under conditions where a fibrous
form of Elvis synuclein seeds,
586
00:40:52,768 --> 00:40:56,579
the accumulation of the structure
which has been given a false color here,
587
00:40:56,619 --> 00:40:59,685
is seen in an image
with a special microscopic
588
00:40:59,697 --> 00:41:02,448
technique called
fluorescence microscopy,
589
00:41:02,488 --> 00:41:07,132
where you can see a discrete particle not
not one that's enclosed within membranes,
590
00:41:07,172 --> 00:41:08,757
but includes, but does include
591
00:41:08,769 --> 00:41:11,165
membranes and filaments
and other proteins.
592
00:41:11,205 --> 00:41:14,112
So given that we
can replicate the
593
00:41:14,124 --> 00:41:17,961
production and build
up of these Lewy bodies,
594
00:41:18,001 --> 00:41:21,598
it may be possible to use
cells grown in the laboratory
595
00:41:21,610 --> 00:41:24,897
to investigate their
influence on cell physiology,
596
00:41:24,937 --> 00:41:29,643
not having to rely on on an
animal or on the human patient.
597
00:41:29,683 --> 00:41:32,017
These can be human
cells grown in the laboratory.
598
00:41:34,223 --> 00:41:38,255
Now, let me tell you,
near the end of what we
599
00:41:38,267 --> 00:41:42,223
know about two other
aspects genetic aspects
600
00:41:43,804 --> 00:41:51,097
that come from different genes that
have been identified in some families
601
00:41:51,137 --> 00:41:54,695
that have a familial form
of Parkinson's disease.
602
00:41:54,735 --> 00:41:57,832
I told you about the first
one that's alpha synuclein that
603
00:41:57,844 --> 00:42:01,006
affects the viability of cells
that are secreting dopamine.
604
00:42:01,046 --> 00:42:02,835
But there are many
other genes, and
605
00:42:02,847 --> 00:42:05,198
each one has a different
story associated with
606
00:42:05,238 --> 00:42:11,923
I'm going to tell you about one
now that affects the ability of cells,
607
00:42:11,963 --> 00:42:14,965
to control the health
of a very important
608
00:42:14,977 --> 00:42:18,421
organelles in the cell
called the mitochondria.
609
00:42:18,461 --> 00:42:23,423
So this is a electron microscope
image of the mitochondria.
610
00:42:23,463 --> 00:42:25,616
It's the powerhouse of the cell.
611
00:42:25,656 --> 00:42:30,779
It's the organelles that makes the
energy currency of the cell called ATP.
612
00:42:30,819 --> 00:42:33,905
And it is highly elaborate
in its mechanism.
613
00:42:33,945 --> 00:42:38,073
We don't have time to discuss this,
but the mitochondria and unlike other
614
00:42:38,085 --> 00:42:41,945
organelles in a cell, even has its
own DNA molecule, its own genome.
615
00:42:43,509 --> 00:42:47,468
That genome has to be housed
protected within the mitochondria
616
00:42:47,480 --> 00:42:51,009
if it escapes from the
mitochondria and for any reason,
617
00:42:51,049 --> 00:42:54,199
the Cell C's DNA in the cytoplasm.
618
00:42:54,239 --> 00:42:59,906
And that sets in train a series of
steps that leads the cells to kill itself.
619
00:42:59,946 --> 00:43:04,016
Because DNA in the cytoplasm is an
indication that something has gone very
620
00:43:04,028 --> 00:43:07,946
wrong and the cell needed to kill
itself before other damage can occur.
621
00:43:11,795 --> 00:43:17,729
So this is a cartoon of the structure
of the envelope of the mitochondria.
622
00:43:17,769 --> 00:43:22,077
The details of this are
not necessarily important.
623
00:43:22,117 --> 00:43:26,274
This is a fluorescence image of a cell.
624
00:43:26,314 --> 00:43:30,273
This is the nucleus of the cell,
and the mitochondria form a kind of
625
00:43:30,285 --> 00:43:34,314
a particular network different
from the air that I described earlier.
626
00:43:34,834 --> 00:43:38,633
But each individual
mitochondria can be highlighted
627
00:43:38,645 --> 00:43:42,603
and shown to contain its own
chromosome DNA molecule,
628
00:43:42,643 --> 00:43:45,911
quite distinct from that found
in the nucleus of the cell.
629
00:43:48,986 --> 00:43:52,940
Now, when a cell senses that
some damage has occurred and
630
00:43:52,952 --> 00:43:56,986
the mitochondria can no longer
contain DNA or oxygen free,
631
00:44:02,655 --> 00:44:08,071
free radicals of oxygen that are
generated during the production of ATP,
632
00:44:08,111 --> 00:44:12,432
the cell has evolved a means of capturing
and destroying damaged mitochondria
633
00:44:12,444 --> 00:44:16,111
and other damaged organelles,
and this is depicted in this slide.
634
00:44:19,022 --> 00:44:23,038
It's a process that involves the
formation of a membrane that surrounds
635
00:44:23,050 --> 00:44:27,022
the damaged organelles, a membrane
that then merges with the lysosome.
636
00:44:30,431 --> 00:44:34,577
Remember, I told you the lysosome
is a is kind of the stomach of the cell.
637
00:44:34,617 --> 00:44:40,174
It has the gist of enzymes that will
chew up anything that is delivered to it.
638
00:44:40,214 --> 00:44:43,319
And so after some time,
these damaged mitochondria,
639
00:44:43,331 --> 00:44:45,789
including their DNA
and their membranes,
640
00:44:45,829 --> 00:44:49,900
are just completely destroyed down
to the nucleotides and amino acids and
641
00:44:49,912 --> 00:44:53,829
sugars and these individual
components and can be reused in the cells.
642
00:44:55,407 --> 00:45:01,280
This is a very important process called
autophagy or selectively for mitochondria.
643
00:45:01,320 --> 00:45:03,758
It's called mitophagy.
644
00:45:03,798 --> 00:45:05,766
Now, why am I telling you this?
645
00:45:05,806 --> 00:45:09,681
It's important because two genes
that have been discovered in recent
646
00:45:09,693 --> 00:45:13,806
years in familial forms of Parkinson's
affect the machinery in the cell,
647
00:45:16,708 --> 00:45:20,815
that is required to recognize when a
mitochondria has become damaged
648
00:45:20,827 --> 00:45:24,708
and to cause it to become engulfed
and degraded in the lysosome.
649
00:45:27,886 --> 00:45:31,165
These jeans are called
pink one and parkyn, it
650
00:45:31,177 --> 00:45:35,029
doesn't matter what these
jeans do for the time being.
651
00:45:35,069 --> 00:45:38,719
Let me just tell you that
it's part of what is has a
652
00:45:38,731 --> 00:45:42,117
general term called a
quality control mechanism.
653
00:45:42,157 --> 00:45:46,057
The quality control mechanism
consists of a sensor that recognizes
654
00:45:46,069 --> 00:45:50,157
if the mitochondrion has lost
some important aspect of its integrity,
655
00:45:55,687 --> 00:45:59,702
and once recognized the damaged
mitochondria and is given a little protein
656
00:45:59,714 --> 00:46:03,687
or fragment of a protein tag, a tag
of a protein that's called ubiquitin.
657
00:46:07,826 --> 00:46:09,359
So it's a little tag.
658
00:46:09,399 --> 00:46:13,197
It's basically a special code
that says this is now damaged
659
00:46:13,209 --> 00:46:17,399
material and it should be engulfed
and destroyed in the lysosome.
660
00:46:20,333 --> 00:46:25,037
So tags are given then to damaged,
but not to healthy mitochondria.
661
00:46:25,077 --> 00:46:26,854
These tags are recognized.
662
00:46:26,894 --> 00:46:29,316
They then become allow
the organelles to become
663
00:46:29,328 --> 00:46:31,761
enveloped and destroyed
in the in the lysosome.
664
00:46:34,472 --> 00:46:39,694
Now, so that's two genes
of some fraction of patients.
665
00:46:39,734 --> 00:46:43,213
So a genetic disease of Parkinson's.
666
00:46:43,253 --> 00:46:50,088
And there are now ongoing
efforts to try to control this process.
667
00:46:50,128 --> 00:46:54,670
Oh, let me actually go back to this.
668
00:46:54,710 --> 00:46:58,831
I forgot to give the punch line,
of course, patients who lack
669
00:46:58,843 --> 00:47:02,710
pink one or parkin now fail to
mark damaged mitochondria.
670
00:47:06,518 --> 00:47:10,976
These damaged mitochondria
then persist in the cell,
671
00:47:11,016 --> 00:47:15,043
and the cells eventually
accumulate so much damaged
672
00:47:15,055 --> 00:47:19,016
material that they die of
other natural processes.
673
00:47:20,862 --> 00:47:23,585
So ordinarily, this would
be taken care of would
674
00:47:23,597 --> 00:47:26,276
be part of the housekeeping
function of a cell.
675
00:47:26,316 --> 00:47:29,754
The cell could survive because the
damaged mitochondria are disposed of.
676
00:47:29,794 --> 00:47:33,214
But when you fail to recognize
these damaged mitochondria
677
00:47:33,226 --> 00:47:36,184
that ultimately results
in the death of the cell,
678
00:47:36,224 --> 00:47:39,222
and as a result, these
patients who have
679
00:47:39,234 --> 00:47:42,684
these mutations lose
progressively many cells.
680
00:47:42,724 --> 00:47:45,938
But most importantly,
they lose those cells in
681
00:47:45,950 --> 00:47:49,450
the brain that make the
neurotransmitter dopamine.
682
00:47:49,490 --> 00:47:52,977
Now, let me to
conclude turn to another
683
00:47:52,989 --> 00:47:57,362
gene that is understood
it now a molecular level.
684
00:47:57,402 --> 00:48:00,751
It's a different gene that
turns up in many patients
685
00:48:00,763 --> 00:48:03,871
who have Parkinson's
disease with familial form.
686
00:48:03,911 --> 00:48:07,759
It's a gene called Il R K
two or look to for short and
687
00:48:07,771 --> 00:48:11,911
some very interesting recent
experiments have illuminated,
688
00:48:14,762 --> 00:48:22,142
how Lark two may control the
viability the survival of doping neurons.
689
00:48:22,182 --> 00:48:26,363
Lark two is an enzyme that modifies
another protein, and this other protein
690
00:48:26,375 --> 00:48:30,182
is required in various avenues of
membrane traffic within the cells.
691
00:48:34,555 --> 00:48:38,451
It's a kind of a molecular tag
this other protein that allows a
692
00:48:38,463 --> 00:48:42,555
protein to move within a vesicle
from one compartment to the next.
693
00:48:43,745 --> 00:48:47,316
And so it's a normal part
of normal cell function.
694
00:48:47,356 --> 00:48:51,313
Now, patients who have the most
common mutations in the last two
695
00:48:51,325 --> 00:48:55,356
gene produce this enzyme that
has even more activity than normal.
696
00:48:59,778 --> 00:49:01,512
It's a kind of an unusual situation.
697
00:49:01,552 --> 00:49:03,906
Mutations most often
cause a protein to
698
00:49:03,918 --> 00:49:06,579
be less active and
enzyme to be less active.
699
00:49:06,619 --> 00:49:10,663
But in this case, these mutations
actually make the enzyme the last two
700
00:49:10,675 --> 00:49:14,619
enzyme more active, and it more
actively modifies its target protein.
701
00:49:17,305 --> 00:49:20,492
And as a result, that
target protein loses its
702
00:49:20,504 --> 00:49:23,499
normal function
because it's over modified.
703
00:49:23,539 --> 00:49:27,410
One of the functions of
this normal protein is to
704
00:49:27,422 --> 00:49:31,539
allow cells in the brain to
make a little appendage,
705
00:49:33,012 --> 00:49:37,610
a little membrane appendage on
the surface of the cell called a psyllium.
706
00:49:37,650 --> 00:49:41,600
Many cells have a psyllium
that serves as a kind of
707
00:49:41,612 --> 00:49:45,650
an antenna as an antenna
on the surface of the cell,
708
00:49:47,465 --> 00:49:52,609
that is open for the receipt
of signals from other cells.
709
00:49:52,649 --> 00:49:56,144
One of the signaling
pathways that operates between
710
00:49:56,156 --> 00:50:00,001
cells as a funny name, it's
called the hedgehog pathway.
711
00:50:00,041 --> 00:50:03,625
And when the target
of LARC two is over
712
00:50:03,637 --> 00:50:08,041
modified, those cells
fail to make the psyllium.
713
00:50:11,356 --> 00:50:15,140
They thus fail to have an antenna
that would allow this hedgehog
714
00:50:15,152 --> 00:50:19,356
signaling pathway that actually
comes from the dopamine neurons itself.
715
00:50:23,155 --> 00:50:28,079
This pathway fails to deliver this signal.
716
00:50:28,119 --> 00:50:30,993
The response is not received.
717
00:50:31,033 --> 00:50:34,968
The dopamine cells then suffer
because this signaling pathway is required
718
00:50:34,980 --> 00:50:39,033
for the target cell to make a growth
factor that sustains dopamine neurons.
719
00:50:45,649 --> 00:50:49,611
A growth factor called GDNF is
manufactured by these target cells and will
720
00:50:49,623 --> 00:50:53,649
only do so when this signaling pathway
elicits a response from the ceiling.
721
00:50:57,154 --> 00:51:01,105
But when the psyllium
gone, this process is arrested
722
00:51:01,117 --> 00:51:05,154
in the absence of GDNF in
these Parkinson's patients.
723
00:51:05,846 --> 00:51:10,632
The dopamine neurons fail
to be nourished, and they die.
724
00:51:10,672 --> 00:51:14,842
So this is a model of
yet another independent
725
00:51:14,854 --> 00:51:18,672
means by which
dopamine neurons may fail.
726
00:51:19,273 --> 00:51:23,645
Now, let me tell you about
my involvement in this process.
727
00:51:26,227 --> 00:51:30,077
Several years ago, after a
long period of suffering, my
728
00:51:30,089 --> 00:51:34,227
wife, who had Parkinson's
disease, died now four years ago,
729
00:51:34,586 --> 00:51:36,827
and at the time I
was approached by a
730
00:51:36,839 --> 00:51:39,923
representative of the Sergey
Brin Family Foundation
731
00:51:39,963 --> 00:51:43,923
to consider organizing an
international collaborative research effort
732
00:51:43,935 --> 00:51:47,963
to understand the molecular and
cellular basis of Parkinson's disease.
733
00:51:51,819 --> 00:51:55,484
We were given an enormous
philanthropic donation, and we
734
00:51:55,496 --> 00:51:59,044
decided to team up with the
Michael J. Fox Foundation,
735
00:51:59,084 --> 00:52:02,820
which is the major philanthropic
organization that looks to
736
00:52:02,832 --> 00:52:06,579
patients around the country
and certainly around the world.
737
00:52:08,520 --> 00:52:12,161
That the donor in this
case felt that in spite of all
738
00:52:12,173 --> 00:52:15,555
of the important clinical
work that was going on,
739
00:52:15,595 --> 00:52:19,123
we still, after all this time
didn't really have a clear
740
00:52:19,135 --> 00:52:22,861
picture of the molecular and
cellular basis of the disease,
741
00:52:22,901 --> 00:52:25,498
unlike the few examples
that I've just given you.
742
00:52:25,538 --> 00:52:30,982
Most forms of Parkinson's cannot
be explained as I've just done so.
743
00:52:31,022 --> 00:52:37,738
Together with the team, we have
decided to create a funding initiative.
744
00:52:37,778 --> 00:52:39,134
And we've done so now.
745
00:52:39,174 --> 00:52:41,951
Over the course of two
years, we've identified
746
00:52:41,963 --> 00:52:45,168
teams of investigators,
not individual investigators.
747
00:52:45,208 --> 00:52:48,250
We feel that people really
on a problem like Parkinson's.
748
00:52:48,290 --> 00:52:52,075
We feel that people really
need to get together to work
749
00:52:52,087 --> 00:52:56,290
collaboratively to try to
tackle this, this terrible disease.
750
00:52:57,175 --> 00:53:00,389
So here are the pillars of our effort.
751
00:53:00,429 --> 00:53:03,614
We've decided to
focus on four themes the
752
00:53:03,626 --> 00:53:07,280
genetics and associated
biology of the disease.
753
00:53:07,320 --> 00:53:14,710
We know that there are, as I said, 20
different genes and probably more loci.
754
00:53:14,750 --> 00:53:17,939
We think there's a great deal to
be learned of the sort that I've just
755
00:53:17,951 --> 00:53:21,197
described about the individual
genes and how they affect the viability,
756
00:53:21,237 --> 00:53:23,466
the survival of dopaminergic neurons.
757
00:53:23,506 --> 00:53:25,774
So this continues to be a major theme.
758
00:53:25,814 --> 00:53:29,433
We also estimate that there is
an impact of the immune system,
759
00:53:29,473 --> 00:53:34,492
both the immune cells of the brain
and the body's immune responses
760
00:53:34,532 --> 00:53:41,276
that may initiate or perhaps exacerbate
the progression of damaged neurons.
761
00:53:41,316 --> 00:53:45,607
There's evidence that lesions in
the brain associated with Alzheimer's
762
00:53:45,619 --> 00:53:49,316
and Parkinson's may be inflamed
by an innate immune process.
763
00:53:50,706 --> 00:53:53,391
And we really don't understand
that and need to work on that.
764
00:53:53,431 --> 00:53:55,123
So that's another area.
765
00:53:55,163 --> 00:53:57,657
A third area is just the circuitry.
766
00:53:57,697 --> 00:53:59,165
The dopaminergic neuron.
767
00:53:59,205 --> 00:54:01,995
The neuron that makes
dopamine is the most common
768
00:54:02,007 --> 00:54:04,809
one of the most complex
nerve cells in the brain.
769
00:54:04,849 --> 00:54:07,203
It's enormously extended.
770
00:54:07,243 --> 00:54:11,764
It makes many different connections
to different regions of the brain,
771
00:54:11,804 --> 00:54:15,563
and we have yet to understand
the circuitry of all the cells that
772
00:54:15,575 --> 00:54:19,804
interact with the dopamine secreting
neuron just in the normal situation.
773
00:54:20,933 --> 00:54:24,613
And we we feel that knowing
that will help us further
774
00:54:24,625 --> 00:54:28,933
understand Parkinson's that
leads to the death of these cells.
775
00:54:29,974 --> 00:54:33,705
And finally, the most
mysterious kind of series of
776
00:54:33,717 --> 00:54:37,974
syndrome precede the eventual
development of the disease.
777
00:54:40,671 --> 00:54:44,401
It's called the prodromal
period that can appear
778
00:54:44,413 --> 00:54:48,384
20 years before the onset
of the movement disorder.
779
00:54:48,424 --> 00:54:50,300
There are certain.
780
00:54:50,340 --> 00:54:54,608
Simple characteristics of patients who
eventually progressed to Parkinson's,
781
00:54:54,648 --> 00:54:58,583
sometimes they very often they report
having a poorly developed sense of smell.
782
00:54:58,623 --> 00:55:00,963
Often they have
problems with constipation.
783
00:55:01,003 --> 00:55:05,974
Obviously, these are not key indicators
of just Parkinson's, they are more common.
784
00:55:06,014 --> 00:55:08,683
But patients who
present eventually with
785
00:55:08,695 --> 00:55:12,161
Parkinson's often have
these symptoms years earlier,
786
00:55:12,201 --> 00:55:16,153
and one that is a more
clear indication of progression
787
00:55:16,165 --> 00:55:20,201
of disease as a syndrome
called R.E.M. sleep disorders.
788
00:55:21,482 --> 00:55:25,339
Patients who have REM
sleep disorder lose their ability to
789
00:55:25,351 --> 00:55:29,482
discriminate their nightmares
or dreams from wakeful thoughts.
790
00:55:30,830 --> 00:55:36,478
They often live out nightmares in
their sleep, flailing around in bed,
791
00:55:36,518 --> 00:55:39,525
sometimes throwing
themselves off of the bed onto the
792
00:55:39,537 --> 00:55:42,556
floor or harming themselves
or harming their partner.
793
00:55:42,596 --> 00:55:46,341
It's a quite frightening syndrome
that's poorly understood,
794
00:55:46,381 --> 00:55:48,681
and what is most
distressing about it is that
795
00:55:48,693 --> 00:55:51,004
within five or 10 years,
80 percent of people
796
00:55:51,044 --> 00:55:55,091
who present with REM sleep
disorder do progressed to Parkinson's.
797
00:55:55,131 --> 00:55:59,038
So we're really keen to have a cohort
of patients who have such symptoms
798
00:55:59,050 --> 00:56:03,131
that could then be used to try to
investigate where the disease originates.
799
00:56:09,367 --> 00:56:13,310
And finally, finally,
let me tell you where
800
00:56:13,322 --> 00:56:17,367
we stand in the course
of identifying teams.
801
00:56:17,560 --> 00:56:21,716
We started last year with
a selection of 15 teams.
802
00:56:21,756 --> 00:56:25,380
We selected these teams
because they contain.
803
00:56:25,420 --> 00:56:29,339
They have assembled four
or five principal investigators
804
00:56:29,351 --> 00:56:33,420
in laboratories, either at
one in one or two institutions.
805
00:56:33,674 --> 00:56:36,913
These investigators, we
we we preferred investigators
806
00:56:36,925 --> 00:56:40,056
who'd already had some
experience in collaboration.
807
00:56:40,096 --> 00:56:43,425
It's very important to understand
how you can interact with
808
00:56:43,437 --> 00:56:46,890
other scientists, it's not
normal, most scientists act alone,
809
00:56:46,930 --> 00:56:50,444
but many collaborate, and we favored
people who had already demonstrated
810
00:56:50,456 --> 00:56:53,789
a facility to engage in the give
and take of a collaborative effort.
811
00:56:53,829 --> 00:56:56,838
We look for those teams
that showed that kind of
812
00:56:56,850 --> 00:57:00,488
interaction that showed a
willingness to share new results
813
00:57:00,528 --> 00:57:04,731
even before publication to
post their work on an archive,
814
00:57:04,771 --> 00:57:07,616
as it's ready to be
published and then to publish
815
00:57:07,628 --> 00:57:10,427
in open access journals,
as I described earlier.
816
00:57:10,467 --> 00:57:14,612
We selected 15 teams consisting
of about 100 different individual
817
00:57:14,624 --> 00:57:18,467
investigators in 60 different
institutions and 11 countries.
818
00:57:18,982 --> 00:57:23,201
We've just concluded another
competition for slightly different
819
00:57:23,213 --> 00:57:26,982
topics within the four that
we that I've just mentioned,
820
00:57:29,291 --> 00:57:33,802
and we've identified
another 16 or so teams,
821
00:57:33,842 --> 00:57:37,897
that find 15 teams that will
join so that we now have thirty
822
00:57:37,909 --> 00:57:41,842
six teams of around one
and fifty different investigators.
823
00:57:43,213 --> 00:57:47,370
These people have been integrated
into an online network and are expected
824
00:57:47,382 --> 00:57:51,213
not merely to share their results
with other members of their team,
825
00:57:52,620 --> 00:57:56,020
but also to communicate
on a regular basis with
826
00:57:56,032 --> 00:57:59,515
other teams with who
have overlapping interests.
827
00:57:59,555 --> 00:58:02,111
So we've created this network.
828
00:58:02,151 --> 00:58:05,667
We were going to do this even
before the pandemic, but it's
829
00:58:05,679 --> 00:58:08,972
worked out perfectly well to
do so during the pandemic.
830
00:58:09,012 --> 00:58:13,331
We will have our first in-person
meeting of the principal investigators
831
00:58:13,343 --> 00:58:17,012
next year, but thus far this
network has become very active.
832
00:58:18,126 --> 00:58:20,796
Groups are expected
to present their work
833
00:58:20,808 --> 00:58:24,001
in an online forum in
front of other individuals,
834
00:58:24,041 --> 00:58:28,257
and they are expected to talk about
new data and not just publish data.
835
00:58:28,297 --> 00:58:31,773
So we're very hopeful
that through this
836
00:58:31,785 --> 00:58:36,058
kind of living network
organism of interactions,
837
00:58:36,098 --> 00:58:39,145
we will bring to bear
one hundred and fifty
838
00:58:39,157 --> 00:58:42,495
six of the finest
laboratories around the world
839
00:58:42,535 --> 00:58:46,523
to challenge the devastation
of this disease, and the plan is
840
00:58:46,535 --> 00:58:50,535
to carry on for 10 years and
to assess our progress thus far.
841
00:58:55,542 --> 00:58:58,152
We've committed of
almost a half a billion
842
00:58:58,164 --> 00:59:00,785
dollars to the teams
that we've assembled.
843
00:59:00,825 --> 00:59:02,766
And there's more where that came from.
844
00:59:02,806 --> 00:59:04,466
So we're very hopeful.
845
00:59:04,506 --> 00:59:11,566
We feel this is going to be more effective
than just funding individual scientists.
846
00:59:11,606 --> 00:59:14,116
So I'd be happy to
discuss this with you if
847
00:59:14,128 --> 00:59:16,593
you have questions
after the presentation.
848
00:59:16,633 --> 00:59:17,800
Thank you for your attention.
849
00:59:20,648 --> 00:59:24,228
Randy, thank you very much
for that. Absolutely fascinating.
850
00:59:24,268 --> 00:59:28,014
And as a non-scientist, clear
and informative presentation,
851
00:59:28,054 --> 00:59:31,394
I'm sure all of us here
wish you and your team
852
00:59:31,406 --> 00:59:34,830
and your colleagues
every success in that park,
853
00:59:34,870 --> 00:59:37,048
to know that I can't
think of a family
854
00:59:37,060 --> 00:59:39,811
where it doesn't, it isn't
infected in some way.
855
00:59:39,851 --> 00:59:41,237
And this is the global conference.
856
00:59:41,277 --> 00:59:47,208
So it's going to be seen by researchers
are all around the world with your...
857
00:59:47,248 --> 00:59:49,820
I'm going to we haven't got
time for questions, and they're all
858
00:59:49,832 --> 00:59:52,295
going to be lots of questions
which will forward answer you.
859
00:59:52,335 --> 00:59:54,673
But I'm going to have
moderator's privilege
860
00:59:54,685 --> 00:59:57,035
just for a second and
ask you one question,
861
00:59:57,075 --> 01:00:02,552
and that is with your if it's possible
with your with your crystal ball,
862
01:00:02,592 --> 01:00:06,850
how long do you think it's going to
be before we have the diagnostic tools,
863
01:00:06,890 --> 01:00:11,449
in place to be able
to identify Parkinson's
864
01:00:11,461 --> 01:00:14,890
symptoms and and treat it early?
865
01:00:15,771 --> 01:00:17,311
Yeah. Right.
866
01:00:17,351 --> 01:00:21,100
Well, even if we could find
a diagnostic molecule, the
867
01:00:21,112 --> 01:00:25,351
progression of disease, there's
still no effective treatment.
868
01:00:26,213 --> 01:00:28,175
So, you know, with cancer and
869
01:00:28,187 --> 01:00:31,249
heart disease, it's
best to catch it early.
870
01:00:31,289 --> 01:00:34,475
But with Parkinson's
or Alzheimer's, you
871
01:00:34,487 --> 01:00:38,309
know, there's so far no
meaningful intervention.
872
01:00:38,349 --> 01:00:41,588
So, but still, it is
important to have a marker.
873
01:00:41,628 --> 01:00:45,961
See what the problem with one
of the problems with Parkinson's
874
01:00:45,973 --> 01:00:49,628
is that the disease appears
with different symptoms,
875
01:00:50,457 --> 01:00:54,923
and then it progresses in different
ways, depending on the patient.
876
01:00:54,963 --> 01:00:58,833
And so a clinician, a neurologist,
is faced with a dilemma how to
877
01:00:58,845 --> 01:01:02,963
advise patients and their families
what to expect in the years ahead.
878
01:01:03,407 --> 01:01:06,264
I found this the most frustrating
aspect of the disease myself.
879
01:01:06,304 --> 01:01:11,892
In dealing with my wife, I had access
to some of the world's best neurologists.
880
01:01:11,932 --> 01:01:17,061
She had developed dementia, a form of
dementia called diffuse Lewy body disease,
881
01:01:17,101 --> 01:01:19,165
because it was based just on her
882
01:01:19,177 --> 01:01:22,292
behavior, not on a
biopsy of her brain tissue.
883
01:01:22,332 --> 01:01:24,481
And I asked every
time, What what
884
01:01:24,493 --> 01:01:27,290
can I look forward to?
Where is this going?
885
01:01:27,330 --> 01:01:31,039
And they would all have answers,
but they were always wrong.
886
01:01:31,079 --> 01:01:33,491
They were always wrong.
887
01:01:33,531 --> 01:01:37,321
We had developments that
that no one could have predicted.
888
01:01:37,361 --> 01:01:41,273
And eventually she died in the middle
of the night, likely of a heart attack.
889
01:01:41,313 --> 01:01:43,910
So no one had told me
that this was one of the
890
01:01:43,922 --> 01:01:46,475
consequences, not that
I could have prepared.
891
01:01:46,515 --> 01:01:49,033
So this is, of course,
tragic and enormously
892
01:01:49,045 --> 01:01:51,574
frustrating for patients
and their families.
893
01:01:51,614 --> 01:01:53,972
But I can understand your
passion for wanting to contribute.
894
01:01:54,012 --> 01:01:55,578
Also activates will do so.
895
01:01:55,618 --> 01:01:58,090
Let me let me tell you
one thing that we are
896
01:01:58,102 --> 01:02:00,696
doing if not to intervene
therapeutically yet,
897
01:02:00,736 --> 01:02:05,051
but at least have a basis
to help patients prepare.
898
01:02:05,091 --> 01:02:08,392
We fund an organization called PMI.
899
01:02:08,432 --> 01:02:11,704
It's Parkinson's Progression
Monitoring Index,
900
01:02:11,716 --> 01:02:15,349
and this is a clinical group
that is assembled now.
901
01:02:15,389 --> 01:02:19,189
Thousands of patients with
different genetic or non-drug forms,
902
01:02:19,229 --> 01:02:22,825
including these prodromal patients
who have REM sleep disorder.
903
01:02:22,865 --> 01:02:27,054
and they are collecting these patients
have committed to providing not only DNA,
904
01:02:27,094 --> 01:02:35,094
but tissue blood samples, urine, spinal
taps and all this material is collected,
905
01:02:35,262 --> 01:02:38,965
stored and made available to
investigators to qualified investigators.
906
01:02:39,005 --> 01:02:43,131
And as a result of
this collection, there is
907
01:02:43,143 --> 01:02:47,005
now one promising
preclinical diagnostic,
908
01:02:47,753 --> 01:02:49,959
which is not yet commercially available,
909
01:02:49,999 --> 01:02:53,529
and that relates to this protein
synuclein that I mentioned.
910
01:02:53,569 --> 01:02:59,344
This protein can be detected
in the Spinal Tap fluid.
911
01:02:59,384 --> 01:03:03,290
The protein itself doesn't appear to
change in its abundance during the
912
01:03:03,302 --> 01:03:07,384
progression of the disease, but the
form of the protein appears to change.
913
01:03:08,295 --> 01:03:12,000
The form that appears to
increase is the form that is more
914
01:03:12,012 --> 01:03:16,295
aggregation prone, which is what
constitutes the core of Lewy body.
915
01:03:16,716 --> 01:03:22,020
This needs to be turned into a routine
clinical assay that can be done in a lab,
916
01:03:22,060 --> 01:03:28,416
a lab that's not equipped with
necessarily with an electron microscope.
917
01:03:28,456 --> 01:03:32,284
Anyway, that's that's a hopeful
development that will allow
918
01:03:32,296 --> 01:03:36,456
patients at least to have some
knowledge and perhaps to prepare.
919
01:03:38,015 --> 01:03:40,879
The most important
thing is to proceed with
920
01:03:40,891 --> 01:03:44,224
these molecular clues that
we have from the genes.
921
01:03:44,264 --> 01:03:48,466
And there are a number of biotech
companies that have very promising
922
01:03:48,478 --> 01:03:52,264
approaches to target synuclein
and its aggregation character.
923
01:03:54,295 --> 01:03:58,121
There's a drug that's being tested
now in phase one clinical trials on
924
01:03:58,133 --> 01:04:02,295
human patients that reduces the
aggregation prone character of of synuclein.
925
01:04:05,416 --> 01:04:09,254
And so maybe that will help mitigate
the progression of the disease.
926
01:04:09,294 --> 01:04:13,131
There are there are two
different drug development
927
01:04:13,143 --> 01:04:17,294
efforts underway to target
this gene, called LARC two.
928
01:04:17,807 --> 01:04:22,560
I told you that mutations in that gene
actually make the enzyme more active.
929
01:04:22,600 --> 01:04:26,089
And so you can look for
inhibitors that dampen that activity,
930
01:04:26,129 --> 01:04:29,440
or you can look for
drugs that affect its
931
01:04:29,452 --> 01:04:33,249
ability to target to
change the target protein,
932
01:04:33,289 --> 01:04:36,100
that we think may be involved
in the production of cilia.
933
01:04:36,140 --> 01:04:39,020
So, there are leads
that come from the
934
01:04:39,032 --> 01:04:42,889
genes, but that that's
only the tip of the iceberg.
935
01:04:42,929 --> 01:04:46,917
You know, there are still many other
genes that cause the disease, and
936
01:04:46,929 --> 01:04:50,929
there are many patients who have
no parents genetic indication at all.
937
01:04:51,467 --> 01:04:53,265
That sounds like it's
going to give you and your
938
01:04:53,277 --> 01:04:55,197
first scientists busy for
many, many years to come.
939
01:04:55,237 --> 01:04:56,447
Yeah.
940
01:04:56,487 --> 01:04:58,250
So better all signs.
941
01:04:58,290 --> 01:05:00,542
But but it's a great challenge. Great.
942
01:05:00,582 --> 01:05:02,992
Randi, thank you very much again
for this inspiring, inspiring thing.
943
01:05:03,032 --> 01:05:07,389
Keynote and thank you again for
addressing the key to the future audience.
944
01:05:07,429 --> 01:05:10,446
As I mentioned earlier, we're
going to be collecting questions.
945
01:05:10,486 --> 01:05:13,042
There'll be lots of questions
which will forward to you,
946
01:05:13,082 --> 01:05:16,162
and those responses will be
published in the U.S.A. future
947
01:05:16,174 --> 01:05:19,161
official report would be
published after the conference.
948
01:05:19,201 --> 01:05:22,403
Again, thank you for
your time and good luck.
949
01:05:22,443 --> 01:05:25,068
And please join us
in a few moment, few
950
01:05:25,080 --> 01:05:28,640
minutes for the next
presentation and say the future.91685
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