BRAIN ORGANOID MAP FOR PRECISION NEUROSCIENCE AND DRUG DISCOVERY

Transcript

• 00:00And finally, we have our
• 00:03tech keynote speaker,
• 00:04doctor Luke Lee,
• 00:06who is professor of medicine
• 00:08at Harvard Medical School and
• 00:10senior investigator
• 00:11at Brigham and Women's Hospital.
• 00:14Doctor Lee has a very
• 00:16illustrious,
• 00:17career.
• 00:18He, was the distinguished
• 00:20professor at UC Berkeley,
• 00:24and,
• 00:24he was the the chair
• 00:26in
• 00:27chair professor in systems nanobiology
• 00:30at the ETH Zurich in
• 00:32in Switzerland.
• 00:33He has received many prizes
• 00:36and is recognized as fellow
• 00:38of the Royal Society
• 00:40of Chemistry
• 00:41and the American Institute of
• 00:42Medical and Biological Engineering.
• 00:45So,
• 00:46Luke, welcome. Good to see
• 00:48you back here, and I'm
• 00:50looking forward to doing
• 00:52clinical trial on your Parkinson's
• 00:55brains on a chip. K.
• 00:56Thank you very much. It
• 00:58is my honor
• 00:59and joy,
• 01:01to be here.
• 01:02Actually, I learned a lot
• 01:03today because I'm not a
• 01:05really Parkinson's disease biologist or
• 01:07clinician,
• 01:08but I'm learning.
• 01:10And so,
• 01:11it is
• 01:12quite exciting because all the
• 01:14speaker
• 01:15actually told me a lot
• 01:17of new things. I realized
• 01:18that, wow, I have to
• 01:19still study more.
• 01:21So,
• 01:22at the beginning,
• 01:23I'll talk about some of
• 01:25the engineering background or molecular
• 01:27diagnostic, which is which you
• 01:29might think that it's nothing
• 01:30to do with the Parkinson's
• 01:31disease, but
• 01:33imagine that, you want to
• 01:35make a very fast early
• 01:37diagnosis
• 01:38of
• 01:39Parkinson's disease or Alzheimer disease,
• 01:42on-site,
• 01:43or every few months or
• 01:45every week, you can make
• 01:47nice diagnostics. So I'll talk
• 01:49about some of the basic
• 01:51oh, sorry.
• 01:55You know, basic,
• 01:56of the device.
• 01:58So our group is known
• 01:59as
• 02:00a patient oriented engineering medicine
• 02:02group. We like to write
• 02:04a poem on the chip.
• 02:07But,
• 02:08William Blake, you already know,
• 02:10but,
• 02:11he summarized my research in
• 02:13four line, but I just
• 02:14introduced you to the time
• 02:15first line, two CO in
• 02:17the grain of sand.
• 02:19To see the world in
• 02:21a grain of sand.
• 02:22Is it possible to gaze
• 02:24at the health status of
• 02:25humanity and the earth in
• 02:27a grain of sand? Can
• 02:28we create smart sands to
• 02:30view DNA and RNA fingerprints
• 02:33from our blood and the
• 02:34earth in real time. Reflecting
• 02:36on Blake's poem in our
• 02:37fast paced world provides an
• 02:39inspiration
• 02:40to find a proactive solution
• 02:42for our global biosecurity.
• 02:44The world is more dangerous
• 02:46today due to the emergence
• 02:48and spread of new infectious
• 02:50diseases.
• 02:50With smart SANS, we can
• 02:52prevent such outbreaks from happening
• 02:54through early detection.
• 02:56We propose
• 02:57SANS
• 02:58speedy analytical
• 03:00nano optofluidic
• 03:02diagnostic systems.
• 03:03Smart SANDS are on chip
• 03:05for rapid and accurate molecular
• 03:08diagnostics.
• 03:09Smart SANDS can be used
• 03:11by anyone with a smartphone
• 03:13even in areas where rapid
• 03:15and accurate diagnostics
• 03:17are usually inaccessible.
• 03:19Smart sands will be globally
• 03:21connected to an integrated data
• 03:23hub. Smart sands rapid and
• 03:25accurate molecular
• 03:27diagnostic
• 03:28network for human, agricultural,
• 03:30and environmental health will radically
• 03:32improve global health care and
• 03:35empower us to create a
• 03:36new proactive,
• 03:38predictive, and preventative
• 03:40paradigm for enhancing global biosecurity.
• 03:42Security.
• 03:43Is it possible to gaze
• 03:45at the health status of
• 03:47humanity
• 03:47and the earth in a
• 03:48grain of sand?
• 03:51So this was actually proposed
• 03:53that,
• 03:54to Singapore government ten years
• 03:56ago.
• 03:57Imagine if we had this
• 04:00molecular diagnostic system
• 04:02that we developed the, photonic
• 04:04PCR on a chip
• 04:06in three minute.
• 04:07The
• 04:08the COVID situation could be
• 04:10completely different.
• 04:11But now, I didn't give
• 04:13up. So I'm trying to
• 04:14add the molecular,
• 04:15biomarker
• 04:17of the different disease, not
• 04:18only infectious disease. So you
• 04:20can think about,
• 04:22monitoring,
• 04:23molecular level informations.
• 04:26So, just for example, this
• 04:28is quite a long time
• 04:29ago. We developed a a
• 04:31smart sand,
• 04:33genomic diagnostic system
• 04:35so that we can really
• 04:36make automation sample of sample
• 04:38to prep
• 04:39detection can be very fast
• 04:41because we integrate
• 04:43sample preparation, which is separating
• 04:45the cell as well, I
• 04:47mean, plasma
• 04:48and then,
• 04:49making,
• 04:50nucleic acid
• 04:52amplification reaction on-site.
• 04:54So this just chip there's
• 04:56no external pump, but it
• 04:58automatically running because there is
• 04:59a mechanical vacuum battery that
• 05:02allow to separate
• 05:04and isolate each chamber. Each
• 05:06chamber will be isolated soon,
• 05:08and then each chamber, you
• 05:09can
• 05:10put different marker
• 05:12so that,
• 05:14you can separate plasma quickly
• 05:17on-site
• 05:19to to the vacuum,
• 05:20battery so you can have
• 05:21a plasma in each chamber
• 05:24that,
• 05:25this is the bad design.
• 05:27And then good design
• 05:29allowed to isolate each each
• 05:31well.
• 05:32So each well can be
• 05:33separated like this
• 05:36and immediately
• 05:37react so that you can
• 05:38detect,
• 05:40different disease.
• 05:41You can really see, even,
• 05:44ten copies per microliter can
• 05:45be detected in a few
• 05:46minutes.
• 05:47This is
• 05:49possible,
• 05:49but, anyway, why I'm showing
• 05:51you this? I want to
• 05:53just give you hope that
• 05:54we can make a very
• 05:55fast diagnostic early diagnostic of,
• 05:58Parkinson's disease or Alzheimer's disease
• 06:01so that we can map
• 06:02out
• 06:03environmental factor because we can
• 06:05detect also,
• 06:07water pollution,
• 06:08based,
• 06:10the marker,
• 06:11can be,
• 06:13identified
• 06:14or even food as well
• 06:15as our body and so
• 06:16on.
• 06:18But now I'll talk about
• 06:20dynamic cell culture.
• 06:21So,
• 06:22since,
• 06:23early two thousand, we've been
• 06:25working on so called cultural
• 06:27revolution
• 06:28in recapitulating
• 06:30physiology.
• 06:31Why I'm so talking about
• 06:32cultural revolution?
• 06:34This is fantastic patronage
• 06:36invention of patronage to fantastic
• 06:38so that, Robert Koch got
• 06:40Nobel Prize because of Petri.
• 06:43His student or technician made
• 06:45the Picchu dish as an
• 06:46invention.
• 06:47This is
• 06:48excellent, invention for
• 06:50static condition.
• 06:51But imagine,
• 06:53our cell and our body
• 06:55is supposed to expose to
• 06:56dynamic flow.
• 06:57It's not static.
• 06:59So if you're still, culturing
• 07:01the cell in static condition,
• 07:02you have to question that
• 07:04whether we are still
• 07:06arguing that earth is flat.
• 07:10Well, earth is not moving.
• 07:12Earth is dynamically moving.
• 07:15Our cell is supposed to
• 07:16expose to dynamic condition. For
• 07:19example,
• 07:21this is
• 07:22oh, sorry.
• 07:25So this is a tissue.
• 07:26Right? There is a circulatory
• 07:27flow as well as the
• 07:28interstitial flow. So we have
• 07:30to provide similar dynamic
• 07:32when we culture the,
• 07:35our cell so that we
• 07:36develop
• 07:37the, microfluidic that allow to
• 07:38have, like, blood flow as
• 07:40well as the interstitial flow
• 07:42with the control with the
• 07:43different,
• 07:45flow rate.
• 07:47And then, we can really
• 07:48study what is the best
• 07:50way to reprogram stem cell
• 07:53as well as manipulating,
• 07:55different concentration
• 07:57exposed so that we can
• 07:58have a nice,
• 07:59dynamic cell culture chip so
• 08:01that, this one was
• 08:03acquired by Merck, but then
• 08:05we're still continuing making organoid.
• 08:08Organoid is different than even
• 08:09typical cell culture. So, this
• 08:11is a beautiful organoid that
• 08:13you already know,
• 08:15by Lancaster
• 08:17and then,
• 08:18they this is a typical
• 08:20procedure and everybody has a
• 08:21different recipe. You might have
• 08:23a different cooking style. But,
• 08:25however, my concern is
• 08:27this
• 08:28is lack of the precision
• 08:30control.
• 08:32How do you deal with
• 08:33this for the drug discovery?
• 08:35Because it's all different stage
• 08:37and different size and different
• 08:39condition
• 08:40even though your culture in
• 08:42same pitcher dish
• 08:44to start with. But when
• 08:45you drop in the bioreactor,
• 08:48you generate all different size
• 08:50and different
• 08:51stage.
• 08:52So, we identify
• 08:54this problem of the non
• 08:55uniformity
• 08:56and
• 08:57and also,
• 08:59oh,
• 09:01sorry. Problem is, also,
• 09:03random screening and operator dependent.
• 09:06So we want to make
• 09:07a solution to make a
• 09:08lab automation and lab
• 09:10skill
• 09:11formation and monitoring.
• 09:14So we call it as
• 09:15a BRAIN MAP,
• 09:17Microphysiological
• 09:18Analysis Platform Map
• 09:20to really make a real
• 09:21time detection and non invasive
• 09:24and sensitive monitoring
• 09:25of neurogenesis
• 09:26or neuropathogenesis
• 09:28as well as a drug
• 09:29discovery.
• 09:31So, the purpose of the
• 09:33map is to provide a
• 09:34dynamic condition
• 09:36and recapitulating physiology and so
• 09:38on.
• 09:39So this give you idea
• 09:40this is the top view,
• 09:41but in the cross sectional
• 09:43view, I'll skip this process
• 09:45processing,
• 09:46but this is a purely,
• 09:48precise engineering
• 09:50issue that we can really
• 09:52think about how to form
• 09:53the brain organoid uniformly
• 09:55and the red channel is
• 09:57a proficient channel that we
• 09:58can provide precisely the transcription
• 10:02factor at specific time and
• 10:04specific amount as well as
• 10:06a different,
• 10:07inflammation factor and so on.
• 10:09So you can control and
• 10:10perturbate precisely.
• 10:12So by doing this,
• 10:14you can also,
• 10:15put integrate
• 10:17this
• 10:18EEG like electrode
• 10:21so that we can detect
• 10:22the brainwave without touching the
• 10:24cell. Many people use MEA
• 10:27but MEA is providing good
• 10:30action potential,
• 10:31local field potential, but you
• 10:33cannot detect the brain wave
• 10:35by touching the cell. So
• 10:37we have to also think
• 10:38about noninvasive
• 10:40way of detecting brain wave
• 10:41as well as exosomes.
• 10:44So this is uniformity
• 10:46that we form due to
• 10:48the this precise control of
• 10:50the forming this cell culture.
• 10:54And then, we can detect,
• 10:56this
• 10:57real time EEG
• 11:00cyst I mean, from either
• 11:01midbrain or cortical. By the
• 11:03way, I really appreciate,
• 11:05the collaborator,
• 11:07doctor Park, at Yale and
• 11:09provide the cortical organoid, but
• 11:11then we compare with the
• 11:12middle brain. So, we can
• 11:15really see,
• 11:16really different, behavior, electrophysiological
• 11:18behavior of this. And then,
• 11:21another factor is when we
• 11:23participate with LPS, inflammation factor,
• 11:26you can see
• 11:28why, there's a beta wave
• 11:30and gamma wave is increasing.
• 11:31So you can,
• 11:33use this kind of the
• 11:34system as a drug screening
• 11:35or
• 11:36pathogenesis,
• 11:38detection.
• 11:39So here, with the Shanjun
• 11:41Dong,
• 11:42we have this r o
• 11:43n. So I am really
• 11:45thankful that I met Clement
• 11:47and Shanjun
• 11:49before they came to Yale.
• 11:51But here, we we are,
• 11:54you know, working on this
• 11:55PD model.
• 11:57And here we show the
• 12:00is just
• 12:01using traditional
• 12:02way of making organoid, but
• 12:04we compare with
• 12:06with the, organoid on the
• 12:07chip. And, we like to
• 12:09really make a correlation with
• 12:12multi omic expression,
• 12:14especially circular RNA,
• 12:16with electrophysiological
• 12:18data. This is still ongoing,
• 12:20so, just
• 12:21wait for us maybe next
• 12:23year. But here, showing that
• 12:25using our,
• 12:26system,
• 12:27and we were able to
• 12:29really capture
• 12:30nice,
• 12:31characterization
• 12:32of this midbrain organoid
• 12:34and expression level can be
• 12:35detected.
• 12:38And, this showing you that,
• 12:40the difference between,
• 12:42our noninvasive
• 12:43EEG like system
• 12:45and compared to MEA. When
• 12:46you drop the organoid
• 12:49and on top of this
• 12:50MEA,
• 12:51as you can see due
• 12:52to the mechanobiological
• 12:54aspect,
• 12:55after a few days you
• 12:57can form
• 12:58the scar and astrocyte
• 13:00so that you you are
• 13:01instead of reading the brainwave,
• 13:03you are reading the response
• 13:04of the astrocyte. So there's
• 13:06the,
• 13:07issue of the, MEA data.
• 13:10You can get data, but
• 13:11that data doesn't mean that
• 13:12the brainwave that is
• 13:15generated by
• 13:16neural network of this organoid.
• 13:23And then, also, you can
• 13:24take advantage of this organoid,
• 13:27to really capture the the
• 13:29optical imaging of the calcium
• 13:31wave.
• 13:33And also, you can see,
• 13:35real time detection of the
• 13:36evolution
• 13:37during the growth, like forty
• 13:39days, fifty days, sixty days
• 13:41of this,
• 13:43the brain organoid can generate
• 13:45different brain, wave.
• 13:47And, also,
• 13:50as you already know,
• 13:52if you treat it with
• 13:53the aldopa, what happened to
• 13:54this brain organoid? It's really
• 13:56fascinating that it responds
• 13:58even though this is tiny,
• 13:59tiny organoid.
• 14:02And we we intentionally,
• 14:04use MPP plus to check
• 14:06how this,
• 14:08this
• 14:09toxin toxin neurotoxin can really
• 14:13show us neurodegenerative
• 14:15progress.
• 14:17So,
• 14:18I'll skip this one but
• 14:19here, as you can see,
• 14:22this is before and early
• 14:23MPP plus and middle of
• 14:25MPP plus and later. So,
• 14:27it takes time to really
• 14:29respond to this neurotoxin
• 14:32neurodegenerative
• 14:33progress and so you can
• 14:35really watch this.
• 14:38Now I'm showing you
• 14:40the exodus
• 14:42because we want to really
• 14:44analyze the EB,
• 14:46from,
• 14:47this brain organoid.
• 14:48So exodus is nothing but
• 14:51exosome,
• 14:52detection
• 14:52using this ultra purification system
• 14:55that
• 14:57that we can really, use
• 14:59acoustic device
• 15:01to, clean out all other
• 15:03unnecessary,
• 15:04stuff and then, purify
• 15:06only the specific
• 15:08size of the,
• 15:10EB.
• 15:11So you can imagine
• 15:13even this is a really
• 15:14small,
• 15:15nanoparticle
• 15:16that you can see hopefully,
• 15:19from this,
• 15:20purified
• 15:21exosome,
• 15:22how this
• 15:24RNA expression
• 15:25or
• 15:26other protein expression can be
• 15:28detected.
• 15:29So this is one example.
• 15:31It's not really a Parkinson
• 15:32disease, but using,
• 15:35basically,
• 15:36the exosome from tiers,
• 15:39we can really analyze,
• 15:42the where the, this exosome
• 15:44is coming from. So some
• 15:45part it's not only the
• 15:47eye disease. I mean, from
• 15:48the eye part but different
• 15:50organs.
• 15:51I mean, this
• 15:52exosome from the tears
• 15:55represent
• 15:56different parts of the organs
• 15:57so that you can really
• 15:58take advantage of the,
• 16:00the diagnostics
• 16:01using tear.
• 16:04So,
• 16:06in the in the future,
• 16:07we are still ongoing. We
• 16:08are really detecting.
• 16:10Okay. Five minutes.
• 16:12I'll speed up.
• 16:14We can we are collecting
• 16:16exosome
• 16:16and then analyze
• 16:18and compare with the healthy
• 16:20NPD.
• 16:22And then this is ongoing
• 16:24profiling.
• 16:26But I'd like to just
• 16:27highlight briefly
• 16:29different design of chip because
• 16:31you might, have a different
• 16:32biological question for PD, but
• 16:34here,
• 16:35it's not really PD, but
• 16:37I like to just show
• 16:38you how we can make
• 16:39a long and brain axis
• 16:41on a chip. So we
• 16:42can develop,
• 16:44the chip that allow to
• 16:45have, both a barrier
• 16:48in the lung as well
• 16:49as a BBB.
• 16:50Then we connect together to
• 16:52understand,
• 16:53how,
• 16:54the infection
• 16:55through the lung can influence
• 16:57the brain. So, you can
• 16:58take advantage
• 17:00of this kind of chip
• 17:02to analyze
• 17:03many different
• 17:05diseases.
• 17:06In this case it's COVID,
• 17:07but however you can think
• 17:08about different
• 17:10neurological toxins
• 17:12influenced to the lung and
• 17:13then goes to the brain.
• 17:15So due to the time,
• 17:16I'm going to skip all
• 17:18the details of this chip,
• 17:20but I hope you can
• 17:22read
• 17:23this Nature BME.
• 17:25And then another one is
• 17:27a gut brain.
• 17:28So,
• 17:29you can imagine this,
• 17:32toxin from,
• 17:33even from the gut, can
• 17:35influence. So, hopefully,
• 17:37you can in this chip,
• 17:39we can drop
• 17:41three-dimensional
• 17:42we can culture three-dimensional,
• 17:45like,
• 17:46neuron astrocyte,
• 17:49like, spheroid.
• 17:50But then, we can also
• 17:52co culture
• 17:53microglia.
• 17:54So you can understand,
• 17:55this together
• 17:57along with, also gut
• 17:59barrier
• 18:01so that, you can really
• 18:03analyze detail of the
• 18:05different,
• 18:06toxin effect
• 18:08due to the, this inflammation.
• 18:10So to I'm gonna just
• 18:12skip this.
• 18:15But I like to just
• 18:16highlight that using this kind
• 18:18of the, technology,
• 18:20you can really connect together
• 18:21different body.
• 18:22How does it Parkinson's disease
• 18:24is connected to lung or
• 18:26gut,
• 18:27so that we can really
• 18:29think about,
• 18:30nice body function using different,
• 18:33the connection
• 18:34of the microphysiological
• 18:36analysis
• 18:37platform.
• 18:38So in summary,
• 18:40I like to just highlight
• 18:41that,
• 18:42we can really create new
• 18:44technology
• 18:44for precision neuroscience and neurology
• 18:47so that we can really
• 18:48work together.
• 18:50We not in order to
• 18:51really work together we have
• 18:53to converge the physical and
• 18:54life science and engineering and
• 18:56medicine to make active learning
• 18:58spirit
• 18:59and then multidisciplinary
• 19:00teamwork,
• 19:01really need a humble spirit.
• 19:03So innovative design really need
• 19:06a a creative spirit,
• 19:08and micro nanotechnology
• 19:09will provide,
• 19:11with a precision spirit and
• 19:13mission oriented action and standardization
• 19:15need intentional
• 19:16spirit. And, hopefully,
• 19:18we have to really remember,
• 19:20this knowing is not enough,
• 19:22we must apply.
• 19:23Willing is not enough, we
• 19:25must do. In the realm
• 19:26of ideas, everything depends on
• 19:28enthusiasm.
• 19:29In the real world, we
• 19:31all
• 19:32rest on perseverance.
• 19:34Thank you.