Herald: So, willkommen zusammen. Heute Abend gibt es den Talk von Andrea über den
"Corona Virus Structural Task Force". Ich bin melzai_a Herald für die Session. Wir
haben einen Signal Angel, Dia, sie wird die Fragen sammeln, die in den Chat
gestellt werden und am Ende gehen wir im Vortrag über diese Fragen. So viel zum
Ablauf. Der Vortrag wird aufgezeichnet. Und ist danach nachträglich verfügbar auf
Media.ccc.de irgendwann in den nächsten Tagen oder Wochen. Und damit würde ich mich
freuen, Andrea, du als Nachwuchsruppenleiterin an der Uni
Hamburg, du hast die letzten zwei Jahre mit den Codona Virus beschäftigt, und
daraus wunderbare Visualisierung gemacht. Wie lief es denn ab und wie sieht Corona
eigentlich aus?
Andrea: Ja, vielen dank! Erstmal danke für die Einladung. Und ja, genau darum geht es
in dem Talk jetzt, was wir die "corona virus structure task force" nennen. I'm
going to give the presentation in English; so that international listeners can also
listen in. But you can ask your questions in, well, any language anyone here speaks.
I understand German, English and Japanese. And I want to start with a quote by Marie
Curie. I know the room Mary is not named after Marie Curie, but she said something
that is very true in this pandemic, which is: "nothing in life, is to be feared,
only to be understood. Now is the time to understand more so that we may fear less."
And indeed, this holds true for the corona virus more than anything, because as you
all know, you cannot see the virus. You can only see it indirectly visualized by
science or you can see the measures against it or you can see ill people. But the
virus itself is invisible. And I'm going to start this talk with questions. There
will be many questions. And the first one is, what does the corona virus look like?
Now you may think, you know, but the reality of it is that even German news has
no idea. And I know that ZDF is now using a different picture, which looks more
similar to what I'm going to show, but it's very wrong as well. This picture? Is
what most people think the virus looks like. And I also brought you like two top
model and models of the virus. One can even make sounds. Any spiky ball of
this days really passes as a corona virus because no one seems to know what the
thing really looks like. Only it's like crowned. And it has spikes. That's the
only thing that all the models have in common. But some things look like you can
just, you know, like they are little Shrek ears type things or have tentacles. No
one really knows. So how do we know as scientists and can viruses, be seen? If we
imagine so, this is an electron microscopic picture of a human hair. It's
0.1 millimeters. It's the length of this line, so the hair is a little bit less.
The little red dot, which you may or may not be able to see inside that circle is
the size of the corona virus. Now if we zoom into the picture of the hair, you can
see, I hope, a little red dot here. And that's the corona virus to measure. So it
is 150 nanometers, or 0.0001.5 mm large. That is tiny
even by scientists sentence. However. Even smaller than the virus with 150
nanometers. It's a single atom, which is represented here again by a
dot, which is barely visible and is 0.1 nanometers in diameter or one. Angstrom.
Atoms are tiny, even compared to the virus. A virus is composed being matter of
very, very many atoms. How can we visualize something this small? Can we see
it with a light microscope? And what color would the virus be? This is to scale.
Yellow light. It is 600 nanometer wavelength meaning from this point to
this, it is 600 nanometers. So the wavelength of visible light, which ranges
from 400 to 780 nano meters, is actually longer than the virus is white. So there
is no chance whatsoever to ever observe a single virus with light just physically
not possible. We need something that has a smaller wavelength, and there are two
things we use X-rays, which have 0.1 nanometer wavelength. So they
are very, very small. They're like light. They're also photons. We call it
also X-ray light (Röntgenstralung, Röntgenlicht). But they have so high energy
that their wavelengths are tiny. The other thing are electrons, which have even
smaller wavelengths. If you choose to regard them not as particles, but as
waves. So we can use electrons and X-rays to observe the virus, and we do. And for
this, we have several possibilities. One of them is large particle accelerators
like the one I'm working on in Hamburg, which produces very intense X-rays.
Another one is an electron microscope. So here is a model of an electron microscope.
In order to use it, you need a scientist and then you shoot an electron beam from
an electron cannon. That's the official scientific term. It's an electron cannon
onto both an electron gun electron cannon electron gun. You shoot your electrons
through lenses, which are magnetic. Electrons are negatively charged so the
magnetic field can be used as a lens system onto a sample. For example, the
virus and then you have a detector. What do we see on this detector? We should
viruses with electrons and record how many electrons pass through the sample? What we
see looks like this. So of course, it's black and white because electrons come.
There's no colors involved. And what you can see is a dark shadow. And then around
it, a little bit of bright spots, almost like a corona during a sun eclipse. So
this is why the corona virus is called corona virus, because it spikes under the
electron microscope look like a corona. And these pictures have no colors, but
scientists like to colored them in particular in order to tell people that
this is a dangerous virus and that is the background. So if we colored, it may look
like this. And this is an official picture released very early in the pandemic by the
National Institutes as one of the first pictures of the new corona virus. We can
also do scanning electron microscopy, which is a similar measure where you coat
the entire surface and then you get a pretty three dimensional picture. What you
can see here are lung cells, the lung carpet like the like hairy structure here.
That's lung cells that are single type two alveolar epithelial cells. So there are
like a little like their job is to get rid of stuff the lungs don't want
there, like a carpet, they can move and they get rid of stuff for you. However,
these cells, you have a problem. They're infected with corona virus. You can see
some slime or mucus here, and you can see the viruses here. Because of the coating,
they look a little bit like cauliflower. So that's nice. But it doesn't give us the
full picture, but so much for people who say we cannot isolate the virus. We can
actually even like, make it visible. So we can make this invisible enemy visible. It
is just a question of having the right equipment and a good sample of the virus
and many hours of work. The virus therefore exists and can be made visible
using electron microscopes or, for example, as a particle accelerator. But
I'm not going to go into detail here. We have not enough time tonight. I'm only
going to talk about electron microscopes here. So what is the virus made of. Those
This is the virus. We're going to talk about this picture later in the talk when we
talk about model a little bit more. But here is one Spike, I think you've all
heard in news from spike proteins, which cover the surface of the virus or the
virion. If we draw this schematically, as Thomas Splettstösser presented for us, he's an
illustrator, burst in Berlin, it looks like this. And then we take only the head
of the spike, which is the region of the spike we know most about, and then comes
an animation that I did. So it's not quite as pretty. If we zoom in, we see the
surface and below that surface we see things represented as a ribbon. However,
we can show this differently. We can show the individual atoms connected to each
other. The problem with this display is that it's really hard to find anything
here. It is super difficult to get an overview with this picture, so we prefer
to show these complicated and fake molecules made up of atoms as surfaces and
ribbons. And this ribbon diagram, by the way, has also been found by a great female
scientist, Jane Richardson, several decades ago, which was quite revolutionary
for my field. So the virus is made up of atoms and molecules, and they are
structures can be found out by NMR, X-ray crystallography and electron microscopy.
For now, this is all I'm going to tell you. We're now going to dive very deeply
into the biology of the virus and what the structures tell us. And then in the end,
I'm going to tell you a little bit more exactly how we actually get from the
measurement to the model, which holds some pitfalls and problems for us. And it's an
area in which I do usually my research. But first, I'm going to talk about the
model, you all know this picture from the CDC, right? And by the way, this thing for
a scientist, this thing is not a virus, it's a variant. It's only the transport
form of the virus, the virus. That's a few more things that are not contained in this
little show. That's just a transport form for its RNA to get into a whole cell. We
call this a variant. But most people, even scientists, can also refer to it as the
virus. So this is the CDC model, right? That's the picture that went all through
the press around the world. That's like THE picture of this pandemic, and it was
made by the CDC very early on by two scientific illustrators there. However,
already then it had some problems. They made it in quite a rash and it has some
errors. So we decided to make a new picture, which looks like this. And. If
you compare it, two pictures, here are the differences. The head of the spike in this
illustration sits directly into the surface, while in reality it is singing
sitting on a long, very bendy like rope like structure that tethers it. So the
virus, the head of the spike, which binds to the host cell, is quite flexible. The
surface is not quite as coarse as shown here. It's smaller. The virus actually
relatively large for a virus, and it's got other proteins swimming in its surface. If
you look exactly, you'll see the virus is also not exactly round. Now we thought
this is not enough. It's nice to have a picture, but wouldn't it be nice if we
could actually touch it? So we made a 3D printable model for those interested. You
can find also all that information on our homepage. I'm going to show you the 3D
model. Let's see. So. This is the virus model. As you can see, the virus is not
exactly round because it's outside, it's very soft. It's like a soap bubble. It can
change its shape quite drastically. It's wobbly and the spikes are actually
stochastic highly distributed. They're not like regularly arranged and they are
swimming in the skin. And there are other proteins in the surface as well, which you
can perhaps see whether they really formed as little flower shapes, we don't know.
And the virus is huge. So this on the same scale, one to one million as a rhinovirus
for the common cold. The corona virus is huge. 20000 base pairs RNA makes it one of
the largest virus genomes we know. And a virus, therefore as soft on the outside,
while rhinovirus has a very hard and rigid shell that is always composed the same.
And we need this model in the hopes that, like other scientists and perhaps schools
would like to print it at home and actually like, get something tangible and
it turned out they did. So we got quite a few requests from people, from child care
facilities and from schools and from other scientists. And even my administration
like to have them printed. One even proposed we may have them as Christmas
ornaments, but I found that a little bit like tasteless. We didn't do it. And like,
just before I left Hamburg, we got a new model. This model is now already a year
old, and in 2021, signs made quite a lot of progress. So we now know there are
fewer spikes and a virus. All in all, it's a little bit smaller, so it's not quite
like this, but perhaps less so. It's not 15 centimeters in diameter. The model is
12, and it is still like potato shaped. It's not round because now what's
important for me to show, and I would have like to show you this model like in front
of the camera tonight, but. It went into the museum, it was the first one we had,
and we brought it to the opening of this exhibition in Hamburg "Pandemierück in ide
Gegenwart" the gigawatt, so you can now see it in the museum and we'll be back in
my office when they have assembled theres. And this also holds true. I'm going to
talk about the task force in the second half of this talk. But one thing that is
really true and what's true for this project as well is the task force is
typically more interested in new communication projects than in all the
pile of stuff we need to finish. You may notice from home. Right. So this is how
our model. Now, let's dive deeper into the thing, because so far we have only talked
about the virion and only about it's outside. So the virion has to spike
proteins on the outside. Two other proteins M and E protein, it has a double
membrane hull, which is very thin and nucleocapsid, which is wrapping the RNA.
The RNA of actually containing the genes for everything that the virus needs in
order to like, take possession of the host cell. So the RNA is the important bit the
virion is transporting and nucleocapsid and everything else kind of packs it and
makes sure it gets into the host cell. And I'm going to show you quickly a video
because I think this is so nice to understand, and it's the answer to the
question why does soap help against corona virus? Because very many, like other
viruses, are relatively hard to wash off, but not corona virus, because it's so
large, it has only a double membrane shell. And this is a very nice video from
the protein data bank from our colleagues there. So this is the virus double
membrane. It has lipid molecules. You can see there are hydrophobic on the inside
and hydrophilic on the outside, so they lock water on the outside, but not the
inside. Green molecules are soap. Soap also has a hydrophobic tail and a
hydrophilic head. So unlike the water which stays outside the soap just gets
into the membrane and kind of like goes in between the lipids. And then they make
whole sort of water molecules can get inside the virus. They can even assemble.
In around bits of the membrane and get it out of the virus hull or around a spike
and remove to spike, which is hydrophobic to stock out of the virus. This leads to a
total decomposition of the membrane and therefore it can be completely dissolved
by soap. As soon as the nucleocapsid and an RNA are exposed, the virus is no longer
infectious. It needs a spike in order to infect so, you don't need to disinfect
your hands. You can just wash them with soap, which I find is so lucky in this
pandemic because, you know, it would be really ugly if we would need to disinfect
everything all the time, but we can actually just use soapy water. Although,
let's be honest, I like to use disinfectant every here, and then it gives
me just a feeling of more safety. It's kind of like a ritual to protect me. I
suspect several of you are the same. So, so much for the virion, that's like the
outer shell, that's like the transport form. But there is more much more. This is
the corona virus life cycle, or I should be more correct. It should be called
infection cycle because technically speaking, viruses are not life. They need
a host cell to reproduce. So we're going to come back to this picture. We're going
to take this apart bit by bit. First of all, there is entry entry into oh yeah.
Let's quickly go back. The thing at the bottom here, the big thing here. That's
the host cell. And a little one is the virus, right? We're clear on that
Holbrook's here, right? And is the outside. So this is like your lung
outside. That's your lung cell inside or hopefully not your lung cell, right?
There's the virus. And this is the spike, the spike as a vaccine target, as you
know, it's what's encoded in RNA vaccines and it's also contained in all the like
vector vaccines we see. And I brought you another model for that, which saw the
picture here. So this is one to 10 million scale model of the spike. And this is an
antibody. Now if you are vaccinated either by RNA or by a vector vaccine, your body
overproduce as far as injected with spikes, which are usually on something to
carry it a host cell or a cell of your body if it's an RNA vaccine or a vector.
Your body needs a few days to recognize this thing, so once it has, it will build
antibodies that perfectly fit onto that they can recognize the spike very, very
exactly. They have a specific binding site, which is much more rigid than
anything else the antibody can bind to. Then this gets decomposed because the
vaccine is not viable. What remains in your body is information for these
antibodies. So now if you get infected with corona? The immune system antibody
recognizes the spike it has previously seen in the vaccine, and that is how the
vaccine actually works. So having this protects you, one of the biggest problems
with COVID 19 infections is that the immune system responds too late. And then
too much. So having these makes much more certain that you will not get severe
COVID, which is, I think, very nice. And what we also did, together with the
animation lab in Utah is not only make those life life cycle or infection cycle,
we also made an animation the scientifically most accurate animation
available on how the virus actually binds onto the whole cell. There's a lot we
don't know, but everything we do know we have shown here. So here is the virus. You
know the spike protein already. Yes, nucleocapsid inside there is RNA, which
encodes for the rest, we're going to go into the rest after this. And then at the
bottom here is the host cell. So lung cells actually have ACE2 receptors shown
in purple, and a spike protein recognizes those specifically meaning that items like
a puzzle piece fit exactly onto the purple receptors on the lung cells. The spikes
bind there and then something else happens. Another enzyme also being in the
membrane of the host cell cuts the spike, so it's not like the name spike suggests
it would like shoot something into. But that's not the case. It gets cut and then
comes to bed where we are a little bit unclear how this happens. So what we know
is after it's cut, it somehow ends up being tethered into the host cell and we
don't know the mechanism of this. So we decided to illustrated here with like a
refolding process and then it's energetically unstable. So in order to
become more stable, the whole thing clamps and folds together, thereby dragging the
virus and the host cell membrane together, the two membranes to buy a lipid membranes
Fuze. The virus material is inserted into the cell. The RNA is now inside the host
cell, and this is how infection happens. So we felt it was particularly important
to show this to people. We have made this animation Creative Commons, but
unfortunately only American television caught up on it, so we're really hoping
that one of the German like documentaries will show this, because we think it's
really nice to see this process like as accurately as we can depicted. So here is
the spike. That's the role of the spike. Now the nucleocapsid, an RNA a half
entered into the host cell. What happens now is that the nucleocapsid dissolves.
How that exactly happens, we don't know, but it dissolves and RNA gets immediately
translated into protein. So the genome gets RET inside the cell because the cell
believes it's own either comes from the host cell and it starts building. The
proteins encoded in proteins are again molecules. And actually, it makes one
very, very long protein chain really long, which is called the poly protein, which
then gets cleaved. So D'Souza's in this case, the thing that cleaves all the long
protein chain into individual molecules that don't actually can work is called the
main protease because it's cutting protein that's called the protease. And these are
the little triangle shaped things here. Only when that happens to these bits
become functional. So if it doesn't happen, if we can like hindered this like
cutting off the long polypeptide chain, we have an efficient drug against corona,
which is why main protease is a major drug target. And what you can see here in red
is the drug actually bound two main protease. So that's what it looks like. We
are looking specifically for inhibitors, which will stop this molecule from
function. So you can imagine this like a screwdriver that we put out of right point
in a machine where it fits and it stops the entire machinery. That's what we want.
And that's like called structure based drug design. When you actually know the
structure of the molecule and then you find a molecule, a small molecule, a drug
molecule that specifically stops whatever that protein molecule is doing. It's also
how many antibiotics work or, for example, if you've been up long yesterday aspirin.
Then. From here, where we have the poly protein thing. Something happens inside
the cell, the cell is making some kind of foam, which is connected to the
endoplasmic reticulum. That's just warm and inside it. These like enzymes that
have now been cut in our functional start, like a copy machine to make more and more
copies of the RNA genome of the virus. The whole cell kind of like foams up and makes
more RNA. And it does so by a copy machine, which is called RNA polymerase,
because RNA is a polymer and a polymerase is an enzyme that's making polymers and an
RNA polymerase is an enzyme that makes more RNA. So one way to block that process
of making more RNAs, which was similarly, you know, stop the infection cycle because
if it can't produce more RNA, it's got nothing to put into new viruses is to use
remdesivir or so we thought for a long time. So does this remdesivir. Remdesivir
looks to the host cell and to RNA polymerase in particular, like a
nucleotide, like a building block for RNA. So basically, things are it's new paper it
can copy on when in reality it's kind of explosive like blocks the entire
polymerase. So you can imagine this like a Trojan horse, remdesivir is the Trojan
horse and RNA dependent RNA polymerase is sure looks like RNA to me and just built
that into the strand. So we'll have a look at this molecule. This is, by the way, I
should probably go back and explain this for a moment. This is what we get out of
our measurements and electron microscopy. So this is the so-called reconstruction
density, and that's what we built a molecule in. So that's like what the
measurement gave us, everything else we have to do by hand. So here is the
density, and this is what the researcher built into it. The template strand, the
old one, which is to be copied, is green, the new one is orange. Remdesivir is
purple and connected to the end, although the program doesn't display it as such.
What you can also see is free magnesium ions. That's their own thing and a de
phosphate. So what are more molecules that researchers modeled in there? Where are
around it as the protein? So I've just quickly depicted it without so you can see
what's happening because it's all very crowded and difficult to see around it as
the protein and a jump of two proteins to copy the RNA and to attach one after the
other, another building block to the bottom of the orange chain. It's gotten a
remdesivir and it tried to put it there and it successfully did. And this
structure was taken as to prove that remdesivir will stop corona. But if you
look at the density, you can see that the free magnesium ions and DIPHOSPHATE has no
density and are not covered by this great cloud, right? So we think they were never
really there. And the remdesivir itself is also not having so much density. So it
turns out that a structure is not quite seeing what the researchers did because
the density doesn't match up with the structure they built. And as we later
found out in clinical trials, is that remdesivir, in fact, doesn't really do
what people hoped, which, among other things, has to do with the fact that RNA
polymerase from corona virus is able to proofread go like, Oh, there's a
remdesivir, then go back free nucleotides take rip out the remdesivir, throw it away
and get the proper nucleotide to build in. So. We're hoping that one over pea-rel will
be better, which, by the way, uses a similar mechanism. It's called a
nucleotide. Yeah, it's similar to a nucleotide. Here's another arrow we found
in the bottom of the structure, only going to show you because I think the software
by Tristan Kroll is so cool, it does a real time molecular dynamics simulation
while you're dragging around your structure. We found that there is an error
in the way the whole molecule was arranged. If there's any specialist, there
was a nine amino acid out of reach associate. OK, I'm going to stop like
geeking out. There was just an error. Let me show you how he correct that. So first
you marks up the wrong region and then he releases it and *quickly flying-away noise* it goes where it's up to
go. I wish my life would always be like this, you said were free days glasses in
front of your computer. You need hours to do this by hand, but his software just
does it. Sorry. It's just if you've spent months doing this, you're totally excited
by this wobbly molecule. I just wanted to show you because I think it's so cool. All
right. Back to a more general content. We have an hour RNA and a let's imagine we
didn't get any like good drugs so far, so the infection cycle is still ongoing. The
RNA now is exported from the endoplasmic reticulum. By the time we make this, we
didn't know how. But Hamburg researchers and Dutch researchers have now found out
how this actually works as a pore here and the pore gets the RNA out. The RNA then
gets packed into new nucleocapsid were also coded by the genome
of the virus, then gets wrapped into a new double membrane, which is host membrane.
Just it has no spikes, which also were produced from the genome. And then, of
course, due the Golgi apparatus is somehow involved, it gets exported. Of course, for
everyone that infected a cell, there will be thousands that are produced and that's
the entirety of the SarsCoV 2 viral life cycle. I know, this was a little bit
much, but I think this is cool and exciting and just about what, you know. I
hope the public can understand about this. It hopefully also tells you why molecular
structures are important, so they let us understand how the virus works, how host
cells are infected. They can help us to find drug targets and to do structure
based drug design, where we find drugs that specifically block these big
molecular machines from doing their work. They also help us to understand the
structures of vaccines and antibodies, and they also let us understand changes due to
two mutations, I haven't got an example because of the time. But when we get a
mutation with the structure, I can kind of tell you, that it is going to change or
that it is going to change only by knowing the new genome. I can already make a
prediction about what the mutation is going to change in a functionality. That's
really important. So in my group, we have some theories what a Micron actually does.
We haven't published and we haven't even tweeted about them yet because we're still
waiting for research results. But it's important to understand these molecular
structures, however, is not very easy to get them. So what are the problems? When we
do our measurement, we get density in this case, the density is blue. It's from the
spike head that I've shown in the beginning, right? So the top that you may
recognize, this looks a little bit like the blue density here. This is the result
from our research. And in this case, I have built almost all of the molecule
already, so I'm going to show it. This is like the software. We're actually using a
tenfold to speed I'm usually using, and I would usually be sitting there with 3D
glasses. So here's the density. I said that with my 3D glasses and this bit
hasn't been built, so you can now see me like by hand. And one bit of molecule
after the other trying to get the murder ought to be, and you can quite well see
that the computer is not able to do it all automatically. So I have to help it a
little bit. And as I said, it's about 10 times the speed. It's even got like the
warning from the bin program not reacting all of the software, it's also not
commercial. This has been developed by other scientists, so the usability is like
so-so cool, just an amazing program. But if you want some new functionality, you
better program it yourself, because perhaps no one else is going to do it. And we have
actually contributed with a plug in or two to cut. Yeah, you can see it's not always
easy, so I try and go, like, now it's good. Settings should nicely in the
density and here it's fairly easy. My students love doing this is like for them.
It's like computer gaming. They do it for three months straight. If you don't like,
get them off the chair, go right up your physics. They'll do it forever. And
secretly, I'm jealous. Because I also like doing this. I don't know if you can
follow, but this is like playing a game. Away, if you're interested in playing this
game, we are also having. Like practical places and stuff. Right! So building,
building, building, going like, oh, there's another alanine, I need a pralines
or mutated it. I go like, Yeah, OK, now it's all nicely sitting. So that was easy.
But what do I do here? So I've built for something here. But is it correct? The
density does not really tell me what's going on here, and I'm going to show it
this to you in slower again. So you understand the problem, right? In this
then part of the density, I can really not tell only from the density what's going
on. I know approximately what a molecule must look like due to the sequence. So
I've got some information. I know which Atom is connected to which, but how it all
three dimensionally fits in here, even if I know which lines have to go in, there is
super hard. So it would be very easy for me to make an error here, because the
measurement data don't tell me enough about what the model actually should look
like and several interpretation., everal models would all be possible. So this is
kind of difficult. I'm just seeing a questionnaire that I may want to answer
right away. Within could is it possible to verify if you have chosen created the
right building blocks, you know, the building blocks because of the genome? So
Gene tells you the order of amino acids you want to put after each other. So if
you started at the right point, the rest will also be like the correct atoms and
the correct connection. But how it like three dimensionally faults, you don't
know. You have to make that on the density. So it is possible to do it. You
have to write building blocks at hand. Usually if there are if there is like, you
know, if a magnesium ion, for example, is sitting there, the magnesium ion was not
in your genomic information. You just need to know what you're doing to recognize
this is a magnesium ion ore does this a diophosphate or something like this?
Right. Going to answer the rest of the questions later. Molecular models need to
be built by hand. This can lead to errors. There a few automatic algorithms do work
under favorable circumstances, but most of the stuff still has to happen by hand. As
of today, and I got my postdoc from like holidays for 15 minutes today, and he gave
new numbers. So we've got 1909 molecular structures
today. New structures come out every Wednesday. There are 1334 from X-ray
crystallography. That's the thing. With the particle accelerator in Hamburg, I
thought, they have been measured at synchrotrons all over the world. Not only
Hamburg, where BioNTech structures have been measured, but also had SARS. There
have been large screens a diamond in Japan and China at Sesamia, at Solemy, in
America. Synchrotrons all over the world contributed to this. 35 from nuclear
magnetic resonance, which is a little bit of a niche method for this type of study.
And 566 from electron microscopy. So 1909 molecular structures
of different states of 17 macromolecules, 17 proteins from a total
of 28. So corona virus in total has 28 different genes, 4 proteins. There are 28
proteins. And we only structurally know 17 of them. And then we have like different
versions of them, different ph, different temperatures, spike, head bit of spike
head, spike head with antibody, things like that. So a 1900 data sets that's in total.
Errors and structures, as we've just seen, can happen because fit between
the data and model is bad, because complete automation is not possible. Models are
built manually expertize in many different areas needed. You need to be good
software. You need to have done all the lab work. The measurement needs to be done
right. Processing needs to be made. You need to know your statistical validation.
You need to know your chemistry. You need to know your biology. So it's really not
easy and you need to know your 3D goggles unless you get sick from them, in which
case you can't use them. One of the major aspects of software, the methods you're
using and this is where we come in. Small structural errors can lead to big
structural problems downstream. Imagine the bid was to remdesivir, the diphosphate
there, the fact that there was something bound into that structure that was not
really there. But the model had dose like additional free magnesium ions down the
line, as I know from insiders, led to like waste of hundreds thousands of dollars
and many hours of work time in drug discovery because they kind of like fed
this model in order to find a drug that ultimately never bound because of
magnesium ion wasn't actually there. So if we make small structures, that builds
up hugely for the downstream applications where they need these molecular
structures. Errors are common. And now we add to this an ongoing pandemic. Right.
And her scientists are there to rescue today. Lockdown happened, you're sitting
at home, there are no colleagues to help you. Your child is home schooling. The dog
wants to be fed, your grandma calls, because she's worried and you've got to
solve the spike structure on which lives will depend as fast as possible. Normally,
we take a year to five to solve a structure, and in the pandemic you only
got three months. Of course, errors are going to happen. So that's well, just a
matter of fact. We've got to arrange ourselves with it. It's not the fault of
individuals, it's how the whole thing works. It's such a complex process. Errors
are going to happen! Now in normal life my team and I methods developers and
structural biology. We are the people, who give us the experimental techniques and
software to solve their structures as best as we and they can. We're not usually in
the in the stage like we're usually, you know. For every Nobel Prize, there have
been like dozens of Nobel Prizes in structural biology has been methods
developed in the background to develop the methods that made it possible to see, you
know, the structure of the DNA double helix or structure of the ribosome, or the
structure of the influenza virus. It's just that normally we're just enablers.
However, here was the pandemic and very many structures that had errors. So we did
what we needed to do. We came together as a relatively large team under my
leadership, we are today 23 people, we peaked at 27 last year from nine countries
to check an improve the molecular structures of SARS-CoV-1 and SARS-CoV-2.
So. We are methods developers, most of are methods developers, we are specialists in
solving structures. We evaluate all the published Structures and Protein Data
Databank or PDB from SARS and SARS- CoV-2. We reprocess all of them and we
remodel them, although not all are looked at manually, because that would be just
too much. We also do a scientific dissemination, putting these structures
into context for people who want to start doing molecular research on corona virus.
And we do public outreach. I'll give you a quick insight into our pipeline because I
thought the software might be interesting for you. So every Wednesday come new
entries of molecules in the protein databank, which is, by the way, the World
Wide Protein Databank is an open, open resource. Everyone in the world can
download the new structures, and all the journals require people who make new
structures to put them there, which is nice. I'm really privileged to be in a
field where the data are public. We compared the new structures with the NCBI
proteomics, so the genes from corona virus to find the structures that belong to
corona virus, put everything into an sql metha database. Then we calculate how
different the structures are from the ones we already know. We look whether all
measurement data available, so we have a big problem of not all measurement data
being published. I hope we are going to be like astronomy one day, where everything
gets published. I am sitting in the some German cometies to that end STIKO AM which
is a very new hub. And then we run a number of specialized programs which all
do validation and put the results on GitHub immediately. On Thursday, at the
latest, researchers can find our elevation, remodeling and the quality indication for
the structure everything, that can be done automatically online. We then, for some
structures, manually rebuilt them, so we actively look weathered our problems, that
was, for example, the case with the remdesivir structure. We tried to do this
for those structures that we think drug designers will use the most or that are
really important. And when we find errors, we contact our original office first and
tell them we found an error here is the corrected structure. Use our data, you
don't need to cite us, just correct your structure in the database, please. This
means we won't get credit, but I meant that at the beginning of the pandemic,
people were adjusting their structures already when the preprint was out, so
there would not be problems downstream. And I have often been asked I would like
to like this again. That was really like why people accepted our corrections,
because they didn't need to give anyone credit. They could just like change them.
And the database is also online, so everyone from the Philippines to the U.S.
can just use them, whether it's like a commercial person or a taxpayer, or a
private person research institution, a foundation, everyone can use our data.
They're just online there for everyone, and we only ask them to give us credit in
the form of a reference citation. We disseminate the data via GitHub via
Twitter. 3D bio notes, which is a three dimensional database linking directly into
our database, we contact the offers. We also have entries in Proteopedia. Molprobity,
which is a virtual bioinformatics institute, links directly into our
database. So they're always like up to date showing what we are doing. We have a
homepage and we do reviews. There's a lot of downstream users. The biggest ones are
the EU Jedi Grand Challenge folding at home, which peaked out in July last year.
I think a 2.4 xTFLOPs computing power for molecular simulations and used in the
majority our models to start from. And also very big is IBM open pandemics. But
there are a number of others, plus many individual apps. So we found a great new
many friends. Here is our homepage, that's where you can find it. There's also an
English version, you can find blog posts for the public and for scientists. And in
the end, I would like to talk for like five minutes about daily life in ritual
mobility. So my team is over 20 people from nine to ... we cover nine time zones,
right? Where nine hours time shift apart. And we had several lockdowns. So.
Actually, the majority of people in the task force, about half of them don't work
for me. They are volunteering their researchers elsewhere that volunteer to be
a part of this effort. And there are many people in the task force who have never
like personally met. So how do you make group coherence if you are working for 20
months or 22 months by now in an environment like this, right? We founded
ourselves in March 2020 as a chat group called the Coronavirus Structural Task
Force, which was a job back then. It didn't remain a joke. But that's how life
plays. We have everyday Zoom meetings at 10 o'clock, one time per week in the
afternoon. So do people from Oregon can join us. We do a lot of like media
outreach in international and German media. We've been like on nano and Terra X
and Planet E, we've been in breakfast television. That was a particularly
interesting experience. My email got link to Querdenker and I got a few very
interesting email exchanges. I also must say I never got insulted or frightened by
anyone, so I just discussed with them and it worked out. And I'm happy because like
I understood, like how, what the theories are, and that was very interesting. Keep
the media also like to write about my hair, my eyes, blah blah blah on these
things. I just want to note that Streeck is about my age, and Drosten is only nine
years older than me. So really? OK, whatever. Most importantly, they're
talking about our research. We also did a lot of social media. I got a Twitter
account. Everyone else did as well. You can watch us work on Twitch if you're
interested. We found that people find it soothing to see us modeling these
structures. I was requested to make stickers for the team as soon as we got a
grant and we got funded by the Federal Ministry for Research and Education in
2020. We have a YouTube channel where you can, for example, see the entry animation
and the students brought a cactus, which is called Corina the Corona Cactus. I
know. It looked like we had fun, and we did. I can tell you being caught, you
know, being at home, having to care for your children. Having people dying. Having
an ongoing pandemic, knowing that I 'd be more open pandemics is going to spend
another million based on your research. And also that ZDF wants to talk to you and
the Berliner Abendblatt. This is so stressful! Think about all the
responsibility we had, and it was really terrible for us, so we needed to cheer up
every here and then, the whole group kind of like grew together and we all became
friends. This was unheard. For us, it was very uncommon as researchers. Typically,
our behavior with each other is much more formal than their behavior and this group
was. But these were like exceptional times, and we wanted to fight the pandemic
and inform the public. That's what we were there for and was not so much about
personal gain. And that was nice. We have a group chat. You know, I mean, I'm
talking to right audience, right? We have a group chat. Do you know what that looks
like? Let me tell you. Typically, professors don't communicate with this.
We have a virtual, Oh, we have a virtual space. We hope to change to work
adventure soon. We all want to play games in the evening occasionally with the
group, so we do some team building efforts. When people can meet in person,
they usually do and sometimes they go and travel and like, meet each other. But this
has been very limited. And we did grow together as a network, that will be there
after the pandemic, so we are 25 people all over the planet that did this
together. And even if we wouldn't have made any difference against the virus, I
would still be happy to have done it for the friendships I made. However, we did
make a dent. We don't quite know how big it is because our science was open science
and the results could be gotten by everyone without reference. But we know a
few things wouldn't have happened without us. And I'm. Deeply grateful for having
had a purpose during this pandemic. In the end, I have a little bit of a more serious
topic. My contract is going to run out in May. I think it's going to be prolonged.
When it will, I'll be signing my 14 work contract since 2008. 14, like I had 13
year contracts already out of all my task force members, there is only one holding a
permanent position and two which are retired. Everyone else, including six
people whose contract is going to run out next year, are on temporary contracts and
not students. Students are extra. That the students are on time limited contracts is
OK, but Germany's got a problem. 84 percent of academics in German
universities are on time limited contracts. So are we. Only one task force
member has was a permanent position signed, and that's not me. And this is not
so much on my behalf, because I'm going to find my way through life. Look at all the
exposure I had, but there are people out there who are single moms and dads, who
come from less privileged backgrounds or had a harder life and who can just not
afford to be on one year contracts all the time while holding a Ph.D.. We're losing
all these bright people and I'm seeing them right. They leave my institute and
they go to industry. And then the universities complain that they're not
competitive. We need to change the system. We need to have more permanent positions
in science. I promise we won't perform worse, if you give us permanent contracts.
We love what we are doing. So back to the corona topic. In order to understand the
virus and its life cycle, we need to understand its molecular biology. This
will help with the design of therapeutics. We evaluated these molecular structures
with a bespoke pipeline, an expert knowledge provided context and reached out
to the taxpayer and the general public to inform them. We also wrote a paper
together with long off a list making the invisible enemy visible, which is our
motto. And as we started this all with questions, I'm going to end with
questions. Structural biology remains difficult. What can we learn from our
findings? Should we, as a scientists community, change our attitudes towards
errors? Should this serve as a model for other projects, cannot serve as a model
for other projects? I hadn't thought about this, but a nature editor asked me when I
was writing a comment whether we believe that science should always be like this?
My God, that would be awesome. I would totally be up for it if science would
always be like this! Come together with a bunch of friends, but without funding!
Start doing something to, you know, fight a global pandemic, then get some funding.
Still, having like no senior people on a project. Can open science compete? I don't
know. We get pretty little credit. It would, definitely. OK, science compete. I
don't know, it doesn't quite look like it still getting measured only by the
citations my paper gets. And well, at least a paper is not behind a paywall, but
if we would have published all our stuff in like papers would possibly get more
credit. I really don't know, but we need to work on this. If we want science, we
need to change how people are rewarded. How senior they really need to be. I'm 39.
It seems I'm called a junior group leader. All of us are young. The youngest is 24.
He's writing our first Alpha article about a corona virus protein. I feel that the
German academic system and all over the world, actually you need to be older and
older to become a professor and be permanent and be like a grant holder. I
don't think it's necessary, I think that professors could be 30 and the world
wouldn't, you know, like, go down. Well, what will change in science after a
pandemic? We had like large exposure. It certainly will also have to do with like
questions like did the virus now come from an app or didn't it? That, you know, would
change how people view science, I'm sure. How will scientists be viewed by the
public? Right. Right now, of course, you know, mom and dad are very proud, but.
What's going to change? Are we going to still be the bad guys because we often
are. But I'm like general, exclusively taxpayer funded. I never took any money
from the pharmaceutical industry. I have like, you know, no stakes in this game.
I'm just like earning tax money, so I feel that, there is a whole complex of
difficult things there, how people regard science, but definitely the pandemic is
going to change, how science is going to be viewed. What's that going to be?
*Exspiration* In the end. I'd like to thank all the task force members and all
our collaboration partners and our scientific fairy godmother, Alvin Pearson,
who had little role in this research but much role in our mentorship and bringing
us forward. My home, the University of Hamburg, the Coronavirus Structural
Taskforce, our we are funded by the Deutsches Officials Command Trust and the
Federal Ministry for Research and Education. I would like to point out that
we are looking for student assistance, not only for scientific work, but also for
social media video and programing work and 3D printing. So if you know anyone who's
interested, please point him in my direction. My email is there. We are also
offering Bachelor, Master and Ph.D. thesis in areas that cover both Lab work and
computer work, which is a rare thing these days. You can find us on YouTube and the
internet and on Twitter and. I'm looking forward to the discussion. And thanks for
listening. melzai_a: You write it, so.*laughing*
Andrea: I just brought it up, must have bmbF because I'm now sitting on the screen
on dislike committees more and more, I'm reaching an age where I'm sitting on
committees and I told them legacy software is a problem.
melzai_a: It's a real.big problem. Andrea: You know, it's very troubling that
the software is written in Fortran. Not every second Linus go to, so it's written
like assembler. No one knows what's in there anymore. And if a person dies, we're
not going to be able to do anything about the algorithms. They're just going to be
lost. melzai_a: Exactly. And they are. So you
have to first influence to grant writing institutes that there are grants out so
that this software can read is reversed. And this software is not easy. So that's
not your typical web page, so you need to work together in such groups. And so it's
a very interesting piece of the problem, I have to say. So sadly, as a PhD student went,
we weren't we were looking into this for the second. Ah.. This is too big of a cake
to eat. *laughing* It was very interesting. So I can also this and you
let you do it. The nudel tool suite, and that's also only maintained by, I think,
three people also. So even that one, it's with many more. It's still not good. So
just my sense of that one. Andrea: So I brought my Ph.D. thesis. I
worked on chalex?? and that faces similar problems.
melzai_a: Yeah, it's it's just used in the entire world to solve every small molecule
structure. There is more or less it was like, Yeah, so questions were the
questions. Frankly, we ain't got a first question, I think around 20 or 30 minutes
ago, if we yeah, that's that's why that was so great as a signal angel, she's
picking up all of these points. And so the first question was how do the virus
variants affect the shape or form of the virus?
Andrea: I think they so no matter like, OK, this is the old model as we know, then
there should be fewer spikes and should be a bit smaller. But nothing would change on
this view, like the scale is way too large. The mutations each change about 10
atoms, so every like amino acid at this different, it's about 10 atoms. And those
changes would be so small you could not see them on the virus model. You'd
actually need to look at the head of the spike in order to see the mutation and
what it actually does. So the changes are too small to show them in the model. That
doesn't mean they're not meaningful. So as you've seen, like the head of the spike
binds to the host, to the host cell, to ACE2 receptor, and that binding is highly
influenced by this by the mutations. Now we found that we may end up lucky because
the same paths were to antibody as binding is also the piece that binds to the host
cell. So everything that would mate despite change in a way that the antibody
couldn't bind any more to it. For its head would have also changed how it bound to
the host cell. However, it seems that Omicron is still able to bind human cells
very efficiently, while antibodies cannot recognize it so easily. That may have to
do with like this finger's actually like packed and you could imagine like putting
cotton wool around it. That's called glycosylation. It's got long sugar changes
that are rule, and they're there to obscure the immune system, like the
antibody goes like orders, wool. I can't really find where I'm on to bind. Is it
here? I don't know. And that's changed in Omicron, but it's not fully understand
yet. I saw there was a new structure this week, but I haven't looked at it yet.
However, the changes are too small to show it in the virus model. They're like really
tiny changes. And another change that happens in Omicron as well is the
proofreading mechanism. When the RNA is copied is like damaged and we think it's
damaged. So their so-called eNd RNA, which is a proofreading protein, its sharp is
like to go like a star and correct? Yes, correct, correct. Correct. That seems to
be a little bit broken. So it could be that Omicron is accumulating so many
mutations because it's RNA copy machine. It's like not working as it should is
basically not proofreading. That would mean that more viruses are produced that
are not viable and cannot survive. But it would also mean that it mutates much
faster, and we think that may have an influence. But that's just theory. So far
this hypothesis, we haven't proven it yet. So this is why I haven't tweeted about it
yet, because it's just a theory, but it would make sense, right?
melzai_a: Connected to that, I would have a question the ice receptor of small children
is a little bit different than that one of the adults to you do know about that
because all the concern to what's more, the smaller children are the defense.
Andrea: I can't. I have read that, but I haven't looked into it properly. So I'm
I'm afraid I'm not going to answer this question because I feel I would rather not
say anything about it than say something that's wrong especially.
melzai_a: Well. We're looking forward to the secretary's right in the public PDB so
that everybody can look at them and. Andrea: Know we live in an age of
preprint, and very often the PDB papers are there when a preprint comes out, which
is how we called so many errors, right? They published a preprint, they put out a
structure. We went like, there's errors in the structures. And then when they
published actual paper, everything was corrected.
melzai_a: And she's agreed that believe the changes, I think are checked on the
PDB. melzai_a: This is, in fact, because yes,
that's that's what IT people like because then that, you know, there's a
history is very important. And there's a second question and it goes towards the
tools that I use to simulate those molecules.
Andrea: Wait, wait, wait, wait. I have a follow up to this: thing that I would
really like to see, but it hasn't happened yet. The PDB is a very static repository
where only original offers are allowed to change their structures. Now, imagine if
the protein data bank would be like GitHub with pull requests. We could go like, go
like, changed the molecule around. Go like, no, it's a better fit to your data.
Please pull. Herald: That would be a very subversive
proposition. I would say. Andrea: Yeah, wouldn't that be nice? I'm
like, Why aren't we doing this? It's like the system is already there. It happens
that we have like repositories for a while in software development. We could do the
same thing with models fitted to our experimental data. But I think I need to
go into more committees. melzai_a: Yeah, it sounds like this. I
would agree for that proposal. There was a person that was asking about the toolsset
that you would use to simulate those molecules and structures and so on. And if
you then create these more usable pictures for the public, how do you balance
artist's impression simplified models and while keeping the scientific truth as
much as well as possible. Andrea: The question you don't need the
public even to have this problem. You have it already when you make pictures
scientifically. Because sometimes you want to show our certain aspects of a molecule
very clearly, which means you have to cut away, for example, a part of the molecule.
So one answer to this is the program that does. The modeling is not a program that
you use to make the pictures. That's the first thing you do. So you make your model
with one program and then you take all the coordinates of the atoms and you throw
them into a professional rendering program that like, we'll do it all pretty. But you
still have to make an executive decision on what to show in your graphics, in your
paper. And I think that in particular, structural biologists, who deal with three
dimensional and two-dimensional pictures, we would do very well to think a lot more
about scientific illustration. So all my team likes thinking about these things,
which is, I think, how we got where we are now, right? They actually like stuff like
this. They go like, Oh, we can print it 3D and we can put a magnet on it and it's
going to stick. But it turns out that scientists also need these tools to
understand what's going on. It's like actually having a 3D model helps you so
much with thinking about things. Crick and Watson. They build a model of their DNA in
metal for a reason. Because we're looking at three dimensional things, making them
like understandable with our hands. So yes, as a good researcher, you're not only
able to explain your research to the cleaning woman, you should also be able to
visualize it properly. And it's part of the art. If you are a structural biologist
and you're not able to make good pictures of your molecules, you're not a good
structural biologist. End of story. You're in the wrong discipline, you should have
possibly chosen something where you need less graphics.
melzai_a: And I think one of your industry does is actually a of biologist by
training. Right? I think you've got... Andrea: Tomasello is a proper biologist.
Thomas Splettstössersplit shrews as a prop about like a Ph.D. in bioinformatics and Janet Erosa,
and LiU are both scientists who are having a group that only deals with illustration.
So it's actually in science. We have several groups in the world and structural
biology who only do illustration as science. So David Goodsell with his
watercolors, is very well known, but Janet Erosa is another one. So actually making
these animations and pictures is so complicated that television can't do it.
And the ZDF made a series of animations, so they made very nice ones for Planet E
Rizzo and Nano with us. But then they asked my expertize to make another
animation. And they only had like a call with us, and they never came back and then
published a completely wrong animation of the entire viral mechanism under my name.
And I'm still sad every time I see it three times a day. Heute Journal shows a
wrong structure of the virus for which they claim that I helped them make it, and
I wrote to them and told them, Your depiction of the virus is wrong. I can
help you make a new one. But it seems that it's 2. deutsche Fernsehen der heute Journal at least didn't
care on. I guess they think it's not important enough, but I think with a
threat like this where we really cannot see the virus, it is important to bring to
the public the best possible depiction we can deliver. Sometimes, however, as I
said, you omit certain aspects, for example, to show the effects of a mutation
yet only showed a side of the mutation. You don't show all the atoms. But. That's
really an important part of what we are doing. Like pointing out the important
bits of ... melzai_a: Scientific information is so
important, I think we have one final question, which I would say comes out
comes towards the direction of the immune system. And the question would be can you
can you define vaccine on purpose so that the immune system can forget how to
produce the antibodies after a defined period of time? And I think the concern
here is about increasing your financial gain in the crisis, for example.
So programed obsolescence, as both of those mentioned. So you're a bit late. So
if you could keep it short, that would be great. OK? Andrea: The quick answer is no,
that's not possible. You can make. You can enhance how long vaccines and how much
immune response you get from a vaccine or certain additives. But you can not, like
make them a definite time because everybody is different. So even when you
get your booster shot, they say six months, but you may need it after three
months or you may need it after 12 authorityto. It's very hard to tell. And
pharma industry does not have tools that would allow them that, to my knowledge. So
I think that's not a risk. melzai_a: I mean, it's it's a human
system, and so complex is the rocket to the Moon. So.
Andrea: I think it's a it's a valid concern. It's just technologically not
possible. Luckily, I guess. melzai_a: The final and really last question, I think,
is where can somebody find the 3D models out there?
Andrea: Oh, you can go to inside Corona..de and find a blog post about a 3D
thing or you go to Thingy Reuss and you look for inside corona. I can. Yeah. Yeah.
I just go to. I just put it in. Why not that? That's our home page and then on
thingy worse. It's also called inside corona. And you can also write me a
message on Twitter if you don't find it at a turn up. And remember, we're going to
put out a new model soon in January, but I'm still waiting for the final files and
holiday. So it will be a few more weeks. melzai_a: So but that trend in January,
not in December 2008. Yeah, exactly. Or printed?
Andrea: Yes. So thank you very much for having me.
melzai_a: Yeah, it was good. Thank you. And I think if they are no more questions.
Everybody. All right. Oh, you know how it looks like? I think that's really
important. I think one and a half years ago, I came across the first pictures was
like, This is how it looks like. Now I can tell it to the people who who don't read
the scientific original papers because they are so difficult to read. So. Yeah.
Good. You know. And thanks for being here and looking forward to hearing and seeing
more and hopefully once this will be over. I think
Andrea: I hope so too. Going back out of the spotlight to being just a Methods
developer, that would be nice. Herald: That would be nice, yes.
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