Conversations with scientists

Proteins are twirly, curly, dynamic structures. Crucial for life, complicated to study. Predicting protein structure has been tough but it's now easier as AlphaFold enters the scene. That doesn't mean that AlphaFold has solved all challenges, of course. AlphaFold was developed by DeepMind Technologies, a company that was bought by Google in 2014. Lots of protein puzzles remain. Dr. Janet Thornton from the European Bioinformatics Institute and Dr David Jones of University College London talk about what AlphaFold can do and what it cannot yet do. They look forward, backward and all around on this subject. He says, laughing, he has "extreme cautious optimism" about the prospects of this field. You can also find my feature story about protein structure prediction, which is the Nature Methods method of the year for 2021, here: https://www.nature.com/articles/s41592-021-01359-1
 

To go along with my investigative story The CRISPR Children in Nature Biotechnology, I am producing a rolling series of podcasts. This episode is a chat with Dr. Eben Kirksey, an anthropologist at Deakin University, which has campuses in and near Melbourne, Australia. 

He has written a book called The Mutant Project, Inside the Global Race to Genetically Modify Humans.  It's dedicated to Lulu and Nana, two of the three children who are known to have had their genomes edited before their birth. Their birth in 2018 caused a global uproar. there is also a third child, whom I call Amy, who also has a gene-edited genome. Dr. Kirksey talks about the lab that brought them about and offers some background about the social, political, cultural aspects that made the experiments possible. 

The CRISPR Children is a podcast series about the children whose genomes were edited before their birth in 2018. The podcasts accompany a story I did about these children in Nature Biotechnology by the same name. You can find the story here: https://rdcu.be/cB7Nx  

The children were born somewhere in China. They came about due to experiments performed in the lab of He Jiankui at Southern University of Science and Technology in Shenzhen. These were unethical experiments. How are the children? And how could you assess their health and possible future risks? And why are they genetically mosaic? There is a lot of secrecy and rumor about these children. One has to maintain their privacy and dignity. They are celebrities and victims. They and their parents might be helped if the biomedical community tried to understand more about the experiments. But that is far from straightforward. Especially because many scientists declined to talk about them. But a number of them kindly did speak with me and I am grateful for that. Here is some of what I heard.       

The CRISPR Children is a series of podcasts about the children whose genomes were edited before their birth in 2018. The podcasts accompany a story I did about these children in Nature Biotechnology by the same name. You can find the story here: https://rdcu.be/cB7Nx  

The children were born somewhere in China and the result of experiments performed in the lab of He Jiankui at Southern University of Science and Technology in Shenzhen. These were unethical experiments. But how are the children? And how could you assess their health and possible future risks? There is a lot of secrecy and rumor about these children. One has to maintain their privacy and dignity, of course. But they are also victims. They and their parents might be helped if the biomedical community tried to understand more about the experiments. But that is far from straightforward. Especially because many scientists declined to talk about them. But a number of them kindly did speak with me and I am grateful for that. Here is some of what I heard.  

This episode is with Dr Kiran Musunuru of the University of Pennsylvania, a physician-scientist who works in genetics and gene-editing. He has also co-founded a company called Verve Therapeutics. He has written a book about the children called: The CRISPR generation The Story of the World’s First Gene-Edited Babies.

Neuroscientists use models of the brain to study the brain. One of those model types: organoids. One way to get a conversation with a neuroscientist started badly is to ask them about the 'mini-brains' in the dish on their lab bench. It’s not that the blob in the dish doesn’t somehow look like a piece of living tissue that could be a piece of brain. 

Or that this blob isn’t relevant to studying the brain. It is. Organoids are grown from stem cells that were coaxed to become neurons. They differentiate and grow into a three dimensional object. And these objects are becoming more complex and more dynamic in labs around the world. Dr. Eve Marder from Brandeis University talks about what organoids can tell researchers about the brain and what they might be less suited for. And why they are biological theory. 

This podcast is with Dr. Hongkui Zeng who directs the Allen Institute for Brain Science and Dr. Bolisjka Tasic who directs Molecular Genetics at the Allen Institute for Brain Science. It’s about how spatially resolved transcriptomics, a Nature Methods Method of the Year, can help to understand the brain. I did a story about it here: https://www.nature.com/articles/s41592-020-01033-y .

This is a podcast series that shares more of what I found out in my reporting. The piece is about smoothies, fruit salads, fruit tarts, genomics and a big puzzle called: the brain.

Transcript of podcast
Note: These podcasts are produced to be heard. If you can, please tune in. Transcripts are generated using speech recognition software and there’s a human editor. But a transcript may contain errors. Please check the corresponding audio before quoting.

Not lost in space Episode 2

Hi and welcome to Conversations with scientists, I’m Vivien Marx. This podcast is about space--space in biology, actually.

Talking about the role of space and spatial analysis in biology is a chat about food. About smoothies, fruit salads and fruit tarts. Here’s Dr. Hongkui Zeng and Dr. Bosiljka Tasic from the Allen Institute for Brain Science.

[0:30] Bosiljka Tasic 

Fruit salad and smoothie. 

Fruit tart is spatial transcriptomics.

Smoothie is Bulk RNA-seq. Ok passé

Hongkui Zeng

Forget it. 

Bosiljka Tasic 

You have fruit salad, you have dissociated cells you are profiling, you have lost the context, you have a context in the piece of tissue you have dissected. 

Then there is the fruit tart. You know exactly where each piece of fruit.  Relationship to the other

Vivien

Ok so spatial analysis in genomics is understanding a fruit tart. Knowing which genes are expressed where and what the relationship is of the genes to one another. The two scientists will talk more about this shortly. There’s Dr. Bosiljka Tasic, she directs Molecular Genetics and her research is for example on cell types in the mouse brain. And Dr. Hongkui Zeng who is director of the Allen Institute for Brain Science. Before they explain more about this science, here they both are, kindly teaching me how to pronounce their names. As ever I will try to do this right. And likely fail. 

[1:37] Bosiljka Tasic and Hongkui Zeng

I'm Bosiljka Tasic. Bosiljka Tasic. OK, got it 
 
 Hongkui Zeng. You don't pronounce the G at all, just, well, Zen, yeah, Zen G Zen. Yeah, yeah. It's very, very almost not there. 
 
 How would you how would you pronounce that if you emphasize the G . ZengG. So I think g you hear much more but it's not the correct way. I mean I've given you my Americanized way of saying my name. I see. Well I'm going to, I'm going to do it wrong anyway. But but at least for me, don’t  worry.

Vivien

Next, before we get back to their thoughts and research, just a bit about this podcast series. 

In my reporting I speak with scientists around the world and this podcast is a way to share more of what I find out. 

This podcast takes you into the science and it’s about the people doing the science. You can find some of my work for example in Nature journals that are part of the Nature Portfolio. 

That’s where you find studies by working scientists and those are about the latest aspects of their research. And a number of these journals offer science journalism. These are pieces by science journalists like me. 

This podcast episode about space in biology harkens back to interviews I did  months ago. Back then I asked scientists about their work and their thoughts about spatially resolved transcriptomics, which is a Nature Methods method of the year. In my slow pokey DIY podcast production this is episode 2 in a series about this field of study. 

Spatially resolved transcriptomics helps with studying the brain, which is the giant puzzle that Hongkui Zeng and Bosiljka Tasic work on. Among their daily puzzles is: How many different cell types are there in the brains of mammals such as mice, primates or humans? There are lots of them.  

And scientists want to be more precise than just saying there are lots of cells, of course. They want to know which ones there are and where they are. 

In the brain, another puzzle is where are cell types when. Cells are born and then often move to other areas of the brain where they will tend to all sorts of tasks. It takes a number of techniques to address these questions, including spatial techniques. 

The US National Institutes of Health—NIH--has many research projects, one of them is the Brain Initiative, NIH's Brain Research through Advancing Innovative Neurotechnologies Initiative. 

Part of that is the NIH Brain Initiative Cell Census Network (BICCN). One big BICCN project is to build a high quality atlas of cell types in the entire mouse brain. 

Many labs are working together to produce human, mouse and non-human primate brain atlases, these are intended as references for labs around the world. The scientists use imaging, electrophysiology and molecular genetic analyses including analysis of gene expression, which is transcriptomics. 

BICCN phase 1 is underway and phase 2 is getting underway. The project has started with the mouse brain and is moving toward an atlas of the non-human primate brain and the human brain. 

One big challenge in this venture is distinguishing cell types. Cells may look very different but they might also look quite similar to one another. Here is Hongkui Zeng talking about BICCN

[5:20] Hongkui Zeng

We are currently in phase one, BICCN phase one, building this brain-wide cell type reference atlas. We are doing quite well and we expect to complete phase 1 in the next two years. And then phase 2 is starting, BICCN, phase 2 what you heard at SfN. There are several major themes for phase 2 that were announced by NIH. 

The three major themes are building cell-type targeting tools, moving into the study of primate brains including human brain, cataloging cell types in the human brain and then finally studying the connections, the connectomics of the human brain. 

Bosiljka is very active in one of those initiatives, which is building in one of cell type targeting tools 

Bosiljka Tasic 

You want to define a cell type first, but then you want to be able to access it for experimental examination perturbation. You want to form causality connections between a cell type and, let's say a specific behavior. So in order to do that, you need to build usually a genetic tool that is based on genes that are expressed in the cell type or maybe regulatory elements, enhancers that are active in that cell type. You can you can create a transgenic mouse or a viral tool that will then deliver a particular transgene, a particular perturbing or labeling gene to that cell, and then you can visualize the cell, monitor it, maybe monitor its activity or perturb it and ask for 
 Phenotypes effects at the level of that cell, at the level of the circuit, at the level of the whole organism.

And both Hongkui and I, we are we have a just...

This podcast is about two scientists, Dr. Patrik Ståhl and Dr. Fredrik Salmén, who are joint first authors of a paper that kickstarted a field. It's about finding work they did with colleagues to enable finding out where in tissue gene expressions is happening. It's called spatially resolved transcriptomics. It is a Nature Methods Method of the Year and I did a story about it here: https://www.nature.com/articles/s41592-020-01033-y . 
This is a podcast series that shares more of what I found out in my reporting. The piece is about patience, stamina, friendship, surfing the Baltic Sea, genomics and imaging. 

[00:00:05.560] - Vivien Marx
Hi and welcome to Conversations with Scientists, I'm Vivien Marx. This podcast is with and about two scientists and about space space in biology. Actually, you'll meet Patrik Ståhl. He's on the faculty of KTH Royal Institute of Technology in Stockholm, Sweden, and Fredrik Salmén, who is currently a postdoctoral fellow at Hubrecht Institute in the Netherlands. They will talk about a field.

[00:00:33.280] - Patrik Ståhl
The whole field. It's really it's it's an awesome field.

[00:00:36.940] - Vivien 
That's Patrik Ståhl. Their work led to a major publication in the journal Science, and they are both joint first authors of this paper,

[00:00:47.710] - Patrik Ståhl
We share the honor

[00:00:47.710] - Fredrik Salmén
and the pain.

[00:00:47.710] - Vivien 
The honor and the pain. That's research for you. Just briefly, before we get to that about this podcast series, in my reporting, I speak with scientists around the world, and this podcast is a way to share more of what I find out. This podcast takes you into the science, and it's about the people doing the science. You can find some of my work, for example, in Nature journals that are part of the nature portfolio. That's where you find studies by working scientists.

[00:01:19.960] - Vivien 
And those are about the latest aspect of their research in a number of these journals offer science journalism. These are pieces by science journalists like me. This podcast episode is one of several I'm producing about space in biology. Months ago, I interviewed researchers who work on Spatially resolved transcriptomics for a story and in my slowpokey DIY podcast production. This is part one in a series about this field of study. So Patrik Stahl and Fredrik Salmen here they are introducing themselves to help me learn how to pronounce their names.

[00:02:02.890] - Patrik Ståhl
Fredrik you go first.

[00:02:03.560] - Fredrik Salmén
Fredrik Salmén. 

[00:02:12.290] - Vivien 
All right. I have to practice. OK, so in

[00:02:16.750] - Patrik Ståhl
English it's Patrick. It's Patrik Stahl.

[00:02:21.650] - Vivien 
Patrick Sahl?  So no t, Stahl

[00:02:29.210] 
all right, you have to brace yourselves.

[00:02:33.980] - Patrik Ståhl
Stahl means steel in English,

[00:02:36.393] - Patrik Ståhl
Patrik Ståhl

[00:02:36.780] - Vivien 
Wow I apologize . Despite their lessons, I am doing the Swedish pronunciation of their names badly. I hope they and Sweden will forgive me. So I interviewed these two Swedish scientists together and when we started to chat, I noticed a poster on the wall behind Fredrik Salmen. It showed a surfer riding a big wave. So I asked about that.

[00:03:03.530] - Patrik Ståhl
Fredrik actually quite advanced surfer, like wave surfer  at the time when we started this project.

[00:03:14.540] - Fredrik Salmén
Yah, it's true. Oh, it's actually me.  It's a little bit self-centered, I guess, to have their own picture on the wall. But it's fun, though. It's

[00:03:27.620] - Vivien 
where was this taken?

[00:03:30.290] - Fredrik Salmén
This is actually Sweden. So it's the Baltic Sea.

[00:03:35.900] - Vivien
The Baltic Sea is cold. You need to wear a special suit if you want to surf there.

[00:03:41.240] - Fredrik Salmén
Yeah. It's like a frog suit with hood and gloves and boots.

[00:03:45.920] - Vivien
So do you still do this or.

[00:03:48.320] - Fredrik Salmén
Yeah, I still do. I'm a little bit, I would say much less nowadays and I'm also a little bit heavier these days, so not as agile anymore. But still when I get the opportunity I try to surf, it's nice. 

[00:04:06.020] - Vivien 
The two researchers worked together along with many others, but their connection was quite intense and you will hear more about that in this podcast.

[00:04:13.260] - Vivien
It was work that took around six years and led to a publication in the journal Science. And that publication kick-started a field. And there was a company spin out to the field of study is called spatially resolved transcriptomics, and it was crowned a Nature Methods method of the year. In this area of spatially resolved transcriptomics, scientists want to know where something takes place. It's part of understanding larger issues, such as why does the head grow where it does?

[00:04:44.750] - Vivien 
Why does a part of the brain develop where it does? Why does a tumor grow where it does? It's genes that tune such events, genes are turned on or off, they are expressed at high levels or low levels or silenced, their expression can shift. With gene expression, it's like tissues are playing a kind of music, just one you need to find ways to hear. Patrik Stahl and Fredrik Salmen and their colleagues found one way to do just that.

[00:05:15.370] - Vivien 
The work took place in Sweden. It involved surfing the cold waves of the Baltic, as you just heard. It's about friendship. It's about patience, about science, careers. If you're interested in any of that, as well as biology, genomics and imaging, please stick around. So this work in particular took six years and Fredrik Salmen and Patrik Stahl worked intensely together. They are the first authors of this paper in Science published in 2016, and it led to a company called Spatial Transcriptomics.

[00:05:45.790] - Vivien 
What these scientists and their colleagues developed was a way to see where, for example, in a tissue genes are expressed. It's not the first way to do this, but it was a way to analyze a lot of mRNAs, a lot of gene transcripts at the same time. To understand why this matters, we can step back for a moment and consider a practical example that they told me about. A pathologist gets a tissue sample. It might be from a person who was just on the operating table.

[00:06:13.300] - Vivien
The tissue is prepared with chemical stains and then studied. The pathologist interprets what is going on in this tissue. Sometimes pathologists look at many tissue slides from many patients and want to compare them. In other cases, it is information that has to travel quickly to determine how a patient might need to be treated. Or the analysis is for a basic research lab that is studying a particular disease or development. As Patrik Stahl explains, scientists can look at a tissue slide and use stains and dyes to see what is happening there.

[00:06:46.630] - Vivien
Well, sort of. This immunohistochemistry doesn't always answer all the questions of pathologist or other scientists might have

[00:06:55.990] - Patrik Ståhl
So I think this was like late 2009 and it was Jonas Frisen, who is a who is, s stem cell professor working at Karolinska Institute who is subjected to this kind of immunohistorchemistry a lot during his daily work. And I think that he was the one who first grew tired of a lack of spatial information that they could get out of a stain. And so late 2009, he contacted  Joakim Lundeberg and they together in early 2010, initiated this project , trying and then...

Marine echinoderms speak to developmental biologist Dr. Paola Oliveri at University College London for many reasons. Their evolution of a novel body plan is one of them. In a conversation she talks about teaching evolution, her training, her students and her love of science. 

COVID-19 has been bad. Many, likely millions of people, who have survived their COVID-battle, face a difficult array of symptoms. Breathing problems, joint pain, heart palpitations, brain fog are a few of them. This is part 3 of a three-part podcast series on long-COVID. This episode is a conversation with Dr. Terina Martinez, a field application scientist at Taconic Biosciences, which develops and sells mouse models. She talks about the challenges and possibilities of modeling long-COVID. There is also an article in Nature Methods to go along with this podcast series. 

COVID-19 has been bad. Many, likely millions of people, who have survived their COVID-battle, face a difficult array of symptoms. Breathing problems, joint pain, heart palpitations, brain fog are a few of them. This is part 1 of a three-part podcast series on long-COVID. You can also find my piece in Nature Methods on long-COVID here. Dr. Nadia Rosenthal, who directs science at the Jackson Laboratory, and her team are working on ways to model this diversity of symptoms, which can help figure out what is amiss in long-COVID and indicate how one might treat it.