Music:  Winnie the Moog, Funky Energetic Intro and Acid Trumpet by Kevin MacLeod Free download: https://filmmusic.io/song/3340-acid-trumpet License (CC BY 4.0): https://filmmusic.io/standard-license0 

(Art J. Jackson, Music: Funky energetic Intro by WinnieTheMoog. Another piece used in this media project: Paper Flakes by Rafael Krux. Free download: https://filmmusic.io/song/5695-paper-flakes License (CC BY 4.0): https://filmmusic.io/standard-license Artist website: https://www.orchestralis.net/)

And we played a nerdy game with them. It's 'we' because this podcast episode is co-hosted by Dr. Jean Zarate, senior editor at Nature Neuroscience, who is also a musician and an actor. This podcast series expands on the things I hear and read and offers conversations with people I meet in the course of my science journalism adventures.

(Art J. Jackson, Music: Funky energetic Intro by WinnieTheMoog. Another piece used in this media project: Legend of One by Kevin MacLeod: Free download: https://filmmusic.io/song/3973-legend-of-one License (CC BY 4.0): https://filmmusic.io/standard-license Artist website: https://incompetech.com)

These embryo models, models of the embryo's 8-cell stage, of the blastocyst or of the gastrula are emerging and they are ones that labs can use to characterize the molecular and physiologic events that take place during early embryogenesis. My story in Nature Methods about some of these embryo models is here. For this story, I spoke with Christine Mummery, a researcher in the anatomy and embryology department at Leiden University Medical Center. In this podcast, she talks about models of the blastocyst and the gastrula, about the updated International Society for Stem Cell Research (ISSCR) guidelines, and shares some thoughts about about what is involved when assessing a model. "If I'm claiming this is a liver cell, what does it have to show? And this is a tricky, tricky thing," says Christine Mummery. 

When the government asked her to certify a lab not up to biosafety levels, she said no. "Even if I was to be killed, I don't mind," she says.

This is episode 1 of a series of podcasts about the grit and determination scientists in the Global South are putting to work against COVID-19. It's not, in my view, a downer of a story. It goes along with a feature I did for Nature Methods called 'Lessons from the Global South’s fight against COVID-19.' That story is here: https://www.nature.com/articles/s41592-022-01439-w

Note: Some cautions for you. If you don’t like meat, you might not like this podcast. Although you might want to hear about projects related to livestock health and breeding in the tropics or about reviving and restoring endangered species. You might not like this podcast if you do not want to hear about animal experiments. Although we do also know that many things intended for use in people are tested in animals first. And that is indeed fraught. Even if you have aversions of this kind, I would like to invite you to tune in to hear more about Alison van Eenennaam’s work. 

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 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 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.

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. 

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...

[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...

This episode focuses on brain fog, one of the difficult symptoms of long-COVID. It's a conversation with neuroimmunologist Dr. Avi Nath, who is intramural clinical director of the National Institute for Neurological Disorders and Stroke (NINDS) at the US National Institutes of Health (NIH). There is a story in Nature Methods to go along with this podcast about long-COVID.

Pipelines can be simple and pretty complex. And maintenance of pipelines also ranges from simple to complex. They can run like a dream, they can get stuck, they can break. To talk about trends in this area, I sat down, virtually that is, with two scientists at DNAnexus: John Ellithorpe who is DNAnexus executive vice president and chief product officer and George Asimenos chief technology officer at DNAnexus. 

Commenting on AACR II and about virtual conferences more generally: 

Dr. Elaine Mardis: the current president of the American Association for Cancer Research. She is co-Executive Director of the Institute for Genomic Medicine at Nationwide Children’s Hospital and the Nationwide Foundation Endowed Chair in Genomic Medicine. 

And Dr. Antoni Ribas, the incoming AACR president. He is at the University of California Los Angeles. He directs the Tumor Immunology Program at the Jonsson Comprehensive Cancer Center and is director of the Parker Institute for Cancer Immunotherapy Center at UCLA.

This episode is with scientists talking about their hopes and allergic points as they job-hunt. It’s based on conversations with job-hunters last year and this year. The guests on this episode are: Dr. Antonio Ward of the University of South Alabama, Melat Gebru from Penn State University, Paul Tran from Augusta University and Dr. Sadr-ul Shaheed from the University of Bradford. 

Yang is a die-hard Manchester United. Among other aspects, he talks about how he organizes his lab for open communication. He is modeling the the culture of the Jaenisch lab at The Whitehead Institute. That's where Yang was a postdoctoral fellow.