Transitions in development – an interview with Dorit Hockman Free

Let's start from the beginning, when did you first become interested in science?

I used to watch a lot of BBC nature documentaries when I was little and read a lot of National Geographic magazines, or at least look at the pictures a lot. Growing up in South Africa, my family used to go to the game reserves, like the Kruger National Park, so I was exposed to the amazing natural world around me. I started becoming more interested in understanding how the natural world works as I went through high school. I didn't do biology though. My only science subject was physical sciences. My other main subjects were history and art, which I think ended up as a useful preparation for my future studies, because our teacher made us write properly referenced essays using books and articles from the library. When I had to pick a topic to study at university, I chose molecular and cellular biology, as it sounded interesting and completely new to me.

After your undergraduate and Master's at the University of Cape Town (UCT), what made you decide to pursue a PhD in Cambridge, UK?

My undergraduate lecturer, Prof. Nicola Illing, who taught us developmental biology, focused on limb development in our third-year lectures. Even though her lab wasn't doing limb development research, she was hoping to get into it. My fellow student, Mandy Mason, and I joined her lab as Honours students, and started the bat limb project from scratch. My project focussed on what genes were expressed during limb development in bats compared to mice, with a focus on sonic hedgehog signalling. I stayed on for 2 years to do my Master's project. In South Africa, our Master's program is almost like a mini-PhD. During that time, one of my colleagues told me about the Wellcome Trust Developmental Biology PhD programme at the University of Cambridge. Up until that point, I hadn't even thought that doing a PhD outside of South Africa was an option. It was a fully funded programme, and we could rotate around labs during the first year. I was keen on the fact that I could explore different labs and learn different techniques before I decided what to do for my PhD project.

What did you work on during your PhD in the lab of Prof. Clare Baker?

I did my third rotation in Clare's lab, and we got on really well. The appeal of Clare's lab was that they worked in many different organisms and did a lot of evo-devo work. I wanted to learn as much as possible, rather than pigeonholing myself into one system, so I joined her lab. My PhD focused on looking at the evolution and development of the hypoxia-sensitive cells of the carotid body in different vertebrates. These cells are responsible for sensing changes in oxygen levels in our blood. Before I started my PhD, these cells were already shown to be neural crest-derived in the chicken and the mouse. Fish also have similar oxygen-sensitive cells. My project was to do lineage tracing experiments in fish, frog and lamprey, and then repeat the experiments in the mouse and the chicken to check whether these hypoxia-sensitive cells are neural crest-derived. It turned out that they aren't neural crest derived in aquatic organisms but are in fact endodermal in origin. The best part of my PhD was the fact that I worked in all these different systems and learned how to do lineage tracing in a lot of different ways.

After your PhD, you went to the University of Oxford for your postdoctoral research. What was your research about?

For my postdoc, I was keen to build my skills in genome-wide analysis and bioinformatics. I was awarded a Junior Research Fellowship at Trinity College, Oxford. The college would pay my salary, but I had to be a member of a research lab, so I approached Prof. Tatjana Sauka-Spengler. I knew her from my lamprey work during my PhD, when I went to Prof. Marianne Bronner's lab and Tatjana was there as a Research Fellow. Tatjana had recently moved to the Weatherall Institute of Molecular Medicine to start her own group and had been focusing on the chick and fish as models to study the neural crest, so the lamprey work was available for someone to explore further. My project involved using genome-wide approaches to disentangle the neural crest gene regulatory network and look for conservation between mouse and chicken, and all the way down to the base of the vertebrates in the lamprey. Tatjana's lab had optimised the ATAC-seq and RNA-seq techniques in the chicken and so I was tasked with getting these techniques to work in the lamprey. We collaborated with Prof. Sebastian Shimeld from the University Oxford, who worked on a local lamprey species in the UK, the brook lamprey. I would do test runs using the brook lampreys they collected from the New Forest. Then I would go over to Marianne's lab at Caltech to apply the techniques to the sea lamprey, for which we have a genome. The existing genome at the time was a blood-based genome, but it wasn't the complete genome, because not all the cells in lamprey have the same genetic material. Prof. Jeremiah Smith at the University of Kentucky was also working on a germline genome at the time, and I was luckily given access to early drafts of the genome assembly. We did RNA-seq to get gene expression data and ATAC-seq to get chromatin accessibility data across three different stages of lamprey neural crest development. We looked at how gene expression changes over time, and then identified enhancers that are being dynamically used over time as the neural crest developed.

When you started planning your own group, what were your most important considerations?

I always knew I wanted to go back to South Africa. Being in the UK was amazing, but my aim was to take everything I'd learned back to Cape Town, where I could build something new and train students to use techniques they otherwise would not have access to. I applied for the Sydney Brenner Postdoctoral Fellowship, which was specifically for postdocs to work in South Africa. That fellowship allowed me to start spending time in my old Master's supervisor's lab at UCT. Prof. Nicola Illing's lab had moved into doing genome-wide analysis in various plants and animals. They had bioinformaticians in the lab who I could learn from and continue growing my bioinformatics skills. That was a bridging period when I was moving between Oxford, Cape Town and Caltech to collect data.

In 2018, you returned to South Africa to start your own group at UCT. How was the application process and the transition into a PI?

The process of establishing my independent lab wasn't as straightforward as I'd hoped it to be. My partner, who was a geologist at the University of Oxford, managed to get a job at UCT before I did. I applied to a few positions but I wasn't successful. In the end, I applied for a job in my current department, the Department of Human Biology, in the Faculty of Health Sciences. I didn't get that job, but the person who did, who's now my colleague, Assoc. Prof. Joseph Raimondo, was really keen on me joining. There was also a new Neuroscience Institute being envisaged at UCT at the time. Together with Joseph and the Head of Department and the director of the Neuroscience Institute at the time, we managed to find funding to support a contract post for me to work in the department. I was lucky that during that time, one of the developmental biology and embryology lecturers, Prof. Susan Kidson, was retiring from the Department, so a space opened up for me to apply for a permanent position and, luckily, I was successful.

One of my main tasks when I first started in the Department of Human Biology was to start convening the Medical Cell Biology Honours programme, and I had to come up with an Honours project for a student in my lab. Luckily, Prof. Susan Kidson offered to support the project. Justine Van Greenen, who is still with me now, was my first student and worked with me on continuing the lamprey project. Her project was to compare one of the lamprey neural crest enhancer sequences that I found across different lamprey species. We were also trying to electroporate that enhancer into chicken embryos, which was challenging because we didn't have the same equipment I had used previously at the University of Oxford, and had to try use electroporation cuvettes instead. Once I got the permanent post, I started applying for my own grants so I could start to kit out my lab with the necessary tools. Luckily, during my postdoc, I had a lot of practice applying for grants to support the lamprey work that I did in the Sauka-Spengler lab.

Can you summarise the research themes of your group?

Initially I kept working on the lamprey neural crest. During my postdoc, we found some interesting enhancers in the lamprey that were driving gene expression in the neural crest. We found that we could put those lamprey enhancers into the chicken, and the enhancers could activate gene expression in the neural crest, even though there is no conservation of those enhancer sequences in the chicken genome. Somehow that enhancer can drive expression across species in the correct place. This work was continued by one of my first Master's students, Mayur Prag.

I was also keen to expand my work into the field of human biology, moving into a more medical space, where I could apply the skills I had gained from my evo-devo work to understanding human neurodevelopment. To make this leap, new collaborations would be very important. Joseph's lab works on brain physiology and function, and how certain brain infections cause epilepsy. When I started at UCT, they were building a new collaboration with neurosurgeons from the UCT Neuroscience Institute and local hospitals to start collecting donated brain tissue samples from surgeries. Together with the neurosurgeons and Joseph's lab, we came up with projects that would allow me to bring developmental biology into understanding how gene expression changes over the course of human brain maturation using our biobanked brain tissue samples, which come from both children and adults. This work was pioneered by Master's students in my lab, Stephanie Fillmore, Ruvimbo Mishi and Christina Steyn. Our first project, which used single cell gene expression analysis and spatial transcriptomics to explore gene expression dynamics in the brain, is going to be published soon in Nature Genetics as part of the Human Cell Atlas publication bundle.

What have been the highlights and challenges of starting your own group?

The main highlight was moving into a new department at UCT and having incredibly supportive people around me who are keen on my lab being successful. I have a lot of support from my colleagues here, who are very open to collaboration and have helped me to expand my research focus.

The biggest challenge was getting funding to support my new research focus. Luckily, when I started my post at UCT the Royal Society (UK) had just started their FLAIR programme to support emerging African independent researchers. This was also when the Human Cell Atlas project had started, and more people were doing single cell RNA-seq; however, very few researchers were using it in Africa. The FLAIR fellowship allowed me to get enough funding to start setting up single cell gene expression analysis in Cape Town, but it wasn't enough to fund setups like the 10x Genomics system. Luckily, my colleagues that I was working with on the brain studies invited me to join a National Institutes of Health application for an exploratory/development grant. That grant allowed us to set up the 10x Genomics system in my lab. I need to emphasise that none of this would have happened if I didn't have these collaborators. The continued support from Tatjana in Oxford was also vital. All FLAIR fellows could apply for a collaboration grant with a UK lab. Tatjana and I were successful in getting that grant. It meant I could send my students to Oxford and allow them to benefit from training in the Sauka-Spengler lab. In terms of other challenges, I think a common problem when people start a new lab is that we're not trained to manage labs as PhDs and postdocs. I didn't do much supervising of students during my postdoc, because I was out in Caltech a lot. So, it was a challenge learning how to manage people and manage funds.

How do you approach hiring new members of the lab?

My first student was from the Honours programme at UCT. From then, I relied on different UCT Honours programmes for students to join my lab and some of them stayed on for a Master's. I have also been approached by a few students from other universities, and I'd make sure to get references from their supervisors from their past projects. In South Africa there is an option to upgrade a Master's to a PhD. A couple of my students, Justine Van Greenen and Sahar Jamal, have stayed with me as PhD students, currently working on the human brain project. I've had one postdoc so far, Dr Imadeldin Yayha, who joined my lab from Khartoum University in Sudan. He's an embryology lecturer in a veterinary school there and was taking a sabbatical to do a postdoc with me, continuing similar work he did during his PhD in Germany. My current challenge is to recruit more postdocs, which is really hard in South Africa, where funding is limited and the pull to work abroad or move into industry is very strong for most PhD graduates.

What advice would you give to people starting their own labs?

If you're in a resource-limited place like South Africa, I think it's good to have a group of collaborators around you. Don't think you need to do everything yourself, because that's not the way science is done anymore. Don't be afraid to approach your colleagues and find out how you can use your skills to contribute to their projects. I wouldn't have been able to start in a completely different field without having support from collaborators. Being involved in teaching programmes is also useful. Because of the Honours programme, I get a flow of excellent students through the lab. Even though there is very little funding to support the Honours projects, it's a good way to find talented students. Finally, keep in touch with your mentors, like your PhD and postdoc supervisors, who are hopefully supportive. I am lucky that my old supervisors have been so encouraging of my career. I think it's all about being humble and not being afraid to ask for help.

Speaking of mentors, how important do you think mentorship is in navigating an academic career?

Having mentors at different levels is really important. I have mentors who are my scientific grandmothers and mothers. They are experienced and have the resources and know the people to introduce me to in order to further my career. It's also useful to have mentors who are closer to your career stage. My colleague Joseph is just a couple years ahead of me and remembers what it's like to be a new PI. These ‘peer’ mentors will help you with the nitty gritty tasks, and you don't have to feel stupid to ask them a question.

You are involved in re-establishing a South African Developmental Biology Society. Can you tell us more about that work?

This is still very much in its baby stages. I am the president of the society, but we're very small. I am hoping we can organise some proper events in the coming years. I am also hoping to convince more people from South Africa to attend the International Society of Developmental Biologists (ISDB) conference next July. It's been really nice, even just for me, to be part of the ISDB community, as a way to keep in touch with the international developmental biology community.

Did you ever consider a non-academic career path?

Occasionally I did when it was hard trying to get a job. I thought about working in a pathology lab or an IVF clinic. I think I'm lucky that my father is a doctor and my mother is a maths professor, so academia was considered a ‘proper’ job to me. I like the freedom that academia gives you, so I never really considered leaving, and hopefully it stays that way – as long as I can keep getting funding!

Finally, what do you enjoy doing outside of the lab?

One of the main reasons why I wanted to come back to Cape Town is the natural environment. Table Mountain is my favourite place to be. I spend a lot of time trail running on the mountain. The fact that I can look out into the distance and see mountains, the sea and sometimes snow is such a privilege.

Dorit Hockman was interviewed by Joyce Yu, Online Editor at Development. This piece has been edited and condensed with approval from the interviewee.