Advancing our understanding of human tissue development: Q&A with Dr Sid Lawrence

College Research Associate Dr Sid Lawrence grew up in Somerset. He first came to Sidney in 2006, securing an undergraduate place to study Medicine. He qualified as a doctor in 2013 and has since specialised in trauma and orthopaedics, ‘basically bone and joint surgery’.

A decade later, and over 16 years after arriving at the College, he currently supervises Sidney students in Anatomy while completing his PhD, which looks at the earliest stages of human development and how they might inform treatments for osteoarthritis and other musculoskeletal illnesses.

A lot of medics decide to specialise during their training. Was there one key moment that made you think, ‘Yes, it’s trauma and orthopaedics’?

“Yes, I remember a clinic where I met three patients, one after the other.

“The first patient was a lady who had terrible arthritis in her hip. She was really beside herself, as you or I would be in that situation. These people just don't sleep. They are in so much pain. Their quality of life has gone, they can't get around. She needed a hip replacement.

“The second patient I saw that day had had a hip replacement six months earlier and she was one of the happiest patients I've ever met. So that combination, those two patients, was a really easy ‘A to B’ sort of thing. I thought, ‘Well that could be a nice thing to do for people, to help relieve that pain.’

“And then the next patient - it was like they lined them up for me - was this lady who had been driving along when a deer ran out. She had swerved to avoid the deer and hit another car. She had been horrifically injured. She had required neurosurgery because she’d had a bleed on the brain, and she had broken all the long bones on one side of her body, so she had sustained really severe injuries.

“When I met her, it was nine months after the crash. She was there to discuss her final surgery, which was to repair her knee ligaments. So, looking at her experience, the neurosurgeons were the ones who stopped her dying, but the orthopaedic surgeons were then the ones who would really give her her life back. What is your life? Well, for a lot of people, it's about doing things they enjoy and a lot of those things are linked to mobility, or musculoskeletal health.”

So, in terms of your PhD research, what are you looking at?

“I study foetal development as it relates to musculoskeletal tissues, and I am looking specifically at the spinal cord and associated structures, and the foetal limb.

“My PhD is at the Wellcome Sanger Institute in Hinxton, supervised by Dr Sarah Teichmann and Dr Sam Behjati, and we work with in partnership with the Wellcome-MRC Cambridge Stem Cell Institute. Professor Roger Barker, who was one of my supervisors at Sidney, is one of the Principal Investigators there

“The tissue bank is an incredibly rare and special resource. The foetal tissue has been donated by women who have undergone a termination.

“Being able to study human development is an incredibly rare and privileged thing to be able to do.

“If you start to gain a deeper understanding of human foetal development, the obvious connections that throws out are to developmental disorders. There are about three thousand single gene disorders of which about five or six hundred have a musculoskeletal pathology. So, if you understand normal development, then you can start to understand what role the genes that are implicated in congenital abnormalities play in health.

“That greater understanding will also improve our ability to model development and disease in a Petri dish – or in vitro, as the lingo goes.

“Probably the main part of my PhD has been about using foetal skeletal development, so the growth of the human skeleton, as a benchmark for growing skeletal tissues from stem cells in the lab.

“There are various protocols for growing cartilage or bone from stem cells. People use those recipes to create cells, and then they do things to those cells to better understand how a disease might affect them. That’s called disease modelling, but you have to be able to evaluate those models, and so what I've been trying to do is take a range of different protocols for growing cartilage and, using the actual truth of the foetus, looking at how well the in vitro cells actually replicate human biology.

“I’m doing that using a combination of genetic and computational techniques, basically, and we have been collaborating with a team at the University of Manchester. That team has been growing cartilage in the lab - we found what they produced was a very close match to the real thing, so then we have been able to start fine tuning.

“So that's the kind of big thinking: you compare human to in vitro cartilage and then you edit in vitro to coerce it to be more human.

So is the end goal to inform stem cell treatment or to use this greater understanding to inform more conventional treatment for people?

“I think there are two things you can do from improving stem cell differentiation.

“One is to model disease. If we can make sure that the ways in vitro cells are being grown is replicating true development, we can the then compare how cells carrying disease-causing mutations and normal cells grow, with the ultimate hope that we identify pathways in their aberrant development that you could modify or inhibit to coerce the disease and bring the mutated cells back to a more normal state.

“So that's one thing, and then the long-term vision, which is a big long-term goal of orthopaedics and rheumatology and musculoskeletal science, is to be able to engineer tissues to the point where they can be used as a treatment.

“In the UK, eight million people have osteoarthritis, which is essentially a breakdown in the structure and function of the cartilage that lines your joints and which results in stiffness, pain, swelling and generally a reduced quality of life.

“So, the question is, can we engineer cartilage, or a cell-based therapy that could regenerate cartilage?

“Exactly what shape that therapy is going to come in is not clear, but in order to even think about doing it, you have to be able to reliably engineer cartilage at scale. There are a lot of people working on the same issue, but we're very lucky as we have this resource – the tissue bank - that allows us to look at it in a particular light.

Looking beyond osteoarthritis, are there other diseases that this greater understanding could help treat?

“Yes, one other thing the development of bone and cartilage clearly connects to is cancer in children and young adults.

“So, if you get a bone or cartilage tumour when you're eight or ten years old, it’s not because you’ve been exposed to things that cause mutations and cause cancer in the way that we probably think, like with smoking and lung cancer.

“What you’re suffering is an anomaly of development, driven by genetic events that happen in the early embryo.

“It's clear that, with different musculoskeletal cancers of young people, a lot of them very closely resemble states in the normal developing human.

“So in the long term, with greater understanding, we might ask why development has gone off track in these cases, and if it is possible to force it back on track by understanding how these cases relate to normal biology.”

So, what is your day to day?

“My PhD involves a mixture of laboratory and computational work, but actually most of my work is computational.

“Particularly with genomics and related techniques, you need a rich mix of skill sets. The team I work in is divided between a wet lab team, but the computational side is really larger than that more traditional lab-based side.

“So, my group includes an astrophysicist, mathematicians, all these kind of people. I have a reasonable understanding of the biology I'm interested in, but I have almost no understanding of the high level maths that goes into being able to produce and analyze the data produced. So, I'm guided by these brilliant mathematical minds to then be able to put the data into a biological context.

“It's a wonderful collaborative environment where you are mixing with people from different backgrounds and with very different skill sets. At the Wellcome Sanger Institute you're incredibly well supported by these different disciplines. We have huge computational support, but equally huge laboratory support. In terms of doing a PhD, I can't imagine it being any better.”