Building a new brain for dementia research

Writer Philip Ball has granted Created Out of Mind and UCL researchers access to his “mini-brain”, all in the name of science and a deeper understanding of degenerative brain diseases. Here, he reflects on this experience.

Phil Ball's growing mini-brain! Biopsy through the eye piece with an iPhone, using a light microscope. Credit:  Chris Lovejoy and Charlie Arber, UCL Institute of Neurology

Phil Ball's growing mini-brain! Biopsy through the eye piece with an iPhone, using a light microscope. Credit:  Chris Lovejoy and Charlie Arber, UCL Institute of Neurology

‘I didn't feel a thing. Harvesting skin cells that can be transformed to the versatile form of “induced pluripotent stem cells” (iPSCs) is, I now know, more than a matter of scraping off a bit of your arm, because the cells that matter are in the lower layers of the skin, requiring removal of a rather more substantial plug of tissue in the biopsy. But with some local anaesthetic it was painless and, as far as I dared look, relatively bloodless.

If all goes according to plan, these skin (fibroblast) cells will be cultured into neurons that will develop into a so-called “mini-brain” before the end of the year. It will be – as we have perhaps somewhat cavalierly put it for this project – a “Brain in a Dish”. Indeed, my Brain in a Dish.

It’s a part of this whole, open-ended project for Created Out of Mind to examine exactly what that strange notion can mean. A small interdisciplinary team from the Created Out of Mind team – me, BBC broadcaster Fergus Walsh, artist Charlie Murphy and University College London neurologist Nick Fox – will take part and reflect on their growing “brains” through scientific, personal and creative responses. We’ll compare our experiences with those of people living with Frontotemporal Dementia (FTD) and Familial Alzheimer’s (fAD). We hope to stimulate curiosity about the healthy and ageing brain, and explore whether this kind of research can increase our understanding of degenerative brain diseases. 

At this stage, I don’t really know how I will feel about my “brain in a dish”. I do have some idea of the process, however. Stem cells are cells that can grow into any tissue type in the body – that’s all “pluripotent” means here. Cells in the early embryo are like this, so that they can become a human body. Some will become fibroblasts, some neurons, others cells of the heart or kidneys, or those responsible for bone growth. This specialisation, called differentiation, results from cells acquiring different patterns of gene expression: all have the same complement of genes, but in different tissue types certain genes are activated or deactivated.

It used to be widely thought by biologists that this process of differentiation is one-way: once a cell has become specialised, there’s no going back. Genes didn't appear to be lost, but the switches were set in place. We retain some some stem cells even into adulthood – they’re found in many organs and tissues, including muscle, skin, heart and liver. But these adult stem cells are not pluripotent, as embryonic stem cells are: they can’t generate any tissue type, but only the type of tissue they reside within. They are there to help us maintain and repair those tissues. 

So cell biologists and geneticists were stunned when, in 2006, Shinya Yamanaka and his postdoctoral researcher Kazutoshi Takahashi at Kyoto University announced that they had transformed skin cells from adult mice into what looked like pluripotent stem cells. By using a virus to introduce a small number of genes into the skin cells, the Japanese researchers seemed able to reverse the differentiation process.

By the following year, Yamanaka and coworkers, and independently a team at the University of Wisconsin-Madison, had managed to induce this pluripotency in differentiated adult human cells. It’s no exaggeration to call the technique revolutionary, as recognized by the award of the 2012 Nobel Prize in Physiology or Medicine to Yamanaka. (He shared it with British biologist John Gurdon, who showed as far back as 1962 that cells could be reprogrammed after they had begun down the road to specialization.)

"If adult cells can be reprogrammed by converting them first to iPSCs, then it looks feasible to grow tissues and organs in a dish, outside the body, to replace damaged ones".

Stem cells are of immense interest both to researchers engaged in fundamental life science – for example, to understand the genetic, biochemical and cellular mechanisms of how organisms develop from eggs – and to biomedicine. If adult cells can be reprogrammed by converting them first to iPSCs, then it looks feasible to grow tissues and organs “in a dish”, outside the body, to replace damaged ones. A person with a dysfunctional kidney, for example, might not have to rely on a donor, with all the potential complications of immune rejection. Rather, a replacement organ might be grown in tissue culture from their own iPSCs and then surgically implanted. Already researchers have grown miniature kidneys and other organ types – “organoids” – this way. In general, organs contain more than one tissue type, not least because they need a vascular system of blood vessels to supply the cells with nutrients and oxygen needed to sustain them. So growing an entire replacement organism is a much bigger challenge. 

An incipient “organoid” after 30 days of culture – not yet a true mini-brain – grown from cultured neurons by Selina Wray and her colleagues at UCL. The green regions show areas rich in the protein Ki67, a marker of dividing cells; the red regions contain the Tbr1 protein, a marker of the first born neurons which form a layer above the diving cells. The blue regions is a DNA stain, so it highlights all of the cells. Credit: Chris Lovejoy and Charlie Arber, UCL Institute of Neurology

An incipient “organoid” after 30 days of culture – not yet a true mini-brain – grown from cultured neurons by Selina Wray and her colleagues at UCL. The green regions show areas rich in the protein Ki67, a marker of dividing cells; the red regions contain the Tbr1 protein, a marker of the first born neurons which form a layer above the diving cells. The blue regions is a DNA stain, so it highlights all of the cells. Credit: Chris Lovejoy and Charlie Arber, UCL Institute of Neurology

That objective is helped, though, by the fact that cells are smart. To some degree, they “know” what is required of them as they develop into tissues and organs, sending out signals in the form of chemicals that diffuse through the tissue that enable the cells to orchestrate their own growth and patterning. This has become plain from the work so far on “mini-brains” – organoids made from iPSCs that have specialised into neurons. These structures are typically no bigger than a full stop or a fly’s eye, but they’re not just a uniform clump of neurons. The cells automatically start to differentiate into some of the different types of neuron found in different regions of the brain, and the cluster even starts to take on some of the characteristic “folded” shape of a human brain.

"The immediate reason for making mini-brains is that they can help us study and understand the onset of degenerative conditions, such as Alzheimer’s, Parkinson’s or multiple sclerosis".

It’s not yet known how far this process can proceed towards an organ with the full complexity of a human brain, because the mini-brains can’t get bigger without a blood supply: the innermost cells would start to die. All the same, experiments have shown that the neurons are able to send electrical signals to one another, as they do in normal brain tissue. You can argue about whether this qualifies as “thinking” in any meaningful sense, but it has some relation to what goes on in the early stages of the formation of an embryonic brain.

It’s not beyond hope that this kind of brain tissue could be used to help repair that damaged or degenerated in people with brain injuries or neurodegenerative conditions. But that’s a distant prospect. The immediate reason for making mini-brains is that they can help us study and understand the onset of degenerative conditions, such as Alzheimer’s, Parkinson’s or multiple sclerosis. For example, by culturing these organoids from the iPSCs of people with genetic predispositions to such diseases, researchers might be able to figure out what goes wrong at the genetic level to cause them – and then perhaps to seek treatments.

These are the motives of Created Out of Mind and the team at UCL’s Institute of Neurology who are doing the cell culturing for the Brain in a Dish project. This aspect of the team’s work is being led by Selina Wray in the Department of Molecular Neuroscience at UCL; my own biopsy was taken by Ross Paterson. With the samples taken, the next step is to treat the fibroblasts with the ingredients needed to turn them into iPS cells. After that, they needed to be given the signals that will make them “decide” to become neurons. I’ll explain how those steps are done in later posts. Ultimately, our mini-brains will be used as anonymized healthy control samples for the UCL research.

For me, though, this process is an illustration of an astonishing wider perspective opened up by the work of Yamanaka and others. It’s now clear that our cells have far more plasticity than we imagined. There’s no obvious reason why almost any part of us can’t be transformed into almost any other part. Where this becomes truly mind-boggling is when we start to consider using iPSCs to make gametes: the “germ cells” responsible for reproduction, eggs and sperm. Already the transformation of human adult iPSCs to the precursors of germ cells – an embryonic cell type that later become sperm or eggs – has been demonstrated.

Such work could lead to fertility treatments, for example for people lacking sperm or eggs. But one can also imagine some extreme, even lurid, theoretical possibilities for human reproduction. Technologies like this clearly need responsible regulation, but the point of principle is that the human body is not exactly the hermetically sealed organism we have become accustomed to imagine. It may be that the sight of my “second brain” growing in a dish (if all goes well) will bring that home to me in ways I haven’t anticipated. We’ll see'.