When brain development goes awry, neurodevelopmental disorders can result. These conditions can affect cognition, communication, sleep, motor skills and behavior. Some common neurodevelopmental disorders include autism spectrum disorder, attention deficit hyperactivity disorder and schizophrenia, among others. However, most neurodevelopmental disorders are rare. Dr. Helena Kilpinen explains, ‘developmental disorders’ is an umbrella term for a lot of different rare syndromic, genetically-caused disorders. Under this umbrella, there are some that one might know, such as Kabuki syndrome. But most of them just don't have a name, let alone a genetic diagnosis.”

Such conditions are caused by rare genetic mutations. For example, a family could carry a unique heritable mutation, or a child could have a unique de novo genetic alteration. 

The symptoms of these rare disorders vary widely, depending on gene affected and genetic background of the individual. Intellectual disability is one of the most frequently occurring symptoms. There are no cures and very little or no treatments available.

While individually rare, neurodevelopmental disorders affect between 2-5% of children globally and present a challenge of life-long disease management. “One of the challenges with all rare diseases is the diagnostic odyssey that the families have to go through,” says Dr. Kilpinen. Getting the genetic diagnosis and appropriate therapeutic intervention can be hard due to the rareness of the disorders.

Recent research has begun to shed light on some of the genes behind these rare developmental disorders, and the consequences of genetic alterations on neuronal function at the molecular level. Dr. Kilpinen explains:

The genes that cause these disorders are being identified through large genetic      studies; for example, a major study in the UK called ‘Deciphering Developmental Disorders’ has identified hundreds of new genes and mutations. The biology that's starting to emerge is that oftentimes these mutations hit the chromatin machinery of the cells.

Finding the genes that cause the disorders is only the first step. Dr. Kilpinen and her research team use human induced pluripotent stem (iPS) cell technology to model rare brain-related diseases based on the genetic mutations uncovered. She explains: 

Our aim is to better understand the cell-level underpinnings of these rare disorders and other brain-related traits. And by discovering the cellular mechanisms, we’ll be able to identify targets for therapies that might improve the quality-of-life of the persons affected. These are congenital disorders; what if some of the effects could be reversed if caught early, such as in utero? It might sound crazy, but it's not completely impossible. 

And continues:

There is a very interesting duality regarding many human chromatin-related genes. If a person is born with a germline mutation in one of these genes, they may get a developmental disorder. But, if the same gene is hit with a somatic mutation later in life, the person could get cancer. What this means in practice is that these genes are studied a lot. And it also means that there are already drugs out there that target many of the gene products. Perhaps we could repurpose some of these drugs for the treatment of neurodevelopmental disorders.

This presents an interesting gap: the genes are known, and targeted drugs exist. But everything in between is poorly understood.

Induced pluripotent stem (iPS) cells are the key

Dr. Kilpinen’s research team uses both computational and experimental approaches to fill that gap, and human induced pluripotent stem (iPS) cells serve as their primary research model. 

iPS cells are derived from somatic cells and reprogrammed into an embryonic-like pluripotent state. For example, in the HipSci Initiative that Dr. Kilpinen was involved in, “iPS cells were made from skin cells; a small skin punch was taken, made into fibroblasts, and then reprogrammed with a transcription factor cocktail, reverting the fibroblasts      back to a pluripotent state,” she explains. Owing to their pluripotency, iPS cells can be differentiated into any type of cell, a most powerful feature. 

Dr. Kilpinen’s group cultures and differentiates these lab-generated stem cells, from either patients or healthy individuals, into various types of brain cells. This research model enables their work along their three central lines.

First, the group models cellular disease mechanisms in rare neurodevelopmental disorders with a focus on chromatin-modifying enzymes and the epigenome. They also examine the effects of genetic background, e.g., causes of variability in disease severity in persons with the same mutation. Last, they continually develop methods to improve their approaches to the first two aims. For example:

We are scaling up iPS-based experiments for more robust studies. To do this, we're culturing and differentiating cells in pools of 10-20 lines, rather than individually. We measure the transcriptomes of these cells using single cell technologies and map the cells back to the individual samples they came from using natural genetic variation. This saves both time and money, and there are fewer batch effects. Of course, there can be unexpected population dynamics happening in the dish that we have to deal with, but the pros still outweigh the cons. 

Explains Dr. Kilpinen. The group uses a variety of readouts to answer their scientific questions, but their primary interest is in the transcriptome and epigenome. Single-cell multiomics to capture the chromatin state of individual cells has also become an important approach. Dr. Kilpinen describes an additional, recent angle:

We're using an imaging-based assay called ‘Cell Painting.’ It's a way to get quantitative measurements of key cellular compartments and their features. We're doing this in collaboration with Drs. Lassi Paavolainen and Vilja Pietiäinen and the FIMM High Content Imaging and Analysis unit. The assay was developed at the Broad Institute (USA), and we’ve now adapted it to neurons enabling us to look beyond the transcriptome and the molecular level to a whole cell level.

Repatriation for genetics and neuroscience

Dr. Kilpinen recently relocated her research program from the UK to the University of Helsinki, particularly to the Institute for Molecular Medicine Finland, FIMM, a Nordic EMBL Partnership institute, and the Neuroscience Center. Both research centers are part of the Helsinki Institute of Life Science (HiLIFE), which has provided her with a tenure-track position. 

One of the goals of her position is to provide a point of research connection between FIMM and the Neuroscience Center. Dr. Kilpinen describes the two environments:

FIMM is a strong center, a flagship, for human genetics research. With the incredible resources in studies like FinnGen, somebody like me can leverage thoroughly genotyped and studied cohorts to identify individuals that carry interesting variants, mutations, or phenotypes. And, in the case of FinnGen, these individuals can be recalled for collecting cells to make iPS cells. This is very powerful, compared to just using generic cell lines. 

She continues, “and, at the Neuroscience Center, they have the neuroscience expertise and community. So it's a really nice match for me.” 

To see some of her ideas to fruition, Dr. Kilpinen has developed important collaborations. For example, with support from the Academy of FInland, she is planning to work with Andrea Ganna at FIMM on a study to recall FinnGen participants. 

The FIMM Technology Centre is also proving to be essential with projects in the High Content Imaging and Analysis and the Single Cell Analytics units. In addition:

The Neuroscience Center has recently established a neuro-iPS core. They will start offering different types of neuronal cells differentiated from iPS cells, as a service. It has been started by Prof. Jari Koistinaho, former Director of the Neuroscience Center, and we're working closely with him with the goal to run our experiments on a bigger scale in the future.

Dr. Kilpinen also has established collaborations outside of Finland, primarily in the UK.

One of our bigger ongoing collaborations is with the Wellcome Sanger Institute and Open Targets, a public-private partnership between a number of pharma companies and academic institutions in Cambridge, UK. I have a research grant from Open Targets with Dr. Matthew Hurles at Sanger and Emmanouil      Metzakopian in the UK Dementia Research Institute. We're doing similar things with iPS-derived neural cells, but the genes of interest are being knocked out using CRISPR in an isogenic background. It involves drug screening, too.  

When it comes to Nordic partners, Dr. Kilpinen is looking forward to exchanging ideas with neuroscience experts at DANDRITE, the Danish node of the Nordic EMBL Partnership. She already got started with that at the recent EMBL Partnership Conference in September 2022 with a presentation about her group’s work and networking with DANDRITE members on-site. 

Following a path of scientific interests from genetics to computation 

One of Dr. Kilpinen’s early career decisions might just be the reason she is where she is today. As a young student, her interests took her into the natural world, making biology an easy choice. Early on in her studies she got interested in human genetics. With a summer traineeship she joined the group of the late Prof. Leena Peltonen-Palotie at the University of Helsinki and later, to complete her PhD, at the Wellcome Sanger Institute. She reflects on the experience:

I didn’t realize what research was before joining Leena’s group. It was such a good place for a young scientist to be. It was full of people passionate about their work. It was international. I got a glimpse of the big world of research, and it was really inspiring. It was cutting-edge human genetics, nothing like what I had learned from my studies.

Initially trained as a wet-lab scientist, Dr. Kilpinen dipped herself into computational work during her PhD studies with Prof. Leena Peltonen-Palotie. And, then, in what turned out to be another big influence on her career, she switched entirely to computational biology during her postdoctoral training. She recalls:

It wasn’t a conscious choice. I was just interested in the science that the groups did, and my projects turned out to primarily involve analysis of large-scale genomic data. It's been a huge benefit for me that I made the switch to computational work. It’s easier to connect fields and approaches, something I’m doing in my own group now. 

It was during her second postdoc position in the UK that Dr. Kilpinen was introduced to iPS cells:

During my postdoc at EMBL-EBI, there was an opportunity to work with data from a large collection of human iPS cells. HipSci was a research project funded by the Wellcome Trust and the UK Medical Research Council during 2013-2018 to create an open, large and well-characterized cohort of human iPS cells for research purposes. I interacted with different experts in iPS cell biology and got a good overview of what they can be used for and the pros and cons. 

And, her biggest breakthroughs in science followed:

The major outcomes from my two postdoc positions demonstrated the concept that when you measure phenotypes from cells, whether it is gene expression, chromatin, transcription factor binding, or other, the whole genetic background of the individual will affect the phenotypes - not just the primary mutation you may be interested in.     

And, now that she is a group leader, Dr. Kilpinen finds motivation from people:

Something that has become particularly clear to me during the past few years is that if you give people freedom, they usually step up to the challenge and run with it. Generally, in a research group, there are lots of young, smart people who can oftentimes take an idea and a project much further than the seniors could. That's the best part - to see an early idea develop into something completely different.

From basic research to societal impact

Even in the most fundamental research, one can usually find a connection to improving the world for others. For Dr. Kilpinen this is two-fold. First:

Even though we're doing basic research, there is the genuine idea to reverse developmental disorder-related phenotypes. Early evidence in mouse models suggests that this could be done, at least for some features. So this is our dream - when a child is born with a rare developmental disorder, that something could be done for them.

And, second:

iPS cells are an amazing resource. Still unknown to many people, these artificially generated stem cells can be made from any individual. If you're a patient we can study your cells, your mutation, and your genetic background to figure out what’s wrong. It's personalized medicine!   

Brief career summary

Dr. Helena Kilpinen was initially trained in human genetics. In 2011, she completed her PhD with Prof. Leena Peltonen-Palotie and Dr. Iiris Hovatta where she studied the genetic mechanisms of autism spectrum disorders at the University of Helsinki. Dr. Kilpinen then moved to the University of Geneva, Switzerland for postdoctoral studies in functional genomics with Prof. Emmanouil Dermitzakis. She then continued postdoctoral work with Dr. Oliver Stegle at EMBL-EBI (European Bioinformatics Institute). In 2016, she began her career as a group leader with a joint position at the University College London Great Ormond Street Institute of Child Health and the Wellcome Sanger Institute in Cambridge, UK, where she held an MRC eMedLab Career Development Fellowship in Medical Bioinformatics. Dr. Kilpinen and her group joined FIMM and the Neuroscience Center in mid-2020 as a HiLIFE (Helsinki Institute of Life Science) tenure-track assistant professor  in genome biology. She is also affiliated with the Faculty of Biological and Environmental Sciences. 

The article is published as part of the “Behind the Science'' profile series, taking an in-depth look at a scientist or group within the Nordic EMBL Partnership.