Use single cell biology to shed light on pediatric diseases

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T.Here are some harder things a doctor can say to a patient than, “I don’t know what’s wrong.” That is even more difficult to say when you are seated across from the parent of a child with an undiagnosed condition.

And as I’ve learned from experience, working in a national pediatric rare disease referral center is even more difficult because you are a family’s last hope: the doctor they see after months or even years of searching Help and exhaustion of any other option. My heart broke every time I had to say, “I’m so sorry, but I don’t know what’s going on.”

Even after this revelation, my colleagues and I at the University of California at San Francisco searched patients’ medical histories and medical records to determine the causes of their illnesses. We have pondered any research that might help us understand the cellular mechanisms involved. And we have listened to and learned from our patients and their families.

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We have solved some puzzles. In most cases, however, the parts were missing and there was little we could do to address the underlying causes of our patients’ illnesses.

That was most of a decade. Today, thanks to the great advances in single cell biology and the application of technologies and techniques to enable researchers to study the building blocks of life – single cells – things will change.

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In recent years, researchers have created reference maps for every cell type in adult human bodies. The abundant data and resolution that single cell technologies provide is already changing our understanding of human biology. They could also uncover the cellular mechanisms underlying diseases, including rare diseases, by identifying the activity of disease-associated genes in individual cells, as well as gene activity in healthy individuals. For example, researchers used single-cell RNA sequencing to identify a new type of cell in the human airway that could help scientists develop new and improved therapies for cystic fibrosis.

Single cell technology has also allowed scientists to quickly identify cell types in the nose that are susceptible to infection with SARS-CoV-2, the virus that causes Covid-19.

The problem is that this revolution in single cell biology and medicine has not yet fully reached pediatrics. There is no lack of energy or passion for single cell research in this community. However, a number of systemic barriers prevent it from taking off.

One of these obstacles is funding, or more precisely, underfunding. As a percentage of the National Institutes of Health budget, support for pediatric research has steadily declined from 12.8% in 1998 to just 1.7% in 2015. Although NIH support for pediatric research has increased since 2015, it is still not enough. Pay is another problem: pediatricians earn less than almost any other type of doctor, resulting in many of them working longer clinical hours and foregoing research that they might otherwise be doing.

The challenges don’t end there. Single-cell researchers who are able to secure funding also need tissue samples in order to examine not only sick but also healthy patients. However, both types of samples are in short supply. There is not always a clear reason for patients and their families to donate healthy tissue, such as tissue removed during surgery. And the process of contributing a sample can be particularly difficult. Families may be concerned about privacy or feel suspicious of historical and discriminatory practices in medicine. Or they do not know that it is even possible to participate in the research.

As massive as the barriers to research are, leaders in the pediatric community have shown that they can be overcome. Take part in the Children’s Oncology Group, which brings together more than 10,000 experts from over 200 children’s hospitals. Since its inception in 1955, this community has helped families feel safe and informed about participating in childhood cancer research and contributing tissue samples to it. The group worked directly with parents to implement effective privacy and consent standards. And it has helped establish a paradigm where data sharing between pediatric cancer research groups is the rule rather than the exception.

The results speak for themselves. With the onset of childhood cancer research, survival rates have increased from less than 10% in the 1950s to almost 80% today. In other words, hundreds of thousands of children who would otherwise have died grew up to lead healthy and fulfilling lives.

Pediatrics has reached a turning point at which single cell biology can help decipher the causes of many childhood diseases.

In this sense, the Chan Zuckerberg Initiative (CZI), the philanthropy I co-founded, supports this type of collaboration. The aim is to bring patients, families, clinicians and researchers together to advance single cell research and ultimately create and share an open source reference map of all healthy pediatric tissues that scientists can access and analyze.

Several principles guide this approach. The CZI funds interdisciplinary teams of data scientists, experts in single cell biology and – key – pediatricians who continue to see patients. The aim is to ensure that any collaboration reconciles basic research with clear practical applications and is informed of the needs of families who have volunteered to provide samples.

These teams will contribute to open science projects, including the Global Human Cell Atlas, which aims to map all cells in the human body to help scientists understand how healthy cells work and what goes wrong with disease. Of course, there are limits to the amount of data that can or should be shared in the pediatric research community. But as the Pediatric Oncology Group has shown, it is possible to maximize collaboration while protecting patient privacy – and making extraordinary progress in that way.

I and my colleagues at CZI firmly believe that single cell reference data must include people who have historically been underserved by pediatric research initiatives and who suffer disproportionately from teething problems, including black, Latin American, Asian and indigenous populations. These children need to be part of the hope and progress before us, so this research needs to be done with partners from these communities.

While the research networks for single cell biology are still small, I hope they will grow as more patients, parents, clinicians, researchers, and institutions see where this research could lead. Imagine a future where researchers have mapped a wide variety of pediatric cell types and know how they develop over time. With this knowledge, a clinician could sequence a patient’s genome and predict when, where, and how a disease is likely to manifest itself. If we understand what the onset of a disease looks like at the cellular level and are able to identify features that change before the pathology sets in, we can even prevent disease rather than treat disease after the fact – a development that children do and adults.

These advances would be life changing for patients and families. The therapeutic possibilities are even more promising. With the right data on gene expression and cell types, scientists and paediatricians could develop targeted therapies for any number of diseases. We could identify new ways to use existing therapeutic strategies.

Of course, this future is beyond the reach of a research group, network, or organization. It will require sustained investment in a variety of institutions, from patient networks to the federal government to philanthropic funders. And it will be important to develop a common understanding of the value of pediatric research, and particularly of single-cell research.

When I think about the work ahead, I remember “Fiat lux” – let it be light – the UCSF motto. It should serve as an indictment for the pediatric community: let’s shed new light on diseases that remain in the dark. And let’s be the light for children who need it most.

Priscilla Chan is a pediatrician, co-founder and co-CEO of Chan Zuckerberg Initiative.



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