State of BBS Research

Background

The first pointer to a BBS gene was discovered in the early 90s with the first definitive gene identified in 2000 (what came to be known as BBS6 or MKKS). The early discoveries paved the way for the understanding of the role of primary cilia in cells and that BBS is a ciliopathy, or disease of malfunctioning primary cilia. The BBSome, a group of seven proteins that work together to move molecules into and out of the primary cilium was described in 2007. Today there are 25 published BBS genes with several others implicated. These genes code proteins that include the BBSome, proteins that assemble, manage or assist the BBSome, proteins directly involved in moving molecules along the cilium, as well as others (with some not yet fully understood). 

These identified genes account for about 80% of all people clinically diagnosed (i.e. based on symptoms, not genes) with BBS today. There remain a number of outstanding questions on the basic science of BBS genes and proteins. 

Key Questions:

1. What is the cause for the ~20% of people who don’t have a genetic diagnosis? How much of this remaining 20% can be accounted for by variants of unknown significance in known genes, unknown genes, and/or misdiagnosis?

2. Why does BBS vary so widely in terms of symptoms and severity, even when caused by the same gene, or even the same variant?

3. What is the function of each BBS protein in diverse cell/organ types during all stages of life (development, homeostasis, regeneration) and how can we comprehensively study these functions? 

4. What are the overlapping biological (and ultimately clinical) features of BBS and other syndromic ciliopathies such as McKusick-Kauffman, Joubert and Alstrom Syndromes?

5. What are the non-ciliary roles of BBS proteins (e.g. why do some BBS proteins localize to the nucleus of cells)? 

6. Do BBS proteins participate in any cellular pathways not previously reported and could these be leveraged for gene-agnostic therapies?  

7. Where are there meaningful population-level differences in BBS, BBS gene and BBS mutation prevalence?

Basic Science Research

Basic science research is generally funded by governments via competitive grants and carried out at academic research centers/labs. Some of this research focuses on basic biological processes and mechanisms and is conducted with model organisms such as Chlamydomonas (green algae) and C. elegans (roundworm). Other research is focused on specific cell types or organs and may use tools from cellular models, small animals such as zebrafish and mice, or organoids (living models of organs). Cellular and small animal models and organoids are useful, but they differ from humans in important ways. Larger animals, in general, have organ structures closer to humans and can be more informative for studying human diseases. There are very limited large animal models for BBS: a BBS7 Rhesus macaque (a type of monkey), and dogs with mutations in BBS2, BBS4 and BBS8 which mimic some features of BBS. The lack of large animal models, and especially primate models, is a barrier to definitively understanding aspects of BBS and ultimately in translating basic science research into clinical treatments. 

Basic science researchers typically specialize in protein biochemistry, cell biology,  developmental biology, or genetics; they often specialize in certain techniques, animal models or organs.  

Key active basic science researchers include:

Jeremy Reiter — Developmental biology, US

Max Nachury — BBSome, US

Martha Neuringer — Primate retinal degeneration, US

Erica Davis — Genetics, US

Helen May-Simera — Cell biology, Germany

Ronald Roepman — Protein biochemistry, Netherlands

Ruxandra Bachman-Gagescu — Developmental biology, Switzerland