Creative Minds: A Transcriptional “Periodic Table” of Human Neurons

Posted on June 8, 2017 by Dr. Francis Collins

Caption: Mouse fibroblasts converted into induced neuronal cells, showing neuronal appendages (red), nuclei (blue) and the neural protein tau (yellow).
Credit: Kristin Baldwin, Scripps Research Institute, La Jolla, CA

Writers have The Elements of Style, chemists have the periodic table, and biomedical researchers could soon have a comprehensive reference on how to make neurons in a dish. Kristin Baldwin of the Scripps Research Institute, La Jolla, CA, has received a 2016 NIH Director’s Pioneer Award to begin drafting an online resource that will provide other researchers the information they need to reprogram mature human skin cells reproducibly into a variety of neurons that closely resemble those found in the brain and nervous system.

These lab-grown neurons could be used to improve our understanding of basic human biology and to develop better models for studying Alzheimer’s disease, autism, and a wide range of other neurological conditions. Such questions have been extremely difficult to explore in mice and other animal models because they have shorter lifespans and different brain structures than humans.

Kristin Baldwin

The focus of Baldwin’s work will be the thousands of proteins, called transcription factors, that switch genes on and off in our cells and play key roles in determining cell fate. Groundbreaking research several years ago in the lab of Marius Wernig at Stanford University, Palo Alto, CA, established that forcing the activation of three preselected transcription factors in mature skin cells, or fibroblasts, could convert them into neurons [1]. Baldwin wondered whether greatly expanding the list of transcription factors might produce a diverse array of neuronal subtypes. She likened the idea to chemists using the periodic table to find elements that can be combined in different ways to make larger organic molecules.

In a recent preliminary screen of 60 transcription factors, which were paired in hundreds of different ways, Baldwin and her colleagues found that 75 combinations were able to convert mouse fibroblasts into neuron-like cells within 2 weeks. Some of these so-called induced neuronal (iN) cells expressed nicotinic receptors, which are involved in addiction and anxiety. Others expressed serotonin and dopamine receptors, which are common targets for many drugs that treat mental illness. Interestingly, all of the transcription factors interacted with a core group of genes that seem to serve as a circuit board for establishing neuronal subtypes and maintaining their identities.

Now, with her Pioneer Award, Baldwin will begin creating a guide to converting human fibroblasts into nerve cells. She and her coworkers will start with induced pluripotent stem cells (iPSCs), which can differentiate into nerve, heart, and many other cell types. They’ve already created the iPSCs from blood cells donated by a group of American seniors age 80 and older [2]. These extraordinary seniors, whom researchers have nicknamed the “wellderly,” have no major chronic medical conditions and take no long-term medications. This makes these volunteers an ideal source of healthy cells, which Baldwin said will help to ensure reproducibility of the results.

Baldwin’s lab will convert these iPSCs into fibroblasts and then screen combinations of transcription factors to see if they prompt the fibroblasts to turn into iN cells. If so, the recipe of transcription factors will be recorded, and each type of iN cell will be analyzed for its genomic profile, biochemical properties, and functional characteristics. Baldwin plans to fold all of this information into a free online database that will be available 24/7 for researchers in need of guidance.

In addition to creating a valuable scientific resource, Baldwin’s project could also lend a hand in efforts to address an important research question: just how many different types and subtypes of neurons does the human body have? Current estimates range from hundreds to thousands, with each of these diverse neural cell types responsible for distinct aspects of behavior, cognition, and potential to play a role in neurologic disease.

References:

[1] Direct conversion of fibroblasts to functional neurons by defined factors. Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Südhof TC, Wernig M. Nature. 2010 Feb 25;463(7284):1035-1041.

[2] Influence of donor age on induced pluripotent stem cells. Lo Sardo V, Ferguson W, Erikson GA, Topol EJ, Baldwin KK, Torkamani A. Nat Biotechnol. 2017 Jan;35(1):69-74.

Links:

Baldwin Lab (Scripps Research Institute, La Jolla, CA)

Baldwin NIH Project Information (NIH RePORTER)

NIH Director’s Pioneer Award Program (Common Fund)

NIH Support: National Institute on Aging; Common Fund