For many people, the idea that someday incurable diseases will be cured by regenerative medicine and cell-based therapies is what makes stem cell research so exciting. But there is another avenue of research being pursued that is equally promising, where stem cells aren’t the treatment, but rather the tool that will help uncover potential cures.

An important technology in stem cell research and drug discovery is high throughput screening (HTS), which is done using special plates that contains 384 small divots called wells. Cells, proteins, or other biological material are first put into the wells, and then different small molecules, drugs, or biologics are added. Each well is like a miniature experiment. This powerful technology makes it possible to test thousands of small molecules in a short amount of time.

At HSCI’s Therapeutic Screening Center, headed by Lee Rubin, PhD, Director of Translational Medicine at HSCI, researchers perform screening assays against stem cells or cells grown from stem cells in order to identify small molecules, compounds, gene products, and proteins that could be turned into diverse therapeutics to cure diseases.

The use of stem cell lines allows for a new type of screening because large populations of similar cells are required in order to generate useful and accurate data. Our ability to grow both embryonic and adult stem cells now makes it possible to achieve both the quality and quantity of cells needed. For example, in order to run drug toxicity screens against human cardiac or neuronal cells, stem cells could be directed to differentiate into the needed cell type. This creates a large enough population of cells to use in the screen, and does it in a reproducible way – a critical element when conducting experiments.

Another reason why stem cells are so important to HTS is that “disease- specific” cell lines can create in vitro models of diseases. These stem cell lines are generated from patients with a given disease – either through somatic cell nuclear transfer or reprogramming – or from an embryo that has tested positive for a disease. Facilities such as HSCI’s Therapeutic Screening Center can use these cell lines to study the cause of the disease and search for possible therapeutics.

Cells are put in plates and exposed to factors (top left). Hits, including controls, are shown as green squares (top right). Increased numbers of cells express green fluorescent protein (GFP) in a hit (bottom right) relative to a control.

One way that screening assays use disease-specific cell lines is to look for drugs that help to treat a given disease. For example, at the Therapeutic Screening Center, researchers are using a screen focused on identifying molecules or pathways that prevent degeneration of stem cell-derived motor neurons that carry the mutation causing Spinal Muscular Atrophy (SMA). The screen tests for molecules that can cause more motor neurons to live and express higher levels of the protein that is missing, or under-expressed, in the disease. Testing early in the drug development cycle is much more effective and efficient than testing later in humans and potentially discovering problems after significant time and money have been committed.

Other types of screens address questions about the underlying mechanism of disease. In the case of SMA, many questions exist about why the motor neurons are so sensitive to the SMA mutations relative to other cells and whether this is due to cell-specific regulatory pathways or unique functions in motor neurons. The stem cell-based screens done by Rubin and his team are addressing these questions on two levels. The first asks mechanistic questions about SMA biology, in order to determine how SMA influences motor neurons. The second explores  how these mechanistic insights can be translated into the search for therapeutic targets.

Screens can also be used to search for drugs or biologics that direct stem cells into becoming a specific type of cell – a process known as targeted differentiation. Knowing how to generate a certain type of cell from stem cells is very important for treating conditions where cells have been injured or died, such as in diabetes.

The challenge in diabetes is to replace pancreatic beta cells, the cells that make insulin to regulate the body’s blood sugar, which are destroyed in the disease process. To address this challenge, Douglas Melton, PhD, co-Scientific Director of HSCI, and HSCI Affiliated Faculty Richard Maas, PhD, are working with Rubin and his team to conduct two types of screens. In the first they are looking for factors that stimulate beta cells to proliferate into more beta cells – knowledge that could be used to create a self-repair type therapy. The second types of screens are looking for ways to direct the differentiation of stem cells into pancreatic beta cells, which could be used in cell-replacement therapeutics.

The Therapeutic Screening Center is an important hub of collaboration at HSCI, as the state-of-the-art technology is an invaluable resource across different disease areas and model organisms. When stem cells are used as tools, researchers are able to ask key questions about disease mechanisms by modeling diseases more faithfully than in the past. And the answers to these questions will eventually identify new treatments for diseases that have been previously difficult to study.