The liver is the largest internal organ in the body and is essential for bodily function. It metabolizes the food we eat and the drugs we take and detoxifies foreign compounds that we are exposed to. It produces proteins that circulate in the blood that carry lipids, vitamins and hormones, as well as enzymes that help our blood clot. The liver has a legendary capacity to regenerate and repair itself but many times it cannot. Excess alcohol, exposure to chemicals and viral infections can all cause the liver to become permanently diseased and fail to carry out its essential functions.
Liver failure results in more than 40,000 deaths annually in the United States. Currently, the only viable treatment for liver failure is liver transplantation. However, liver transplantation as a treatment can be problematic due to a shortage of available donor organs (particularly in the U.S.), risk of rejection and complications due to chronic treatment with immunosuppressants. An alternative approach for treating acute and chronic liver failure is hepatocyte transplantation therapy. Hepatocytes are cells in the liver that carry out liver functions. Hepatocyte transplantation has several advantages over whole organ transplantation but is still limited by a reliable source of hepatocytes.
Hepatocytes are also important for drug testing. Before a drug can be tested in humans it must undergo pharmacokinetic and toxicological tests in the liver. In the past, these tests were done in animals (usually rats, mice or dogs) but we now know that there are many important differences between humans and other mammals so it is preferred to test drugs in human systems in vitro (i.e., in a petri dish) before they are given to humans. These in vitro or cell-based assays also save the lives of millions of animals that in the past had to be used for this testing. To do perform the in vitro testing, pharmaceutical companies typically buy freshly isolated human hepatocytes from organ donors who die in accidents. However, this supply of hepatocytes, like that for treating liver failure, is erratic, not well controlled and extremely expensive.
Both of these problems – a shortage of hepatocytes to treat liver disease as well as to use in pharmaco-tox testing – can be solved using human embryonic stem (ES) cell technology. ES cells are cells that have the capacity to regenerate themselves (i.e., “proliferate”) as well as to turn into any other cell type in the body under the proper conditions (i.e., “differentiate”). Hepatocytes are among the cell types that researchers have been able to derive from human ES cells, however much more work needs to be done in this area. In this proposal, we will establish an optimized protocol to differentiate human ES cells into hepatocytes. These hepatocytes can be used as a reliable, controlled source of material to treat liver disease as well as to test new drugs for treating other diseases.
Statement of Benefit to California:
California will benefit in many ways from this research. It has been estimated that it requires hundreds of millions of dollars and at least 10 years for a single new compound to reach the marketplace as a new drug. There are many hurdles that contribute to this long lag time and costly process. One of the main hurdles is toxicological testing. In order for pharmaceutical companies to develop new drugs to treat diseases they must first test them to determine whether the drug is toxic to human cells and how it will be metabolized in the human body. The current gold standard for toxicological testing are primary human hepatocytes. Pharmaceutical companies spend over $4 billion per year on drug testing using human hepatocytes. This need for human hepatocytes is greatly increasing as companies are automating the drug discovery process using high throughput screens done by robots. Between that automation and the human genome sequence that is now available, the number of new drug candidates is increasingly exponentially. That means that the need for human hepatocytes to test these drugs on before they can be tried in humans is also increasing greatly.
The problem is that the supply of human hepatocytes is very limited and is not well controlled since it must rely on organ donors who typically die in accidents. There are several companies that sell human hepatocytes for drug testing, and research, but none of these major companies are based in California. This proposal aims to develop a viable, renewable source of human hepatocytes using embryonic stem cells. Companies will then buy their hepatocytes from California, bringing large amounts of revenue into the state.