Interviewed by Marilynn Larkin

Since the launch of SBS/NIH Connections, we have been looking at various facets of the Molecular Libraries Initiative (MLI) and the Molecular Libraries Screening Center Network (MLSCN; see p. 4-5 in this issue). Chris Austin, MD, Director of the NIH Chemical Genomics Center and Co-Principal Leader, NIH Roadmap Molecular Libraries and Imaging Implementation Group, noted in an earlier article (August 2005) that since the MLSCN assays are coming from academic researchers looking for probes of their experimental systems, the palette of assays submitted is reciprocal to that of pharma. NIH’s HTS technologies are being applied to a different set of targets, most of which fall into the traditionally “nondruggable” genome or are targets for rare diseases.

In this interview, Chris Portier, PhD, former Associate Director of the National Toxicology Program (NTP) and newly appointed Associate Director of NIEHS for Risk Assessment, explains how scientists also are using the initiative to identify toxins. “Our goal is to see what screening tells us about the thousands of compounds people are exposed to daily, and to use that as a guide,” says Dr. Portier. “Essentially, we’re doing what pharma does, but instead of targeting a drug, we’re targeting the toxic effects.”

What types of toxins is the NTP screening?

CP: We study everything—drugs, pesticides, cosmetics, nanoparticles, solar radiation and other things that are normally in the environment. Think about it. You eat a particular food for lunch. How do you know it’s safe? If it’s a burger, for example, you know the meat will be subject to inspection by the US Department of Agriculture. However, before it hits the supermarket shelves, the burger may have products added to it, such as preservatives for longer shelf life, something to make the meat a nicer color or smell better as you cook it. Or it may be wrapped in plastic, and plastic has chemicals that leach into the meat. These additives and chemicals are added by a manufacturer who thinks they can help sell the product. Who’s responsible for making sure these compounds are safe? Many of them fall outside of mandatory testing requirements. That’s where the NTP comes in. Right now, the NTP has active testing programs on an average of 200 chemicals and products at any given time.

How do you get leads?

CP: We get leads in a variety of ways, but most notably because someone on our staff, or the staff of other government entities such as the Food and Drug Administration or Environmental Protection Agency, asks us to look at the safety of a lead. We do a literature review and decide whether to go further.

The problem is, there are an enormous number of things to look at. Herbals and other dietary supplements fall under the NTP purview because, again, there are no safety requirements before they’re put on the market. But there are tens of thousands of compounds that make up the natural world. Which do we go for? Do we go for Echinacea itself or an Echinacea extract? Is St. John’s Wort toxic or just some part of it?

In addition, although we don’t test individual drugs, we do test combinations, because there’s no legal requirement to test the safety of combinations of drugs. We look, for example, at HIV combination therapies to see which may be toxic because one company owns one drug, another company owns another, and so forth. If someone wants to show a combination is therapeutic, they must do a clinical trial. But safety testing is done only on the individual drugs.

Where does the MLSCN come in?

CP: The NTP is benefiting from the MLSCN’s ability to do HTS, which will tell us something about the toxicity and toxicology of specific groups of compounds. This will help us focus better and build more definitive and extensive assays. We’re not simply sitting back, of course. We’re also suggesting assays and sponsoring some RFPs to get assays targeted for toxicology developed. We’re participating in the RFP for ADME, since knowing how compounds are absorbed, distributed, metabolized, and excreted is just as important to us as it is to drug companies.

What we’ve contributed to the MLI at this point is known toxins, so either we know a compound is safe or we know it’s nasty. Nasties include metals such as mercury, lead, chrome, and tin; plastics and phthalates, which are reproductive toxins; dioxins and dioxin-like compounds that bind to a hydrocarbon receptor causing a broad spectrum of problems, from developmental to reproductive, to cancer, to neurological disorders; pesticides; and certain herbals. They’re in the library so people can screen against them to see whether their targets are affected by these compounds.

It’s really great, because as people are looking at the other compounds as molecular targets, and flagging compounds that are very similar to the toxin, we are doing the same thing: looking at the other compounds after we know they’re toxic and saying, ‘well, now can we actually begin to prove that screening works.’ A drug firm would never choose compounds that acted like our toxin, but we may actually take one of those compounds and test it to show that we get the expected response.

Some people have speculated that HTS may lead to a reduction in animal testing. Do you agree?

CP: I don’t really foresee NTP reducing its reliance on animals. Rather, I see HTS helping to focus animal studies much more effectively—that is, instead of testing 10 compounds in one chemical class before we decide it should be regulated or it’s safe, we might only test three. HTS would allow us to cover more chemicals faster, remove them from the environment faster, and maybe eventually in the future, our reliance on animals will drop significantly.

Since its inception some 30 years ago, NTP has looked at roughly 3,000 compounds. With HTS, I would hope that five years from now, we’ll be studying 50,000 or 60,000 compounds per year. The protection of the American public demands HTS. It’s not an option. Of course, the jump will not be from a molecular screening tool to humans. We also have intermediate screens and model organisms to study. Simultaneously with HTS, we are choosing organisms with shorter life spans, such as C. elegans, where we know more about their genetics. We’re not dumping the entire typical testing program in favor of going to cells. What we’re doing is restructuring to take advantage of a much more scientifically rigorous screening and selection process.