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Vol. LIX, No. 23
November 16, 2007
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From Natural Products, New Drug Discoveries

On the front page...

This is a true-adventure story spanning the globe, over land and sea. This is a modern quest with many heroes—and heroines—fanning out like spokes on a wheel, with its hub at NCI in Frederick. That’s where you’ll find a program unique in government, representing a trend that’s not confined to one IC or a single study.

“Our mission is not basic research: It is to find, develop and get out the drugs,” says Dr. David Newman, chief of NCI’s Natural Products Branch (NPB). “We’re part of what we can call Uncle Sam’s non-profit pharmaceutical house, and our job is to find leads to compounds that ameliorate cancer.”

Continued...


  Shake hands with a star: This deep water starfish is only one of 60,000 samples in NCI’s Natural Products Branch. The NPB brings in raw materials from terrestrial and marine environments worldwide to be held in its Frederick repository.  
  Shake hands with a star: This deep water starfish is only one of 60,000 samples in NCI’s Natural Products Branch. The NPB brings in raw materials from terrestrial and marine environments worldwide to be held in its Frederick repository.  
Tucked inside Ft. Detrick, an active U.S. Army base, NPB brings in raw materials from terrestrial and marine environments worldwide to be held in its repository. Samples are then catalogued, tracked and ground into sawdust, powders and gums. These extracts are tested, purified, screened and selected for preclinical evaluation. “Compounds from these extracts which show promise,” Newman says, “will progress toward animal trials.”

It’s a team effort—or, more accurately, teams of teams—and is only the start of a process involving complex negotiations, permits and treaties. Expert botanists and divers are retained to search the hills of Madagascar, the sea trenches of the South Pacific and the desert flats of South Africa. Newman himself travels internationally to manage, liaise and teach.

“We scout plants, microbes and fin-less marine animals in deep and shallow seas,” he explains. Studding the map in his office are sites in Asia, Africa and the Americas, including the arid lands of the southwestern U.S. “We have even had collections in Antarctica,” he says.

The results are impressive: “We have collected 60,000 plant samples and around 15,000 marine samples, including 3,000 algae and microbes,” Newman reports. To put these numbers in context, he reckons that there are around 350,000 plants worldwide, “and at least a million fungi described.” As for bacteria, “We have no idea how many [there are].”

Dr. David Newman, NPB chief Dr. Tom McCloud, natural products support group manager

Above left: Dr. David Newman, NPB chief
Above right: Dr. Tom McCloud, natural products support group manager

Not a Jigsaw Puzzle

Why go so far afield? Why not just make up drugs from scratch? Newman explains: “Chemists started making libraries of hundreds of thousands to millions of compounds. But these were simple compounds. Mother Nature doesn’t make simple compounds. Mother Nature makes compounds that fit into particular places.”

Moreover, “no chemist in his or her right mind would make up [these compounds] because they don’t know what to make—it’s not a jigsaw puzzle. The intellectual input Mother Nature has is astonishing.”

He tells the story of penicillin, which started as a blue-green mold and a lowly contaminant—an accidental “visitor”—on a hospital lab’s plate culture. Even now, Newman says, when there are over 40,000 variations on the penicillin molecule—almost all made in labs—only 40 have been or still are in use. Chemically tweaked versions of penicillin have been used in the past few decades to make new antibiotics, even an anticholesterol drug.

Natural products make sense, Newman argues, because they work.

The Nautilus in the Freezer

Newman displays chambered nautilus.
Dr. David Newman, NPB chief
Top: Newman displays chambered nautilus.
Bottom: Dr. Mike Iadarola, chief of NIDCR’s neurobiology and pain therapeutics section

All this borrowing from nature takes time and space, enough to house three-quarters of a million vials, bottles and bags of raw material. “Unfortunately we haven’t gotten Mother Nature to barcode yet,” Newman jokes. “Where it comes from, who collected it and any results—we can see all that by just hitting a button and scanning the barcode.”

A warehouse containing large freezers at minus-20 degrees Celsius stores the treasure trove. Here’s a deep water starfish from Palau. A sea fan. “Shepherdia” that looks like a charming arrangement of twigs. And a rarity—“We had to get special permission for this,” says Newman—a chambered nautilus.

These beauties prompt the inevitable question: What of the risk that people will enter an “exotic” site, steal local knowledge, patent it and not give anything back? “We never wish to be accused of biopiracy,” Newman says. It’s his responsibility, together with the NCI Technology Transfer Center, to work out collection agreements with host countries: “We are extremely careful about what we collect, who collects for us and under what conditions.”

Tom McCloud, manager of the natural products support group, oversees its laboratory. It is a formidable place that does massive extraction and initial analysis of screening “hits” to find leads to potential drugs. Some of the compounds that his lab has worked on in the past have shown “interesting new biological activities” as anti-HIV and anti-tumor leads.

Other materials from his group include the fungal metabolite wortmannin (a modification of which is in clinical trials for cancer), together with a significant number of other natural products from many sources, now acting as “templates on which to build novel structures” by other chemical groups.

“In my opinion,” says McCloud, “the most important aspect of the DTP Natural Products Repository is that it is available not only for NCI-Frederick, or other NIH researchers’ use, but [also for] research organizations across the country and around the world. We have over 200,000 extracts available for high-throughput screening in both 96-well and 384-well formats, perhaps the largest and most diverse screening library of its kind anywhere.”

McCloud’s lab produces 3,000 extracts a year. How long it takes to separate and identify “actives,” he says, “depends on the number of possible ‘hits’ in a sample,” not to mention funding. As things stand now, “a good chemist with a good tech can separate 10 active extracts in a day in the initial stage of the analyses. And then the time required depends upon the complexity of the compounds and the turn-around time of the biological assays involved.”

While his group does all the extraction and microtiter-plate preparation, “we are not the only ones,” he says, “to do isolation and structure- elucidation work.” This effort is shared by Dr. Jim McMahon’s group in NCI’s Molecular Targets Development Program.

Compounds that pass muster may end as candidates for phase I clinical trials, which, in the life story of a drug, is a turning point. Back on the main campus is an example.

Biography of a Drug: the Next Chapter

The plant called Euphorbia resinifera is the source of a new drug called resiniferatoxin, or RTX. Dr. Mike Iadarola, chief of NIDCR’s neurobiology and pain therapeutics section, is leading an effort to bring RTX into phase I clinical trials. These studies, designed to prove safety and tolerability, are the first stage of testing in human subjects. In the life story of any drug, phase I is crucial.

“We performed animal studies with good results,” says Iadarola. “We may be able to start clinical trials [very soon]. Here’s a plant providing a solution to something that’s really difficult”—that is, the problem of intractable pain, which

RTX can alleviate, he says, with only a single injection. It works by killing a sub-population of pain-responsive neurons, an effect noted in cell culture and in vivo using dogs with naturally occurring bone cancer. RTX is non-opioid—it doesn’t act like morphine, with its attendant risks and side effects—and it is non-addictive. “It binds to the nerve and turns it off chemically,” Iadarola says.

In collaboration with NIDCR anesthesiologist Dr. Andrew Mannes, Iadarola will soon be working with cancer patients in the Clinical Center. And although Iadarola and Newman are in different institutes, on different campuses, they seem to be on the same wavelength—both want to ameliorate cancer and both acknowledge that Mother Nature has a brilliant chemistry set.

That set includes the Euphorbia, the genus name of a rather large group of plants with about 1,600 members—perhaps the most familiar being Euphorbia pulcherrima, the poinsettia.

Euphorbia resinifera, a type of spurge that grows wild in the Atlas mountains of Morocco, looks to the untrained eye like a cactus that gets bulldozed to build a mall in Arizona. Yet its milky white, latex-like sap, which can be harvested without harming the plant, may prove enormously valuable in relieving suffering.

And although Euphorbia has been known for its medicinal properties for thousands of years, it could, like so many other invaluable species, become endangered only too quickly. In this light, something Newman stressed rings true: Protecting endangered species is closely related to the NPB mission of finding new plant compounds and new drugs.

“This is why we have to stop clear-cutting [forests],” Newman said. “We have no idea what we are losing.” NIH Record Icon

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