Stanford chemists produce chemical — originally from marine creature — needed for new drugs

Photo by Fitzgerald Marine Reserve Docent

One person’s weed is another’s flower. A good example of this is spiral-tufted bryozoan, an invasive marine organism that fouls up marine environments. Although considered a pest by many, spiral-tufted bryozoan is much sought after by researchers since it can produce biostatin 1 — a chemical critical to the development of promising new drugs to treat HIV/AIDS, Alzheimer’s disease and cancer.

Although this bryozoan is abundant, bryostatin 1 is very scarce because it’s difficult to harvest from the sea creature and complex to synthesize. In fact, the National Cancer Institute’s stock of bryostatin 1 is nearly depleted from supplying over 40 clinical trials. So Stanford chemists have developed a new, easier way to synthesize bryostatin 1, as recently reported in Science.

Paul Wender, PhD, a professor of chemistry and of chemical and systems biology at Stanford, has been working for years to develop bryostatin analogs that are more effective for drug development. However, the dwindling supply of bryostatin 1 inspired him to synthesize the drug itself.

“Ordinarily, we’re in the business of making chemicals that are better than the natural products,” Wender said in a recent Stanford news release. “But when we started to realize that clinical trials a lot of people were thinking about were not being done because they didn’t have enough material, we decided, ‘That’s it, we’re going to roll up our sleeves and make bryostatin because it is now in demand.’”

The researchers devised a much simpler synthesize process, cutting the steps down from 57 to 29. They also dramatically increased the yield, making it tens of thousands of times more efficient than extracting bryostatin from spiral-tufted bryozoan and significantly more efficient than the previous synthetic approaches. And they confirmed with a wide range of tests that their synthetic bryostatin was identical to a natural sample supplied by NCI.

So far, the team has produced over two grams of bryostatin 1, and a single gram can treat about 1000 cancer patients or 2000 Alzheimer’s patients, according to their paper. After scaling up production, they expect manufacturers to produce about 20 grams per year to meet clinical and research needs, Wender said in the news release.

They also expect their work could facilitate research using bryostatin analogs derived from their synthesis process. The paper explains that these analogs “are proving to be more effective and better tolerated in comparative studies with cells, disease models in animals, and ex vivo samples taken from HIV-positive patients.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Mowing down cancer: A podcast featuring Stanford chemist Carolyn Bertozzi

To explain her work, Stanford chemistry professor Carolyn Bertozzi, PhD, often turns to analogies. Cancer cells, she says, are like M&Ms with a hard sugar coating. As she recently explained on the “Future of Everything” radio show, the coating’s function has remained a mystery for years, but now researchers are making real progress.

“We have come to think of these sugars as kind of a 2D barcode. The patterns are different on different cell types, and yet all of the cells of a certain type have a common pattern,” Bertozzi told show host Russ Altman, MD, Phd. “So there is a code there, but we don’t quite have the means to scan it and we don’t yet understand it.”

So what do the barcodes look like on cancer cells? Bertozzi describes them as a superposition of two barcodes — the original cell’s barcode and a new cancerous one. And the cancerous barcode looks similar for many different cancers. Researchers have found that these sugar barcodes on cancer cells can promote disease progression by turning off the immune system. “They basically tell immune cells, ‘There’s nothing to see here. Move along. I’m perfectly fine and healthy,’” Bertozzi said.

Using an analogy, she explained in the podcast that the cancer cells put on makeup to look fabulous and mesmerize the immune system, fooling it into thinking that the cells are healthy so the cancer can progress unimpeded. Her lab is developing a way to strip off this makeup.

Her team has developed a way to use enzymes to cut off the sugars, making the cells available for immune cells to target. She explained: “They were enzymes that normally play a role in digesting sugars. So what we’ve done is repurposed these enzymes so we can target them right to the surface of the cancer cell. And literally they’ll just go across the surface of the cell mowing off the sugars, like stripping off the makeup. And then the cells can be seen for what they truly are.”

Bertozzi is also involved in a company that hopes to bring this “lawn mower” technology to the clinic within the next two years, but they first need to get good preclinical data as proof-of-concept. The company is currently focused on developing new treatments for breast, lung and kidney cancers.

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

The Workings of Fireworks

fireworks racks
Racks of cylindrical mortars used to shoot off shells into the air. Each has a fireworks shell inside, with only the main fuse visible.

My friend is a licensed pyrotechnician. Every July 4th, I help her setup and fire off a local city’s fireworks show. When you experience a fireworks show from below, you see, hear, feel and almost taste the fireworks. You are also privy to the behind the scenes drama as the fireworks is hand lit, like watching a play from back stage. It is hard to ever go back to watching the pretty lights up in the sky from far away. And it has made me appreciate fireworks more, even from a scientist’s perspective.

There is more to fireworks than pretty lights up in the sky. How are the bursts of colored light created? How do they make the different effects? How do they get up so high in the sky? There is plenty of science behind a fireworks show.

Shell being placed into a mortar.

Black powder is used to lift each fireworks shell into the air. It has been around for many centuries. It is a combination of potassium nitrate, charcoal and sulfur. If you burn black powder in the open, the heat and gas from the explosion quickly dissipates. So you put the black powder inside the bottom of the fireworks shell and place the fireworks shell inside a mortar (launch gun). This allows you to trap the heat and gas from the burning black powder, causing the gas pressure to build up until an explosion launches the fireworks shell high into the air. The fireworks shell must fit snugly in the mortar, or pressure will escape and cause a misfire. A variety of different sized shells and corresponding mortars are used to create an interesting fireworks show.

Lighting fireworks
Lit fireworks shell just before it shoots into the air.

The heart of a fireworks shell is the multiple compartments of combustible materials, called stars. Each kind of shell consists of different kinds of stars, in order to get the different colors and effects that we all enjoy. Great care goes into a shell design. Each star is made from a combination of binders, oxidizers and coloring agents. Binders (typically dextrin) are used to hold everything together. Oxidizers are used to produce the oxygen needed for the mixture inside the star to burn. The most common oxidizer is potassium perchlorate. Perchlorate ions have a chlorine atom bonded to 4 oxygen atoms, so perchlorates are relatively stable compounds that release a lot of oxygen. The fireworks colors are imparted by different metal compounds, such as: magnesium or aluminum for silver; strontium carbonate for red; calcium salts for orange; sodium oxalate for yellow; barium nitrate for green; and copper carbonate for blue.  As a star burns, the perchlorate releases oxygen and its chlorine combines with the metal compounds to form metal chlorides. These metal chlorides release energy in the form of visible light when they reach high temperatures. The color (and wavelength) of the emitted light varies with the temperature and metal compound. Blue is the hardest color to produce, because it requires a higher temperature.

A fireworks shell is ignited by lighting the main fuse. This simultaneously lights both a fast-acting side fuse and a slow time-delayed fuse. The side fuse quickly ignites the black powder to launch the shell high into the air. The time-delayed fuse burns slowly into the center of the shell as it hurls into the sky, causing the aerial fireworks display when it reaches and ignites the stars. The amount of black powder in each shell is precisely determined so that the time-delayed fuse ignites the correct star compartment when the shell is reaching the apex of its upward flight.

Fireworks Finale
Fireworks display.

A shell can also contain sound charges, creating the exciting crackling, bangs and booms to accompany the light show. When you watch fireworks, you see them much sooner than you hear them because light travels much faster than sound.

So when you watch fireworks on Sunday, you may want to think about all the science that goes on to produce the show. Or you may just want to “ooh” and “ah” in appreciation of the beautiful aerial display. Just make sure that you verbalize your pleasure, because the crew working the show will love hearing your encouragement.

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