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Phil Baran

Converting Compounds Derived from Nature to New Drugs

Scripps Research Professor Phil Baran is driven by the desire to create, the exhilaration of discovery, and ultimately the promise of saving lives.

At an age when most researchers’ careers are just ramping up, the 32-year old is already a standout in the field of organic chemical synthesis, making great strides in developing innovative ways to synthesize chemicals well.  His laboratory’s work has already advanced an array of biomedical studies by synthesizing promising potential drugs and creating new chemicals. 

As the candidate drug pipelines at major pharmaceutical companies are drying up, it could be increasingly important to explore new compounds derived from nature as potential new drugs. 

A range of drugs from aspirin to the widely used cancer treatment Taxol have been discovered in nature, but the complexity of producing natural products has made some companies reluctant to focus on them.

“Natural products have an unparalleled track record in the betterment of human health,” said Phil.  “In fact, nine of the top 20 best-selling drugs were either inspired or derived from natural products.  Even the best-selling drug of all time, Lipitor, was based on a natural product lead – and it has helped prolong many lives.”

Phil and his team have developed new techniques that dramatically reduce the time, complexity, and cost of synthesizing natural products with pharmaceutical potential.  Their work dislodges previously entrenched beliefs in the organic chemistry field about how such products must be produced, and could help to advance and expand the use of natural products in drug discovery programs.

“There is this far-ranging and damaging perception that natural products are too complex to be used in a drug discovery setting despite their overwhelming track record in medicine,” said Phil.  “I think if our work has helped in even a small way to revive the use of natural products, then we’ve served our purpose.”

“We focus on inventing new science and exploring uncharted realms of chemistry,” said Phil.  “That’s the idea.  That is our passion.”

Target molecules often show great promise but come from sources that would be difficult or impossible to collect in sufficient quantities to support initial studies of their efficacy as disease treatments, much less in the quantities needed to support clinical trials.  Short of decimating a marine ecosystem, researchers can typically only isolate milligrams of a given natural product from marine species.  In contrast, Phil’s work often leads to the production of gram quantities of these products.  In some cases, other research groups have been able to reveal a product’s medical bioactivity only because he has produced the synthetic product.

Phil has collaborated with Genentech on compounds isolated from a sea squirt, or marine tunicate, showing potential for killing colon cancer cells in laboratory experiments.  The natural supply of these molecules, known as the haouamines, was drained and only through total synthesis could the biological activity be explored.

He and his colleagues, through some inventive steps, also established the first technique to synthesize kapakahines.   These marine-derived natural products isolated from a South Pacific sponge in trace quantities, have shown anti-leukemia potential.  Phil’s group synthesized kapakahines in large quantities, more than a decade after their discovery.  With supplies now in hand, and unlimited production potential established, research on the compound can proceed and may eventually lead to new drug treatments.  This is currently being pursued with pharma giant Bristol-Myers Squibb.

His team of scientists has also developed an inexpensive and in many ways astonishing new method for economically producing a pharmaceutical steroid.  The molecule, called cortistatin A, which was isolated in 2006 from a marine sponge discovered over 100 years ago, has shown huge promise for treating conditions ranging from macular degeneration to cancer.  The achievement marked the finish line in a race that saw numerous research laboratories working to accomplish the feat.

Synthetic chemistry, says Phil, is something like mountain climbing.  Except rather than simply reaching a new peak that nobody has climbed before, you are also inventing new harnesses, ropes, and climbing tools as you go.  And you are finding ways to ascend with fewer steps than anyone has ever done before.

“It’s very difficult and very rewarding,” said Phil.  “You have do develop new tools as the dynamics are constantly fluctuating.  Invention is a prerequisite for success.”

Phil found his passion for creating early on.  “In high school I discovered the joy of mixing things to see what happens and eventually found out you can get paid for doing that – and help humanity at the same time” he said.

Phil received his graduate degree right here at Scripps Research in the Kellogg School of Science and Technology.  “Phil was a phenomenal student at Scripps Research – tenacious, enthusiastic, brilliant, imaginative, and so much more,” said former Scripps Research Professor K.C. Nicolaou.

While Phil finds the discoveries that result from his research a high point, he says he counts success as a teacher as the greater prize.  “For me, the most exciting and rewarding thing has been watching students go from naïve and not so focused to brilliant, independent researchers who are creative, imaginative, and able to think outside the box,” he said.  “That has been the best.”

Most of the students in his lab spend at least 12 hours a day at work – but they say the benefits are clear in terms of thinking of problems in new ways.

Phil is a firm believer in the need for philanthropy at Scripps Research.  “We rely on philanthropy to survive.  We don’t have a billion dollar endowment here and can’t rest on our laurels.  We need to make discoveries or we’ll be gone.  Philanthropists to Scripps Research are getting a high value for their contributions as their funds are not going into some treasure chest – instead they’re going directly to the education of graduate students or for groundbreaking research.  There is no bureaucracy or red tape here – we work freely and unencumbered on days, nights, and weekends – and no one can stop us.  As chemists, we can impact the lives of millions of people.”

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baran-video
“We focus on inventing new science and exploring uncharted realms of chemistry,” says Professor Phil Baran, who is the Darlene Shiley Chair in Chemistry at The Scripps Research Institute. (Play video.)