Tuesday, November 3, 2009

Meet C. Shad Thaxton, the winner of Bioscience Technology's 2009 Researcher of the Year competition.

By Jeffrey Perkel, Phd

C. Shad Thaxton's is an impressive resume. Bioscience Technology magazine's inaugural Researcher of the Year has a Howard Hughes Medical Institute medical student fellowship, an MD/PhD from Northwestern University , and 23 peer-reviewed publications to his credit. Four of his papers have been cited more than 100 times; one of them, more than 500 times.

Researcher of the Year C. Shad Thaxton

Not bad for a 33-year-old North-western University assistant professor of urology, hired out of grad school, who's been an independent researcher for 10 months.

Yet to those who know him, Thaxton's precocious success is hardly surprising; he's been exceeding expectations for years.

"He's a real superstar," says colleague Reed Omary, Vice Chair of Research for the Department of Radiology at Northwestern.

The road less traveled

Thaxton's road to scientific stardom began, serendipitously enough, with a magazine article.

Though he had pursued research as an undergraduate at the University of Colorado, Thaxton entered Northwestern's Feinberg School of Medicine in Chicago intent on being a physician. Then, during his third year, he started thinking about the road less traveled. It would be nice to get back into the lab, he thought, if only for a little while.

Synthetic HDL scavenging cholesterol from an artery. (Source: Weston Daniel, David Giljohann, and Michael Wiester)

One day, while on a study break in a bookstore, he picked up a copy of Scientific American . The cover story was on nanotechnology, and prominently featured Northwestern University researcher Chad Mirkin.

"Everything just kind of came together," Thaxton recalls. "I knew that I wanted to get in the lab, and this represented an excellent opportunity. I really saw the benefits in the technology and the things he was doing."

Mirkin, the George B. Rathmann Professor of Chemistry, Medicine, Material Sciences & Engineering, and Director of the Institute of Nanotechnology at Northwestern University, is a giant in the world of nanotechnology, with over 300 peer-reviewed publications. Needless to say, he has a sizable lab, and limited openings.

"I thought this was just an overzealous young guy who read Scientific American and got really excited about nanotechnology but didn't really know what he was getting himself into," Mirkin says. He turned Thaxton down.

Yet the student was persistent, and so Mirkin told him that if he could obtain his own funding, he could join the group.

"He calls back and he said, ‘You know, I think I can get an HHMI fellowship,' which of course is one of the best fellowships you can get out there," Mirkin says. "And I thought, boy this guy's really crazy. He thinks he's just going to go out and get a Howard Hughes fellowship."

Nine months later, that's precisely what he did. HHMI fellowship in hand, Thaxton embarked on a one-year research swing through the Mirkin lab. It would prove to be extremely productive.

Second Place: Carolee Barlow Second Place Carrolee Barlow Carrolee Barlow's, chief scientific officer, BrainCells, Inc., research focuses on neurogenesis as a target for small molecule therapies to treat various neurologic conditions. She expects her research to provide insights into what regulates the neurogenic process, both naturally and artificially, its impact on brain function in mood, cognition, post traumatic stress, brain injury and other CNS conditions, and most importantly, how compounds interact with the process to improve function. Neurogenesis is the process by which pre-existing stem cells in the hippocampus of the adult brain produce new brain tissue, including neurons. In 1998 Dr. Fred Gage discovered the process of neurogenesis in the adult brain throughout the life cycle, and later Rene Hen later linked neurogenesis to depression. In fact, antidepressant efficacy correlates with neurogenesis. (Knocking out neurogenesis actually blocks antidepressant action). This research created a new hypothesis: the provocation of neurogenesis in the adult brain may create a more focused approach to drug development for depression. To test the hypothesis, Dr. Barlow developed a unique platform to interrogate drug compounds for neurogenic properties. This platform technology combines in vitro human and in vivo animal neural stem cell assays with parallel anxiety, depression, and cognitive animal behavioral assays to create a fingerprint for each compound's mechanism, convergence point in neural cell growth and likely CNS indication. The platform evaluates numerous characteristics of a compound to determine if it's a clinical candidate. For example, Dr. Barlow's team ran Merck's compound Aprepitant (Emend), which failed in well-designed clinical trials for depression, and demonstrated a clear negative neurogenesis fingerprint. Consequently, her platform would have identified Aprepitant as a "no go" prior to any clinical investment, avoiding the costly clinical failure. To date, her team has interrogated more than 1,500 compounds, resulting in several clinical candidates for the company, including two currently in Phase 2. The first efficacy data from the hypothesis will be released in 2009 for BCI-952, a combination treatment for major depressive disorder, and BCI-540, a compound with a novel mechanism for the treatment of major depressive disorder with anxiety. In pre-clinical studies, BCI-540 was shown to be highly neurogenic in BCI's in vitro neural stem cell analyses and in vivo animal models of depression and anxiety. BCI-540 significantly promoted neuronal differentiation and survival in vitro through novel mechanisms (unrelated to serotonin or norepinephrine) that nonetheless lead to a favorable neurogenic profile similar to known successful treatments for depression. In in vivo studies, BCI-540 substantially promoted neurogenesis with more than a 20 percent increase in new neurons at four weeks, and concomitant activity in depression and anxiety assays associated with neurogenesis.

In the lab

When he entered the lab, Thaxton says, Mirkin's team was using DNA-coated nanoparticles—clusters of gold comprising just a few hundred atoms—to detect nucleic acids. Thaxton's interest, though, was protein-based diagnostics.

Third Place: Ian Macreadie Professor Ian Macreadie, professor, CSIRO Molecular and Health Technologies, developed an assay to screen for chemo preventative agents for Alzheimer's disease. The toxic protein in Alzheimer's disease (AD) is oligomers of Abeta, so preventing the formation of oligomers is key to preventing AD. He fused Abeta to green fluorescent protein. Monomers, but not oligomers of the fusion protein, give high fluorescence in a particular proportion of yeast cells. The cell populations can be used to screen for AD chemo preventatives. Macreadie and his team have identified novel compounds that will now require testing in animals, but have also validated the assay with known chemo preventatives of AD. "The yeast assay is the most convenient high-throughput assay for AD chemo preventatives, and, at the time of testing, toxic compounds can also be identified and excluded," say Macreadie. "In addition one can test the effects of yeast and human genes to identify those that affect outcomes in AD." Macreadie has been involved in yeast research for his entire career, but switched to using yeast to provide solutions in Alzheimer's disease just five years ago. "The challenge was immense because at the time plaques were thought to be key, but now it is clear that the oligomers are toxic—even in yeast," he says. Yeast work is much more tractable for research than working with animal models. The only valid studies are on humans, where folate and simvastatin have been shown to be chemoprotective. Macreadie's research has shown both to be positive in his yeast Abeta oligomerisation assay.

So, he blended the nanoparticles with a solution-based sandwich antibody assay and PCR to produce a "DNA bio-barcode" assay with unprecedented sensitivity; when applied to prostate-specific antigen, he could detect the protein at attomolar levels—six orders of magnitude below the detection threshold of traditional ELISA. ¹ Later, he helped develop a therapeutic application for the gold nanoparticles, using them to silence gene expression inside cells via antisense DNA. ²

"He's one of these guys that is able to make connections," says Mirkin. "There are very few people like that in science, that can connect the dots between different fields, and see how a certain type of material or new type of chemistry can impact different aspects of medicine. From a translational standpoint, I don't think there's anybody out there that does this type of work better."

By the end of the year, Mirkin figured Thaxton had earned himself a PhD in all but name; he encouraged his student to apply to the graduate school to make it official. But Thaxton wasn't following the standard MD/PhD course track; he was proposing to complete his PhD—taking the courses, and writing and defending his thesis—during his internships and residency, when his medical training would already amount to 80-hour weeks. ?That, says Mirkin, "is an incredible thing in its own right: to do a residency and get your PhD at the same time. I don't know if it's ever been done before. But he did it."

Three years into his urology residency, Thaxton broke with medicine altogether, opting for a tenure-track research position instead. He applied to Northwestern in Chicago, and in summer 2008, he took his place among the Urology faculty.

"He clearly is a very talented scientist, but he's also a very talented medical doctor," says Anthony Schaeffer, Thaxton's department chair. "He's in a unique position right now. As an MD/PhD with this kind of surgical experience, it provides him with unique access to medical problems and challenges that can be solved with nanotechnology."

Giving back

There's a dictum they teach in medical school: "See one, do one, teach one." Perhaps not surprisingly, given his medical training, it applies to Thaxton.

The beneficiary of an HHMI medical student fellowship found himself, shortly after starting his independent career at Northwestern, mentoring a student who was applying for a fellowship of his own.

Thaxton met the student through Omary, who happened to attend a meeting with Thaxton shortly after the junior faculty member was hired. At that meeting, a roundtable discussion to bounce around ideas for a grant proposal, Thaxton so impressed Omary (an interventional radiologist) that Omary contacted him shortly thereafter to suggest a collaboration.

"He really just had some very innovative ideas," Omary recalls. "I think that's what attracted me the most, that he at once had very innovative ideas and he was very approachable"

The two discussed a number of potential collaborative projects and applied for grants to fund them. One of them, a Rosenberg Family Cancer Research Fund, was funded for $75,000. The other, the HHMI student fellowship, also came through.

"It's nice to see that baton being passed," says Omary. "I love the concept of Shad having been a recipient of one [HHMI fellowship], and now he becomes a mentor. That's what it's all about, right? You learn and then you teach."

Synthetic HDL

The beneficiary of that fellowship will be working with Omary and Thaxton to combine the nanoparticle-based therapeutics Thaxton codeveloped in Mirkin's lab with the interventional radiology approaches Omary specializes in to target pancreatic cancer.

Thaxton's other research focus—and the work for which he was named Researcher of the Year—is wholly unrelated, and was initiated during his transition from medical student to independent researcher. It involves cardiovascular disease.

Most therapies for heart disease involve low-density lipoproteins (LDL) and cholesterol; lower LDL levels, for instance with statins, and you can improve clinical outcomes. But what about high-density lipoprotein, the so-called "good cholesterol"?

Both HDL and LDL are naturally occurring nanoparticles, Thaxton saw. So, he thought, why not make "biomimetic" HDL and use it to scavenge cholesterol in vivo ?

It is a solution that dovetails with Thaxton's general research approach, which involves answering two main questions: what is the problem, and how can it practically be solved.

Honorable Mentions Judging for the 2009 Researcher of the Year competition was conducted by the staff of Bioscience Technology, Steve Ernst, Mike May, and Jeffrey M. Perkel. The following researchers each contributed stong entries and are recogized as honorable mentions in the inaugual Researcher of the Year competition. Suresh Sharma, Pennsylvania State University J. (Hans) van Leeuwen, Iowa State University Yousef Haik, University of North Carolina at Greensboro Rakesh Rathore, University of Cincinnati, Genome Research Institute Elizabeth Frayne, Frayne Consultants Lynn Kirkpatrick, Ensyce Bioscienc/Phusis Therapeutics Rigoberto Advincula, University of Houston Guruguhan Meenakshisundaram, Ohio State University Ying Liu, Life Technologies Peter Hauer, Johns Hopkins University Arnold Ruoho, University of Wisconsin-Madison Nienke Van der Stoep, Leiden University Medical Center

"I really try to use the framework of, is it going to be practical in the future? I use that when I set about figuring out ways to solve a problem," he says.

Using the same nanoparticles he cut his teeth on in Mirkin's lab (and in collaboration with Mirkin), he added lipids and protein to create something that in size, shape, and surface chemistry acts like HDL; it can even bind cholesterol. ³ He and Mirkin even determined the particle's affinity for cholesterol—a value that had never been calculated, even for natural HDL.

"What we ended up with is a binding constant, which will serve as a benchmark going forward as we develop new structures and even for naturally occurring HDL," Thaxton says.

Now, he and Mirkin are working to translate their development to the clinic. First though, they must see how their biomimetic HDL will perform in animals.

"This is a new approach to HDL drug development," says Mirkin. "And that's just an example of incredible innovation in large part on behalf of Shad."

Crossing research boundaries

With extramural funding and a paper under his belt in less than a year, Thaxton's department chair says his performance has been exceptional. "Based on his past performance nothing surprises me. But you'd have to say his trajectory is unusually high," Schaeffer says. "His success is amazing not only in its elegance and sophistication of the nanotechnology, but the way he applies it."

Credit for that inventiveness, at least in part, must go to Thaxton's unusual cross-disciplinary training. Indeed, the sources contacted for this article were unanimous in their praise for his ability to cross research boundaries.

"I think that's one of his greatest strengths, is that he is able to bridge the traditional gap between basic scientists and clinicians," Omary says. Schaeffer adds, "He's unique in that he has the scientific acumen to perform at the highest level, he has the ability to translate the science from bench to bedside, and then he has the ability as a physician to understand the problems."

The result, Mirkin says, has been "infectious." "We have collaborations with 15 different medical doctors, in part because he's drawn the link between the new nanomaterials and different applications in medicine."

Reflecting on his former student's achievements, Mirkin likens Thaxton to another well-known Chicagoan.

"I call him a Michael Jordan," Mirkin says, "he's not only fantastic, but he makes everybody else around him better."

Given that he has accomplished all of this at so young an age, we may assume that, like Jordan, his talents will only improve with time.

References

1. J.M. Nam, C.S. Thaxton, and C.A. Mirkin, "Nanoparticle-based bio-bar codes for the ultrasensitive detection of proteins," Science, 301:1884 – 6, 2003.
2. N.L. Rosi et al., "Oligonucleotide-modified gold nanoparticles for intracellular gene regulation," Science, 312:1027 – 30, 2006.
3. C.S. Thaxton et al., "Templated spherical high density lipoprotein nanoparticles," J Am Chem Soc, 131:1384 – 5, 2009.

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