DAHLMAN LAB
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We apply systems biology and big data to nanomedicine.

DNA Barcoded Nanoparticles

We can test thousands of nanoparticles directly in vivo; this is new to nanomedicine.
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How can we make genetic therapies (siRNA, mRNA, CRISPR, etc.) safer? We need to deliver them to diseased cells and make sure they avoid healthy cells. We do this using tiny structures called nanoparticles. A lot of labs study nanoparticles, so what makes us different? Simply put, we apply 'technology development' principles typically used by genomics labs to nanoparticles, in order to develop entirely new nanoparticle experiments. Our goal is to use these 'big data' approaches to generate nanoparticle drug delivery data that are more meaningful, predictive, and meaningful than 'traditional' data.
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For example, we are known for creating DNA barcoded nanoparticles. Like many other labs, we can make thousands of different nanoparticles with interesting chemical structures. What sets us apart is that we all of our nanoparticles directly in in vivo; this is very different than testing them in vitro (cell culture dishes). In order to test thousands of nanoparticles directly in vivo, we have developed a big data approach to test how hundreds of nanoparticles deliver drugs to many cell types, all in a single mouse. This combines high throughput chemistry, high throughput nanoparticle formulation / characterization, microfluidics, FACS, and even next generation DNA sequencing. Using this approach, we can simultaneously perform 6,000 drug delivery experiments in a single mouse. Put another way, we can find nanoparticles that deliver nucleic acid drugs (like siRNA, mRNA, CRISPR, etc.) by performing experiments at a scale that, until now, was not possible in the field. 

This work has led to a number of high-impact publications, the creation of a biotech startup company, funding from companies who want us to identify nanoparticles for the clinic, and was even named 1 of the Top 10 Emerging Technologies in the World for 2019 by the World Economic Forum. 



The Biology of Drug Delivery

Certain genes control whether nanoparticles are safe, toxic, effective, etc. But which genes?
What happens after you find a nanoparticle that delivers siRNA, mRNA, or CRISPR drugs to a new cell type in a mouse? Well, that nanoparticle is tested in a number of other species before, hopefully, it is tested in humans. But can delivery in a mouse predict delivery in a human being? Can safety in an animal predict safety in a human being? We believe that in order for us to predict efficacy and safety in humans, it is critical understand the biological pathways and specific genes that dictate nanoparticle efficacy safety in other species. 
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Why? Pretend gene A is required for the nanoparticle to work in a mouse; if you remove gene A from the mouse, the nanoparticle stops working. If gene A is not expressed in humans, or if the human version of gene A is very different than the mouse version, the nanoparticle may have less of a chance to work in humans. If gene A is present in human beings and is similar to the mouse version of gene A, it does not guarantee it will work in the humans, but it stands to reason the odds of it working increase. So far, we have found that cell metabolism and inflammation potently affect nanoparticle delivery in mice. We are now looking at other genes and pathways, to see whether these genes matter as well.

In vivo Multigene Editing

Using nanoparticles and Cas9, we can study how many genes work together to promote disease.
Many diseases are caused by a combination of genes working together, not a single gene. However, it has been hard to manipulate several genes at once in a specific cell type, in vivo. We are developing new methods to facilitate high throughput, multigene editing in specific cell types. 
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Dahlman Lab for Precision Therapies
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