K-12 Fellowship Profile: David Machado-Aranda, MD

A contused lung 72 hours after an incident. 

A contused lung 72 hours after an incident. 

Thanks to NIH funding, the University of Michigan Center for Integrative Research in Critical Care (MCIRCC) now offers a multi-year, multidisciplinary training program for advanced training in emergency critical care research. In this two-part series, we will be profiling the fellows selected for this year’s K-12 program. This month we interview David Machado-Aranda, MD, whose research focuses on using gene therapy to treat trauma-related pneumonia and sepsis.

If a patient suffers a lung contusion from a trauma-related incident (e.g. car accident), they have the potential to contract severe pneumonia. According to Dr. Machado, a large portion of these patients do not survive this life-threatening infection trauma combination , even if they survive the original incident. Machado’s research hopes to answer why some patients survive and some fail to fight these diseases.

“In my mind, trauma resuscitation and surgery have improved survival after an accident but we have plateaued in our progress to impact mortality. . We are still seeing that major problems arise several weeks after the original incident. I wanted to find a way to improve this recovery process post-trauma and post-surgery,” Machado said.

Contused lung with pneumonia 72 hours after an incident.

Contused lung with pneumonia 72 hours after an incident.

Using a data set from a previous study, Machado’s team discovered that the FER-gene was playing a prominent role in the recovery of patients who survive pneumonia or sepsis. It appeared as though the FER-gene had the ability to recruit White Blood Cells to the areas of concern and better fight off infection like “super cells.”

“I wanted to find a way to replicate this same body process, in other words, use your own genetic potential to treat diseases. Our bodies do this naturally already. It’s just a matter of telling the body to activate or deactivate genes at a necessary time and at a necessary rate,” Machado said.

Using an electroporation gene delivery system, they are able to introduce the FER gene to cells within seconds. In current trials, mice breathe the FER gene directly into their  lungs. Immediately they are given a small electric charge (electroporation), to open up pores of lung cells so the gene can be delivered effectively.

Machado and his team found that using the human version of the FER gene, mice were able to actually dramatically improved their survival under the stress of pneumonia and contused lung. Now through the K-12 program, Machado hopes to expand this model and replicate it many times not only in mice but  eventually in large animals and humans. With the help of MCIRCC, Machado sees this as a huge step forward for treatment of sepsis.

The electroporation delivery system used for mice. The thin tubes near the top of the device are placed in the nostrils of mice.

The electroporation delivery system used for mice. The thin tubes near the top of the device are placed in the nostrils of mice.

“The bottom line is that other diseases such as cancer or cardiovascular disease have had a dramatic improvement in survival rates. Sepsis is one of the few diseases in which progress  has become stagnant and has now been called a national emergency,” said Machado.

Eventually, Machado wants to see this technology implemented as a portable device. This could also have a huge impact in military applications in the field for combat-injured soldiers who might not receive proper ICU treatment up to several days after their incident. By using gene therapy, soldier-patients could start recovery processes, get stabilized while they’re being transported, and kickstart their immune system to fight off infection.

This study is particularly interesting for MCIRCC because it spans across several fields. First, emergency room, surgeons and critical care doctors will have input on where they see patients needing this treatment most. Secondly, it will require input from engineers to develop the necessary electrodes to administer the electroporation. Third, it will require the resources of MCIRCC’s large animal unit to further develop appropriate injury and treatment models and test their hypothesis.

“MCIRCC brings a significant amount of technical resources and expertise — which will serve not only as a catalyst for my research but also the forum for bringing perspectives outside of my own discipline,” said Machado.

Next month we’ll profile the other K-12 fellow, Cindy Hsu, MD, and her research on the efficacy of valproic acid for out-of- hospital cardiac arrest survival and neuroprotection.