Engineering cures for metabolic diseases: A conversation with a Stanford biochemist
This is part of a series of articles featuring biopharma experts from Stanford University. The articles are sponsored by the Stanford Center for Professional Development, and independently reported by BioPharma Dive staff.
Right before last Christmas, the FDA approved Denmark-based Novo Nordisk's Saxenda (liraglutide [rDNA origin] injection) as a weight management treatment for obese adults and overweight adults with an accompanying related condition such as hypertension, diabetes, and high cholesterol.
Saxenda was the latest FDA approval in a small sect of chronic weight management meds to reach the U.S. market over the last three years, including Takeda's Contrave, Vivus' Qsymia, and Arena's Belviq. It's a reformulation of Novo's blockbuster type 2 diabetes treatment Victoza, which contains the same active ingredient (liraglutide) but in about half the dose that Saxenda does. The drug works using a roundabout method of appetite control, tricking your brain into thinking the stomach is more full than it actually is by mimicking an intestinal hormone.
Humans: A little too good at overcoming hunger
Given the reality of America's obesity, diabetes, and CVD epidemics, one might think that there would be an even larger number of effective drugs to control weight. Yet bariatric surgery generally remains the most effective method for excess weight control in the most obese patients, and market penetration of obesity-control drugs (rather than for co-morbidities such as hypertension and high cholesterol) remains relatively weak.
"Billions of dollars have been cordoned to appetite suppression, so far to little effect," said Alexander Dunn, Assistant Professor of Chemical Engineering at Stanford University, in an interview with BioPharma Dive. "Relatively old and simple treatments such as metformin are kind of magical, they work better than they arguably should. But there's still a humongous unmet need—human life expectancy."
As Dunn puts it, humans have actually managed to overcompensate for our predilection towards hunger to the point of creating enormous new disease classes that threaten to kill many of us. "Humans evolved to basically be hungry most of the time—that's sort of our default evolutionary state, is to be not-quite-starving," said Dunn. "And we don't like that, so as a society we've worked extremely hard to fix that. And we've exceeded, at least in the developed world, to the point that we actually have to be mindful not to ingest excess calories all the time."
But if we do keep ingesting those excess calories, our bodies, anchored by the history of human evolution, gets confused. "Our bodies just have no clue what to do with this," said Dunn, "and in my view if you were working in the field of molecular diagnostics, or even drug development, there's a huge unmet need for drugs that target obesity, which really in some sense is secondary to our body's inability to handle excess blood glucose."
Dunn is blunt about what an influx of more effectively engineered medications to control such disorders could mean. "Conquering this is going to change society in the same way that antibiotics did," he said.
The promise of biotechnology
Dunn teaches biochemistry, including courses for Stanford's online Biotechnology Graduate Certificate program. The program isn't meant for complete newcomers to the sciences—you need to have a BS in a scientific or engineering field and familiarity with chemistry in order to enroll—but non-Stanford students looking to enhance their biotechnology backgrounds or seeking careers (including as managers) in the field are free to enroll in the four-course program, which takes one to two years to complete.
In his course, which is the second term of a three-term series on biochemistry, Dunn focuses on "central metabolism"—a subject central to understanding the biological roots of major diseases and engineering new value-added molecules like medications and fuels.
"The material I teach is vital and important to understanding the origin and progression and treatment of things like cancer and diabetes and heart disease," said Dunn. "Diabetes in particular is not understandable without this course... Cellular metabolism is deeply deranged in cancer, too, and that's the basis of quite a number of chemotherapeutics, so we talk about that as well."
Engineering a value-add
Things get even more interesting when Dunn discusses metabolic engineering and synthetic biology, which is "where scientists and engineers attempt to re-program bacteria or yeast cells to make value-added chemicals," as he explains. "So, sugar goes in one side and drugs that sell for tens of thousands of dollars per kilogram come out the other."
This field has critical implications for everything from health and medicine (to name just one example, in the production of certain antimalarials) to fuel creation, including the production of ethanol and ethanol derivatives.
Cell metabolism basics could also form the basis of future treatments for things like cancer. For instance, Dunn recalls a recent conference he attended where scientists (in the preclinical setting) presented research about cysteine metabolism in cancerous versus non-cancerous cells.
"It turns out some cancers have lost their ability to make their own cysteine, but most of the other cells in our bodies make cysteine just fine," said Dunn. "So some people are developing systems that target that little quirk. And that's pre-clinical right now, but I just think it's really remarkable that... something so simple as starving [the cancer cells] out has not been explored, as you might expect," even while companies like Roche/Genentech pursue far more complex and targeted methods.