Faculty Spotlight: Ethan Weiss, MD

Through several surprising turns in his career path, Dr. Ethan Weiss’s touchstone has been the joy he finds in the process of discovery.

As an undergraduate at Vassar College, he dreamed of becoming a professional jazz musician, and played trumpet in the school’s jazz ensemble. “I fell in love with jazz, but realized I probably wouldn’t have the talent to be a musician,” said Dr. Weiss. He turned to medicine because he had worked in a hospital during high school, and was accepted at Johns Hopkins University School of Medicine.

His father is a cardiologist at Johns Hopkins, but Dr. Weiss intentionally steered away from that specialty, wanting to try something different. As a psychology major who had taken very few science classes in college, he also struggled during his first year of medical school. “I had probably the least science experience of any of my classmates, so I decided to spend my first summer in a lab to really learn the nitty-gritty of science,” he said.

Within the first couple of days, he was hooked. “Some people really enjoy cooking – measuring different ingredients and putting them in,” said Dr. Weiss. “Some people really enjoy tasting the final product. I’m definitely one of those people who enjoy the process as much as I enjoy the finish, which is what drew me to science. It’s also very satisfying to design an experiment to try to answer a question.”

He ended up spending a year in the lab with Dr. Pascal Goldschmidt-Clermont, a cardiologist, and Dr. Paul Bray, a hematologist-oncologist. Dr. Weiss studied the biology of thrombosis, or abnormal blood clotting. Ironically, this led him to choose a career in cardiology, just like his father.

Dr. Weiss came to UCSF for his cardiology fellowship, spending three years continuing his thrombosis research in the in the lab of Dr. Shaun Coughlin, director of the Cardiovascular Research Institute. Dr. Weiss then completed the clinical years of his fellowship training. He was recruited to the UCSF Division of Cardiology faculty in 2003, and established his own laboratory.

'Foie Gras'

Dr. Weiss spends about 20 percent of his time seeing patients. Luckily, the new Cardiovascular Care and Prevention Center at Mission Bay allows him to zip downstairs from his lab to the clinic. He spends the rest of his time conducting research. Until about four years ago, he continued his investigations of harmful blood clotting, which can lead to a heart attack or stroke.

Then in 2009, something odd happened. He and his lab technician had developed mice with a protein called JAK2 knocked out, or disabled, specifically in their liver cells. “The effect on blood clotting wasn’t very exciting, but the mice got profoundly fatty liver,” said Dr. Weiss. “It was sort of grotesque, but every time, we noticed that the knockout mice had these big, yellow, nasty-looking livers that looked a lot like foie gras.”

He and his technician consulted with a pathologist, who told them that the knockout mice had fatty liver disease – a condition that affects about 20 million people worldwide, and can lead to cirrhosis and permanent damage of the liver.

This unusual development was so intriguing that Dr. Weiss eventually decided to shift the focus of his research away from thrombosis to this new discovery. “Especially in today’s difficult funding environment, it’s very difficult to do more than one thing well,” said Dr. Weiss. “I spent a lot of time struggling with whether I should stay in my comfort zone – thrombosis was a big area for me for 15 years – or invest time and energy in studying this new finding. I got a lot of advice, and everybody said, ‘This seems really interesting – go for it!’”

Beyond learning more about fatty liver disease, his lab is now investigating the role of JAK2 in other metabolic diseases, including obesity and type 2 diabetes. Dr. Weiss and his team are exploring the effects of knocking out JAK2 in specific types of cells. “If you knock it out in all tissues in the mouse, the animals die while they are still in the uterus because they don’t make any red blood cells,” said Dr. Weiss.

They also are experimenting with mice that have JAK2 knocked out only in their fat cells. “We’re really excited, because it looked like this protected the animals from getting diabetes, even though they were slightly obese,” said Weiss. “It was very puzzling to us, and remains a paradox.”

In fact, humans with a condition called Laron syndrome – often caused by a genetic mutations in the growth hormone receptor gene – demonstrate a similar phenomenon. “They’re very short and stout, but they don’t have diabetes,” said Dr. Weiss. These patients also appear to have protection from developing cancer, and many of them are long-lived.

“We’ve been thinking about how blocking the activity of the JAK2 protein might be a viable treatment for type 2 diabetes, therefore protecting people from developing it, or for making it get better once they have it,” said Dr. Weiss. “The biology is really interesting. The reason the mice in our experiments don’t get diabetes has to do with an effect that’s happening in the liver, although our knockout in this experiment is only affecting fat cells. So somehow what we’ve done in the fat can ‘talk’ to the liver and protect from diabetes.”

Targeting Drugs by Cell Type

Although Dr. Weiss has been fascinated by the discoveries in knockout mice, he also wrestled with the fundamental problem of translating these discoveries to humans. “While the mouse has been a phenomenal tool for biological discovery, a lot of things that we test and validate in mice turn out not to be true in people,” he said. And while mice can be bred with JAK2 knocked out from their fat cells, it’s not possible to genetically knock out JAK2 from human patients’ fat cells.

So far, it is also not possible to target drugs to specific cells or tissues – often a deal breaker when promising therapeutics produce unacceptable side effects in other parts of the body. For example, there is a new class of drugs that were originally designed to treat blood cancers, and that block the activity of JAK2. Unfortunately, they have significant side effects, including causing anemia.

But what if scientists could somehow deliver a drug that only affected fat cells? Dr. Weiss is collaborating with two other scientists – his fellowship mentor, Dr. Coughlin, and Dr. William DeGrado, a chemist with decades of experience in academic research and commercial drug development – to pursue this question.

“When you take a drug by mouth or injection, that drug goes everywhere the blood goes, and it acts on all the tissues pretty equally,” said Dr. Weiss. He and his collaborators now want to develop a way to target drugs to specific cell or tissue types. Oncologists have been pursuing this idea for a while, trying to localize the toxicity of cancer drugs while sparing normal, healthy cells.

Dr. Weiss and his collaborators hope to do something similar for other types of drugs. Drug compounds each have a specific three-dimensional molecular structure, like a key with a unique pattern of notches and teeth. The surface of each cell in the body is coated with receptors, each structured like a lock. When a drug reaches a compatible receptor, it fits into the receptor like a key in a lock. In some cases, the receptor will then pull the drug through the cell wall into the interior of the cell.

Dr. Weiss and his colleagues want to identify and catalog the receptors that are unique to certain cell types, such as fat cells and liver cells. They also want to determine which of these pull the drug into the cell. Then they hope to develop a “Trojan horse” model of drug delivery by developing conjugates – two different drugs that are chemically welded together. One drug – the “Trojan horse” – would be tailored to a cell type’s unique receptors, such as those found only on fat cells. The other drug – the “cargo” carried by the Trojan horse – would be the medication, such as a growth hormone inhibitor that could potentially treat a patient’s diabetes.

“We envision a platform that, down the road, would allow you to mix and match different cargos with different delivery vehicles, so we could take any of these cargos to almost any particular cell type,” said Dr. Weiss. “We think we could improve both safety and efficacy of drugs, because if you could really specifically target these drugs only to certain cell types, you could increase the dose. Right now, the dose is limited by the toxicity, because the drugs are acting everywhere in the body. You could also imagine taking drugs that failed during the clinical development process, and making them safer.

“We also think this could potentially be an important tool in doing experiments in people that were never possible before,” continued Dr. Weiss. “Because biology is so complicated, and there are so many interrelated feedback and feed-forward loops, we often don’t understand the specific action of a certain molecule on a certain cell unless we can really isolate it.” Dr. Weiss and his colleagues are currently meeting with potential investors to form a startup around this concept.

Dr. Weiss cautions that this research is in the earliest stages. “The most important caveat is that this is in the fantasy phase right now,” he said. “We’re really excited about the potential, but we have a lot of work to do to demonstrate that it’s possible, and then to take this to a point where it actually happens. But because the reward is potentially so high, we’re all energized to do it.”

Unexpected Results

Dr. Weiss appreciates his mentors and the generosity of philanthropic donors, both of which have allowed him to pursue these research endeavors. “Both of my direct supervisors, Dr. Shaun Coughlin and Dr. Jeff Olgin, have continued to support me in doing work at a time when funding is very tight, and a lot of people around the country don’t have the opportunity to do that,” he said. “My existence at UCSF has been a direct result of the Cardiology Council over the years. Also, the Cardiovascular Research Institute has built an amazing endowment from the generosity of donors over the years, and that’s allowed us to do some of this cutting-edge work that would otherwise be impossible to do, because it just wouldn’t be funded by a traditional mechanism.”

And although his research focus has transitioned from abnormal blood clotting to metabolic disease, it all ties back to the kinds of issues facing his patients every day. “I’m a cardiologist, and there is a lot of overlap between endocrine diseases, metabolic diseases and cardiology,” Dr. Weiss said. “If you look at the reasons that people die from type 2 diabetes, it’s almost exclusively from cardiovascular complications.”

He said that following the unexpected twists of his research is part of what makes science so enjoyable. “The theme for me is that we do these experiments, and most of the time what we predict is completely wrong,” said Dr. Weiss. “We expect that it’s most likely going to produce result A, but it could be B, C or D. Then sometimes we’re getting F, and Q and Z, and things that weren’t even on the menu of options. It’s both humbling and really cool.

“A lot of the success that we’ve had in our lab comes from a bit of naïveté,” he said. “We didn’t have preconceived dogma that said, ‘That’s a dumb experiment to do.’ So we did a lot of dumb experiments, but a lot of those turned out to be incredibly important.”

To find out more about how you can support innovative research in the Division of Cardiology, please contact Director of Development Eileen Murphy at (415) 502-0746 or [email protected].

– Elizabeth Chur