Thursday, June 29, 2017

The Role of Basic Research in Precision Medicine


Me and Johnathan outside his lab in Charlestown, MA

I had the privilege of interviewing Johnathan Whetstine, a cancer researcher at Massachusetts General Hospital, at his laboratory to get his perspective on precision medicine. Johnathan’s field is cancer epigenetics. His lab investigates how the microenvionment around DNA controls gene expression while maintaining a stable genome. I thought he’d be the perfect person to give me historical context of precision medicine and what role basic scientific research plays in the process. “If you ask me as a basic scientist, the beauty of precision medicine is that you are starting to apply mechanistic knowledge in the context of how individuals will be diagnosed and treated.  By applying knowledge from laboratory settings, the medical community can make better decisions about what biomarkers to use as well as make predictions about the response,” said Johnathan.   He added, “By taking this approach, you’re now tailor-making a treatment to a person and cancer sub-type. This approach is in contrast to the one drug fits all policy.  Personalized Medicine is embracing individuals and cancer sub-types. Human variation in the population and the fact that tumors can change requires this in depth evaluation that will change medicine moving forward. The beauty of personalized medicine is it benefits from discovery!” Basic scientific labs like Johnathan’s are critical to the ecosystem as more targeted treatment of cancer evolves.


The example Johnathan likes to give to describe basic research and precision medicine is comparing an old car to a new car. He says, “If you open the hood of a ‘64 Chevy Impala you can see where all the parts are, it’s all connected so you can fix it – it’s very simple. New cars today are typically cased, all electronics, you can’t see what some of the parts are so it’s hard to figure out a problem. I can mechanistically see what’s inside the old car and the average mechanic can fix it. On the new car, the average mechanic can’t just pick it up and fix it because they don’t always understand the mechanism.”  So in other words, Johnathan thinks precision medicine is the process of starting to simplify and map a complex engine so better diagnosis and treatment can be made. Precision medicine is a combination of scientists and physicians building tools to understand what is ‘under the hood’ so treatment is more effective long term.” And he adds, “If you know more about what is inside the tumor, you can deliver more optimal therapy, you can go after cancer sub-types. Look at lung cancer obviously, between the ROS mutations and the translocations and various EGFR mutations, you can predict if someone is or isn’t going to fail on certain treatments. Why? Here’s the gene, here’s the information that’s biologically linked in the lab – that together gives you precision medicine.”

Me and Johnathan and our wives at the MGH 100 2016


Johnathan says he likes to remind people that the advances in precision medicine, and the breakthroughs in targeted treatments we have seen are a result of all of the investment in research that came before him.  In his words, “Something that was invested in 20 years ago doesn’t mean it’s not going to pay off today. A big example of this is sequencing. We take for granted that we can go to an office at Mass. General or other places, and they can take your tumor and tell you the gene(s) that are changed and possibly impacting tumor action and therapeutic options.  This exists because of the earlier investments both in the technology as well as the science to identify the genes that are important.” He’s referring to the investment into the Human Genome Project, and the impact genomics has had in the United States. Between 1988 and 2012, the federal government invested $14.5 billion in the field of genomics, with an enormous economic and societal impact from that investment. It’s estimated this returned $966 billion in economic impact in the United States, according to the advocacy group United for Medical Research. Johnathan added, “I would challenge anybody to answer the question, where can you make a $14.5 billion investment and turn it into a trillion dollars today?” And amazingly, while it took almost $15 billion and more than a decade for the government-funded DNA effort to fully sequence a human genome for the first time, companies can now sequence a whole genome for about $1,000 and do it in a day.


I asked Johnathan what he sees in the future for precision medicine. In his words, “I predict that the more we start to break apart various pathways in the cell that are involved with drug resistance, or pathways that are involved in certain therapeutic sensitivities, we’re going to find commonalities across tumors, and also tumor specific properties, which provides a collection of names to mark and develop drug targets.” He sees initiatives like the Cancer Center tumor profiling and MGH Biobank as important to the future of precision medicine. He thinks it’s great that everyone who walks in the door is asked if they want to contribute. Even John’s mom asks the question, “why would I want to do that?” He calls it putting your DNA in the game. In his words, “There have been something like 115 published studies using this biobank where they’ve established unique genetic relationships to disease to direct responses.”  He adds, “Let’s look at lung cancer. Some of the mutations are rare – as small as less than 1% - but when you have over 2 million people diagnosed across the spectrum, that’s a lot of people. The problem is that so many people are not connected. People need to empower themselves. If you live in an area with limited tools in America, you’re not required to get treated there. There are many big hospitals that want to help. You have to be your own advocate.”

Johnathan giving me a tour of his research lab


John believes that we must continue to fund basic cancer research so we can find more targeted treatments for more cancer patients. “Basic labs help put the narrative together – when you have the narrative then you have precision medicine. If I give you 2 nouns and ask you to write a story, you’re going to have to put it into context. We’re identifying nouns and by identifying them through sequencing and disease associations, you’re getting context.”, says Johnathan. He also believes it’s a generational thing. “Science is not just about today. Just as our children are the future of America, my protégés, the people who train with me are the future of this field. The cool thing is I now have my trainees going off to other institutions such as University of Colorado and Stanford, so it’s literally like a family tree – and that family tree has lasting impact. Each discovery gets seeded in a new location and we haven’t even touched the tip of the iceberg.” As for his advice to cancer patients, he says “I always recommend that you give yourself the power to go to places that have precision medicine as a focus. The best way to be empowered is to make sure this is a big focus of the institution – that gives it credibility. Go to trusted sources and get educated – get connected to people you can identify with.” 



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