Michael Rapé is head of UC Berkeley’s new Division of Molecular Therapeutics (often shortened to “MTx”), an emphasis within the Department of Molecular & Cell Biology that will begin admitting students in the fall. The field focuses on innovative approaches to treat diseases, and the division hopes to accelerate the drug discovery process from idea to laboratory to clinic.
Rapé is a professor of molecular therapeutics as well as an accomplished researcher and entrepreneur with major discoveries and successful companies to his name. Despite his achievements outside the classroom, teaching remains close to his heart.
According to Rapé, the shared commitment to public service and the deep level of faculty expertise make Berkeley an ideal location to develop this new program. Not only will the Division of Molecular Therapeutics strive to expand treatment options for major diseases, but the hope is that it will democratize the industry so brilliant researchers won’t need luck and connections to develop cures.
Rapé talked about his groundbreaking research and the many ways that the new division seeks to benefit humanity.
What attracted you to this field?
There was one watershed moment for me: Towards the end of my postdoc, my mom passed away from a cancer that was detected a month earlier. Seeing that there was literally nothing that could be done, I recognized that if you’re interested in developing medicines, it’s not enough to propose something — you have to take that idea further by yourself and be the proponent.
For that reason, when I started my lab at Berkeley, we were interested in disease-relevant biology from the beginning. We first focused on cancer, but now much of our research addresses neurodegeneration. These are disease areas where there is still a big need, and there was nothing that could be done for many patients of neurodegenerative diseases, such as Alzheimer’s Disease.
Then luck came about. I was introduced to a venture capital group that was looking for new ideas in therapeutics development, and I proposed an approach to change the behavior of proteins that cause disease by inducing their degradation and removal. That led to a company that is now successful in the clinic, on the stock market, and has more than 300 employees, many who came from Berkeley.
One of the happiest moments in my scientific life was sitting in a presentation of clinical trial data where the company showed that, in certain patients, a cancer that was previously abundant was not detected anymore. If you see that science can have this profound impact, you have an extra drive to tap into the steep knowledge base and deep societal drive that people have at Berkeley.
What is the status of the new Division of Molecular Therapeutics?
The division officially launched last year, but it was first “in transition” to put the organizational framework into place. New classes have now been developed and accepted. We recruited faculty members from chemistry and toxicology, and at our first retreat, you could sense the energy from connecting different research groups around campus.
One of the reasons we are so excited to start this new division is that it is truly interdisciplinary. We have chemists, biochemists, geneticists, and physiologists, all having different ideas and approaches on how to tackle disease. You can instantaneously create collaborations that span across many areas of expertise. That enriches how you think and the scale of problems you tackle. The hope is that this will allow us to develop new therapeutics that are not just a next step from what is existing but are completely different.
This year, the big change in the fall semester is that teaching starts, and students can earn a degree in molecular & cell biology with an emphasis on molecular therapeutics.
How does this degree specialization benefit students?
Once students declare their emphasis, they take a molecular therapeutics class where they are taught drug discovery: how to identify a target for which you want to develop a drug; how to find the first molecules that could get after that target; what to do if you negotiate with the FDA. They see the entire spectrum of what’s needed. Starting next year, they will have a hands-on therapeutics discovery lab to study the therapeutics invented or being developed at Berkeley, such as genome editing and targeted protein degradation, which are both leading areas in clinical development.
Students will also be connected to scientists from many areas outside of the university — working on drug discovery in biotechs, thinking about business development or company creation, helping to communicate scientific discoveries. They will be able to build networks of like-minded peers in biomedical research that will help them get started in their own careers.
In the course of this program, we will train a new generation of scientists. Undergraduates will gain a strong basis in biochemistry, chemistry, genetics, and the implementation of drug discovery. They are set up for going to biotech companies or performing translational work in graduate school.
What was the rationale behind the creation of this new division?
For many of our students and postdocs, the outlook they have on their careers has significantly changed in the last decade or so. When I started my lab, people wanted to become academics. Now, many students want to go into biotech. One of the reasons is that it became much more feasible to take early ideas and turn them into new drugs.
We’ve shown this with our own work here in the Department of Molecular and Cell Biology: Jennifer Doudna with CRISPR and Jim Allison with oncology. That’s something of a tradition here. We, therefore, need to make sure that our students are well trained for the next steps in their professional development, and MTx will help them in this endeavor.
We also want to tap into the amazing science that is being performed here at Berkeley and make it as quick as possible to translate new discoveries into novel therapeutic ideas and concepts. We’re not interested in making the hundredth kind of inhibitor work a little better. We want to change what you target, how you target it, and how you can modulate disease progression or outlook. There is hardly a better place for molecular therapeutics than the Department of Molecular & Cell Biology at Berkeley, where you have world leaders in practically every field of biology and many researchers who already have experience in building new therapeutic approaches.
Another important aspect is democratization of the process of drug discovery and therapy development, much of which occurs at biotech companies. It is very difficult to get into the network of people who can help you start companies and know who to recruit for building an organization that can go all the way to the clinic. We want to help students, postdocs, and faculty members build these networks to allow them to move drug discovery forward as rapidly and as efficiently as possible.
If you start companies, it is very important to project a market to raise the funds you need to push your therapies through the different stages of clinical testing. So companies are often somewhat conservative in what disease areas they research, but diseases that affect fewer people, and thus might yield less profit, are still important to investigate. These diseases might also be good test beds for new ideas in how to develop medicines, and principles learned could later be applied to larger disease areas as well. This is a unique niche where Berkeley can move therapies development for patients of rare diseases.
Your lab played a major role in developing a new approach to disease treatment. Can you describe “induced proximity” and its potential benefits?
Typically, a drug binds to one side of a protein and turns it off. The problem is you need a lot of that drug, since proteins are only turned off with one drug at a time. We came up with the idea to make compounds that recruit cellular garbage disposal units called proteasomes. Instead of turning off a bad protein, it is shredded into pieces, and your compound can turn its attention to its next target.
As a result, these new drugs work at much lower concentrations and are very effective. Giving less of a drug to the patient means there is less danger that it binds to something that it shouldn’t. The efficacy is higher because it is much more powerful to get rid of a disease-linked protein than to simply turn it off. We can clear cancers that were deemed untreatable before.
A cancer can evolve proteins that don’t bind the drug very tightly anymore, then, suddenly, the drug doesn’t work. This is the heart of how resistance emerges in cancer. With a come-and-go mechanism that binds and then shreds, the drug doesn’t need to stick around for long. I think it is going to be much more difficult for a cancer to develop resistance. I really hope that this new approach will add many more years to a patient’s life. I think this is why that particular approach is taking over drug discovery.
What divisional priorities would benefit from philanthropic support?
There are three main areas: teaching, research, and infrastructure.
The teaching part is very close to my heart. We will build a world-class drug discovery teaching lab that will be, to my knowledge, new for a university. We need to find people who teach more innovatively, especially considering the therapeutics lab’s hands-on training. We would like to expand our symposiums and internship programs to network with companies and give our students an ability to judge for themselves what it would actually mean to make drug discovery work.
A second focus should be on attracting postdocs or scientists who have a strong interest in bridging disciplines and are driven by the desire to put this into action for therapy development. That is not necessarily what one typically gets from their time as a postdoc. In an academic career, it is safer to be in one discipline so that everybody knows you and to ask the next question that will get you a paper. We have a more ambitious goal to support postdocs in asking bigger questions that open new fields, and that will require help in terms of postdoc fellowships and science seed funding.
The biggest item will be funding to build the infrastructure so we can quickly identify and test creative ideas, then speed up the process to get them into the clinic. You can think of the Innovative Genomics Institute as a guide post. This will require new ideas to connect basic and translational science in the context of a university that is embedded in one of the most exciting biotech environments.
Are there areas of molecular therapeutics where you feel, 10-20 years down the line, there will be a major breakthrough?
One of the most promising areas that will be part of our program is how machine learning and artificial intelligence (AI) approaches determine how you treat and diagnose disease. Berkeley has a deep history in computer science and molecular biology. If you bring those together where it’s more than the sum of the parts, you can create something where Berkeley stands out from the rest.
Another area engineers proteins to boost immune systems and achieve other positive health outcomes. We may be getting to the stage where we can predict protein structure from sequence and design a protein from scratch that will have therapeutic benefit in the clinic.
Then, of course, you have gene editing, where Berkeley has a significant stronghold, and Jennifer Doudna and Fyodor Urnov are faculty members in molecular therapeutics. The biggest breakthrough will probably be getting those powerful gene editing machines into the right cell at the right time.
This is the time to start a new division focused on bridging basic and translational science because we are at the cusp of so many discoveries that will completely change how we do therapeutic development and how we treat diseases in the clinic. We can now tap into the deep understanding of basic science and biology to innovate drug development as never before.