By Hui Cai, VP of Corporate Alliances at WuXi AppTec (@HuiCai2)

UNITY Biotechnology CEO, Nathaniel David

Basically everything I work on has to be cool. That’s the common thread. People look at that and say, ‘Dude, that’s cool.’ That’s the honest to goodness truth.  I will continue to work on things as long as they are indisputably cool.”

As the leader of multiple successful startup companies, Nathaniel “Ned” David’s coolness meter has been running pretty high over the past several years. David – named one of the Top 100 innovators in the world under 35 by the MIT Technology Review – is a molecular and cell biologist who has a penchant for beauty and Star Trek, and absolutely no fear of failure. The serial entrepreneur’s latest venture, UNITY Biotechnology, which recently emerged from stealth mode, aims to develop drugs that could clear away senescent cells to prevent, halt, or reverse numerous age-related diseases.

I recently had a lively and inspiring conversation with Ned to learn more about UNITY, what keeps him going, and his quest for the next “big idea.”

Hui Cai: I know UNITY has been in stealth mode for a few years. So why come out now?

Ned David: We would have stayed in stealth for another five years if we could have. But we had this (Nature) paper publishing that describes the effects of senescent cell removal from naturally aged animals. Because I can’t slow down the pace of science, nor would I want to, we had a choice if we wanted it to be secretive or tell people that we did this work. So we were thrust into telling the story publicly.

Hui Cai: So what is the UNITY story?

Ned David:  At UNITY, we design therapeutics that prevent, halt, or reverse diseases of aging. If you look at the Nature paper, what happens in mice is not only do they live longer but a bunch of diseases in aging are delayed or do not occur. So, what’s the potential value of these types of drugs? One of the things we cured in mice is kidney disease. To put things into context, the budget for the NIH is $33 billion, and in the United States we spend $25 billion just doing dialysis on kidney patients. What we show is when we clear senescent cells in mice they don’t get kidney disease. What this means is the NIH budget for that never gets spent, and this is one disease out of dozens. So when you ask what’s the value of this, it completely changes health care economics because these diseases do not occur.  I’m talking about a single disease. People won’t have to do dialysis anymore. It will be something you read about in history books like smallpox. The really cool thing is what if we wind up getting rid of 2/3 of health care costs in the United States?

Hui Cai: I noticed you picked two initial indications. One is osteoarthritis and the other one is glaucoma. Is there any particular reason you chose those two areas?

Ned David: Those are two diseases that have both published data and data we created that implicate senescent cells as causal in these disease states. We have evidence that senescent cells are necessary for these diseases to proceed, and that the clearance of senescent cells from these diseases can block the disease progression. With these indications you can access them locally, that is to say that you can get to the site of disease with a needle. You can treat it with one of our agents and establishproof-of-concept in man prior to actually destroying all senescent cells in the body systemically. So it’s a setting you can get an answer with a local therapy.

Hui Cai: That’s very good. Right now you are at the animal proof-of-concept stage right?

Ned David: Yes. When we try to prove a biological hypothesis, we use both animal models of the diseases as well ex vivo of human tissue. We have a concept called Deep Proof, which is the highest standard you can achieve in proving a disease hypothesis absent the human clinical experiment. Deep Proof uses animal models and tissue from a diseased patient where it is still alive, and we try to revert aspects of the disease in the tissue by clearing senescent cells with drugs.

Hui Cai: When would you anticipate to move the first program to clinic trial?

Ned David: We have molecules we think that could be development candidates, but we have not formally declared them. Our plan is to declare two development candidates during 2016.

Hui Cai: Are you facing a lot of competition?

Ned David: There are lots of groups that will have some anti-aging programs, certainly (Google’s) Calico, and I know Novartis has an effort in this space. I think it would be very unusual if we were working on an important piece of biology not to have a half a dozen competitors.

Hui Cai: If you look from an outsider perspective, UNITY is a very early and high-risk value proposition. In such early stage programs what worries you the most?

Ned David: I agree with you that what we are doing is incredibly high risk. And statistically it is far more likely we will fail instead of succeed if history is any teacher. I will say, however, that every one of my biopharma companies has worked: Syrrx has an approved drug, Achaogen is in Phase 3, Kythera has an approved drug and we sold the company. We also sold Syrrx. So I have had, bizarrely, a 100 % success rate, compared to the normal 5 % success rate. You can say I’ve been super lucky. But all of my efforts to make energy companies failed.  I like to say I have an untarnished record of failure in the energy business.

While making drugs, in my view, is statistically more likely we should fail, the upside of what happens if we succeed is so tremendous that people are willing to try. It’s really that simple. My intuition, based on the (UNITY) biology we have seen thus far, is that we may yet prevail.  The broad sweep of the impact of this biology is very compelling. It’s difficult for the scientist to ignore it. That’s why I’ve spent the last four years of my life working on it. And the truth is we are just starting. This company will start to get very interesting say 3 ½ years from now once we have human proof-of-concept.

Hui Cai: Out of the five companies in your career, each of them is so different – from technology platform like Syrrx to energy to cosmetic drugs to antibacterial. If you look back and reflect is there any common thread?

Ned David: Basically everything I work on has to be cool. That’s the common thread. People look at that and say, ‘Dude, that’s cool.’ That’s the honest to goodness truth.  I will continue to work on things as long as they are indisputably cool.

Hui Cai: Everybody likes to work on cool stuff, but it’s not easy. How far is the distance between staying cool and staying successful?

Ned David: I’m highly aware of the things I do wrong all the time. I am someone who is incredibly self-critical. All I see are my weaknesses. I think that is a strength. I am also missing a fear chip. I never get frightened of this kind of thing. I think many people are actively frightened of failing. The reality is I’m a coward physically. I don’t jump out of airplanes or jump off cliffs into the ocean.

Hui Cai: Aging is definitely hard science. What do you see as some of the major challenges in the anti-aging R&D space?

Ned David: The first one is how do you resource clinical validation in an area which has no clinical validation. Much like with the early colonists in the United States, there will be a lot of dead bodies. You have to accept there will be tragedy as we attempt to finance our way to the first clinical validation of anti-aging agents. Obviously, we have our strategy around this, but I think there will be many others that participate as part of this collective effort. The big challenge is how do you finance that? History could happen the following way: If we succeed, let’s say, in choosing the right molecule, and we choose the right indication, and we flip the data card in people clinically and the first try works. That’s almost unheard of in biology, but let’s say we are smart and lucky. The first success will drive a lot of resources into this space. So either there will be great tragedy and there will be a great slowdown of resources or there will be an early success and an acceleration of resources. I hope it is the latter rather than the former.

Hui Cai: Now let’s look at our broader industry. Most would agree that 2015 was a good year, and I see mixed feelings about 2016. What is your take on 2016?

Ned David:  I’ve been through three downturns in biotech. We raised ours series B for Syrrx during one of the boom times. Other than that I seem to raise money only during the most depressing downtimes. I am very familiar with this pattern. It exists for a while and then some event happens that generates irrational exuberance and then there is an exuberant amount of capital available. My view is we will go into a period where we are capital constrained and only the best ideas will secure funding. And that’s OK.

Hui Cai: Any closing comments?

Ned David: I’m fundamentally optimistic about humanity, but I believe that it’s our duty as scientists to try to build a better future for our children that is characterized by fairness and humanity. I think that for me a future that in which there is greater opportunity and less suffering is something we should try to build for our children.  My closest version of that is to lead groups of people on technically challenging missions. So my goal is to have a future that is more beautiful and more humane than the present by building a series of technologies through the arc of my life.

Another thing is I wish that our societies were run with deeper respect for scientific values. The United States is an example of which we have a big challenge with that, where knowledge is politicized. That’s a shame and I’m not sure what I can do about that. What if UNITY ultimately works and we create a class of drugs that never existed that dramatically improves the quality of human life. I would like to believe that doing so would earn a point with society, and people would say, maybe you should try science for other things too like climate change or sharing of resources.  My goals are societal.