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The Jesuan behind the Covid-19 drug Remdesivir

How do you go from studying Natural Sciences at Jesus into leading a team to develop a drug against a virus that has changed the world?

Richard Mackman (1985) is Vice President of Medicinal Chemistry at Gilead Sciences in California and is currently working on new formulations of the drug Remdesivir (GS-5734) for the treatment of Covid-19. Remdesivir is a nucleotide analog which inhibits many viruses from replicating inside infected cells. Originally, Remdesivir was discovered by Richard and his team, in a program for another respiratory virus, RSV, and was later developed to combat Ebola. When Gilead tested Remdesivir in a randomised clinical trial it was found that the drug helped Covid-19 patients recover more quickly. Now it has been authorised for emergency use to treat Covid-19 in the UK, in addition to the USA and other countries. For Richard, it is moments like these, when it is possible to directly see the impact that his research has in improving patients lives, that really makes all the months and years spent in the laboratory, worthwhile.

We recently interviewed Richard on his time at Jesus:

What made you choose Jesus College in Cambridge?
When I was in sixth form my teachers had recommended I look at Oxford and Cambridge. I looked at the courses, and I really liked the Natural Sciences course at Cambridge more than I did at Oxford. One of my teachers had a contact at Fitzwilliam, so I came down and I spent a day in Cambridge. It was absolutely fantastic; I loved the place. I knew: I want to go to Cambridge and I want to do Natural Sciences. But then I wasn’t sure about what College I wanted to go to – I liked Fitzwilliam but I thought I should check out some of the others in the centre of town that had such magnificent and wonderful architecture. My teacher knew someone at Jesus so I went to have a look. And that’s when I fell in love with the place, the beauty of the buildings. I’m a sports person, so having all the playing fields around the College was the best of everything for me. I totally fell in love with it, and I was sold from that time on. All of my teachers and even my parents encouraged me to apply to Fitzwilliam because they thought it would be easier to get in! But I said, ‘I don’t want to cycle down Castle Hill every day thinking, I could have been at Jesus but I never tried’ . It wasn’t easy from that point forward, trying to get in! But that was how I chose Jesus. I wanted to follow my first choice, and Jesus was the College I wanted to try for.

And it didn’t disappoint?
No, I loved my time at Jesus. They made it hard for me to get in because the grades they asked for were quite high. I was at a comprehensive school in the north of England, Garforth Comprehensive. My offer included having to get a Grade 1 in a special paper, but the school had never done one before. It was actually my chemistry teacher, a former Cambridge alum – David Morris was his name – who tutored me. Through those teaching moments – those 1:1s, going through those special papers on chemistry – it really opened my eyes to that field of science. If you ask me where the spark came from for what I’m doing today, that’s where it all started and I guess the offer from Jesus has a lot to do with that!

Did you come to Cambridge as an undergraduate with the intention of continuing onto postgraduate studies or decide later to carry on?
It really developed over time. I was really captivated by organic chemistry, I thought that was kind of cool. But I was still really interested in maths and physics and the other parts of science. It really came out probably around the end of the first year at Jesus, going into the second year, when you have to choose various offshoots in the course. I had more of an interest to delve into chemistry and biology – I’d missed that part at school since my school hadn’t been able to teach me all the science subjects. When I first applied I really thought I was going to be a physicist or a mathematician. But by the end of the second year I was more caught up with chemistry, biochemistry and pharmacology.

How did you find the course? Did it became more interesting once you specialised?
I did find it very challenging that first year; I felt very out of my depth. I clearly wasn’t as strong as some other students in certain areas of the course. But chemistry was something I felt I could do, I actually had a grasp on it! I was better at chemistry than I was at the other subjects. So it was sort of a natural progression and it aligned with my developing interests, so yes it became more interesting as I specialised. I knew that I had to focus down because I couldn’t cope with doing all the subjects and stay up with the class. It was helpful to go to College, without deciding on a specific course like physics, so I could get that broad science experience in the first year, and then choose what I wanted to do.

So you decided to specialise in organic chemistry?
Organic chemistry was the subject that most captivated me. I was certainly doing more lab work in organic chemistry than in the other subjects. I think in part it was the practical nature of it. You can visualise it, you can go into a laboratory, mix things together, sometimes make something new no one’s ever made before – and that just resonated more with me, that practical element of building new molecules using organic chemistry.

How have your studies at Jesus and Cambridge fed into what you currently research now? Did you start to develop an interest in synthesizing drugs whilst you were a student?
My school tutor had spent a few years working in the pharmaceutical industry before teaching. He’d told me about the work he’d done on a cancer drug in industry, and it totally blew me away. They were making these complex compounds and trying to treat cancer. I thought that was amazingly cool. When I got through the second year at Cambridge, I had a singular vision. I wasn’t interested in doing agrochemistry, or paints, or oil chemistry, or anything like that. I wanted to do medicinal chemistry.

How did you weigh up the decision of staying in academia or working in industry?
For me, this was quite a personal decision. Cambridge is a tough place, but it’s a fantastic educational experience. I really felt that after those first couple of years, I’d worked so hard and not experienced a lot of what Cambridge has to offer that I wasn’t ready to leave Cambridge yet. That was the bottom line. So I decided that if I got the chance to do a PhD, I really should take it. Because that’s a chance in a lifetime. So I was looking at jobs but I was also hoping that I’d get one of the funding awards to carry out research. And it worked out.

Were there certain individuals or academics in Cambridge who had a big impact on your time there?
Professor Ian Patterson was my tutor at College, and a great mentor for me over those years. When I told him exactly what I wanted to do, in the third year he advised me to meet with Sir Alan Battersby. He told me to let Professor Battersby know how interested I was in his research and in doing a PhD with him. I met with Professor Battersby that first time, and it was great. I told him exactly what I wanted to do, and from that point all I had to do was well enough in my exams to get into his group and do research.

Could you tell me about doing your PhD, and how you’ve used that knowledge subsequently?
In the PhD I worked on natural products. Professor Battersby worked on the biosynthesis of vitamin B12, which is a complex organic compound that is built from a simpler compound we call a ‘pyrrole’. A lot of his research was trying to understand how nature uses enzymes that interact with molecules containing pyrroles to build up the more complex structures. Drug discovery programmes are quite similar in some respects. It’s about having a target protein or enzyme that has an important function especially in the life-cycle of a virus because the viruses ability to survive depends on that enzyme. So we want to block that viral protein with a drug. What I do now is similar to what I was doing for my PhD; I just have a different target now, a virus protein instead of the enzymes that make vitamin B12. And we’re trying to design compounds that can engage with the virus protein and in this case cause it to be dysfunctional. Curiously enough Remdesivir also has a ‘pyrrole’ in its chemical structure so that’s another connection to my early PhD research. As a medicinal chemist, you’re very versatile; you could work on different viruses, or cancer, or heart disease. It’s all about using chemistry to interfere and disrupt a biological process. 

What is your fondest memory of being at Jesus?
I was at Jesus College for six and a half years, so it’s hard to pick out one memory. They were fantastic years, they really were. Most of my memories revolve around sports and the people. I played football and tennis for the College but the two things I was most heavily involved with was karate and rowing. It was tough on the body to say the least – I was at that time fitter then than I’ve ever been my whole life since! My fond memories are of the Bumps and other rowing races, the Boat Club Dinners. It was the people, the teamwork, the friendships that you build that I remember most. And I think it was also part of the reason I wanted to stay in Cambridge, because of those friendships I had built. Rowing in the Bumps and at Henley was absolutely fantastic. My one regret is that I never did get a blade!

Richard is the third rower from the left

I guess you get a sense of camaraderie from being part of something like that?
As a manager I talk a lot about teamwork, and how teams work effectively together. And I think, for me, that started with sport. There’s no hiding in a rowing boat. It’s a rule for life: a team works best when it’s aligned. I started rowing in my third year, and I always thought it was hard work and then there was the bitterly cold early morning outings. But you’re part of a crew, a team, and you have to show up.

Do you still have contact with people from Jesus?
I came back to a Reunion in 2002, maybe 2001. The reason I remember is because I came back for this Reunion and I reconnected with a bunch of friends from Jesus College which was great. But I also remember because I asked my wife to marry me in Jesus College Chapel on that trip. We’re married today and we have a son, 7 years old. Cambridge was such a big part of me that asking her to marry me in Chapel seemed appropriate.

Could tell me a little bit about your early career, and how you progressed from doing your PhD into the first years of working in industry?
It was hard to leave Cambridge, but you have to at some point! I wanted to do drug discovery for a career but I really felt like I wanted to see the world too, I had a bit of itchy feet, I guess. The logical thing to do was a postdoc. And whilst I did consider staying in the UK I kind of felt that the two year opportunity to do a postdoc is an opportunity to see the world a bit, and get a different experience. My professor at the time, Sir Alan, had recommended a few researchers, some in Australia, some in San Francisco. I applied to the one in San Francisco and they accepted me into the group. I thought – this sounds pretty good – San Francisco, the Bay Area, why not? As a stepping stone from Cambridge this seemed like a pretty good one and I could get excited about that.

I backpacked across the world for six months to get to San Francisco. That was a great experience, totally cool. And I arrived in San Francisco with my backpack of clothes and only two dollars: I hadn’t enough money to get out of the airport! I had been backpacking around some parts of the world I probably shouldn’t have gone to for six months, so I was feeling invincible, let’s put it that way so I planned to sleep in the airport. Then some guy who ran a hostel saw my backpack and invited me to stay there and pay him the next day once I’d got myself settled. And that was the start of my life in America. I did my two year postdoc in San Francisco. At the time, in the 1990s, San Francisco was really the hub of biotech innovation in America, so I was really in the best place to work. So I decided to stay here in America. Of course 26 years later, I’m still in the Bay Area and never left.

The Third Men's VIII after May Bumps 1990 (Richard is sitting second from the left)

My first job was with a small, pre-public company, and I was doing cardiovascular research for a year. That was my first experience of drug discovery. The company ran into trouble in the first year and I was going to get laid off, so I went through that experience of the lawyers telling me that I had literally four weeks to leave the country and go home, having been in the states for 3 years. That was just terrible.

But I had some friends at other companies that I’d met through various sporting activities. I managed to get a job at another company in the Bay Area that was a slightly bigger, more stable company, with about 40 chemists. I spent five or six years at that company doing oncology research. And that was really where I started my drug discovery career, I would say. I was working with other individuals, very bright people. We were trying to find new treatments for various cancers, and I managed to move some programmes forward there and get some publications in scientific journals. So things were going pretty well until that company was bought out, and it didn’t fit with where I wanted to go in my career.

It was at that point – around 2001 – I was getting calls from Gilead Sciences. They called me up and asked me to go check it out. And I felt, when I went to Gilead, that this was a place where I could make a difference. That was 2001 and I’m still at Gilead in 2020 so there you go.

It sounds like you always give careful thought to your career and planning your next step. Would you say that is a fair assessment of your character?
I would say that is a fair assessment of my character. It’s a piece of advice I give to many of the people that work for me. No-one will look after your career better than yourself. It’s really up to you what you want your career to be and if you don’t want to look back with regrets, then manage your career. Be conscious of the decisions you make. If you feel that you want to be somewhere else five years from now, then start thinking about how to get there. Don’t expect somebody to give it to you. It doesn’t work that way.

What part of your academic or professional career are you most proud of?
The proudest thing for me is being able to contribute to making people’s lives better through medicines, whether that’s to improve their health or even to save lives. Remdesivir is a compound that we first moved into development for Ebola, back when the West African crisis took place in 2014, and we felt we could contribute. There were some ‘compassionate use’ cases. The Scottish nurse Pauline Cafferky was treated with Remdesivir when she had a relapse. There was an infant born to a mother in Africa who had the Ebola virus and this infant also received various treatments including Remdesiivir and survived. This was the first infant to survive being born with Ebola. Those kinds of things are what makes me feel good about what I’m doing, proud if you want to use the term. Because I feel I have somehow contributed to making people’s lives better.

I guess they really give a human face to what you’re doing in a lab.
That’s the perfect way of putting it. Working in a lab can be hard; you spend years doing research, you get setbacks all the time and you have to persist and really stick with it. And you don’t have successes every day. They only come around once in a while. You can’t predict these things but it’s nice when they happen because for everybody who’s worked on Remdesivir at Gilead, they’re all really proud of what we’ve been able to accomplish in terms of helping patients. Putting faces to what we’ve done really helps with that motivation.

 What is it like being part of the team working on the frontline efforts against Covid-19?
What we have here in California is similar to what you have in England, in that we have this shelter-in-place, or ‘stay at home’ order, and can only go out for essentials. The biotech industry can continue to work, and our management at Gilead decided that we should continue the work on Remdesivir, because of its importance. Therefore there is a lot of activity going on in research that I’m involved in, whilst under this stay at home order, in terms of trying to develop other ways we can deliver Remdesivir to patients. We’re trying to develop an inhaled version of Remdesivir, and that’s the thing that I’ve been working on the past few months. So it’s been pretty intense work given the situation here, life isn’t as normal as it could be. We’ve had to knuckle down and try and keep things moving forward despite the disruption. And that’s been hard work but also exciting - everyone’s been interested in what we’re doing both inside and outside of Gilead.

What advice would you give your younger Jesuan self?
Coming from a comprehensive school background, the traditions of Cambridge were somewhat alien to me - the gowns, the Formal Hall, Latin grace. To be honest, my first year in Cambridge was difficult because I wasn’t sure if I belonged, my background was just so different. So there was a certain amount of doubt. The advice I would give to myself is: don’t be afraid of getting out of your comfort zone, be adventurous from day one. Go out there and do things, whether it’s sports or clubs or other things. Embrace everything Cambridge has to offer, good or bad, and don’t let your personality hold you back. Because you only get to do it once.

Finally: tea or coffee?
I’m drinking coffee right now, but my wife actually runs a tea business here in San Francisco. Crucially though, it’s Chinese tea, not Indian tea. So my PG Tips is taboo here!

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