FOCUS IN SOUND - Pardis Sabeti

FOCUS In Sound #16: Pardis Sabeti

Welcome to FOCUS In Sound, the podcast series from the FOCUS newsletter published by the Burroughs Wellcome Fund.  I’m your host, science writer Ernie Hood.

In this edition of FOCUS In Sound, we meet Dr. Pardis Sabeti, a geneticist who won a Burroughs Wellcome Fund Career Award in the Biomedical Sciences in 2005, and has gone on to enjoy a very distinguished career, culminating this year in being named one of the 100 Most Influential People in America by TIME Magazine.  That recognition follows her inclusion as one of TIME’s Persons of the Year in 2014, celebrating her role as an Ebola fighter.  Although Pardis has a long list of accomplishments in her years of research on the genetics of infectious diseases, for this edition of Focus In Sound we want to concentrate on the incredible story of her work on Ebola.  I’m sure everyone will recall how Ebola nearly spun out of control in 2014, threatening a worldwide epidemic.  That didn’t happen, fortunately, but the deadly disease claimed more than ten thousand lives in Sierra Leone, Guinea, and Liberia before it was finally reined in by the heroic efforts of thousands of dedicated workers. 

By rapidly sequencing the genomes of the Ebola Virus Disease particles present in the blood of dozens of West African victims, Pardis and her colleagues at the Broad Institute in Massachusetts played a central role in determining where the outbreak came from, how it was evolving, where it was likely to go, and how to bring it under control.

Pardis did her undergraduate work in Eric Lander’s lab at MIT.  She got her doctorate degree in biological anthropology at the University of Oxford, where she was a Rhodes Scholar, and her MD at Harvard Medical School.  Today, she is an Associate Professor at the Center for Systems Biology and the Department of Organismic Biology at Harvard, and her lab is closely associated with the Broad Institute, which is a partnership comprised of faculty from MIT, Harvard, and the Harvard-associated hospitals.  Despite her incredibly busy research life, in her spare time she is the lead singer and co-song-writer for the indie rock band Thousand Days.

Pardis Sabeti, welcome to FOCUS In Sound…

Well thank you, it’s a real pleasure to be here. 

When and how did it become evident that the 2014 Ebola outbreak was going to be unprecedented in scope, and how did you and your colleagues respond?

As soon as we noted in March of 2014 and saw the alert that there was Ebola in West Africa, in our minds we thought that it could be unprecedented in scope, and so anyone who works and does the viruses the way we do, you have to almost always assume the worst.  Prepare for the worst, hope for the best.  And I think that as soon as we saw in March, we prepared for the worst.  And we became involved because the centers that we work in in Sierra Leone and in Nigeria have been working with another deadly virus called Lassa virus for many, many years now, and we knew that we were positioned to be sort of on the front lines if these outbreaks were to hit those two countries.  We moved to put surveillance in those countries as soon as the outbreak began, and our collaborators there were involved in the first diagnoses in those two countries.

The theory used to be that Ebola outbreaks would burn hot for a while in a contained area, but would quickly run out of hosts to infect and would basically burn out…what happened to make this outbreak different?  How did this one spin out of control for quite a while, spawning such dire projections?

A lot of people like to think about what a virus might do, but the fact of the matter is, viruses are very variable in how they behave.  I mean, in senses there’s probably a lot of Ebola infections that don’t even make people ill.  Just as every human being is different, every virus is a little bit different.  And so, it may well be that some infections of Ebola virus don’t cause illness, and maybe that some cause illness that don’t lead to other human transmissions, and maybe that some have properties that make them burn out quickly.  But there’s always a possibility that a version of the virus will come out that’s more effective at spreading.  In addition to the viruses being different, and us not being able to know, is there a biological underpinning to this change, there’s also just the fact that this virus outbreak began in West Africa where you have not only dense populations but a lot of road networks, good infrastructure that allowed many individuals to kind of interact with each other.  And you have this interesting space where this outbreak began at the border of three countries that have a lot of crossflow between them.  So you had this instant ability to move across national borders and escalate very quickly. 

What were the major questions that you and your team were tracking on an ongoing basis?

My team and I had been in Sierra Leone and in Nigeria for many years studying another virus called Lassa virus, and it’s also another disease virus like Ebola, with very high fatality rates and this possibility of transmission that makes it a bioterrorist threat.  And in 2012, we actually published a paper in, a Perspectives piece in Science called “Emerging Disease or Diagnosis?” where we began to suspect that not just Lassa virus but also possibly Ebola, and as the two viruses we portray in that article, are circulating in these populations.  And we are genomicists, we use genomic data both to understand the biology but also importantly in diagnostics and surveillance, and so we had been proposing that we could do much better at detecting microbes that are circulating in populations now, to help those populations and also to be able to head off possible global pandemics, because the more we know the better off we are, and prepared.  We really as a group are focused on using genomics for diagnostics and surveillance, as well as to get to biology. 

Why is a quick diagnosis so important to the disease outcome?  Or is it ultimately more important for containing the overall outbreak itself?

I describe diagnosis as an enabling technology.  It enables you to know who the individual is so that you can get rapid treatment, and it enables you to identify cases so that you can help stop transmission.  And in that way, to answer your question, it really enables both of those things extraordinarily.  The diagnosis is that first key piece of information you have to have to get every other aspect of care and prevention going.  Many people have also shown that for different diseases the sooner you know an individual’s status, the sooner you can initiate treatment and the better the outcomes.  So it’s critical to the patient, and it’s critical to stopping the spread to others. 

Why is tracking the mutations of the virus on an ongoing basis, in real time, which I know is a major element of your approach, why was that so important?

The thing is, the diagnostics that you use to detect Ebola virus, as well as the vaccines and therapies that are used to prevent and treat it, are all based on targeting an entity, a virus, and the foundation of that is its genome sequence, which drives its protein sequence, which drives what it sort of makes of itself.  And so, if the virus changes, it can affect those things in ways to make them less effective.  You always have to know what you’re targeting, and so we need to be aware that viruses in particular mutate quite rapidly.  RNA viruses like Ebola virus are going to continue to mutate, and if they mutate, then all of those things that we’ve designed to an old version of the virus may no longer work.  And so it’s critical to track that in real time. 

It’s also very important just to the biology and the other understandings of disease epidemiology and understanding is, genomic information can provide all sorts of really intriguing insights into the virus and how it spreads, and so it’s both critical to the diagnostics, vaccines, and therapies, but also to understanding the disease and its progression and its spread, so that we can launch better campaigns.

How will your sequencing of the Ebola genomes, as you did through the course of several months, how will that contribute to an improved response to the next epidemic?

I think that there’s a couple of things that we’re sort of focused on in what we were doing.  One was showing that there’s nothing that beats data, and that we need to provide data in real time.  And we had that opportunity.  Modern medicine is at the point where the technology is there to make a major impact in outcomes, to allow us to know what the virus is tracking at any point, develop the most rapid diagnostics and care.  But the other part that was really important was getting the data out and collaborating with others.  And that is one of the things that I think that we were most surprised to see how there aren’t really things in place to really allow for open, positive collaboration.  And fundamentally, if another outbreak strikes, the only thing that we have going for us is that ability to communicate, interact, and work positively.  If we then turn and work in siloes or, at worst, against each other, that’s when the virus slides and succeeds.  And so I think that it’s not just the fact that there’s nothing that beats good, rapid data in real time, but also that we need to set up an infrastructure and a culture by which everyone is sharing data and working together. 

Could you have done what you did even five years ago, or did we just recently reach a threshold in terms of sequencing rapidity, reduced cost, and increased computational firepower that allowed you to do what you did?

I think that the technology is definitely in a sweet spot, where the technology is there and it’s expanding, but we were doing work like this even five years ago, not within an outbreak but within cases of Lassa virus; we’ve been generating sequences of Lassa virus for a long time.  I think that the technology has been there, and there have been some good instances.  But I think, again, the technology is now very much there, and it’s about getting the culture to match the technology, to get us to have an understanding that data in real time, research in real time, is the way that we can prevent these things from escalating.

We talked a little bit about the importance of mutation in the Ebola picture, and I wanted to read you a quote from Richard Preston’s article in the New Yorker from October 2014.  He of course was the author of The Hot Zone, and he wrote, and I quote, “As Ebola enters a deepening relationship with the human species, the question of how it is mutating has significance for every person on earth.”  Would you agree with that rather alarming statement?

Yeah, I don’t consider it an alarming statement, I consider it a very practical statement, and I absolutely agree that you of course always need to pay attention to these things.  I have a lot of different mottoes and lines that come up over this, but I always say, “Don’t be scared, be prepared.”  We’re not saying these kind of comments should alarm individuals, and a lot of the ways this has been misinterpreted, you know, is that the virus could go out airborne tomorrow and all sorts of things.  Those are dramatic statements, but saying that a virus is changing and we need to pay attention to those changes is a very practical and important comment to make.  We know viruses mutate, that’s what they do, all organisms do, and they have a very high rate of doing so.  And most of those mutations will have no impact, but the fact that the more we know the more we can head off a single mutation that might have an impact.  I think that it’s important to think about that, absolutely we need to know how the virus is mutating at all times. 

As recently as last month, some new findings about Ebola and the 2014 epidemic were published, and I’d like to get your reaction. A group studying the recent Ebola outbreak in Mali showed that the Ebola Virus is not undergoing rapid evolution in humans, with no major change in modes of transmission, suggesting that current methods of prevention, containment, and treatment apparently are appropriate.  How do you feel about that piece of work that just came out?

Yeah, this is a paper analyzing four genomes from Mali and adding them to the 99 genomes that we’ve sequenced, and looking at an overall picture.  In the data actually that they used in the paper and in the analysis that they performed, gave very similar and gave very similar results, which is that the virus is mutating, it’s mutating at a rate similar to what it has done in the past, and that’s what we had also said.  It hasn’t fundamentally changed in how it’s mutating, but what we said, and what their data also supports, is that there are many mutations that have occurred, which happens when an outbreak is allowed to have this many transmissions.  We think the data is very consistent with our results as well, but it’s a matter of interpretation.  It’s important to kind of stop people from saying, oh the virus will go airborne or change fundamentally, but neither we nor they can say anything about whether or not there’s a biological impact with any of the mutations that have accumulated.  And at this point, there have been hundreds of mutations that have accumulated.  I think that it’s very important that we’re neither complacent nor alarmist, that we just continue to be very, very vigilant in what we do, and I believe that every one of those mutations should be investigated.  We don’t believe that this virus is doing anything fundamentally different, but all viruses continue to mutate, and their mutation rates are much more rapid than, say, mammals like us, and so we have to pay extraordinary attention to what’s going on. And it’s very important, again, that we are neither complacent nor alarmist, and that we continue to be vigilant and get down to zero cases.  

I see.  So what you’re saying, really, is the jury is still out and vigilance is still very important.

Absolutely, yes, absolutely.  We should be all working collaboratively, connectedly, over time to understand what this virus does and to get to zero. 

What are you and your colleagues working on now?  Are you developing a method, perhaps, for rapid, on-site Ebola diagnosis?  What impact would a capability like that have?

We’re doing a number of things right now, and one of them is working very, very closely with our partners in Sierra Leone, Senegal, and in Nigeria, to make sure that they all have sequencing capacity, so the work that we did in collaboration with them, but doing the sequencing in the US, we now have going on in West Africa, and that’s critically important.  And a number of other groups; we’re working with USAMRIID [US Army Medical Research Institute of Infectious Diseases], we have this great paper that our colleagues with USAMRIID led coming out, with new sequences out of Liberia.  The more that we can move to doing sequencing on the ground in countries the better off we all will be for global surveillance. 

That’s one big component of it.  We’ve released all of our sequencing protocols to the community, and many of them are being used by others to do sequencing in house.  We’ve got some new papers.  We’ve done a lot of work in combination with our partners at Tulane and elsewhere on clinical data analysis, and now we have some new analyses that we’ve done showing how well we can start predicting prognosis based on clinical data.  And it points us again to the very important thing of – we need more data.  In my group personally, and all over the world, there are extraordinary people who are poised and ready to take advantage of the new data and to come up with new insights, and we need to make sure the community that data is available so that more science can move forward. 

That sounds very promising, and it sounds like if there is another outbreak, significant outbreak, that is, that you’ll be able to turn around the sequencing much more rapidly.

I hope so.  I think that there is definitely progress in that direction. I’ve seen a lot of heartwarming examples of collaboration and partnership and movement forward, but there’s I think a very long road ahead, and I think we should never be complacent.  I think that we need to continue to develop that culture, develop the infrastructure, and partner most importantly with our colleagues around the world.  This is a place where us as American scientists are not the ones that are leading anything; we need to partner with the local communities and make sure they’re best poised, because they are the hope for the future.  They diagnosed the first cases in Sierra Leone and Nigeria. Without them, we would be in a very different position, and I think that is one of the extraordinary messages from that, which is the better we partner, the more strength we’ll have across the world. 

I know that beyond the compelling scientific questions at play here, this has been an intensely emotional experience for you and your people, including the death from Ebola of five of your close friends and colleagues…what has the whole experience been like?  How has the emotional aspect affected your approach?  Has it affected it in any way?

There’s no way that it couldn’t affect the way that we approach.  I think that what I would say is that seeing the individuals that we work with in such risk, seeing the slow response that allowed this virus to escalate the way it did, it gave me the sense of presence, as well as a fight.  And my feeling is that it can never happen again, and for all of those individuals, I think we as a global community owe it to all of those individuals who sacrificed their lives in this outbreak to learn something from this and work together.  In a very major way we are continuing to feel that we are personally connected to all of those individuals and to their families, and that we are in this fight with them, always.  And so I feel a great sense of purpose and resolve that we need to continue. 

Well you are certainly very much an inspirational example for all of us, Pardis.  I know that one outlet for your emotional response to the experience was to write a song in tribute to your fallen colleagues, called One Truth.  Would you tell us about the song, and where it came from, and what you were trying to express in the music itself?

You know, I am a singer, and a musician in a band, but a lot of times it’s not something I’m planning on doing or trying to do at any point.  A lot of times things come out organically for me, and as it turned out, during this summer that we were the outbreak had happened, we were supposed to have our colleagues from Sierra Leone, Nigeria and Senegal with us doing a summer training program, for two months.  And our colleagues from Sierra Leone couldn’t attend, but those from Nigeria and Senegal did.  They had come year after year, and when they come, we always have a tradition of singing together on a weekly basis, and going in and recording together.  So this is a wonderful collaboration that we have both in science and in music.  But it was interesting, because that was our one standing thing that we had going amidst the chaos around us.  And of course you think, you know, that you should stop doing these things, because you have to focus, but I’m glad that we did, because I think that sometimes you need this one outlet.

Over the two-week period was probably the height of the outbreak for us, where in a short period of time we’d heard that a number of the nurses had been exposed at the Kenema Government Hospital [in Sierra Leona], and soon after a number of them died.  And then Dr. Khan, our close colleague and the head physician at Kenema, also contracted Ebola, and then in that same time frame, our colleague Christian Happi diagnosed the first case of Ebola in Nigeria.  And so we were sitting in this period of immense devastation, on the precipice of potential cataclysm as Ebola might have struck a city of twenty million.  There was so much going on, there was so much stress that we all felt, that it was kind of unbelievable to sit in this room together to sing.  But in that moment of great despair, there was this song that kind of came out of hope, and it just was borne from the light and the smiles and the glances, as well as the fear and the despair of the individuals in this room.  And the lyrics of the song that just kind of came out of me while we were all singing together was … the song is sort of about looking at the world and not understanding where you are or what your purpose is, why you’re here, then singing in a room with Christian women, with Moslem women, with people from all backgrounds and saying, I don’t understand what we’re doing here.  But I have a lifetime to one truth, that I’m alive and so are you. We are here, we are the proof.  Yes, like, we’re here together and it sort of says, you know, we write, we laugh, we cry, we pray, there’s a hunger in us that will never die, and I am in this fight with you always.  And that is really the sense I found myself speaking to our colleagues in Sierra Leone across the ocean, saying I’m here with you always, we are all here in this fight with you always.  It was an amazing moment.  I’m so thankful to have music in my life to be able to give a voice to the feelings that are within me and within others, and we kind of continue on with that.  And those words will always ring true to me, that I am in this fight with you always, and that’s where I hope to always be with the extraordinary individuals who sacrificed their lives on the front lines. 

It is quite a moving tribute, and we certainly want to alert our listeners that there is a very compelling video of the song available on YouTube, so they can just probably Google One Truth and get right to that video.  And with your permission, we would like to end this podcast by sharing the song “One Truth" with our listeners…

I would be honored. Thank you.

Thanks, and Pardis, we wish you the best of luck for continued success in your very impressive and vitally important scientific pursuits.

Thank you so much.  I really appreciate it.

Thank you for joining us for this edition of FOCUS In Sound…and now, please enjoy One Truth, by Thousand Days featuring Pardis Sabeti.