Scientist of the year, R & D 100 Magazine

Mosaics: Recollections of a scientific endeavor.
Note: There is some scientific jargon in this remembering; if you not a scientist in my field, but curious about the vaccine, please excuse me and just skip those bits.

This award was a lovely surprise. It took a "village", lots of folks many years, get this vaccine into clinical trials. So here is some history if anybody is interested, of those who moved this concept along. I was initially inspired to try this idea based on the global database that my team at LANL keeps -- HIV diversity is an incredibly challenging problem for a vaccine, and minding the HIV database convinced me we needed to try to address the diversity directly, by trying to "see" the virus the way the immune system does. I wanted to design a vaccine that could trigger immune responses by allowing recognition of the most common forms of an epitope simultaneously, and cross react with diverse HIV strains (an epitope is a small bit of viral protein that an immune response recognizes). I also wanted to leave HIV proteins intact in the vaccine, so they would be easy to deliver and be processed naturally, and so antibodies that recognized folded proteins might be elicited by the vaccine as well as T cells. I came up an approach to the problem, evolving sets of protein sequences on a computer, that in combination could potentially optimize immunological coverage. The idea was partly inspired by the way HIV evolves in nature, partly by a machine learning concept called a genetic algorithm. It took me a couple of tries at a grant to get it funded; the first reviewers thought the idea was completely nuts, that this kind of thinking could never EVER work. I eventually got funded to bring together the scientists I needed to do the "theory" part of the project through an internal LANL internal grant which fostered exploratory research (a DR). A wonderfully talented machine learning computational scientist, Simon Perkins, was on the team, and with input from my also wonderfully talented husband James Theiler, Simon fine tuned the algorithm, got it in a good computational framework, and coded it up.

I tried to get my old friend Satish Pillai to come work on this project with me as a postdoc, but he was busy with a new job at UCSF, and even green chili couldn't get him back to New Mexico. (See, Satish, I _told_ you it was going to be a good project!) Satish of course now has his own lab, and 2018 found us still working together -- a bit on music, and a bit on an HIV therapeutic strategy, tugging on some crispr threads. But back in the day, Satish was a no, and so I hired Will Fischer instead, an unknown at the time, but a man who very clearly loved to think about evolution, so the project was a very good fit. Now Will is a long time friend and colleague, but then he was a newly minted postdoc. He helped me put Simon's code through its paces, and we explored together how it performed "in theory", working out ways to visualize the comparisons we needed to make (James also helped a lot with this part), and how to best inform the design of the actual vaccines for testing: global versus regional, one, two, three or four proteins sets, which proteins to include. Karina Yusim, Carla Kuiken, and Tanmoy Bhattacharya also helped us think about this. Mosaic code does not require a fancy computer, and we never used supercomputers on the mosaic project. Still this was all tricky business, with multiple false starts and restarts as we were getting going (like initially trying to add in HLA, then realizing, partly inspired by Steve Self, and partly simply by the very high density of epitopes in the database, that we could just treat every epitope-sized bit of the protein as a potential epitope and leave aside HLA complexity and frequencies). Once we had the basic code, we needed to address parameter optimization, tweaks were added to make the code run faster, and we made gradual improvements in output and interpretation. Our goal was resolving what might matter biologically as well as we could based on information in the database. For me it was several years of very very long days, and this comes with a high life-cost. And it wasn't trivial; things always seem more obvious in retrospect than when you are in trenches making something new.

As we worked, I regularly talked through the progress of the theory, for over a year, with my dear friends who were experimentalist colleagues, Bart Haynes, Beatrice Hahn, and Normal Letvin (now passed away), getting their input and advice. They shared good ideas. The four of us had gotten some NIH funding so we could turn the mosaic design theory into some experiments to test it. Bart and Norm did some initial studies, and Bart continues to work on mosaic related vaccine concepts with me currently, and we are working on second and third generation developments. We shared the mosaic concept with Dan Barouch in early days, and we made him some global designs, and happily Dan ran with them. Dan wanted us to only have two mosaic components per protein; given that constraint, we tried to design something with a chance at being able to work all over the world, Africa, US, Europe, Asia... It was Dan's experiments over many years that lead to the current clinical trial, and it is Dan's "vector" that delivers the HIV mosaic vaccine. The mosaic would not be in human efficacy trials now without his many ideas about good ways to express the vaccine insert, and his thoughtful and careful preclinical experimental work, and his collaborative spirit bringing in an industry to help take it forward.

We won't know if this vaccine will protect people from HIV for another couple of years; so this "scientist of the year" is a bit premature, though I'm really happy and honored that it happened. On the hopeful side the mosaic vaccine does significantly slow down infection of virus exposed monkeys, and if vaccinated monkeys finally do become infected after multiple exposures, they stay healthier and don't progress to AIDs. We don't know if this will translate to preventing infection in people who will be confronted with HIV in all its natural diversity "in the wild", or if it will help them fare better if they are infected. We cannot know that until it is tested, and it takes time. But I harbor hope. If it doesn't protect people, still we will learn some things from trying.

Meanwhile, there are many other good HIV vaccine ideas in the pipeline -- and a few of them are my own! Its why I can't retire yet, I want to see the ones with promise through.

Thanks to everybody who has sent kind notes and good wishes.

I'm keeping some pretty classy company in this award, the nerds among you will know some of the names of past recipients:

Dr. William Pickering 1967 JPL
Dr. Wernher von Braun 1969 NASA MSFC
William Lear 1971 LearJet
Dr. Mary Good 1982 DOC
Dr. Justin Rattner 1989 Intel
Dr. Kary Mullis 1991 Nobel Laureate
Dr. Susan Solomon 1992 NOAA Ozone Hole
Dr. Tim-Berners Lee 1996 WWW
Dr. J. Craig Venter 1998 Human Genome Project
Dr. Eric Lander 2003 MIT/Whitehead Institute
Dr. Anthony Faucci 2005 NIH
Dr. Steven Chu 2011 DOE
Dr. Robert Langer 2012 MIT
Dr. James Tour 2013 Rice Univ.
Dr. Karl Deisseroth 2014 Stanford Univ.
Scott Kelly 2015 NASA
Dr. Dharmendra Modha 2016 IBM
Dr. Cori Bargmann 2017 Chan Zuckerberg Initiative

TALK for the March for Science

TALK for the March for Science, Santa Fe, New Mexico April 22, 2017

With thanks to my friend Elena Giorgi, who helped make it happen, and Josip Loncaric who took my picture, and A Bone Martinez, who kindly taped it -- see the link at the end if you are interested.

 

I’m going to start this talk with some time travel. Many of you have embarked on time travel yourselves, by exploring family trees, or by genetic testing to discover your roots in your DNA, reaching back to try to imagine the world of your ancestors. But there is one profound difference in their lives that is very hard us to imagine. And it is not the lack of cell phones. It is this: throughout the arc of human history, people were intimate with death in a way that we are not.

When a new baby is born into our families, our expectation is that, of course, we will get to see that little one grow up. That children will outlive their parents.  This is not the way it’s always been. This is a gift that science gave us.

So, our first stop in our journey through time: Catalhoyuk, in present day Turkey. We will go back about 7,000 years, and stop there. (People were just beginning to figure out how to brew beer, so let’s not go back any further.) 1000 years of burials in Catalhoyuk tell this story to the scientists who can read the bones: 

       - 40% of babies died before the age of 5. 

       - Only 1/10 people made it to 40 years old.

       - Please raise your hands if you (like me) are over 50 and willing to admit it.

We’re all right out – because nobody, nobody at all, lives to 50 years old. 

OK, let’s fast forward to ~1730, London. Now, not only is beer on tap, but we can get a good cup of coffee and some lively political debate in the local coffee house. A gentleman named John Marshell is busy compiling the Bills of Mortality, he’s documenting the cause and age of every death in London, death by death. 7000 years have come and gone, but surprisingly little has changed:

       - Things are worse for London’s babies, ~45% won’t make it to 5, nearly half die.

       - If you do make it past childhood, the odds are better: 20% make it to 50 years, a few people even make it to old age.

So what were all these young Londoner’s dying of? If we peer over John Marshell’s shoulder, we’ll get a grim glimpse: most often, it’s infectious disease. The Kings Evil (TB), worms, “the purple and spotted fevers”, infected teeth...   Death by infected teeth? I don’t know about you, but I’m ready to high tail it outta’ the 18^th century.

So lets come home. Our time. Our place. Our America, 2017. Age of miracles and wonder.

       - Our babies almost always get to grow up; only ~6 out of 1000 don’t make it.

       - Heart attacks and cancer are the leading killers, diseases of old age.   95% of us live past 50. On average, we get 79 years of life.

What has changed?  Clean water. Antibiotics. Vaccines.

But something more subtle as well.

Louis Pasteur, the man whose experiments led to the acceptance of the germ theory of disease said, “Chance favors only the prepared mind”.

So another change in our times: Through science, we collectively have a “prepared mind”. We discover new disease outbreaks swiftly when they arise. And we have clarity of purpose when we discover something new and dangerous. We isolate the bug that causes the outbreak, figure out how it’s transmitted, how to treat it, and how to vaccinate against it. Recent decades have brought us nightmares: Ebola, SARS, Zika, HIV, drug resistant TB, and Hanta virus (in New Mexico). And we respond. Sometimes the science is very difficult.  Still, we respond.  Your tax dollars pay for America’s response; I think it’s a good deal.

My life’s work focuses on HIV vaccines. To this day, I’m motivated by witnessing first hand a turn around in the expectation that children should get to outlive their parents. I watched helpless as two dear friends of died of AIDS in the 1990s.  They died in their 20s. One was my next-door neighbor growing up, Kevin. The sweet little boy I had babysat had grown into a fine, funny and generous man. HIV took him. The other was my housemate for 5 years, Brian, one of the most extraordinary scientific minds I’ve ever encountered.  AIDS kills in many ways. Brian’s beautiful mind was lost to AIDS dementia; it was the one thing he feared the most. My friends’ deaths were slow and hard.  Their brave moms were by their sides constantly to help them endure the pain of the last months of their lives. These memories I hold in my heart: these wonderful men, their beautiful families, what they suffered, what was lost.

AIDS was discovered in 1981. It was 16 very long years before we figured out how to treat it with good success. But still, even now, HIV infections are never cleared.  Antiretroviral therapy is hope and life. But it is also expensive and arduous: a lifetime of 3 drugs a day, drug resistance can evolve, the drugs can have hard side effects, and too many people still don’t have access to treatment.

The HIV pandemic is not over, but is no longer news, so it falls away from our attention. The WHO estimates 37 million people are living with HIV, that there are over 2 million new infections, and over a million AIDS deaths, each year. The sorrow of million deaths is impossible to comprehend. When I try to begin to understand it, I remember that every one of them is someone’s Kevin, someone’s Brian. In the US, the CDC estimates 1.2 million people are living with HIV. A working vaccine would turn this epidemic around. How? Now, for some science.

Your immune system has the remarkable ability to distinguish “self” (that would be you) from “non-self” (that would incoming infections). When you get a new infection, your immune system goes into battle, but it takes a while to ramp up. Meanwhile the new pathogen begins to take hold, uses your body to copy itself, and as a conduit to infect others.  When you survive and clear an infection, some of your immune response lingers, harbored as memory cells. These memory cells are poised and waiting to protect you. If you’re ever exposed to that same pathogen again, your immune response will be swift, potent and precise.

The way a vaccine works is by using an inactivated pathogen, or just a fragment, some bit, that doesn’t get you sick, but can still trigger an immune response. Vaccines leave behind the memory cells you need to protect yourself, should you later encounter the real and dangerous pathogen.

We still don’t have an HIV vaccine; it is a particularly difficult challenge. HIV infects the immune system itself. It is highly variable, different in every single infected individual. Still, we are making steady progress, and I’m hopeful about it.

Finally, some thoughts about Trump’s proposed 20% cut to the NIH budget. Much of the human health research done in our country is seeded through the NIH. It keeps us at the cutting edge of medical advances. It is how we fuel innovation, and how we train the next generation of scientists. A 20% cut will close the door on many promising research directions that are currently underway. Momentum will be lost.  

Remember the words of Dr. Pasteur, “Chance favors only the prepared mind”. Our national science programs are our collective “prepared mind”. We need to attend to the health of our people, and the health of our planet; science enables that. Thank you all for doing your part today, for Standing With Science. Never take your citizenship for granted, learn about the issues, seek truth, and then VOTE! 

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Time travel, courtesy of Christopher Will in his book Yellow Fever, Black Goddess

AIDS stats were taken from the WHO and CDC Websites, 2017