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

A Wednesday morning at the Smithsonian, in three parts.

I. The Natural History Museum at the Smithsonian.

Atoms, organize yourselves!

Initially, I was just happy roaming: passing by the elephant, eye level with his knees; gazing at the underbelly of the very impressive life size Right Whale floating overhead; admiring the giant squid in his giant-squid tomb; becoming engulfed in bones and butterflies and emeralds; watching the videos of the strange gelatinous impossible creatures that roam the deep blue sea, some so delicate that they can be shattered by light. All this was spiced with the kids zooming around and the occasional kid-call ringing out, “Daddy, look at THIS!”  A big quartz crystal had a sign that said, “Touch some atoms!” A kid says, “Ooh! atoms” as his fingers traced the golden surface.  

But my museum free-style ramble came to a dead halt in front of my favorite thing of all: the museum volunteer named Henry.

Henry noticed me reading the fine print on the climate change exhibit, and he offered to “bore me to snores” with the history of the Earth’s climate patterns. Henry was a geophysicist by profession, and had spent happy seasons in Antarctica, collecting ice cores, and then doing complex systems modeling of our planet’s changing climate patterns, past and present. He professed his way through a university career, and then retired to become a full time sharer-of-knowledge. He did his best to spin me through 4 million years in less than an hour, talking me through the Milankovitch cycles, cyclical patterns that change the how the sun’s radiation reaches and impacts our Earth’s surface. So I learned: The eccentricity of the Earth’s orbit about the sun cycles about every 100,000 years. Is it more a circle, or more elliptical? So goes the warmth of our mother Earth. Her axial tilt brings the gift of seasons, cycling about every 40,000 years.  Her wobbling precession shapes the seasonal contrast: how cold the winter, warm the summer, cycling every 23,000 years. Our perfect moon, as she whirls around us in gravity’s smooth arch, steadies her dance-partner Earth, keeps her from weather extremes she otherwise might teeter into. Wheels-within-wheels. The intertwining of these intricate planetary cycles help shape our climate, its ups and downs, its transitions.  But that must all be understood together with the chemistry of the biosphere, as earth has wrapped herself in life, and this is impacting everything, and we life forms create complicated webs of chemistry that include the atmosphere, the buried carbon from past life, and the chemistry of the seas. The story is intricate and in continual flux. As we all know, remnants from lives millions of years past, carbon folded deeply into the Earth’s crust, is being released into the skies at an unprecedented rate these past 100 years. Henry shows me, we are at CO2 levels higher than any time in the last 100 million years. So scientists are trying hard to sort out what this means. There were some pretty wild swings in temperature on the Earth in the last 200,000 thousand years, as our ancestors pulled themselves up on two legs and began to walk the planet, but this carbon release is something new.

We have evolved, adapted, and then occupied the earth as we have known her, and know her now – how we will we be impacted by this flood of CO2 from layers of life-past that we are ripping, pumping, pulling from the earth and pouring into the sky? Here Henry’s voice ends, mine starts, as he didn’t want to become political. I do. We continue to play with fire, and justify taking grave risks with our children’s and our planet’s future because our science can’t precisely predict something as complex as the Earth’s climate patterns.  Of course it is difficult, modelers do their best given what we collectively know, and what we don’t know is a lot.  Some would claim models with uncertainty should not dictate policy. But that is absurd when we are gambling with such high stakes. The models show us realistic views of probable and possible futures, try to quantify the uncertainty, and this guidance is more than enough to help map ways for us to make choices that bring hope, rather than continue to invite apocalypse.

Back to Henry: he was busy discussing a trace of the direct interaction between Neanderthal and Homo sapiens (something physical and beyond Neanderthal DNA that spirals through our own). It was the damaged rib bone of a Neanderthal man.  Being at the Smithsonian, my eyes were gazing on his actual bones, not just a cast. His lethal wound had begun to heal over a bit he endured 2 weeks of pain before he died.  The nick in his rib was likely the deathblow that killed him, and also likely to have been inflicted by a Homo sapiens’ rock-tipped spear.  To clarify this “point”, bunches of scientists apparently got to throw rock tipped spears at bones to see if they could emulate his broken rib (I want that job!).  But it startled me to see this. We seem to leave violent traces as far back as history can look.

But there was also this: a clear imprint of beauty too, also tucked back in with our origins. It was time for me to bid farewell to the bones, and I was in a rush to head over to the African American History museum, as my ticket-time had arrived. As I was hurrying out of the museum, I noticed a small broken flute on display, and ducked into a small “cave” area behind it: a replica cave painted with replica cave art. One could hear the sweet sounds of a model based on the small flute in the display, filling the space. The flute was pentatonic, 5 perfect sweet notes, made of mammoth ivory by some expert hand who carved it about 35,000 – 40,000 years old. I’ll dream this dream up: one of us (that would be the little one with the smaller brain) playing it for a Neanderthal friend, sitting by a hearth. My little share of Neanderthal DNA ripples at the imagining.  Flutes and drums, they’ve been with us, as long as there has been there has been an us. Haunting sweet sounds, from that little flute.

II. The Museum of African American History, the Smithsonian.

(This slice of life is for my friend Kshitij Wagh.)

This museum is wonderful and I’m going back. And back. I only had and hour and a half, so the top floor with its music called first. A meteor shower at the Musical Crossroads: A spiritual to bring you in, with a hello nod from Scott Joplin. Chuck Berry’s dazzling red convertible Cadillac, commanding attention. It’s the very one he drove on to the stage during an encore performance at the Fox Theater in St Louis, a theater that had turned him away because of his race when he was a kid. 

Sax and drums and Max Roach’ s Tuxedo: elegance and rhythm. The sounds of hip hop from the Bronx, kids dancing the impossible. Standing in between 4 giant screens with Aretha Franklin demanding just a little bit of RESPECT. Jimi Hendrix’s Star Spangled Banner, howling. ‘Scuse me while I kiss the sky, because the Mothership is landing.

Two stories from the hall ”Making a Way Out of No Way”.  It’s Mexico City,1968. Tommie Smith, the gold medalist, just ran 200 meters in less than 20 seconds. He and his friend and competitor John Carlos, stood on the winners’ podium, bowed their heads, and raised their fists to the sky to protest discrimination; they were shoeless, their black socks and glove a protest. Their white Australian colleague Peter Norman, wore a Human Rights badge in solidarity. They were booed by the crowd and forced out of the games by the president of the International Olympics Committee, and out the American team; they came home to death threats to their families. But they sent a wave of courage and power out.

Then there is a picture of a high school class, all black kids. It’s Virginia, 1951. Looking both sweet and defiant, slim shouldered and bespectacled, 16 year-old Barbara Rose Johns stands in front of the crowd.  She has organized a walkout, a strike of over 400 students, to protest terrible conditions at her all-black school in Farmville. The KKK burned a cross in her yard, her family had to face fear for their amazing daughter, for her safety. But she and her friends won. Their case was one of the 5 cases the NAACP took up, which ultimately gave America the Brown v Topeka Board of Education decision, in 1954. Separate is not equal, the law of the land. Bless you for teaching us, Barbara Rose.

When I was 16, 1974-1975, I was bused from my almost all white suburban high school to a school in the “inner city”, a school with kids of all colors. SEA school was in part a reverse integration project, testing some ideas about “alternative” education.  My dad was a sociologist, taught race relations. In his life, he fought for human rights and human dignity. He was Dept. Chair at Long Beach State, and in the 1960s, he hired black professors into his department and fought to keep them on (his nickname was “Crowbar” for a reason). He brought black activists to campus to speak. He had a gift of listening carefully, and of giving, and so receiving, respect. Over his desk was a big poster of two kids, hands held in friendship, black and white. So when I wanted to do this, volunteer to be bused, my parents let me go. Sept 1975 came round, my best friend Shelly and I linked arms, boarded Ma Padrone’s bus (the red haired and raucous bus driver – you had to love her, but you didn’t mess with her), and we took the ride across town. SEA school was wonderful, and I was blessed to make my first black friends, Mark Patterson among them.  Thank you Barbara Rose Johns, thank you for Mark.

Memories came flooding back, of another friend SEA school gave me, Johnny Kimbrough. My favorite teacher was Hermione Baker, a Quaker with all the gentleness that implies. Her hair a soft white cloud, up in a bun, her eyes bright, always amused. If recollection serves, (its been a long time…) Johnny and I both had a special studies class with her, creative writing. We would pass each other going in to and out of her office. My task for her was every week to find and witness something new in the world to me, and write my impressions.  I remember some of my essays: A black Baptist church service. A walk down into the broken concrete world of the Los Angeles River. Passing through an empty doorframe into an abandoned house, discovering the traces of a family left behind. A time alone with the birds, out on the jetty of the harbor at sunset. Climbing a pepper tree in a warm wild wind, a Santa Ana, on a dark night.

Johnny was black, and we stepped through different experiences. Very Different. If I remember right, his task for Hermione was poetry, but in any case Johnny was a poet. That much is clear. He and I hung out sometimes in a usually empty student lounge, sitting together on a ratty old couch; our space.  He read his poetry to me. I shared my essays with him. We listened. We helped each other find words. His poetry was a kind of RAP before RAP.  It was gorgeous, and fierce, and full of rhythm when he spoke it.  

 

And it dawned on me this morning, a realization, that these little essays I sometimes write, like this one I’m writing here and now, I am still writing for Hermione and Johnny.

There is a new and honorable movement this week, kids leading, shaking America with the pain in their cries. They are rising up in response to the series of school shootings that have left of our country in a stunned sorrow.  Broken all our hearts, but out of their sorrow like a phoenix, is coming their strength.  #Neveragain. Too many killed, too many lost, so the students are demanding good gun laws and safe schools. They will not be silenced.  We have to listen.  Like Barbara Rose Jones, they are right.

III. The Metro

A river of people flowing down the silver cycle of escalator steps, into the crust of the Earth, into the tunnels of rushing trains. As moving stairs take us into the Earth, the subterranean winds whoosh up, the cool breathing of the tunnels. There is a roar of the clapping air that slams into the space the trains leave behind as they accelerate into their next stop. It just one of the sounds of a city's circulation, always exciting to me, though perhaps so familiar to city-dwellers to have faded into their background, just as the swish of the blood through our veins, the beating of our hearts, goes to silence so we can hear beyond them. But I come from a place of canyons and mesas, where humanity does not flow in subterranean streams, so there is still, always, some magic for me in subways.

With my tired feet, I descend into the Earth perfectly still, standing to the right on my claimed step, an eddy in the current of people-flow. A sweet lady claims the step behind me, and she says, with New York in her voice,  "I love your purse, did you know those were Binko leaves?" I say, "Thank you so much", and pet my purse, covered with leather stamped Ginkgo leaves. I am really pleased both that I now have a new term of endearment tucked away, to whisper I next time I encounter a Ginkgo tree, and that this nice lady likes my purse. She is friendly, and so we exchange a list of what we did at the Smithsonian that day, while her husband beams at us. It is nice to share our lineup of adventures, as I am on my own, so happy to have someone to exchange stories with. Common ground: we both LOVED the right whale exhibit.

We part ways. I head for my line, and am swallowed up in the group heading out on the Blue. The train doors open, our invitation in, and we all jostle into our own places and start pretending not to see each other.

Two power-women are loudly speaking in a language I do not follow.  They have Good Hair, in place. (How do they do that?)  Nice pumps.  They say: Jiggering Networks, Approaching Standards, Serious Movement, Facilitating ways to Initiate Improving Interpersonal Stuff, Drilling Down by Modulation, Taking It for What Its Worth, Editing Yourself with a Presence Thing, ‘Twas brillig and the slithy toves did gyre and gimble in the wabe.  Alright, so they didn't really say that last bit. But I do think The Vorpal blade went snicker-snack, a sharp quick attack cleverly disguised in the "Editing Yourself" section of the dialogue. One of the two women, the loudest, looks triumphant, and the other like she is about to cry. Even if speaking in tongues, it doesn't seem right to be attacking a colleague on the metro. Everyone else attempts to turn their attention elsewhere, trying very hard to give the lady with tears brimming in her eyes some privacy.

And so the gentleman with closed eyes sitting next me comes into focus. He must be adept at closing out Jabberwockies, as he looks so calm, a faint quiet smile sometimes twitches at his lips. The gentleman has laugh lines by his eyes, red-gold lashes rest on his cheeks. As he is rocked in the cradle of the subway sway, stop, start, accelerate, sway, there is peace on his face and quiet in his breathing that is speaking a language with a greater clarity than the loud power-woman across from us. I should not be invading his privacy by this scrutiny, but I cannot help it, he is beautiful, and he draws my eye. His grey blue eyes flutter open for a moment, take in the scene, and close again, this simple act a direct transport to another time and place.

There is an old woman, brown skinned, and she is yet more beauty on the subway, chin high, spine straight, eyes wide. Dignity settled in around her. Like me, she is traveling alone, watching, and weary. We see each other for a moment, exchange recognition of this. She has old skin now, like my own, decades of gravity is pulling us both in home towards the earth; we are both sagging bit around the edges.  The bones of her face are elegant and bold, and you can look through time in that face, to see the beautiful young woman she was, peering out through the beautiful old woman she is, and wonder at the stories in between.

She sits next to a young woman, they are strangers pressed thigh-to-thigh with the odd intimacy of a crowded subway. They are separated by 40 years, but both are bound through a similar bearing. The young woman has her long black hair in a hundred braids, which she has woven further into a glorious intricate sculpture, slipping in a few lines of silver thread into the soft blackness of her hair -- an impression that she has woven the night-sky and stars, dark and perfect, on top of her head. The Pleiedes come to mind, but if I tell you she is one of the seven sisters you won’t believe me.

The way her hair sits on her head also brings to mind the sweetgrass baskets I saw in the African American Museum an hour before. Sweetgrass woven based on traditions slaves brought from the rice coast of Africa to the Carolinas, a beauty they carried in their hands, a tradition they carried through lives, held away from their brutal treatment. They then passed on this knowledge through generations. So my mind skitters around, from stars to baskets, and takes a sharp left to land on the thought of the rich sweet smell of the little sweetgrass baskets that were in the Smithsonian gift store. The little baskets looked empty, but in fact held some deep history alongside the smell of meadows, the edge of the sea, and wild green places. The sweet smell of the Earth mixed with a life scent, for sale, right there in the DC Mall. I am regretting not coming home with one of those small baskets.

Our train emerges from the earth, hurtles into the sun, to rumble briefly through a land of giants: the leaf-bare trees, their limbs branching intricate complications against the blue sky and white clouds. The train screeches to a halt at the Reagan Airport. The people re-assort in the leave-the-car shuffle, a wave of push as we leave the train, juggling our luggage. There is tug of urgency, like everybody's just a little later than they should be to get to their planes. I find myself next to two too cool 20-somethings, jeans tight, elegant shirts button down, hair vertical, the men are deep into a conversation that proximity opens up to me -- they are at my ear, just for a moment. One says, "I’m tired of this shit. I feel like I have no control over my own destiny."  The other says, "Yeah man, I know what you mean."

For God's sake! I just left the African American History Museum, that celebration of a whole people taking their destiny into their own hands, and I'm not about to let that comment alone. So I summon all my height and courage, trying to look the part of the Oracle that I want to be for them, and say sternly, "That's not true. You're responsible for your destiny. Choose it." Guy number one says, "Hope you're right." and flashes me a smile over his shoulder. I think, but don't say, "Please, please, please make me right!" as they are already lost in the crowd. 

And then I think that I make a pretty damn silly Obi Wan, an old lady clutching her Binko leaves, hair all akimbo, limping on tired feet, wearing my too-heavy tattered backpack like a shirt-of-hair. Ah well.

__________________________

This essay comes with a link to sweet potato pie recipe, in honor Mr. Coleman of Coleman’s Soul Food in Long Beach.  He served the best pie! After remembering it fondly for all these years, I  finally made my very first sweet potato pie last night, I’m just linking to the recipe as I have no experience of my own to call on. But James, Tango and Grace agree it worked out fine, including the maple syrup in the cream.  

Calley's sweet potato pie recipe

And music to cook by?  RESPECT, of course.