#12 - Memory

A decade long exercise in keeping memory alive. And an Ode to cancer researcher, survivor and eulogist.

Remember me when I am gone away,
         Gone far away into the silent land;
         When you can no more hold me by the hand,
Nor I half turn to go yet turning stay.
Remember me when no more day by day
         You tell me of our future that you plann'd:
         Only remember me; you understand
It will be late to counsel then or pray.
Yet if you should forget me for a while
         And afterwards remember, do not grieve:
         For if the darkness and corruption leave
         A vestige of the thoughts that once I had,
Better by far you should forget and smile
         Than that you should remember and be sad.

 - Christina Rosetti, Remember

Mary Oliver asserted that attention was the beginning of devotion. Remembrances are attention to the past and therefore an inchoate devotion to what once was. And a strain, tense, of how it binds through to us now.

Humans seek to be remembered in many ways: donors leave their names inscribed upon edifices, signatures adorn the corners of paintings and heirlooms, objects once held, worn or gazed upon, are gifted to the future. The contemporaneous fascination with ancestry is an embrace of forebears, who ached to be evoked by their descendants.

Death imprints a permanence on the past. With death the record is fixed and the sole remaining malleability of existence can only be mended further by the imperfect recollections of the complicit living.

Honor, though, is elegiac and transmutes the primary source, twisting memories into new creations. The act of creation is a link between past and future. Like an ekphrastic work of art (like Rilke’s Torso of Apollo) the act of honor, in memoriam, is, additive. Petrarch wrote sonnets to Laura, probably not too dissimilar to Rosetti’s sonnet above, but directed his oath toward God. Like Petrarch and Rilke, my friend Kris Wood, through his oeuvre of science, lifts a light to cast new shadows of honor.

A chemical engineer

This is an old picture of Kris, Michelle and their kids. They’ve added another since.

Kris is a chemical engineer, a University of Kentucky alum, a cousin-brother (it’s a real thing, Kentucky jokes aside) and an associate professor of pharmacology and cancer biology at Duke University. I met Kris in 2002, on a graduate school recruiting visit to MIT. He had been a UROP the summer before in Paula Hammond’s lab and seemed to know his way around Cambridge. We traipsed through the slushy, muddy mid-March snow to speak to professors and party at the MIT Museum. He had a joyful ease about him and we became fast friends throughout our years in graduate school together, after we both chose MIT. Course X (ten), what chemical engineering is called at MIT, does a fantastic job of uniting its graduate students with a delirious elixir of social engagement and shared adversity through classes and qualifying exams. But Kris was a natural uniter, bringing our large class of fifty students together with charm, cooperation, and joy. We spent a lot time together; ski trips in Vermont, festivities at the Kendall Marriott bar, Character’s, the Courtside where we dive-bar karaoked (I do a good rendition of Britney Spears) while dining on three dollar pizza that had the texture of cardboard and flavor of ketchup. He gave a toastmaster-worthy speech at my wedding, traveling across the country to Santa Monica. Indeed significant time amongst us were woven together.

Kris opens this video, during our Stumble for Hunger run, the brainchild of Ryan Bennett, where we raised money for the food security non profit, the Bread Project. A story for another time.

He was productive in the labs of Paula and Bob Langer, working on, among other things, novel bioengineered materials for tumor targeting and electroactive controlled release thin films for drug delivery. After his PhD, he spent a few years working at the Whitehead Institute, in the lab of David Sabatini, who pioneered the biology around mtor (mechanistic target of rapamycin, which may be a separate LiC article at some point). There he honed his research vision to begin tackling various aspects of cell signaling and drug resistance in cancer, publishing work such as MicroSCALE screening reveals genetic modifiers of therapeutic response in melanoma. He often collaborates with his brother Kevin, a professor of physics at Michigan, producing amazingly rad papers with titles such as Conservation laws for resistance to multi-drug treatments in microbes and human cancer cells (scaling laws are beloved by physicists and chemical engineers alike). And in 2012, he joined the faculty at Duke as an assistant professor.

Living and breathing your own work

Kris is also a cancer survivor. Not long after he arrived at Duke, in 2013, he was diagnosed with a mediastinal diffuse large b-cell lymphoma (DLBCL), a relatively rare blood cancer with a difficult prognosis. Indeed some of the first aCD19 CAR-T therapies were developed for DLBCL when chemo-refractory relapses occur. Kris and his wife, Michelle, were optimistic, but as everyone acutely knows, the patient journey is harrowing, lonely and full of the unknown.

It was then when Kim and Kris built a wholly new relationship, much in the same way she and Gus connected as chemo buddies in 2012¹. Kris knew Kim well from our days in Boston, but sharing the exigencies of a cancer diagnosis, treatments and survival are known only to them. Kim was still in remission from AML at that time and I was not particularly privy to their conversations². But I know that those conversations were important, intimate and enduring.

I know this because by September 2013, after a half year of monthly chemotherapeutic interventions, his DLBCL was cleared. When Kim relapsed in January of 2014, Kris was one of the first to point us to CAR-T therapy and offer his friend and colleague, heme-onc, David Rizzieri as a resource. After an introduction from Kris, Kim received a visit from Rob Lindquist, a UCSF physician, who was diagnosed with AML as a child and had been inspiringly in remission since receiving a BMT from his brother³. Kris, an incredibly caring man naturally, cared for Kim, thousands of miles away, in ways that I could only have inklings of, the two of them fused through their aberrant blood.

Ekphrasis

After Kim passed away, Kris, like a eulogist, began publishing a series of research papers on aspects of AML and similar hematologic malignancies, “inspired by Kim.” He went so far as to list her memory in the acknowledgments, usually reserved for funders and scientific collaborators.

From Kris’ 2019 Cell Metabolism Paper

In a 2014 email to me, he wrote:

… I also wanted to let you know that for some time I've been thinking about how I can honor kim and all of you guys in a way that feels proportional to all that you and she have meant to me.  As I'm sure you know, kim was a very present part of my life when I was going through my own illness and treatments, and her little words and acts of encouragement – from weekly emails to notes in the mail and pictures of you and the girls – did me an incredible amount of good, reminding me that I was not alone in a difficult struggle.  I felt that perhaps one of the best things that I could do, then, was try to use my work to help people like kim.  So here's the rundown:  the engine of my lab is a set of technologies we've developed that allow us to go into cancer cells and turn genes and signaling pathways "on" or "off" at will in a very rapid manner.  One of the best uses of these tools is obvious: to turn on/off the pathways and drug targets that are most likely to contribute to oncogenesis, then assess the impacts that these perturbations have on essential properties like cancer cell survival and drug sensitivity.  Now that we've developed these tools, the key is to apply them to critical questions, and we've chosen AML as one of them.  

Our first effort – which began over a year ago - was to look at a relatively rare family of cancers that are known as myeloproliferative neoplasms (MPNs) and that are characterized by the presence of mutations in a gene called JAK2.  MPNs affect 10-15K people per year in the US, and in the worst cases, they morph into AML (these AMLs represent about 10% of all AML cases).  A lot of people are excited about treating these diseases with JAK2 inhibitors, but the results in the clinic so far have been disappointing.  In short, patients don't see improvements in their cancer burden.  So, we set out to understand how to perhaps treat these diseases better.  By using our tools, we found that these cancers evade drug-induced death by activating survival pathways downstream of the oncogene Ras. What's cool about this is that we can potentially fix it by combining JAK2 inhibitors with a drug that shuts off these pathways.  This study is now in the final stages of revision, and we are working hard to start a clinical trial at Duke to study whether this drug combination can improve outcomes in these patients.

That's a neat start, but we want to go bigger.  So our next goal is an all-out assault on AML.  I've recruited an amazing MD-PhD student who is taking on the task. He's going to use the same techniques as above, but he'll study every major drug used in AML, from the old school 7+3 agents cytarabine and idarubicin/daunorubicin to newer drugs like Flt3, IDH, and c-KIT inhibitors.  The idea is that we'd like to map the landscape of genetic events that control responses to drugs in AML.  In essence, we think this information might help us to better understand why certain patients achieve cures while others don't.  The goal is that this could allow us to predict which patients should receive standard therapy (because they are likely to do well) and, further, design drug combinations that work much better for those patients who aren't likely to do well on standard therapy.

And he’s done it! Just this last Tuesday, as I was contemplating writing this article, Kris wrote me again detailing his most recent paper in the corpus of Kim-inspired work, published in Nature Cancer, bringing the total to six. While Kris’ CV details the breadth of his other work, covering drug resistance and mechanistic papers in lung, breast, prostate and other cancers, the AML work remains incredibly inspirational to me, to him, his students and hopefully to the patients and families who await new options. I cherish the way he chooses to memorialize Kim, with action and optimism. Before she died, with an out of the ordinary, melancholy, bemoaning wish: “I hope that I will not be forgotten.”

Through Kris’ research, she won’t be. Ten years later, after the first AML paper, he continues to work with attention and devotion to Kim. And in these acts of creation he joins her, himself, to all of the unknowable future.

And Kris is doing well. His family continues to grow and his onslaught of research is being translated to the clinic to promising results. His research has led to the start of new companies. He is going after cancer with his pipette.

Kris makes a V foundation ad appearance!

The Fray

Finally, musically, when I remember Kris from grad school, I think of the band, The Fray, which seemed to be on the ipod (remember those?) playlist in 2006. They have a song called “Look After You,” which given Kris’ care for Kim and so many other hoping patients, seems appropriate.

The Bibliography (to be updated over time)

1. Winter PS, Sarosiek KA, Lin KH, Meggendorfer M, Schnittger S, Letai A, Wood KC. RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis. Sci Signal. 2014 Dec 23;7(357):ra122.

   1. This article led to a subsequent clinical study published in 2022, that validates its hypothesis that combination of JAK2 and BCL inhibitors would synergize in these NPMs, leading to a near doubling of survival for these patients.

2. Lin KH, Winter PS, Xie A, Roth C, Martz CA, Stein EM, Anderson GR, Tingley JP, Wood KC. Targeting MCL-1/BCL-XL Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia. Sci Rep. 2016 Jun 10;6:27696.

   1. AML can evolve over time, through MCL-1/BCL-XL, to develop resistance to ABT-199 (Venetoclax). Considered selection of initial treatment regimen can limit the acquisition of resistance

3. Lin KH, Xie A, Rutter JC, Ahn YR, Lloyd-Cowden JM, Nichols AG, Soderquist RS, Koves TR, Muoio DM, MacIver NJ, Lamba JK, Pardee TS, McCall CM, Rizzieri DA, Wood KC. Systematic Dissection of the Metabolic-Apoptotic Interface in AML Reveals Heme Biosynthesis to Be a Regulator of Drug Sensitivity. Cell Metab. 2019 May 7;29(5):1217-1231.e7.

   1. Identification of a metabolic pathway, heme biosynthesis, that can modulate apoptosis in AML, via depotentiation of mitochondria, through disruption of the electron transport chain.

4. Lin KH, Rutter JC, Xie A, Pardieu B, Winn ET, Bello RD, Forget A, Itzykson R, Ahn YR, Dai Z, Sobhan RT, Anderson GR, Singleton KR, Decker AE, Winter PS, Locasale JW, Crawford L, Puissant A, Wood KC. Using antagonistic pleiotropy to design a chemotherapy-induced evolutionary trap to target drug resistance in cancer. Nat Genet. 2020 Apr;52(4):408-417.

   1. Induce sensitivity to BCL-2 inhibition by driving drug resistance in other pathways, here BRD.

5. Lin KH, Rutter JC, Xie A, Killarney ST, Vaganay C, Benaksas C, Ling F, Sodaro G, Meslin PA, Bassil CF, Fenouille N, Hoj J, Washart R, Ang HX, Cerda-Smith C, Chaintreuil P, Jacquel A, Auberger P, Forget A, Itzykson R, Lu M, Lin J, Pierobon M, Sheng Z, Li X, Chilkoti A, Owzar K, Rizzieri DA, Pardee TS, Benajiba L, Petricoin E, Puissant A, Wood KC. P2RY2-AKT activation is a therapeutically actionable consequence of XPO1 inhibition in acute myeloid leukemia. Nat Cancer. 2022 Jul;3(7):837-851.

   1. Inhibition of PI3Kγ-dependent AKT signaling increases anti leukemic activity of the FDA approvedXPO1 inhibitor, selexinor.

6. Kelly, L.M., Rutter, J.C., Lin, K.H. et al. Targeting a lineage-specific PI3Kɣ–Akt signaling module in acute myeloid leukemia using a heterobifunctional degrader molecule. Nat Cancer (2024). https://doi.org/10.1038/s43018-024-00782-5

   1. Inhibition of PI3Kγ-dependent, using degraders (PROTACs), decreases AML progression with a better toxicity profile over small molecule inhibitors.

1. I would hear stories only much later from Gus about the many conversations and emails they would exchange - something about Gus getting a tattoo sleeve to protect him from the sun.

2. And super annoyingly, yahoo mail, which Kim used as her primary email, deleted her entire mail history and

3. In a nod to the power of motivation, set in motion by Rob’s childhood diagnosis, all Lindquist brothers are cancer researchers.