David R. Liu
@davidrliu
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Professor at Harvard, Broad Institute, & HHMI. Our lab integrates chemistry & evolution to illuminate biology & enable new therapeutics. IG/Threads: @davidrliu1
Massachusetts, USA
Joined November 2008
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Pinned Tweet
Today in
@Science_Magazine
we report the laboratory evolution of compact degrons that enable targeted protein degradation triggered by an otherwise-inert small molecule, a multidisciplinary study that integrates organic chemistry, molecular glues, protein evolution, genome…
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Alyssa, a 13-year old T-cell leukemia (ALL) patient in the UK, was the first person to receive a base editing therapeutic—T cells with three base edits—and the first patient reported to benefit from base editing: complete remission, 6 months later.
1/3
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Today we report in
@CellCellPress
an engineered virus-like particle (eVLP) platform that mediates efficient in vivo delivery of therapeutic proteins, including base editors and Cas9 nuclease, resulting in therapeutic editing in multiple mouse organs. 1/14
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Today we describe prime editing, a very versatile new approach to genome editing in human cells without cutting the DNA double helix. We integrated a reverse transcriptase with a disabled CRISPR enzyme to copy virtually any edit from an engineered guide RNA into a target site...
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Today we report in
@Nature
a base editing strategy that efficiently corrects the mutation in the β-globin gene HBB that causes sickle cell disease (SCD), the most common deadly genetic disorder, rescuing the disease in mice.
1/11
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Today we report in
@ScienceMagazine
a one-time base editing treatment for Spinal Muscular Atrophy (SMA), the leading genetic cause of infant mortality worldwide, affecting ~1 in 10,000 births.
PDF:
1/17
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Today we report the use of base editing in patient-derived cells and in mice to correct the most common cause of progeria, the devastating rapid aging disease. Progeria is typically caused by a dominant negative C•G-to-T•A point mutation in LMNA. 1/11
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Science educators searching for a compelling way to teach the importance of understanding how small molecules, macromolecules, and macromolecular assemblies differ: your quest is at an end.
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Three of the more costly and frequently used reagents in molecular biology are rolling circle amplification (RCA) mix, chemically competent MachOne (or other E. coli) cells, and Gibson assembly mix. Postdoc Julian Willis—who is starting his own lab in the UK soon—developed…
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Today we report in
@nature
, in collaboration with the labs of Joseph Mougous and
@VamsiMootha
, the development of a new class of CRISPR-free base editors that enable precision editing of mitochondrial DNA (mtDNA) for the first time. 1/7
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In a major milestone for science, for medicine, and for patients, the world’s first CRISPR drug has been approved in the UK.
“A new treatment for sickle-cell disease and transfusion-dependent β-thalassemia has been authorised by the Medicines and Healthcare products Regulatory…
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Every day I pinch myself for having the opportunity to work with such talented and hard-working undergraduates, graduate students, postdocs, and collaborators. I’m grateful to
@theNASciences
for recognizing their creativity and tireless determination.🙏
David R. Liu of
@BroadInstitute
is being inducted as a member of the National Academy of Sciences for pioneering research integrating chemistry, evolution, and engineering into genome editing and chemical biology. Watch the
#NAS159
livestream:
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Today we report in
@NatureMedicine
a study led by Christine & Jonathan Seidman’s lab in which we used adenine base editing in vivo to correct a common mutation that causes hypertrophic cardiomyopathy (HCM), a disease that occurs in ~1 in 500 people (1/8)
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Working with an incredibly dedicated and talented group of students, postdocs, and collaborators has been the honor of my professional life. I'm grateful that their hard work and insights have been recognized by my election to the National Academy of Sciences.🙏
@theNASciences
Congratulations to
@davidrliu
, one 120 new members elected into
@theNASEM
! Liu is recognized, in part, for inventing base editing, a tool that can edit the genomes of living cells with unprecedented precision. Browse the new members:
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Science is not political. It is not an opponent who can be defeated. Science is simply a philosophy that considers all ideas but moves forward those supported by the best evidence. Battling science is like battling gravity. Doing so during a pandemic is deadly & self-destructive.
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Learned to weld during the pandemic, then made this unconventional bonsai pot from a stone, steel chain, welding stick, epoxy putty, petrified wood, resin, and paint. Inspired by brutalist chain art and the floating wine bottle illusion. Build photos below 👇🏻
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I'm humbled to be elected to the National Academy of Medicine in recognition of the remarkable dedication and talents of our students and postdocs, past and present. Congratulations to all in the
@liugroup
, and to the 99 other new members
@theNAMedicine
!
Congratulations and welcome to the 100 new members elected today to the National Academy of Medicine!
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Today we report in
@NatureBiotech
the development of dual-AAV in vivo delivery systems for prime editors that can support efficient prime editing in multiple organs such as brain, liver, and heart.
1/4
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Today we report in
@NatureBiotech
an engineered virus-like particle system for in vivo delivery of prime editor protein-RNA complexes. This PE-eVLP platform can support therapeutic prime editing in animal models of genetic disease.
/1
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Rest in peace, Orion (2003-2023). Thank you for 20 years of love, warmth, and snarkiness. 🙏
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Urging prosecution of a public health official who works tirelessly to provide the public lifesaving advice during a pandemic based on the best science available to date suggests you identify as Uninformed/Gullible,
@elonmusk
. Please use your intellect & resources to do better.
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Three years in the making—and twice postponed—my trip to Africa was breathtaking, inspiring, and humbling. Africa is full of color, texture, energy, and warmth unlike anything I experienced before. Here are photos and brief recounts. (All animals in these images are wild). 1/36
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Wow.
“4 genes were knocked out…including one that encodes a molecule that causes an aggressive human rejection response.
A growth gene was also inactivated to prevent the pig’s heart from continuing to grow…6 human genes were inserted…to make the porcine organs more tolerable”
For the first time, surgeons have successfully transplanted a genetically altered pig’s heart into a patient. The procedure may bring new hope to hundreds of thousands of people with organ failure.
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It’s wonderful to see Jennifer and Emmanuelle recognized with the 2020 Nobel Prize in chemistry. The seminal “Jinek et al.” paper they published together has been cited >9,500 times—approximately once every 8 hours since its publication in 2012. (1/3)
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Today we share in
@NatureRevGenet
a review of prime editing for precise and versatile genome manipulation. The review covers current prime editing strategies, limitations, recent developments, and applications, including work from 148 publications. 1/5
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@TruthHurts_DJT
@chrislhayes
Yes, very good news. There are now multiple reports of monoclonal (we know exactly which protein sequence needs to be manufactured) human (should be quite safe as drugs) antibodies that block the
#SARSCoV2
virus that causes
#COVID19
. Same strategy as was used to treat Ebola.
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Today we report in
@CellCellPress
a suite of engineered and PACE-evolved prime editor variants PE6a-g. These new prime editors improve the activity, in vivo deliverability, and in vivo editing efficiency of prime editing.
PDF:
(1/15)
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Itching to read a 21-page review article (plus 16-page Supplement) on CRISPR nucleases, base editors, transposases, and prime editors with 454 total references? It's your lucky day. Congrats, Andrew and Luke!
Review article:
SI:
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I’m humbled and grateful that the work of our students and collaborators has been recognized with this award. 🙏
Also, I found out via Twitter just now.
Congratulations to “Professor David Ruchien Liu”, laureate of the 2022
#KingFaisalPrize
in Medicine, focused on “Gene Editing Technologies”.
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Simple proposal for the next two presidential debates: when one candidate is answering the moderator’s question, turn off the other candidate’s mic.
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Today we report in
@NatureGenet
a study led by the team of
@JonathanYenPhD
and Mitch Weiss
@StJude
that characterizes Cas9 nuclease and adenine base editing strategies to induce fetal hemoglobin expression, clinical approaches to treat sickle-cell disease & beta-thalassemia. 1/10
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Today we report in
@natBME
the development of a suite of adenine based editors (ABEs) that are small enough to each fit, together with a guide RNA & all needed regulatory elements, into a single AAV to support efficient base editing in animals. 1/4
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Congratulations to Emmanuelle and Jennifer!
BREAKING NEWS:
The 2020
#NobelPrize
in Chemistry has been awarded to Emmanuelle Charpentier and Jennifer A. Doudna “for the development of a method for genome editing.”
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Today we report in
@NatureBiotech
the phage-assisted continuous evolution (PACE) of all-protein, CRISPR-free base editors to enhance their efficiency and expand their targeting scope for mitochondrial and nuclear base editing.(1/8)
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Our lab as well as students in the class I teach this semester enjoyed tasting the first CRISPR-edited salad greens, in which the myrosinase gene that results in the pungency of raw mustard greens (Brassica juncea) has been disabled, yielding a nutrient-dense, tasty, and…
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It is hard to imagine 274 characters more damaging to US efforts to provide medicines for
#COVID19
patients, and to provide vaccines for all of us. Sowing distrust of those who work tirelessly to ensure the safety and efficacy of our medicines and vaccines will kill Americans.
The deep state, or whoever, over at the FDA is making it very difficult for drug companies to get people in order to test the vaccines and therapeutics. Obviously, they are hoping to delay the answer until after November 3rd. Must focus on speed, and saving lives!
@SteveFDA
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Today we report in
@NatureProtocols
detailed procedures for how to design and execute base editing experiments in mammalian cells, with many design steps also applicable to other cell types. Congrats Greg Newby and Tony Huang!
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Today we report in
@natBME
ex vivo prime editing of blood stem cells from sickle cell disease (SCD) patients, followed by transplantation into mice, correcting the SCD mutation to wild-type hemoglobin and rescuing SCD blood abnormalities.
1/12
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Updated
#COVID19
#SARSCoV2
case timeline, with references cited and other improvements. PDF with embedded links to each reference can be downloaded here:
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Today we report in
@biorxivpreprint
twin prime editing, a variant of prime editing that enables in human cells targeted large DNA deletion and replacement, as well as gene-sized integration and inversion when combined with site-specific recombinases. 1/9
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Happy to host Yale undergraduate science major (and reigning Olympic figure skating champion / 3x world champion)
@nathanwchen
& Professor
@jennkwanMDPhD
in our lab for a week of experiments, data analysis, and outreach activities. Thank you
@IPWitte
for showing Nathan the ropes.
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Today we report in
@ScienceMagazine
the development of a continuous evolution system that can reprogram a family of clinically used proteases to selectively cleave protein targets of our choosing. 1/10
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Today we report in
@NatureBiotech
the conversion of adenine base editors (ABE) into next-generation cytosine base editors (TadCBEs) with high on-target activity and reduced off-target activity using phage-assisted continuous evolution (PACE). 1/14
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So true. Most new group members are surprised (and somewhat relieved) to learn that the vast majority of our experiments fail, even though most projects eventually succeed. The essence of experimental science is observing, carefully analyzing, and learning from repeated failure.
“Failure is something that all scientists experience — but it’s hard to tell, looking at our shiny conferences, polished presentations and glossy journals.”
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A while ago I had a dream about an exoplanet landscape, complete with alien vegetation and floating land masses (thank you, Avatar). Today I finished this art project.
Build details below. 1/3
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Early in my academic career I was invited to give a seminar. It was before we had published much, so I was asked to give a talk on our lab’s research plans. Three people total showed up…but two left during my talk. I felt sorry for the last one, who must have felt so trapped.😂
A career low point this evening.
I was the “guest speaker” at a seminar.
Attendance: zero.
ZERO
Literally no one. 😢
But on reflection, that’s less awkward than one person turning up. 😂
I helped myself to wine and kept quiet - no one needs to ever know about this… 🤫
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Excited (and a bit nervous 😅) to give a seminar tomorrow at 4 pm to the home crowd
@broadinstitute
and
@ChemistryMIT
. Zoom link:
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Today we report in
@NatureComms
the development of laboratory-evolved CBE6 cytosine base editors that offer high on-target C•G-to-T•A editing, virtually no A•T-to-G•C editing, low off-target editing, broad sequence context compatibility, and compatibility with multiple Cas…
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For those planning to hold their next Zoom meeting at the
#FourSeasons
...Total Landscaping parking lot, here is an up-rezzed photo suitable for use as a Zoom background. Edited to fix issues in the original photo from
@ratemyskyperoom
; not to be used for documentary purposes.
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The first dosing of a patient in the U.S. with a base-edited therapeutic has taken place. Congratulations to the
@BeamTx
team on achieving this milestone. 🍻
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In addition, the authors observed interesting cross-reactivity of antibodies against SARS-CoV & MERS-CoV trimeric spike protein, but not against SARS-CoV & MERS-CoV spike receptor-binding domain, suggesting unusual antibody response viral specificity (2/2)
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A thread: Many talented scientists including Alexis Komor and
@NicoleGaudelli
worked tirelessly starting in 2013 to develop and apply cytosine and adenine base editors, systems that directly edit targeted DNA base pairs in living cells without cutting the DNA double helix./1
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Today we report in
@CellCellPress
our new PE4max and PE5max prime editing systems that we first presented at
@CSHLmeetings
in August. 1/12
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More encouraging data on
#COVID19
#SARSCoV2
mRNA vaccines, but antibody and T-cell response data suggest that it takes ~6-8 wks from first dose to full protection. People are mistakenly envisioning return to normal as soon as a vaccine is in hand. Don't fumble on the 1-yard line!
Very reassuring strength and durability of the
#SARSVoV2
immune response from an mRNA (
@moderna_tx
) vaccine across the ages and through 4 months
@NEJM
today
@NIAIDNews
@NIH
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Science and bonsai: two endeavors where obsessiveness has a home.
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We report RNA base editors that enable targeted conversion of A to m6A in endogenous RNAs in human cells in
@NatureBiotech
today. We used nuclear-localized dCas13 fused to a truncated METTL3 methyltransferase to achieve high-specificity A>m6A editing.
1/2
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An exciting new report in
@NatureBiotech
from
@WangXiaoLab
’s team led by
@HongyuChenChem
shows that mRNAs with branched poly-A tails yield much higher levels, and prolonged production, of the corresponding proteins compared with conventional single-tailed mRNA. This discovery…
Why can RNA only be linear or circular? It can be branched! We made multi-tailed mRNA, and we had fun! Here is our story led by brilliant graduate student
@HongyuChenChem
: and his cartoon illustration👇
@ChemistryMIT
@broadinstitute
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Today we report in
@NatureBiotech
the high-throughout phase-assisted continuous evolution of compact Cas9 variants that require only single-nucleotide pyrimidine PAM sequences (N4TN and N4CN). This work was a terrific collaboration with
@MoKhalilLab
. 1/8)
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Today we report in
@NatureBiotech
part 1 of our new prime editing systems. We show that degraded pegRNAs poison prime editing. We developed engineered pegRNAs (epegRNAs) that stabilize the 3' extension and enhance PE efficiencies in 5 human cell types.
1/2
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Can recovered
#COVID19
patients be reinfected? In a study in rhesus macaques, the answer is NO, fortunately. "Monkeys with re-exposure showed no recurrence of COVID-19". Let's hope immunity is long-lasting and difficult to overcome by
#coronavirus
mutation
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Today we report in
@NatureComms
the development of compact zinc-finger base editors that edit mitochondrial or nuclear DNA in human cells and in animals, building on our previous development of TALE BEs that enabled the first precise editing of mtDNA. 1/8
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These impressive results from Gilmore et al. show that gene editing technologies, mRNA engineering & manufacturing, and in vivo delivery can already come together into one-time treatments that offer new hope for patients suffering from genetic diseases.👏
A milestone in modern medicine: 1st therapeutic in vivo gene editing in human patients!
From Julian Gillmore,
@intelliatweets
& colleagues out today
@NEJM
:
Here’s an overview of a new potential treatment for transthyretin (ATTR) amyloidosis.
(thread)
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Be inspired in 15 minutes:
@SammyBasso
, the world's oldest living progeria patient, explains how he maintains such a positive life philosophy, working with us every week to advance a gene editing treatment towards the clinic.
Video:
@BrilliantMindsSthlm
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Exploiting the pandemic to wall off the U.S. and dismantle one of our greatest strengths—our ability to attract and retain the brightest minds from around the world—may ultimately cause even more long-term, self-inflicted damage to our country than
#COVID19
. Abhorrent.
ICE is telling international students on F-1 and M-1 visas that if their school is doing online-only courses they must leave the country or transfer to a place with in-person instruction—or they'll be deemed in the US illegally and subject to deportation.
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The first in vivo base editing clinical trial outcomes are now reported, following last year’s positive ex vivo base editing clinical outcomes!
Congratulations to
@kiranmusunuru
,
@skathire
,
@ambellinger
,
@NicoleGaudelli
, & other scientists at
@VerveTx
and
@BeamTx
on these…
The culmination of 10+ years of work to use
#CRISPR
gene editing to fight heart disease!
@ambellinger
@VerveTx
$VERV presenting the interim data from the ongoing heart-1 Phase 1b clinical trial of VERVE-101 base editing for HeFH patients, at
#AHA23
now.
Let’s start!
🧵
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Today we report in
@nchembio
a collaboration led by Haoxin Li in Ben Cravatt's lab to illuminate functional and druggable cysteines in the human proteome by integrated base editing and activity-based protein profiling.
PDF:
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Early advice that “masks are not effective” against
#COVID
may end up being the second-worst misstep of our pandemic response, as it eroded credibility & sowed distrust. The worst might be politicizing mask wearing even after all the data shows it is key.
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First in vivo CRISPR-mediated genome editing in human patients has begun, in this case to treat a genetic blindness. The age of human genome editing continues to advance.
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#CRISPR
jack-o-lanterns. Photo sent to me by
@Yeastdoc1
. Looks like the carvings were done at
@uofg
.
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New study from Ueki et al. with live airborne
#SARSCoV2
virus confirms
1) Masks worn by infected ppl reduce
#coronavirus
transmission.
2) Masks worn by healthy ppl protect themselves from infection.
3) N95 mask>surgical>cloth>no mask
(1/2)
Note log scales.
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2015 paper showing how a Chinese bat
#Coronavirus
recombined with a SARS-CoV can use ACE2 to efficiently enter human airway cells and replicate, suggesting “a potential risk of SARS-CoV re-emergence from viruses currently circulating in bat populations.”
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The first human patients have been treated with base edited cells in an academic clinical trial in the UK led by Professor Waseem Qasim
@ucl
. Allogeneic CAR-T cells containing multiple base edits are infused to treat relapsed or refractory T-cell leukemia.
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Precise gene correction with base editing & prime editing, in vivo delivery of gene therapies, CRISPR-based diagnostics, complete genome sequencing, experimental & computational protein structure solving, & spatial transcriptomics are 6 of 7 techs to watch for 2022 from
@Nature
.
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We report AAV-mediated in vivo base editing (CBE and ABE) of brain, liver, retina, heart, & skeletal muscle, along with partial rescue of a neurodegenerative ataxia mouse model. Congrats to Jon, Ariel, Nachiket, Jessie, Erin, Rossano, Luke, Jason, and Qin!
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We leave a basket of packaged snacks on a porch table for delivery drivers. An unemployed squirrel also uses this basket, which is actually ok because the squirrel & our drivers have complementary tastes. The squirrel drags away quality snacks with nuts, but tosses all raisins.😂
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This could be the first war lost & won by social media-enabled real-time:
1) Situational awareness
2) Strategic requests, foreign policy updates, & PR from a head-of-state (
@ZelenskyyUa
)
3) Public pressure that rapidly shapes key multinational decisions.
I think Putin may lose.
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Henry Kim and coworkers report the use of in vivo prime editing in the eye to treat a genetic blindness and in the liver to treat a metabolic disease, achieving disease rescue in both cases with no detected off-target prime editing.
Application of prime editing to the correction of mutations and phenotypes in adult mice with liver and eye diseases
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Today we share in
@CellCellPress
a new review of current in vivo delivery technologies that have enabled therapeutic in vivo gene editing—including viral vector, lipid nanoparticle (LNP), and virus-like particle (VLP) methods—and application examples. 1/2
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Springer-Nature announces that Nature and most Nature-family journals are joining open access (Plan S). No details yet on how, or at what cost, but this decision substantially advances
#openaccess
for scientific research publications.
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Today we report in
@NatureComms
the evolution of functionalized DNA polymers that bind a target molecule, and the use of machine learning to generate novel polymer sequences that bind the target—but are unrelated to any of the experimental sequences. 1/6
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Today we share in
@NatureProtocols
detailed strategy and experimental procedures for designing and executing prime editing (and twinPE) experiments in mammalian cells. Congrats Jordan,
@AlexanderASousa
, Peyton, and
@PeterJ_Chen
for this thorough analysis.
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Today we report in
@NatureComms
the development of periplasmic phage-assisted continuous evolution (pPACE). PACE greatly accelerates laboratory protein evolution, but was previously limited to the E. coli cytosol, which does not support disulfide bonds.1/2
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2022 looking like 1939.
Video of Ukrainian father saying goodbye to his kids while he stays behind to fight.
Fuck war.
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Alyssa's leukemia went into remission by 1 month, and is clear 6 months later🤞. 9 more patients to follow. Much gratitude to Alyssa & her family, Waseem's team, Alexis Komor (
@KomorLab
) who led the development of CBE as a postdoc in our lab, & many others who paved this path.3/3
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Today we report the evolution of sortase A, which normally cuts & pastes proteins at LPXTG, to instead operate on LMVGG, found in amyloid beta. Evolved sortase can label endogenous ABeta in CSF for detection & can modify ABeta to impede its aggregation.1/2
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Too real 😱
The scariest of pumpkins for our lab nightmares display… the -80 freezer meltdown 🎃
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