Happy 40th birthday to the human mtDNA genome sequence, reported in this classic
@Nature
paper in 1981, by Fred Sanger and co-authors (listed alphabetically, including pioneers in computer biology). The 16,569 bp mtDNA sequence has aged so gracefully.
Breakthrough for mtDNA biology: precise editing via a bacterial dsDNA deaminase engineered it to operate within mitochondria. Led by inter-microbial warfare expert Joseph Mougous
@UW
and DNA base editor-in-chief
@davidrliu
@BroadInstitute
@HHMINEWS
Such good news for our country -- the senate unanimously confirms
@eric_lander
as the first ever cabinet-level science advisor. Congrats Eric, and congrats
@POTUS
for having the vision to elevate this position to cabinet level. Go science!
Today, we and
@ganetzky1
report
@NEJM
a remarkable case of twin boys with euthyroid hyper-metabolism (low body weight despite high caloric intake), due to a de novo mutation in mito CV that uncouples respiration from ATP synthesis.
Fascinating paper showing that anti-oxidant vitamins (GSH, NAC) *accelerate* aging in worms, mechanistically by suppressing the endogenous anti-oxidant stress response. Reminder of the value of randomized trials even for agents we assume “do no harm”
Feel very honored to receive this distinction - I’m so grateful to my many mentors and past and current lab members that have joined me on this quest to study mitochondria.
Here's our contribution to the
#mitoawarenessweek
!
#Superresolution
imaging of cellular membranes (preferentially mitos) in U2OS cells using lipophilic dyes. Reveals
#mitochondria
morphology and
#cristae
. We hope that this is useful to study mitochondria in health and disease
Delighted to introduce SNORCL, a genetic tool for on-demand generation of localized oxygen inside living cells. We harness the power of genetics to express a xporter (NIS) and enzyme (Cld) that together yield SupplemeNtal Oxygen Released from ChLorite.
Our lab turned 15, so we commemorated the event with a socially distanced photograph at the Hatch Shell. Grateful to all current + past lab members, collaborators, mentors for making the journey so inspiring. Thanks to Glenn Wong for the photo!
Delighted to introduce PMF-seq: a new way to link genetic perturbations to detailed bioenergetic phenotypes. We use the method to dissect genetics of mitochondrial ETC branching and acute tBID action. Led by
@broadinstitute
.
The mtDNA has long been known to express a non-coding 7S RNA whose function has been mysterious. This elegant paper now shows it inhibits mtDNA transcription by directly sequestering the mitochondrial RNA polymerase.
A truly historic moment, first CRISPR therapy approved!
Key ingredients: astute clinical observation on HbF and SS (Janet Watson ca 1948), basic developmental biology, human genetics including GWAS for target ID, and of course CRISPR
Our new paper describing in vivo mRNA display is out in PNAS. A new technology developed by our brilliant Panos Oikonomou to perform whole-cell proteomics without mass-spectrometry!
@s_tavazoie
lab
@pnasNews
Albert Szent-Gyorgi said "Life is nothing but an electron looking for a place to rest.”
But what if there are too many electrons?
New work by liver doc
@russpgoodman
shows how it is possible to engineer new ways to park those electrons.
Our brand new therapeutic concept led by
@apatgir
. We directly target circulating lactate with an engineered enzyme (LOXCAT) to catalytically restore intracellular redox balance. Still preclinical, but potential for injectable therapy (think streptokinase).
@NatureBiotech
Researchers have developed a new way to alleviate problems caused by dysfunctional mitochondria, which normally produce energy in cells (via
@medical_xpress
)
Bringing the power of single cell genomics to mtDNA disease: mutant mtDNA accumulates in some lineages, but is purged in others, with important implications for prognostics, pathogenesis. Collaboration led by
@MWalkerMDPhD
@CalebLareau
@LeifLudwig
, with Aviv Regev and
@bloodgenes
Most mitochondrial diseases are caused by mutations in mitochondrial DNA. A new type of genomic analysis provides evidence of selection against mutant mitochondria DNA in human T cells.
30 yrs ago (1988): Harding, Holt, Morgan-Hughes, Wallace reported
@sciencemagazine
@Nature
pathogenic mutations in
#mtDNA
, launching the field of molecular mito medicine. Today: ~290 disease genes (mtDNA+nuclear), 0 proven therapies. Time for
#PrecisionMedicine
for
#mito
disease.
What a story: (1) the quest of a father-scientist, (2) deep basic science, (3) masterful clinical development, culminating in (4) real promise for patients.
A Cure for Type 1 Diabetes? For One Man, It Seems to Have Worked.
Our MGH Department of Molecular Biology is recruiting! This is a basic science department nestled within a great hospital with strong ties to HMS. If you want to pursue curiosity driven research within a diverse environment please apply:
Very elegant (and clarifying) paper
@Nature
reporting two mechanistically distinct forms of mitochondrial fission with distinct outcomes: in the midzone (--> biogenesis) and periphery (--> degradation), important implications for physiology and disease.
Hypoxia rescue (& hyperoxia sensitivity) of mito CI mutants is evolutionary conserved! Harnessing the power of worm genetics, Josh Meisel w/
@gary_ruvkun
discovers “hypoxia mimetic” and “hypoxia resistant” mutants, yielding key mechanisms.
CRISPR is just different — it towers so large, transcends science, so important for all of society and our future. Rarely does such a new discovery feel so long overdue. Hearty congratulations
@doudna_lab
@e__charpentier
!
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.”
If you're interested in mitochondria, mtDNA, or mitochondrial dysfunction, please come to this
@KeystoneSymp
where we'll explore the organelle from ultra-rare diseases to
#aging
.
#KSMitochondria23
A heartwarming story about George Berzsenyi, the mathematician that inspired thousands of high school students (including me)
#mentor
@joesbigidea
@NPR
We know the protein components of the
#mitochondria
calcium uniporter, but are specific lipids required? Vishal Gohil
@TAMU
finds out by reconstituting the human uniporter in yeast mutants that are defective in phospholipid biosynthesis.
#cardiolipin
Gene therapy for
#mitochondria
disease: two papers showcasing the the power of mitoTALEN and mitoZFN technology to target
#mtDNA
mutations in vivo in mice.
@NatureMedicine
Congrats
@eranmick
on his new paper deciphering the logic of the integrated stress response (ISR) to mitochondrial dysfunction. Bottom line: the type of mito dysfunction, combined with cell state, jointly determine if and how the ISR is triggered.
@eLife
In case you weren't already a mitochondriac... Keshav Singh and colleagues report reversal of wrinkled skin and hair loss by restoring mitochondrial function
We’re recruiting! We’re seeking an analytical chemist to direct our lab’s metabolomics efforts. If you’re adept with LC-MS / GC-MS, love biochemistry, and enjoy collaborating closely with students and fellows, please reach out. More info here:
Delighted to share new study by Tslil Ast now
@WeizmannScience
w/ Y. Itoh, D. Suess,
@A_Amunts
showing (1) the Fe-S proteome is destabilized w/frataxin loss, (2) mitoribosome assembly factor METTL17 harbors a 4Fe-4S cluster, serving as an Fe-S checkpoint for mito translation.
See our new pre-print linking frataxin, Fe-S clusters & mito translation!
We discovered a stabilizing 4Fe-4S within METTL17 of the mitoribosome, which ensures mito translation proceeds only when Fe-S levels are replete.
Great collab w/D Suess
@A_Amunts
Join us on Monday, October 25 from 5 - 6 pm EDT for a virtual Science for All Seasons talk!
@VamsiMootha
will present "More than just a powerhouse: Your mitochondria, oxygen, and you." Register at: .
#BroadSFAS
Did you know that uridine (or even RNA!) can be salvaged for its ribose to support growth in the complete absence of glucose? See new work by
@alexisAjourdain
describing this UPP1/2 mechanism and pathway.
The recipe for modern breakthrough medicines: strong human genetics, deep biology, precise therapeutic modality; mix well with vision, rigor, and persistence
Does chronic disease need to equal chronic care? No
👇in
@Nature
from
@VerveTx
One-time base editing Rx (in vivo liver),
durable⬇️LDL-C
In monkeys:
*⬇️90% PCSK9,⬇️60% LDL-C, now out to 10 mos
* VERVE-101: efficacy at LNP doses as low as 0.5 mg/kg
180,000 mitochondria - wow! Beautiful connectomics study reporting reconstruction of a tiny, tiny piece of mouse visual cortex. So many gems here, including a compartment-specific correlation between synaptic density and mitochondria content.
@SebastianSeung
Our newest preprint! EM and neural activity images from three million cubic microns of mouse visual cortex. Four scientific vignettes from organelles to synapses to circuit structure and function
@BCMHouston
@PrincetonNeuro
@AllenInstitute
@IARPAnews
1/20
Leveraging our discovery of markers of mitochondrial disease, our collaborative team
@MassGenBrigham
now reports plasma N-lactoyl amino acids and f-MET as markers of sepsis severity and mortality in the ICU.
@metabolomics
Today, we celebrate the 10th anniversary of our landmark
@Nature
paper showing IDH mutations drive the proliferation of blood & solid tumors, which led to the development of 3 medicines that help cancer patients with IDH mutations every day
#HeritageinHeme
We are so inspired and humbled by Team Abby Mac (=Abby and her father Greg MacCurtain) -- who ran the virtual
@BostonMarathon
this morning to raise funds and awareness for Leigh syndrome, a rare genetic disease that impacts mitochondria.
Leigh syndrome @ 70. It’s a joy to re-read this classic paper on subacute necrotizing encephalomyelopathy -reporting in exquisite detail the neuropathology of this eponymous dz. Today we consider it the most common pediatric mitochondrial dz, >80 genes, but still no proven Rx.
Impressive population-scale analysis of mtDNA heteroplasmy: the female germline allows transmission of some mtDNA variants, but prevents others => important medical and population genetic implications
#mitochondria
@GenomicsEngland
Read about the ATAD3 locus, a hotspot for deletions, duplications, and fusions, now emerging as one of the most "common" genetic causes of ultra-rare mitochondrial disease. Led by David Thorburn
@MCRI_for_kids
So exhilarated by this news - such strong leaders that will unleash the power of science on some of our greatest problems: disease, climate, energy, security
For the first time, the Presidential Science Advisor has been raised to cabinet level.
@PresElectBiden
has appointed
@eric_lander
to the post. And chemical engineer
@francesarnold
& geophysicist
@maria_zuber
will the cochair the council of advisors:
BREAKING NEWS:
The 2019
#NobelPrize
in Physiology or Medicine has been awarded jointly to William G. Kaelin Jr, Sir Peter J. Ratcliffe and Gregg L. Semenza “for their discoveries of how cells sense and adapt to oxygen availability.”
Very excited to follow this space as it matures. The ultra rare, Mendelian mitochondrial diseases may benefit from this “bespoke” approach: >300 nuclear disease genes, most of which impact 10-100 individuals.
Peter Marks/FDA discussing what a Bespoke Gene Therapy Consortium could look like. Need a "cookbook" for development & manufacture of bespoke therapeutics so we don't have to reinvent the wheel every time
#JPM21
NIH researcher Richard J. Youle receives the 2021 Breakthrough Prize in Life Sciences. Dr. Youle has led groundbreaking research into Parkinson’s disease.
This method may have really "deep" impact: it's one thing to predict protein function by first using a multiple sequence alignment; it's an entirely different ballgame if your protein is so unusual or diverged you can't even find sequence homologs. Hope it works!
Congrats
@rahulg603
who shows how the nuclear haplotype can shape mtDNA heteroplasmy in humans.
He treats mtDNA heteroplasmy as a quantitative trait, performs GWAS in >250K people, and finds dozens of QTLs.
Rich
#mitonuclear
biology, with implications for dz + evolution.
Mitochondrial DNA mutations can lead to rare disease and accrue with age. But how does nuclear genome variation influence mtDNA variation?
Here in >250k people, we find that nuclear variants can impact variation in the levels of mtDNA mutations. (1/5)
That time of year!
#NobelPrize
I'm going to guess hepatitis C for medicine (in the Year Of The Virus) and CRISPR for chemistry... but who knows? 🙂 via
@statnews
Delighted to share this new story in collaboration with
@BenGewurz
reporting that shortly after infection,
#SARSCoV2
hijacks host folate / one-carbon metabolism to support rapid viral replication. See Ben's Tweetorial to learn more!
When coronaviruses infect cells, they make hundreds of new RNA virus genomes and produce vast amounts of RNA encoding viral proteins. Ever wonder where all the RNA nucleotides come from?? See our new paper in
@naturecomms
.
#COVID19
Delighted to share a new Perspective on the dynamic nature of Leigh syndrome.
@MWalkerMDPhD
and
@mpilarmirandav
synthesize observations from case reports, brain imaging, mouse models => important implications for clinical trial design and drug discovery.
The awesome power of collaboration -- a host:virus interactome for deciphering COVID pathogenesis. Basic research with huge translational potential that should be explored thoughtfully and responsibly.
@KroganLab
@UCSF
Exciting new paper that mechanistically connects mitochondrial complex I and the uniporter - could have important disease implications. Congrats
@ChaudhuriLab
Presenting✨CLIPT✨(Complex I induced protein turnover), a novel form of
#mitochondria
protein regulation! Thru CLIPT, Complex I impairment stabilizes the mitochondrial calcium uniporter to compensate & preserve bioenergetics. Out now
@NatureComms
A🧵 1/10
Was
#MLK
also a systems biologist? "All life is interrelated. All men are caught in an inescapable network of mutuality, tied in a single garment of destiny.Whatever affects one directly, affects all indirectly.I can never be what I ought to be until you are what you ought to be"
I am very pleased to share our new 'MITOMICS' work exploring mitochondrial protein function and pathogenesis published today in
@Nature
. A great collaborative effort with
@Coon_Labs
, and the groups of Rob Taylor, Nurten Akarsu, and Mark Craven.
Please see our updated agenda, now with >20 short talks. Should be a great Keystone Symposium for anyone interested in the intersection of
#mitochondria
,
#aging
, and
#RareDisease
! Not too late to register!
If you're interested in mitochondria, mtDNA, or mitochondrial dysfunction, please come to this
@KeystoneSymp
where we'll explore the organelle from ultra-rare diseases to
#aging
.
#KSMitochondria23
Thanks
@PeterAttiaMD
for the opportunity to participate in the Drive -- really fun (and deep!) discussion spanning mitochondrial evolution, oxygen and disease.
So how did >600kb of mtDNA get jammed into the middle of Arabidopsis chromosome 2? That’s almost 2x the size of the entire mitogenome! Check out our assembly of this complex region 20+ yrs after it was first identified.
Thanks for sharing. What a beautiful paper, showcasing the awesome power of gnomAD. Our one and only tryst with uORFs and polymorphic uORFs is now some 10 years old:
@Pagliarini_Lab
So excited for the next chapter
@GladstoneInst
@UCSF
!! Thank you to all mentors and supporters over the years - Kathy Iovine,
@VamsiMootha
, Warren Zapol, Erin O'Shea,
@vikram0285
and many, many more. And most of all, to my amazing lab members. PS. We are still hiring, join us!!
🎃 31 of October is not just Halloween...
...but also the deadline 🗓 to apply for the Asst. Prof. position in
#SystemsBiology
@HMS_SysBio
👇🏼
Please submit letters of recommendation before that date to facilitate evaluation.
#SysBioJobs
#ScienceJobs
Generations of HST students (including me) will always be indebted to Patty Cunningham. She was always there, she listened, she cared, and provided a calming aplomb (especially during our breaks between classes). Thank you Patty we will miss you dearly.
From Next Gen Sequencing to Next Gen Synthesis. Hearty congratulations to my former
@MIT
UROP Dan Arlow on his new technology, new paper, and new company
@AnsaBio
. Good luck Dan!
#DNAsynthesis
, which has remained virtually unchanged for more than 40 years, can be slow and unreliable. Researchers at
@jbei
have announced a new way to faster, cheaper, and better synthesize DNA via
@BerkeleyLab
#synbio
Provocative new analysis on the evolutionary origins of
#mitochondria
-- time to update the Mito101 lecture.
Deep mitochondrial origin outside the sampled alphaproteobacteria
Calling all FA Researchers!
#FriedreichAtaxia
has been added to the
#CDMRP
areas eligible for $370M in funding within the
#PRMRP
. Application deadlines are rapidly approaching. Learn more at:
All organizations are eligible to apply.
#CureFA
!
@hoy_Shen
in the opening session
#mitomed18
discovering fundamental biochemistry by studying healthy human CLYBL knockouts. Power of reverse human genomics.
Remembering Irving London. Here's a 1972 article from
@TheCrimson
, announcing his joint appointment to the faculty of both
@HarvardMed
and
@MIT
. Evidently the first ever such dual appointment.
Research on rare diseases can have widespread benefits. As Archibald Garrod (father of biochemical genetics) wrote, rare diseases are “merely extreme examples of variations … which are probably everywhere present in minor degrees.”
#RareDiseaseDay