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Western Blot Protocol & Troubleshooting Guide

Western Blot Protocol & Troubleshooting Guide | 14 Steps + 101 Tips | Assay Genie
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The ultimate Western blot guide

Everything you need for a successful Western blot in one place — a complete 14-step protocol with every buffer recipe, plus 101 troubleshooting fixes for weak signal, high background, non-specific bands, poor transfer and more.

14-step protocol101 troubleshooting fixesAll buffer recipes
Western blot guide
14
Protocol steps
101
Troubleshooting fixes
18+
Buffer recipes
Qual & quant
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What is Western blotting?

Western blotting determines the presence or absence of selected proteins in a sample. It is advantageous over other antibody-based assays such as ELISA because cross-reactivity with non-target proteins can be distinguished from the target based on molecular weight.

Proteins are first separated by size using gel electrophoresis, then transferred to a nitrocellulose or PVDF membrane by an electrical current. The membrane is probed with antibodies specific for the protein of interest, giving qualitative or semi-quantitative information.

Western blot principle

StepProcedure
1Extract proteins from cells or tissue with a detergent lysis buffer, then centrifuge to remove debris.
2Separate proteins by size using gel electrophoresis (agarose or polyacrylamide).
3Transfer proteins to a nitrocellulose or PVDF membrane using transfer buffer and an electric current.
4Detect the target with a specific primary antibody, then a labelled secondary antibody (fluorophore or enzyme).
5For PVDF, re-activate the membrane with methanol, then wash again in TBST.

The 14-step Western blot protocol

A complete, laboratory-tested protocol from lysate to imaged membrane, with every buffer recipe you need along the way.

1Protein extraction

The protein of interest must be solubilised to migrate through the gel. Choice of lysis buffer depends on the protein yield required and the subcellular localisation of the target. SDS and other ionic detergents give the highest yield but are the most denaturing; milder non-ionic detergents (NP-40, Triton X-100) are used when the antibody only recognises native protein. Where protein-protein interactions must be preserved, use a buffer without ionic or non-ionic detergents (e.g. mechanical shearing).

Protein localisationRecommended buffer
Cytoplasmic (cytoskeletal-bound)Tris-Triton
Cytoplasmic (soluble)Tris-HCl
Membrane-boundNP-40 / RIPA
MitochondriaRIPA
NuclearRIPA
Whole cellNP-40 / RIPA

1.1 Extraction buffer recipes

RIPA buffer

  • 50 mM Tris-HCl pH 7.4
  • 50 mM NaCl
  • 2 mM EDTA
  • 1% SDS
  • + fresh protease inhibitors (aprotinin, leupeptin, DTT, PMSF)

NP-40 buffer

  • 150 mM NaCl
  • 1.0% NP-40 (or Triton X-100)
  • 50 mM Tris pH 8.0

Tris-HCl buffer

  • 20 mM Tris-HCl pH 7

Tris-Triton buffer

  • 10 mM Tris pH 7.4
  • 100 mM NaCl
  • 1 mM EDTA
  • 1 mM EGTA
  • 1% Triton X-100
  • 10% glycerol
  • 1% SDS
  • 5% deoxycholate

Laemmli buffer

  • 4% SDS
  • 10% 2-mercaptoethanol
  • 20% glycerol
  • 0.004% bromophenol blue
  • 0.125 M Tris-HCl, pH 6.8

All buffers can be stored at 4°C for several weeks and at −20°C for up to a year.

1.2 Protease & phosphatase inhibitors

Once cell lysis begins, protein degradation begins too. Keep samples on ice at all times and add fresh inhibitors to the lysis buffer each time.

InhibitorTarget
AprotininChymotrypsin, plasmin, trypsin
EDTAMetalloproteases (Mg²⁺/Mn²⁺)
EGTAMetalloproteases (Ca²⁺)
LeupeptinLysosomal proteases
NaFSer/Thr phosphatases
Na orthovanadateTyrosine phosphatases
Pepstatin AAspartic proteases
PMSFSerine, cysteine proteases

1.3 Cell-lysate preparation with RIPA

StepProcedure
1Wash cells with ice-cold PBS.
2Aspirate the PBS.
3Add ice-cold RIPA buffer (~1 mL per 10⁷ cells).
4Scrape adherent cells off the plate with a sterile tip.
5Centrifuge (force/time depend on cell type).
6Remove from the centrifuge and store on ice.
7Aspirate supernatant into a fresh tube on ice; discard the pellet.
8Determine protein concentration by Bradford, Lowry or BCA (BSA standard).
9Freeze at −20/−80°C or prepare for loading.

1.4 Preparing samples for loading

If the antibody recognises native protein, do not denature the sample and leave SDS and reducing agents (β-mercaptoethanol, DTT) out of the loading and migration buffers. For antibodies requiring denatured protein, heat the sample in a denaturing loading buffer (e.g. SDS) at 95–100°C for 5 minutes. The standard loading buffer is 2× Laemmli buffer, which contains a reducing agent, SDS for negative charge, glycerol for density and bromophenol blue as a migration front.

2Electrophoresis

With the sample lysed, quantified and loading buffer added, proteins are separated by SDS-PAGE. A gel has a resolving portion (poured first) and a stacking portion (poured on top, holding the combs). Higher acrylamide percentages give smaller pores for small proteins; lower percentages suit larger proteins.

Acrylamide %Linear separation range (kDa)
5.057–211
7.536–94
1016–68
1512–43

2.1 Gel recipes

10% resolving gel

  • H₂O 5.9 mL
  • 30% acrylamide-bis 5 mL
  • 1.5 M Tris pH 8.8 3.8 mL
  • 10% SDS 150 µl
  • 10% APS 150 µl
  • TEMED 6 µl

Stacking gel

  • H₂O 2.7 mL
  • acrylamide-bis 670 µl
  • Tris pH 6.8 500 µl
  • 10% SDS 40 µl
  • 10% APS 40 µl
  • TEMED 3 µl

3Controls & molecular-weight markers

Use positive and negative controls to confirm the assay is accurate, sensitive and efficient, and a loading control to confirm even loading. A range of molecular-weight markers lets you determine protein size and monitor the run.

Sample typeProteinMW (kDa)
Whole cell / cytoplasmicβ-actin43
α-actin43
GAPDH30–40
β-tubulin55
α-tubulin55
High MWvinculin116
MitochondriaVDAC1/porin31
cytochrome C oxidase16
Nuclearlamin B166
TATA-binding protein (TBP)38
PCNA29
Serumtransferrin77
MuscleSDHA73

4Loading samples & running the gel

Separate proteins by SDS-PAGE at an acrylamide percentage suited to your target. A worked example using a 10% gel:

StepProcedure
1Pour the resolving gel between the plates; let it set for 1 h.
2Level with ~300 µl isopropanol poured gently across the top.
3Remove isopropanol with a gentle flow of water.
4Add the stacking gel and insert the comb, avoiding bubbles; set for 1 h.
5Place the plate in the rig and add ~400 mL of 1× SDS-PAGE running buffer, checking for leaks.
6Remove the combs and rinse the wells with running buffer.
7Load 8 µl of unstained MW ladder and 20 µl of each protein sample.
8Run at 25 mA per gel for ~1 h 15 min.

5Western blot transfer

Western blot transfer

After electrophoresis, transfer the protein from gel to membrane (nitrocellulose or PVDF), most commonly by electrophoretic transfer. The gel is placed in direct contact with the membrane between two electrodes in a conducting solution; applying a field migrates proteins onto the membrane, creating a copy of the gel pattern.

Tip: always probe for your weakest antibody first, as handling and stripping can unstick your proteins of interest.

5.1 Transfer buffer

Transfer buffer

  • 8 g Trizma base
  • 9 g glycine
  • 3.7 g SDS
  • 200 mL methanol
  • dH₂O to 1 L

6Blocking

Block the membrane before adding antibody to prevent non-specific binding and improve the signal-to-noise ratio. Milk and BSA are most common; use BSA with phosphorylation-sensitive antibodies. If the primary was raised in horse, cow, goat or donkey, avoid BSA/milk due to cross-reaction or IgG contamination.

Blocking buffer

  • 5% marvel (milk) in TBS-Tween
  • (1× TBS with 0.1% v/v Tween-20)

7Wash buffers

Wash steps remove unbound reagents and reduce background. Too little washing raises background; too much can elute the antigen. Tween-20 is typically 0.05–0.5%. Make fresh detergent stocks (microbial growth raises background) and use high-purity detergent (peroxides interfere).

Wash buffer (TBS-T)

  • 20 mM Tris pH 7.5
  • 150 mM NaCl
  • 0.1% Tween-20

8Primary antibody incubation

Probe the blocked membrane with a primary antibody specific for your target. Consider species specificity, sensitivity to denaturing conditions and post-translational modifications, and whether the antibody is validated for Western blot. After incubation, wash 5× for 5 minutes with wash buffer.

9Secondary antibody incubation

Because the primary is not directly detectable, a labelled secondary that binds the primary is used. Match the secondary to the host species of the primary (or its tag, e.g. biotin, histidine). Secondaries are conjugated to HRP or AP for film/chemiluminescence, or to a fluorophore for laser detection.

10Antibody dilution

Manufacturers recommend a starting dilution, but the optimum varies with the assay. Strongly expressed targets and highly sensitive assays need less antibody; weakly expressed targets need more. Less antibody decreases background and increases specificity. Dilutions are normally made in wash buffer.

11Blot development

The secondary label determines the development system: chemiluminescence for HRP/AP, or direct fluorescent scanning for fluorophores.

11.1 Chemiluminescence

HRP conjugates are most widely used and generally superior to AP (smaller enzyme, high activity, stable, widely available substrates). The signal is transient; a well-optimised assay produces light for 1–24 h for film or digital imaging. Digital imaging gives a broad dynamic range and quantitative data; chemiluminescent signal is generally semi-quantitative.

11.2 Fluorescent detection

Fluorophore conjugates need fewer steps (no substrate) and a shorter protocol, but require an excitation source. Infrared/near-infrared and quantum dots have improved sensitivity. Fluorescence enables multiplexing and quantitative, consistent results, though auto-fluorescence can reduce signal-to-noise.

11.3 Chemiluminescent vs fluorescent

ChemiluminescentFluorescent
PrincipleEnzyme label (HRP/AP)Fluorophore label
DetectionX-ray film / digital imagingLaser scanning imager
MultiplexNoYes
Signal durationHoursWeeks to months
Linear dynamic range15-fold (film); 3–4,000-fold (digital)>4,000-fold
QuantitationSemi-quantitativeQuantitative
SubstrateLuminolNone needed

12Stripping & re-probing

Stripping removes primary and secondary antibodies so you can probe for another target (e.g. a loading control), saving time and sample. It works best on PVDF. Chemiluminescent reagents like ECL are recommended as they don’t stain the membrane. After stripping, wash thoroughly and re-block before the next primary.

12.1 Mild vs harsh

A mild buffer uses low-pH glycine to dissociate antibodies. A harsh buffer (for high-signal blots) uses low pH plus reducing agents (β-mercaptoethanol, SDS) heated at 50–80°C for up to 45 min; its effect is irreversible, so wash thoroughly before re-probing.

Mild stripping buffer

  • 15 g glycine
  • 1 g SDS
  • 10 mL Tween-20
  • dissolve in 800 mL dH₂O
  • adjust to pH 2.2
  • bring to 1 L

Harsh stripping buffer

  • 62.5 mM Tris-HCl pH 7.8
  • 100 mM β-mercaptoethanol
  • 2% (w/v) SDS

12.2 Stripping protocol

StepProcedure
1Incubate PVDF with harsh stripping buffer 30 min at 50°C.
2Wash 2×5 min, 1×10 min, 2×5 min at RT with agitation.
3Block 1 h at RT with gentle agitation.
4Wash 2×5 min, then incubate with the appropriate primary and secondary.

13Protein gel visualisation

Gel separation can be visualised by Coomassie or copper staining, depending on downstream use.

13.1 Coomassie staining

Confirms uniform, even migration. Use only if you do not intend to transfer, as Coomassie staining is not reversible.

StepProcedure
1Treat the gel with 40% dH₂O, 10% acetic acid, 50% methanol to precipitate proteins.
2Add 0.25% (w/w) Coomassie blue to the same solution.
3Incubate 4–24 h at RT on a shaker.
4Rinse in 67.5% dH₂O, 7.5% acetic acid, 25% methanol.
5Replace with fresh rinse once excess dye is removed.
6Excess stain washes out, leaving a clear gel.
7Stain binds proteins, giving blue bands.

13.2 Copper staining

Use if you wish to transfer afterwards — faster and more sensitive than Coomassie.

StepProcedure
1Briefly rinse the gel in ddH₂O after electrophoresis.
2Transfer to 3 M CuCl₂ for 5–15 min.
3Wash in ddH₂O.
4View against a dark-field background.
5Protein appears as clear zones on a translucent blue background.
6De-stain in 0.1–0.25 M Tris / 0.25 M EDTA pH 8.0.
7Place in transfer buffer and proceed.

14Protein membrane visualisation

Assess transfer efficiency by staining the PVDF/nitrocellulose membrane with Ponceau Red. It is easily reversed by washing, so it does not interfere with subsequent antibody probing.

StepProcedure
1Dilute Ponceau stock 1:100.
2Incubate on an agitator for 5 min.
3Wash with ddH₂O until the water is clear and bands are visible.
4De-stain by washing with TBST.
5For PVDF, re-activate with methanol then wash again in TBST.

101 Western blot troubleshooting tips

No bands, faint signal, non-specific or wrong-size bands, poor transfer, high background — find the likely cause and fix fast. Filter by symptom or search your problem.

All (101)No bandsFaint bandsNon-specificLow MWHigh MWPoor transferHigh backgroundSpeckledWhite spotsBands lowNot fully runDistortedUnevenDiffuse/streakBlurryWhite bands (ECL)
SymptomLikely causeFix
No bandsIncorrect primary antibodyAntibody has low to no affinity for the target.
No bandsInactive antibodyPerform a dot blot to confirm antibody activity.
No bandsInsufficient protein concentrationIncrease the amount of protein loaded and use a positive control.
No bandsPoor transferEnsure the membrane is activated. Transfer buffer must contain methanol for nitrocellulose; PVDF must be pre-soaked in methanol.
No bandsIncomplete transferStain the membrane with India Ink, Amido Black or Ponceau S to check transfer.
No bandsOver-transferReduce transfer time or voltage.
No bandsIncorrect secondary antibodyConfirm the host species and IgG type of the primary.
No bandsAntibodies expiredCheck that all antibodies are in date.
No bandsIncorrect antibody storageStore all antibodies per manufacturer instructions.
No bandsSuboptimal primary incubation timeIncrease incubation time with the primary antibody.
No bandsIncompatible primary and secondaryMaintain a consistent species across both antibodies.
No bandsInsufficient secondary concentrationIncrease the concentration of primary/secondary antibody.
No bandsExcessive washingReduce the number and duration of washes.
No bandsIncorrect orientationMark your membrane to ensure correct orientation.
No bandsContaminated wash or incubation bufferUse fresh, sterile buffer.
No bandsInsufficient exposure timeRe-image the blot with a longer exposure time.
No bandsIncorrect filter settingsEnsure the detection instrument reads the correct wavelengths.
No bandsReduced antibody efficacy from overuseUse fresh primary and secondary antibodies each experiment.
No bandsAbsence of protein of interestRun a positive control.
No bandsSodium azide contaminationSodium azide quenches HRP signal — remove it.
No bandsIsoelectric point >9Use a higher-pH buffer system, e.g. CAPS (pH 10.5).
Faint bandsInsufficient antibody concentrationIncrease antibody concentration 2–4 fold over starting.
Faint bandsInsufficient protein concentrationIncrease total protein loaded on the gel.
Faint bandsSuboptimal antibody bindingReduce washes; reduce NaCl in blotting/antibody solution (0.15–0.5 M).
Faint bandsInactive conjugatePurchase new reagents or switch to ECL.
Faint bandsOld or weak ECLUse new ECL reagents.
Non-specificNon-specific antibodyEnsure the antibody is specific for the protein of interest.
Non-specificProteolytic breakdownUse protease inhibitors to prevent breakdown of the antigen.
Non-specificGel overloadingToo much protein causes ghost bands — optimise protein amount.
Non-specificInsufficient blockingExtend the blocking time.
Non-specificLow antigen concentrationConsider immunoprecipitating the target protein.
Non-specificNon-specific secondary bindingRun a secondary-only control; if bands appear, switch secondary.
Non-specificAnalyte aggregationIncrease DTT concentration.
Non-specificAnalyte degradationMake fresh samples; reduce freeze/thaw; add protease inhibitors before storage.
Non-specificProtein degradationTarget protein has degraded — prepare fresh sample.
Non-specificSplice variantsMay lead to multiple bands.
Non-specificHigh primary concentrationUse a lower concentration of primary antibody.
Non-specificProtein forms multimersBoil sample longer in Laemmli buffer to fully reduce disulfide bonds.
Non-specificCells passaged too many timesUse the original, non-passaged cell line.
Non-specificAntibodies not purifiedUse affinity-purified antibodies.
Non-specificBands are non-specificUse blocking peptides to distinguish specific vs non-specific bands.
Non-specificPost-translational modificationMultiple modified forms (acetylation, methylation, phosphorylation) — check literature.
Non-specificIonic interactionsIncrease salt in incubation buffers; add stronger detergent to washes.
Low MWSamples digested/degradedUse fresh sample and lysis buffer with proteinase inhibitors.
Low MWPrimary detecting splice variantsIdentify splice variants; try a different primary.
Low MWPrimary binding a similar epitopeRun a negative control to detect cross-reacting proteins.
High MWProtein aggregationDecrease protein concentration; prepare new sample with fresh loading buffer.
High MWIncomplete denaturationDenature protein with urea.
High MWProteins are glycosylatedUse enzymatic treatment to strip post-translational modifications.
Poor transferMembrane choiceChoose PVDF/nitrocellulose to match the target molecular weight.
Poor transferDry membraneDo not let the membrane or filter paper dry out.
Poor transferIncomplete protein resolutionUse an optimal gel percentage for the protein of interest.
Poor transferIncorrect sample preparationSample must contain DTT or β-mercaptoethanol and be heated before loading.
Poor transferIncorrect membrane assemblyOrient PVDF/NC membranes on the anode (+) side of the gel.
Poor transferIncorrect transfer timeIncrease transfer time to improve transfer of large proteins.
Poor transferInsufficient power supplyMembranes can be placed either side of the gel if the supply is mis-connected.
High backgroundNon-specific antibody bindingUse the most specific primary antibody available.
High backgroundInsufficient blockingOptimise blocking-time duration.
High backgroundIncomplete blockingOptimise blocking buffer; increase protein in the blocking agent.
High backgroundIncompatible blocking agentCompare different blocking buffers.
High backgroundIncorrect membrane choiceNitrocellulose generally gives less background than PVDF.
High backgroundFilm overexposedReduce the exposure time.
High backgroundSecondary binding blocking reagentAdd Tween 20 to washing and incubation buffers.
High backgroundIncubation temperature too highIncubate at 4°C; keep samples on ice.
High backgroundExcessive incubationReduce incubation time.
High backgroundToo much substrateDilute substrate; reduce substrate incubation time.
High backgroundProtein overloadedDilute the sample or reduce load.
High backgroundMilk contains target antigenSubstitute with 3% BSA.
High backgroundSuboptimal antibody concentrationOptimise antibody concentration.
High backgroundInsufficient washingIncrease number of washes; increase Tween 20 in wash buffer.
High backgroundBlot dried outCover the membrane in buffer during incubation.
High backgroundAntibody cross-reactivityReduce secondary concentration; use a different blocking agent.
High backgroundContamination of membranes, solutions or traysWear clean gloves; handle membranes with forceps; use clean glassware and distilled water; run a cleaning protocol.
SpeckledBlocking reagent clumpedFilter the blocking agent to remove clumps.
SpeckledContamination of gel or reagentsUse fresh, sterile buffer.
SpeckledExposure time too longReduce the exposure time.
SpeckledInsufficient solution during wash/incubationFully immerse the membrane during incubations and washes.
SpeckledContamination of equipmentWash electrophoresis equipment and membrane thoroughly.
SpeckledUneven agitationUse a rocker/shaker for uniform agitation.
SpeckledSecondary antibody aggregationIncrease secondary dilution; spin down aggregates.
SpeckledMembrane dried unevenlyThoroughly wet the membrane and keep it from drying out.
White spotsAir bubbles against the membraneRemove air bubbles between membrane and gel during transfer.
Bands lowGel ran too longRun the gel for a shorter period.
Bands lowToo little acrylamideRun low-MW proteins in higher-percentage gels.
Not fully runGel not run long enoughRun the gel for a longer period.
Not fully runToo much acrylamideRun high-MW proteins in lower-percentage gels.
DistortedVoltage too high during migrationCheck the protocol for the recommended voltage.
DistortedGel too hot during migrationRun the gel at 4°C, on ice or in a cold room.
UnevenGel polymerised unevenlyCheck gel recipe/TEMED; ensure the gel is fully covered in buffer when setting.
UnevenSalt varies between wellsEnsure similar salt concentration across samples.
Diffuse/streakExcessive protein on gelReduce the amount of protein loaded.
Diffuse/streakMembrane slipped during transferAvoid moving the gel or membrane during transfer.
Diffuse/streakIncomplete membrane-gel contactUse thicker filter paper; squeeze out excess buffer and air bubbles.
BlurryElectrophoresis voltage too highRun the gel longer at a lower voltage.
BlurryAir bubbles between membrane and gelRemove bubbles by rolling with a sterile glass rod.
BlurryIncorrect loading bufferPrepare fresh loading buffer.
White bands (ECL)Antibody concentration too highDilute the antibody to the optimal concentration.
White bands (ECL)Excessive signal generatedReduce the concentration of protein or antibody.
White bands (ECL)Overexposure during visualisationDecrease exposure time.
White bands (ECL)Blot moved during transferAvoid moving membrane or gel during transfer.
White bands (ECL)Loading sample too concentratedReduce the amount of sample loaded.

Download the 101 troubleshooting PDF

All Western blot buffers & recipes

Every essential buffer in one place — lysis, gel, running, transfer, blocking, wash and stripping.

RIPA buffer

  • 50 mM Tris-HCl pH 7.4
  • 50 mM NaCl
  • 2 mM EDTA
  • 1% SDS
  • + fresh protease inhibitors

NP-40 buffer

  • 150 mM NaCl
  • 1.0% NP-40 (or Triton X-100)
  • 50 mM Tris pH 8.0

Tris-HCl buffer

  • 20 mM Tris-HCl pH 7

Tris-Triton buffer

  • 10 mM Tris pH 7.4
  • 100 mM NaCl
  • 1 mM EDTA
  • 1 mM EGTA
  • 1% Triton X-100
  • 10% glycerol
  • 1% SDS
  • 5% deoxycholate

Laemmli buffer

  • 4% SDS
  • 10% 2-mercaptoethanol
  • 20% glycerol
  • 0.004% bromophenol blue
  • 0.125 M Tris-HCl pH 6.8

Loading buffer (2×)

  • 100 mM Tris-HCl pH 6.8
  • 200 mM DTT
  • 4% SDS
  • 0.2% bromophenol blue
  • 20% glycerol
  • (add DTT fresh from 1 M stock)

10% resolving gel

  • H₂O 5.9 mL
  • 30% acrylamide-bis 5 mL
  • 1.5 M Tris pH 8.8 3.8 mL
  • 10% SDS 150 µl
  • 10% APS 150 µl
  • TEMED 6 µl

Stacking gel

  • H₂O 2.7 mL
  • acrylamide-bis 670 µl
  • Tris pH 6.8 500 µl
  • 10% SDS 40 µl
  • 10% APS 40 µl
  • TEMED 3 µl

Running buffer

  • 15.1 g Trizma
  • 94 g glycine
  • 50 mL 10% w/v SDS
  • dH₂O to 1 L

Transfer buffer

  • 8 g Trizma base
  • 9 g glycine
  • 3.7 g SDS
  • 200 mL methanol
  • dH₂O to 1 L

Blocking buffer

  • 5% marvel in TBST

Wash buffer (TBS-T)

  • 20 mM Tris pH 7.5
  • 150 mM NaCl
  • 0.1% Tween-20

Mild stripping buffer

  • 15 g glycine
  • 1 g SDS
  • 10 mL Tween-20
  • 800 mL dH₂O, pH 2.2
  • bring to 1 L

Harsh stripping buffer

  • 62.5 mM Tris-HCl pH 7.8
  • 100 mM β-mercaptoethanol
  • 2% (w/v) SDS
Written by Seán Mac Fhearraigh, PhD. Seán is a co-founder of Assay Genie. He completed his undergraduate degree in Genetics at Trinity College Dublin, a PhD at University College Dublin and a post-doc in the Department of Genetics, University of Cambridge. He is now Chief Technical Officer at Assay Genie.

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