📚 Lecture 1 · Introduction to Biologics Dr. Clarence Wong · 2 Sep 2026
Biologics are made by living cells — so the process is the product. This lecture sets up the small-molecule difference, the history, and the peptide problems & fixes.
101 · L1 Introduction to Biologics
Master Logic · 主線邏輯
Biologics are made by living cells, so the process is the product. This lecture sets up three things: how biologics differ from small molecules, the history from empirical medicine to recombinant DNA, and the two problems / three fixes of peptide drugs. The whole course keeps solving the same triangle: specificity, stability, delivery.
Small molecules vs. Biologics (the whole course hangs on this table)
Small molecules are chemically made, oral, intracellular; biologics are cell-made, injected, extracellular — and the process is the product.
| Small molecule | Biologic | |
|---|---|---|
| Size | ~180–600 Da (aspirin 180 Da) | Large (insulin ~58 kDa, antibody ~150 kDa) |
| Production | Chemical synthesis / purification | Living cells (bacteria, yeast, mammalian) — fermentation / cell culture |
| Target location | Intracellular (enzymes, receptors, DNA) | Extracellular (cell-surface receptors, circulating proteins) |
| Administration | Usually oral | Injection / infusion (degraded if oral) |
| Stability | Stable, heat-tolerant | Heat- & light-sensitive, microbial contamination risk |
| Characterization | Precise, fully defined | Complex, batch-variable → "the process is the product" |
Four major types of biologic composition
Four composition types: peptide/protein, polysaccharide, nucleic acid, cell-based.
- Peptide / Protein — chains of amino acids; e.g. insulin, mAbs
- Polysaccharide — sugar chains; immune modulation (e.g. vaccines)
- Nucleic acid — DNA/RNA to alter gene expression (mRNA vaccines, gene therapy)
- Cell-based — living/dead cells (CAR-T, stem cells)
Timeline of biologics (memorize the milestones)
Learn the milestones as a chain; the classic trap is 1977 (first recombinant protein) vs 1982 (first approved drug).
Advantages of biologics
Biologics win on four things — precision, unmet needs, cutting-edge tech, rigorous manufacturing — all downstream of being big and specific.
- High specificity — lock-and-key binding → fewer off-target side effects
- Address unmet needs — complex/rare diseases small molecules can't reach
- Precision medicine — tailor to patient's biology
Peptide drugs (500–5000 Da — "between small molecule and protein")
Peptides sit between small molecule and protein: target-specific yet tissue-penetrating, but cleared fast.
- Composed of 20 amino acids; 9 essential AA (histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine)
- Peptide bond = amide bond (condensation)
- Two core problems: rapid protease degradation + poor oral bioavailability (stomach acid)
| Fix | How it works | Example |
|---|---|---|
| Cyclisation | Rigid ring → resists enzymes, ↑ affinity, ↓ immunogenicity | Ziconotide (sea-snail venom), Kalata B1, Daptomycin |
| D-/unnatural amino acids | Not recognized by proteases | Gramicidin (D-amino acid) |
| Lipidation | Fatty chain → ↑ stability, ↑ cell penetration, self-assembly | Daptomycin (last-resort lipopeptide antibiotic) |
Peptide synthesis pioneers: Emil Fischer (peptide bond) → Vincent du Vigneaud (oxytocin, first peptide hormone synthesized) → Bruce Merrifield (solid-phase synthesis) → James Tam (chemical ligation for full proteins).
Therapeutics before science — ancient drug discovery
Before science there was only trial-and-error: herbs, mouldy bread on wounds, beer fermentation.
- Early humans had limited knowledge and no systematic method — remedies came from plants and herbs.
- Shennong (神农) taught agriculture and medicinal plants; legend has him tasting every plant to test it.
- Empirical knowledge and trial-and-error — remedies developed through observation and experience.
- Ancient civilisations put mouldy bread and moist soil on open wounds to prevent infection — antibiotic effect, millennia before penicillin was understood.
- 350 AD: Nubian extract from beer; beer fermentation involves a specific type of bacteria.
Germ theory — the paradigm break
Pasteur ended miasma and humour theory — germ theory, pasteurisation, vaccination were born.
| Before germ theory | After |
|---|---|
| "Bad air" / miasma from decomposing organic matter | Louis Pasteur (1822–1895), Father of Immunology, together with other scientists developed germ theory, pasteurisation, and vaccination — the birth of immunology |
| Imbalance of the body's humors (blood, phlegm, yellow bile, black bile) | |
| Supernatural forces — curses, demons, an angry deity | |
| No concept of sterilisation |
The cholera vaccine (1879) — how attenuation was discovered (by accident)
Attenuation was an accident: a weakened culture immunised the chickens instead of killing them.
- Pasteur's assistant left chicken cholera cultures out over the summer, causing them to weaken.
- Pasteur inoculated chickens with the aged, weakened cultures, expecting them to become ill.
- The chickens did not get sick — surprising him.
- When exposed to fresh, virulent bacteria, the previously inoculated chickens remained healthy.
- Conclusion: the weakened bacteria had immunised them → discovery of vaccination by attenuation.
Cholera context: acute diarrheal illness from intestinal infection with toxigenic bacterium — an estimated 2.9 million cases and 95,000 deaths occur yearly worldwide.
Insulin discovery (1921–1923) — the first biologic therapy
Insulin: Banting′s hypothesis → dog experiments → Collip′s purification → 1922 first patient → 1923 Nobel.
Disease background. Type 1 diabetes is a chronic autoimmune condition where the immune system attacks and destroys the insulin-producing beta cells in the pancreas → severe deficiency or complete absence of insulin. Insulin is the hormone that lets cells absorb glucose from blood after a meal, for energy or storage.
| Step | Who / when | What happened |
|---|---|---|
| 1 | Early 20th c. | Pancreas known to regulate blood sugar, but the mechanism unclear |
| 2 | Banting's idea, 1920 | Canadian surgeon hypothesised a pancreatic extract could treat diabetes via the pancreas's "internal secretion" |
| 3 | John Macleod | University of Toronto — provided lab space, equipment, and medical student Charles Best |
| 4 | Dog experiments, 1921 | Removed pancreases to induce diabetes, then injected pancreatic extracts to lower blood sugar |
| 5 | After several months | Successfully isolated an extract later named insulin that significantly lowered blood sugar in diabetic dogs |
| 6 | James Collip | Biochemist joined to purify the extract, making it safe for human use |
| 7 | 11 Jan 1922 | First human patient, 14-year-old Leonard Thompson. After an initial reaction, a more purified form was given and successfully lowered his blood sugar |
| 8 | Nobel 1923 | Banting and Macleod awarded the Nobel Prize in Physiology or Medicine; Banting shared his prize money with Best |
Recombinant DNA technology — the enabling platform
Recombinant DNA: concept → 1972 Berg → 1973 Cohen & Boyer → 1977 first recombinant protein → 1982 Humulin.
| Year | Who | Breakthrough |
|---|---|---|
| Early 1970s | — | Concept of combining DNA from different sources → recombinant DNA |
| 1972 | Paul Berg | Combined DNA from two different viruses, proving DNA from different sources could be recombined → foundation of the technology |
| 1973 | Stanley Cohen & Herbert Boyer | Inserted recombinant DNA into bacteria, creating the first genetically modified organisms (GMOs); showed bacteria could express foreign genes |
| 1977 | Genentech | First human recombinant protein — somatostatin — produced in genetically engineered E. coli |
| 1978 | Genentech | Cloned the human insulin gene into E. coli → bacteria producing human insulin |
| 1980 | Paul Berg | Nobel Prize in Chemistry for recombinant DNA |
| 1982 | FDA | Humulin approved — first recombinant therapeutic product for human use, revolutionising diabetes treatment |
Six things recombinant DNA made possible
Six applications: therapeutic proteins, vaccines, industrial enzymes, research, drug discovery, genetic engineering.
| # | Application | Example |
|---|---|---|
| 1 | Therapeutic proteins | Insulin for diabetes, mAbs for cancer, clotting factors for haemophilia |
| 2 | Vaccines | Hepatitis B, COVID-19 |
| 3 | Industrial enzymes | Detergents, food processing, biofuels |
| 4 | Molecular biology research | Studying protein function and interactions |
| 5 | Drug discovery | Targets and therapeutic candidates in trials |
| 6 | Genetic engineering | Engineered organisms and synthetic pathways |
CRISPR-Cas9 gene editing
CRISPR became programmable in 2012 (Charpentier & Doudna); first therapy 2019 (CTX001); Nobel 2020.
- 1987–2000s — discovery: CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) sequences first identified in bacterial genomes, where they played a role in bacterial immunity against viruses. Significance not understood at the time.
- 2012 — the pivotal moment: Emmanuelle Charpentier and Jennifer Doudna showed the CRISPR-Cas9 system could be programmed to target specific DNA sequences — a precise, easily programmable gene-editing tool for any organism.
- 2013–2015 — proof of concept: Multiple teams, including Feng Zhang (Broad Institute) and George Church (Harvard), used CRISPR to edit genes in mammalian cells, proving therapeutic potential.
- 2019 — landmark: A patient with beta-thalassemia treated with CRISPR-based gene therapy CTX001 showed remarkable improvement with a significant reduction in blood transfusions. (The lecture adds a pointed margin note: "Ethical concern?")
- 2020 — Nobel Prize in Chemistry to Charpentier and Doudna for the "genetic scissors".
Beyond genetic disease: cancer, viral infections (HIV), age-related conditions; editing immune cells to fight tumours; disabling viral genes inside infected cells. Gene drives to control malaria-spreading mosquito populations; agriculture for drought resistance and improved nutrition (e.g. GM tomato with blueberry antioxidant and anti-inflammatory compounds) — all with ecological and ethical considerations.
Amino acids — the building block (structure basics)
Amino acid = α-carbon + amino + carboxyl + H + side chain; the side chain defines each of the 20; 9 are essential.
- Each amino acid has a central alpha carbon forming four covalent bonds with four groups:
- Carboxylic group (–COOH)
- Amino group (–NH₂)
- Hydrogen
- Side chain functional group
- The side chain is what makes each of the 20 amino acids unique — and therefore what determines the properties of the resulting peptide.
- Nonessential amino acids = produced or synthesised by our own bodies, not required from the diet.
- Polypeptide = the long chain of amino acids; a functional protein consists of one or several such chains. The amino-acid sequence is determined by the DNA sequence.
Cyclisation — the full benefit list (5, not 3)
Cyclisation gives 5 benefits: stability, affinity, bioavailability, lower immunogenicity, better PK.
| Benefit | Mechanism |
|---|---|
| Increased stability | Protects from enzymatic degradation → longer half-life |
| Enhanced binding affinity | More rigid, defined structure → better affinity and specificity for target |
| Improved bioavailability | Better ability to cross cell membranes |
| Reduced immunogenicity | Cyclised structure less likely to trigger an immune response |
| Optimised pharmacokinetics | More favourable PK profile → less frequent dosing |
Two cyclisation chemistries: (1) disulfide bond (side chain-to-side chain) — see oxytocin; (2) head-to-tail amide bond formation. Note the lecture's striking aside: humans do not produce cyclic peptides in the body — nature's cyclic peptides come from plants and bacteria.
Kalata B1 and cyclotides — where cyclic peptides actually came from
Cyclotides are nature′s ultra-stable cyclic scaffolds — the template for orally active peptide drugs.
This is the origin of the cyclotide field — and the reason Dr. Wong's lab went looking for oral peptide drugs in plants.
Extraction workflow (his lab): plant material from 白花蛇舌草 Hedyotis diffusa and 双花耳草 Hedyotis biflora — 30 kg of fresh plant, extracted with boiling water. Because peptides are more water-soluble than other plant components, they remained in the aqueous layer, identified by MALDI-TOF MS.
The logic: nature evolved ultra-stable cyclic peptides in plants → characterise their scaffold → chemically re-engineer that scaffold with a new sequence to get a new peptide that survives the gut. This is the intellectual bridge from L1's peptide problems to L2's pBsAb work.
D-amino acids & unnatural amino acids (5 benefits)
D-amino acids are invisible to proteases → 5 benefits, all about surviving degradation.
| Benefit | Mechanism |
|---|---|
| Increased resistance to degradation | Proteolytic enzymes do not recognise them → longer half-life |
| Enhanced stability | Improved structural stability, less denaturation |
| Improved bioavailability | Better absorption, remains active in the bloodstream |
| Altered binding specificity | Fine-tune binding properties → potentially higher target specificity |
| Reduced immunogenicity | Less likely to be recognised by the immune system |
Enantiomers are the key concept — and Gramicidin, a bacterial peptide produced to transport potassium ions across membranes, is the classic D-amino acid example.
Lipidation — the full benefit list (6, not 3)
Lipidation gives 6 benefits, including cell penetration and self-assembly — the one that also fixes membrane crossing.
| Benefit | Mechanism |
|---|---|
| Increased stability | Protects from enzymatic degradation → longer half-life |
| Enhanced bioavailability | Improves absorption and distribution |
| Better cell penetration | Facilitates entry into cells |
| Targeted delivery | Directs peptides to specific tissues or organs |
| Prolonged circulation | Increased binding to serum proteins (e.g. albumin) → longer circulation time |
| Self-assembly | Enables formation of nanostructures for controlled drug release |
Daptomycin — the mechanism (not just the name)
Daptomycin: calcium-dependent membrane binding → pore → depolarisation → death without lysis (less inflammation).
Mechanism: binds bacterial cell membranes in a calcium-dependent manner → forms membrane pores → causes rapid depolarisation of the bacterial membrane → loss of membrane potential → cell death without lysis. That last detail matters: because the cell doesn't burst, less inflammatory debris is released.
Why the biologics market keeps growing
The market grows on three drivers: rising disease burden, better tolerability, a strong pipeline.
- Rising disease burden — increasing rates of cancer, diabetes, and autoimmune diseases drive demand.
- Better tolerability — targeted treatments with fewer side effects, preferable for complex diseases.
- Robust pipeline — a strong pipeline of biologic drugs in clinical trials promises new treatments across conditions.
Oxytocin — the first peptide hormone, and what it actually does
Oxytocin — the first peptide hormone; induces labour and stops postpartum bleeding.
The card lists oxytocin only as "the first peptide hormone synthesized" (Vincent du Vigneaud) but omits its biological and social roles from the lecture:
- Facilitates childbirth — as a drug it drives contraction of the uterus to start labour.
- Stops bleeding following delivery (post-partum haemostasis).
- Associated with empathy, trust, and relationship-building — the lecture frames it as the "social bonding" peptide, not just a labour drug.
James Tam — the full protein ligation list
James Tam′s chemical ligation let us synthesise whole proteins (RNase A, ubiquitin, p53, GFP…).
The card names James Tam for "chemical ligation for full proteins" but does not give the lecture's explicit list of proteins his ligation chemistry can build:
| Proteins synthesized by chemical ligation (Tam) |
|---|
| Ribonuclease A (RNase A), Ubiquitin, Histone Proteins, Epidermal Growth Factor (EGF), Human Parathyroid Hormone (hPTH), α-Synuclein, Human Insulin, Tumor Suppressor Protein p53, Myoglobin, Green Fluorescent Protein (GFP) |
Ziconotide — structural specifics the card trimmed
Ziconotide = sea-snail venom peptide; 3 disulfide bonds; a pseudocyclic structure.
The card's cyclisation table mentions Ziconotide only as "sea-snail venom." The lecture gives its structure explicitly:
- Extracted from the venom of a sea snail.
- Possesses 3 disulfide bonds.
- Has a pseudocyclic structure (not a true head-to-tail ring, but constrained by the three disulfides).
Four major biologic compositions — the lecture's fuller definitions
The four compositions, defined in full — the lecture′s complete definitions.
The card gives one-line definitions; the source spells out each type's biological role:
| Type | Lecture definition (expanded) |
|---|---|
| Polysaccharide | Long chains of sugar molecules, derived from biological sources, often involved in immune response modulation or structural functions in organisms. |
| Nucleic acid | Composed of DNA or RNA, designed to provide instructions to cells for producing proteins (gene expression / alteration). |
| Cell-based | Living or dead cells capable of performing complex biological functions, such as repairing tissue or modulating immune responses. |
Course assessment & exam format (admin facts the card omits)
Assessment: participation 10%, midterm 35% (60 MCQ, 1.5 h), final 55% (100 MCQ, 2 h).
- In-class participation — 10%
- Midterm Quiz — 35% (date given as 14 Oct 2026); 60 multiple-choice questions, 1.5 hours
- Final Examination — 55% (date given as Dec 2025); 100 multiple-choice questions, 2 hours
Course map — and what the midterm actually covers
The midterm covers Lectures 1–6.
| Wk | Date | Topic | Who |
|---|---|---|---|
| 1 | 2 Sep | Introduction to biologics | CW |
| 2 | 9 Sep | Proteins, antibodies & related biologics | CW |
| 3 | 16 Sep | Nucleic acids, carbohydrates & delivery strategies | CW |
| 4–6 | 23 Sep – 7 Oct | Bioinformatics — genomics, transcriptomics, proteomics, multi-omics | QM |
| 7 | 14 Oct | MIDTERM — Lectures 1–6 | CW |
| 8 | 21 Oct | Immunology L1 — basic concepts, three lines of defence, PAMP/PRR | WT |
| 9 | 28 Oct | L8 Structural Biology I — X-ray, NMR, SAXS, Cryo-EM | TL |
| 10 | 4 Nov | Immunology L2 — innate & adaptive immunity, antibodies, MHC | WT |
| 11 | 11 Nov | Immunology L3 — complement, MHC presentation, vaccines, hypersensitivity | WT |
| 12 | 18 Nov | Structural biology in drug discovery | TL |
| 13 | 25 Nov | Revision week — no class | — |
| Teaching team | Module |
|---|---|
| Dr. Clarence Wong | Course lead — proteins, peptides, antibodies |
| Dr. Quanhua Mu | Bioinformatics |
| Dr. William Tai | Immunology |
| Dr. Ted Li | Structural biology |
| Assessment | Weight | Format |
|---|---|---|
| Participation | 10% | Attendance + in-class interaction |
| Midterm | 35% | 60 MCQ / 1.5 h — covers Lectures 1–6 |
| Final | 55% | 100 MCQ / 2 h — covers everything |
Source: the course-calendar and assessment slides reproduced in the lecture-recording notes. The immunology block is listed as Weeks 8–9 on the calendar; the teaching-team slide numbers it Lectures 7–9. Where they disagree, the calendar is used here.
Essential amino acids — the mnemonic that survives exam pressure
Nine essentials, remembered as PVT TIM HALL: the body cannot make them, so they must come from food — a rare place where a pure memory aid is actually worth carrying into the exam.
| Mnemonic letter | Amino acid |
|---|---|
| P | Phenylalanine |
| V | Valine |
| T | Threonine |
| T | Tryptophan |
| I | Isoleucine |
| M | Methionine |
| H | Histidine |
| A | Arginine* |
| L | Leucine |
| L | Lysine |
*Arginine is conditionally essential — normally synthesised in the urea cycle, but the historical mnemonic keeps the letter. If the exam wants a strict nine, drop arginine and keep Val, Ile, Leu, Lys, Met, Phe, Thr, Trp, His.