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The Scarab Beetle, The Psyches, The White-Faced Decticus, The Field Cricket, The Sisyphus, Italian Locusts, The Anthrax Fly, The Praying Mantis.

Illustrations by E.J. Detmold taken from ‘Fabre’s Book of Insects.’ Published 1921 by Dodd and Mead.

Smithsonian Libraries 

In a recent report, researchers at Harvard Medical School brought up a promising yet eerie prospect in stem cell research– the development of synthetic embryos. Scientists are now able to assemble stem cells that can organize into embryo-like structures, and the day may not be far off when these cells lead to the development of complex human tissues and organs that can resemble those found in adult humans.  

Sheefs, which stands for “synthetic human entities with embryo-like features”, exist even today but only as simple assemblies of cells. 

From The New York Times’ article:

But in the future, they may develop into far more complex forms, the researchers said, such as a beating human heart connected to a rudimentary brain, all created from stem cells. Such a Sheef might reveal important clues about how nerves control heartbeats. Scientists might be able to use other Sheefs to test out drugs for diseases such as cancer or diabetes.

However, the full potential of this avenue of research may soon push the boundaries of what is currently legally acceptable. A rule that has been in existence since 1979 prohibits lab-raised embryos from being allowed to grow for more than 14 days. Scientists have largely found this to be a reasonable restriction because of how easy it has been to follow—until recently, scientists couldn’t even come close to keeping human embryos alive for even 1 week. But this may soon change.

Last year, two teams of scientists determined how to grow human embryos for 13 days. Those advances hinted that it might be possible to allow scientists to tack on a few days more, by changing the 14-day rule to, say, a 20-day rule.

MUSHROOMS

click images for descriptions

Include alkylating agents, intercalating agents, and chain cutters.

Alkylating agents

Highly electrophilic species, looking for nucleophilic sites to attack, and forming covalent bonds to bases in DNA 

Prevent replication and transcription 

Toxic side effects (e.g. alkylation of proteins) 

Bind in the major groove of DNA

Both types cross-link DNA by covalently bonding to nitrogen of base pairs.

Binding of nucleic acid bases results in miscoding and distortion. 

Distortion of DNA prevents excision by HMG proteins – permanent damage. 

Transcription and replication prevented, tumour growth slows. 

Two electrophilic sites on an anticancer drug can cause interstrand and intrastrand cross-linking.

Preference for 1,2-GG or 1,2-GC linkage sites, with interstrand or intrastrand linkage, is dictated by drug chemical structure 

Other linkage adducts are possible. Eg 1,3-GCG, 1,2-GA. 

Monofunctional adducts are also possible 

Chlormethine (a nitrogen mustard)

 Chlormethine is highly reactive, toxic side effects. 

Lead compound for many less toxic mustard derivatives. 

Methyl (CH3 ) group has positive inductive effect – promotes loss of chloride – see mechanism 

Less toxic chlormethine analogues:

Melphalan:  e- withdrawing ring lowers Nu strength of N, less reactive drug, less side effects, less toxic. Mimics PhAla, carried into cells by transport proteins. 

Uracil mustard:  Uracil ring is e-withdrawing, less reactive alkylating agent. Mimics a nucleic acid base, concentrates in fast growing cells.

Cyclophosphamide:  Most commonly used alkylating agent, Non-toxic, orally active prodrug. Acrolein associated with toxicity.

Busulfan: Causes interstrand cross-linking. Sulphonate group withdraws electrons, adjacent carbon subject to Nu attack by DNA bases. 

Dacarbazine – A diazine:  Prodrug activated by oxidation in liver, decomposes to form methyldiazonium ion. Alkylates guanine groups 

INTERCALATING AGENTS

 Aminoacridines eg Proflavine

Antibiotics - Dactinomycin

Extra binding to sugar phosphate backbone by cyclic peptide 

Intercalates via minor groove of DNA double helix 

Prevents unwinding of DNA double helix 

Blocks transcription, blocks DNA-dependent RNA polymerase 

Anthracyclines eg Doxorubicin (adriamycin) 

 Extra binding to sugar phosphate backbone by NH3 Planar rings and Anthracyclines eg Doxorubicin (adriamycin) 

Intercalates via major groove of DNA double helix 

 A topoisomerase poison - blocks action of topoisomerase II by stabilising DNA-enzyme complex 

CHAIN CUTTERS 

Calicheamicin g1 I antitumour agent 

 Nucleophilic attack on trisulphide chain starts a rearrangement process. 

This interacts with DNA to generate a DNA diradical, which reacts with oxygen, resulting in chain cutting.

Bleomycins (BLM)

Highly active head, neck, testicular cancer (Hodgkin lymphoma) 

Single and double-strand cleavage of DNA with several reduced metal ions and O2 , Fe(II) highest in vivo activity. 

Three regions - 

bithiazole DNA binding domain (DBD) locks BLM into the minor groove, 

carbohydrate domain (CHD) H-bonds BLM to sugar phosphate of DNA 

metal binding domain (MBD) bonds to Fe(II)    

Mechanism

A reaction with hydrogen peroxide gives Fe(III) and hydroxyl radicals which abstract H atoms and cut the DNA chain. 

Fe2+ + H2O2 Fe3+ + OH. + OH− Fenton mechanism 

Lungs and skin have low levels of BLM hydrolase - higher sensitivity and toxicity. Pneumonitis occurs in about 10% of patients, progresses to pulmonary fibrosis. Over-expressed in malignant cells, resistance to bleomycin    

Summary of Anti-Tumour Specificity for DNA 

Major groove alkylators 

GG interstrand - N-mustards, nitrosoureas. 

GG intrastrand - methanesulphonates. 

GC-interstrand - nitrosoureas, triazines. 

Minor groove intercalators 

GG interstrand – anthracyclines. 

GC-interstrand – actinomycins, acridines. 

Minor groove chain cutters 

Stuff in My Office

Dr Warhol’s Periodic Table of Microbes

Virus trading cards

So cool!

To make the 3D animations I used UCSF Chimera, a free molecular modeling program. When scientists discover a new protein structure they upload it to the worldwide Protein Data Bank. Each entry is assigned a unique ID number, which you can use to call up the structure in programs like Chimera or PyMol.

Source & credits: Tabletop Whale

By Elia Pellegrini