2019-10-12_The_Economist_

The EconomistOctober 12th 2019 Science & technology 83

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1

cosmological—almost invisible to the out-

side world. Yet together William Kaelin, Sir

Peter Ratcliffe and Gregg Semenza have an-

swered an important question: how cells

detect and adjust to the level of oxygen

available to fuel their activities.

The crucial molecule in the system that

matches cell physiology to oxygen avail-

ability is a protein complex called hypoxia-

inducible factor (hif). hifwas discovered

and named by Dr Semenza, who works at

Johns Hopkins University, in Baltimore. In

the 1990s Dr Semenza was studying eryth-

ropoiesis, the process that generates red

blood corpuscles. These are the cells that

carry oxygen in the bloodstream, and their

number depends on how much oxygen

there is around. Professional athletes, for

example, often train at high altitude, where

the thin air means oxygen is scarce, in or-

der to grow extra red blood cells that will

assist their respiration when they compete

nearer to sea level.

The hormone that triggers erythropoie-

sis is called erythropoietin, or epo. Indeed

epo, which is manufactured as a drug to

help those with anaemia, is also used ille-

gally by some athletes to boost their red-

cell count without the trouble of visiting

high altitudes. (In cycling, for example, it is

notorious.) Dr Semenza was looking at a

stretch of dna, located within the gene that

encodes epo, which switches that gene on

and off. In doing so he discovered hif, a

protein complex that, by attaching to or de-

taching from the dnaswitch (see diagram

3), does the switch-throwing. Since Dr Se-

menza’s discovery, 300 genes similarly reg-

ulated by hifhave been found.

Dr Kaelin’s contribution was to discover

a further protein, vhl, that regulates how

levels of hifin a cell are controlled by oxy-

gen levels. hifactually consists of two pro-

teins, now known as hif-1 alpha and arnt.

arntis always present in a cell, but the lev-

el of hif-1 alpha depends on the amount of

oxygen present. More oxygen means less

hif-1 alpha. That, in turn, means less of the

hif complex. Genes like that for epo,

which rely on hifto switch them on, thus

remaininactive.

DrKaelin,whoworksattheDana-Far-

berCancerInstituteinBoston,wasstudy-

inganinheritedgeneticillnesscalledvon

Hippel-Lindau’sdiseasewhichgreatlyin-

creasesthelikelihoodofcertaintumours

(sometimes benign, sometimes malig-

nant,affectingorgansincludingthekid-

neysandeyes)developing.vhlisthepro-

tein encoded by the gene that, when

mutatedandthusnon-functional,causes

von Hippel-Lindau’s disease. Dr Kaelin

showedthata non-functionalvhl-encod-

inggenecausedmanyhif-regulatedgenes

togointooverdrive—whichistheunderly-

ingcauseofthetumoursinquestion.

Thepiecesofthepuzzlewerethenput

togetherbySirPeter,whoworksatOxford

University.Heshowedthatvhlandhif-1

alphainteractwithoneanother,andthat

thisinteraction,whichincorporatesmole-

culescalledhydroxylgroupsintothemix,

makeshif-1 alphasusceptibletodegrada-

tioninthepresenceofoxygen.Thedegra-

dationisnotdirect.Itisnotthathif-1 al-

phaisbeingoxidised,andthusdestroyed.

Rather, the hydroxyl groups, which are

createdbya reactionbetweenhif-1 alpha

andoxygen,markitfordestructionbya

cell’sprotein-degradingmachinery.

Thepracticalupshotofallthisisa better

understandingofthebiologyunderlying

anaemia,tumourssuchasthoseencour-

agedbyvonHippel-Lindau’sdiseaseand

many other oxygen-sensitive processes.

Theseincludethehealingofwounds,the

growthofbloodvessels(onereasonforthe

linkwithtumours,sincetheseneedextra

bloodvesselsinordertogrow),and the

likelihood of heart attacks and strokes.

Withluck,drugstailoredtoregulatetheac-

tionsofthevarioushif-controlledgenes

involvedwillbeabletopromoteorprevent

thesephenomena—and,albeitmorequiet-

lythanisthecaseforlithium-ionbatteries,

theintentionofNobel’swillwillhavebeen

fulfilledinthiscase,too. 7

An aerobic workout

Sources: Nobel Foundation; Guido Hegasy

Howcellsadapttooxygenavailability

3

Normal oxygen levels Lowoxygenlevels

VHL

O2

OH

OH

O2

O2

OH

OH

→→→

VHL

Nuc

leus

↘

ARNT HIF

→

1

1

2

2

3

3

A

t the turnof the millennium it was

clear a new approach was required in

the war against three of the biggest threats

to human life and development. There was

need for a trustworthy international orga-

nisation that could solicit donations from

rich countries and wealthy organisations,

and spend that money on combating those

threats in collaboration with the govern-

ments of afflicted poor countries, but with

appropriate oversight to ensure effective-

ness and avoid theft. The result was the

Global Fund to Fight aids, Tuberculosis

and Malaria.

And it worked. Though it is impossible

to say what would have happened without

the Global Fund, as it is now formally

known, the fund’s officials claim to have

saved 32m lives since it opened in 2002. As

with liberty, though, the price of success is

eternal vigilence—and many in the field

fear further progress is under threat. To re-

main on course to hit its self-proclaimed

target to save 16m lives by 2023, the fund

says it will need pledges of at least $14bn by

the end of this year. This week, at a so-

called replenishment meeting in Lyon,

France, it has been setting out its stall.

Fourteen billion dollars is a 15% in-

crease on the fund’s current three-year

budget. It will, though, be more than

matched by $46bn raised to combat the

diseases in question by recipient countries

themselves. And that spending will be a

good deal. The returns on the best health

investments are between 900 and 2,000%.

Conversely, as with all infectious diseases,

if efforts slacken, those illnesses will be

back with a vengeance.

Of the three targets, tuberculosis (tb) is

the worst. Every year, it is estimated, more

than 10m people catch the bacterium

which causes this illness, and 1.6m die of it.

Tuberculosis, though, is an odd infection.

Often, the bacteria remain dormant and an

individual hosting them presents no

symptoms. As a consequence (and also be-

cause some people delay seeking treat-

ment) nearly 40% of cases are missed. At

the same time, there has been a worrying

rise in drug-resistant forms of tb. These are

a challenge everywhere—including rich

countries—and cause a third of all deaths

from the disease. The un’s goal is, with 2015

as the baseline, to reduce the number of

deaths by 95% and the incidence of the ill-

ness by 90% by 2035. That goal, most agree,

will be missed without shifts of strategy.

How to defeat AIDS, malaria and

tuberculosis

The global burden of disease

Building tomorrow

Listen to our discussion about the Nobel

prizes at economist.com /nobelprizes2019