The end of men? The woman growing testicles in a test tube - and how her research could save the human race from the male fertility crisis

People ever inquire maine if nan purpose of my activity is 1 time to get free of men,' says biologist Nitzan Gonen. It doesn't look an unreasonable query, given that, successful a world first, Dr Gonen precocious managed to turn miniature versions of antheral testicles successful a laboratory.

And though they were grown from cells extracted from mice, immoderate time now Dr Gonen will displacement to utilizing quality cells.

The goal? Ultimately to create cells successful nan laboratory that are tin of producing quality sperm.

This isn't a distant dream. Dr Gonen, who heads nan Sex Determination Laboratory astatine Bar-Ilan University successful Israel, hopes this could beryllium a reality wrong 5 years.

And what is singular is really she intends to spell astir it: utilizing stem cells isolated from a miniature flake of tegument taken from a man's arm.

Dr Gonen, a mother of four, says her activity will thief those men who can't nutrient sperm — for whom presently location is nary different measurement to begetter a kid — alternatively than being utilized arsenic a measurement to make babies without a man.

It will besides thief further investigation into really to safeguard nan wellness of sperm, nan request for which is becoming ever much pressing.

'Male fertility is successful crisis, and unless we do thing astir it nan quality title is going to beryllium successful a full mess,' is really Christopher Barratt, a professor of reproductive medicine astatine Dundee University and a personnel of nan World Health Organisation's committee for semen analysis, sums up nan situation.

His grim study is based connected studies specified arsenic 1 that recovered that betwixt 1973 and 2018 sperm attraction (the number of sperm per portion of semen) fell by 1.2 per cent a twelvemonth — and aft 2000, by an alarming 2.6 per cent a year, according to a reappraisal of much than 200 studies published successful nan diary Human Reproductive Update successful 2022.

A fertile man produces 66 cardinal sperm per millilitre of semen connected mean — a man is said to beryllium infertile if he produces 16 cardinal per millilitre, according to World Health Organisation definitions, and nan number affected appears to beryllium increasing.

'Not only is nan sperm count dropping — that is, nan full number of sperm per ejaculate — but truthful excessively is nan sperm concentration, aliases nan number of sperm per millilitre and nan value of sperm [ie factors specified arsenic really good they move],' says Professor Barratt.

'We utilized to opportunity that successful 99 per cent of cases, if a mates were struggling to conceive, past it was usually owed to a problem pinch nan woman; but now we opportunity that it's arsenic apt to beryllium owed to nan man,' he adds.

Professor Barratt says astir 7 per cent of men successful nan UK person fertility problems, though that looks definite to rise.

'In nan past 20 to 30 years, nan commencement complaint has reduced importantly mostly owed to societal reasons, specified arsenic group delaying having children.

'But nan effect of nan driblet successful sperm count is going to footwear successful soon — and nan situation is that we person nary curen for it,' says Professor Barratt.

'Male fertility is wholly under-appreciated and nether researched, and location is simply a genuine origin for concern.'

Judging really heavy nan situation is is not straightforward, arsenic methods for analysing sperm counts person changed complete nan decades and immoderate experts, specified arsenic Allan Pacey, a professor of andrology astatine nan University of Manchester, opportunity that not each nan information show sperm counts are falling.

He co-authored activity published successful June successful nan diary Human Reproduction based connected much than 6,000 sperm donors successful Denmark that showed nary alteration successful their sperm count betwixt 2017 and 2022 — though nan investigation did show that nan attraction and motility (sperm's expertise to swim) declined by 16 per cent and 22 per cent respectively betwixt 2019 and 2022.

Yet moreover he agrees that 'male fertility is successful crisis' — though for different reasons we will travel to.

Sperm originates arsenic 'germ' cells successful infinitesimal tubules successful nan testicles, which are 'nursed' by Sertoli cells. These 'nurse' cells nonstop chemic messages and nourish nan germ cells to thief them mature into sperm cells — a process that takes astir 74 days.

'Germ cells are conscionable for illustration a pebble aliases shot of cells and acquisition this metamorphosis almost for illustration a tadpole does, to create a extremity and a tail,' says Professor Barratt. 'No different cells successful nan assemblage acquisition arsenic large a grade of alteration arsenic a germ compartment that becomes a sperm.'

Leydig cells, extracurricular nan tubules, thief this on by pumping retired nan hormone testosterone.

It is harm to nan supportive Sertoli cells that is thought to underpin overmuch of nan evident autumn successful antheral fertility.

One mentation is that, during pregnancy, biology factors — specified arsenic vulnerability to plastics aliases hormone-disrupting compounds recovered successful galore family items — harm nan improvement of nan testicles and these cells.

Other suggestions are that nan infinitesimal particles of aerial pollution, called PM2.5, origin nan damage.

One study, involving 33,876 men successful aliases astir Shanghai successful China whose female partners were seeking assisted thief pinch conception, measured aerial contamination levels crossed nan metropolis successful nan run-up to nan men giving a sperm sample.

The results, published successful nan diary JAMA Network successful 2022, recovered that nan higher nan levels of PM2.5 during nan 90-day run-up to them giving a sample, nan little nan full sperm and their 'motility'.

'One thought is these factors [such arsenic aerial contamination and infinitesimal integrative particles] trim nan number of Sertoli cells and/or make those cells that are location little efficient, truthful that they can't thief nurture arsenic galore germ cells into sperm,' says Professor Barratt.

It whitethorn beryllium that these factors trigger inflammation and it is this that does nan damage.

Around 1 per cent of men and 10-15 per cent of infertile men person a much aggravated problem — azoospermia, meaning they person nary sperm successful their semen astatine all.

For immoderate men that will beryllium owed to a beingness obstruction successful nan reproductive ducts owed to, for example, wounded aliases infection — and successful immoderate cases sperm tin beryllium extracted from nan testes.

But for others it tin stem from harm to nan sperm-making cells successful nan testes, arsenic a consequence of genetics — for example, vulnerability to radiation aliases chemotherapy.

While men pinch a debased sperm count whitethorn still beryllium capable to begetter children pinch nan thief of successful vitro fertilisation (IVF, wherever sperm is mixed pinch their partner's eggs successful a Petri crockery successful a lab), aliases intracytoplasmic sperm injections (ICSI, wherever a sperm is injected straight into an egg), for those pinch nary sperm this isn't an option. And it is these benignant of cases, successful particular, who mightiness use from Dr Gonen's work.

The miniature testicles she's produced are a shape of organoid — essentially, a microscopic type of an organ — pinch nan captious components, Leydig, Sertoli and germ cells.

Scientists astir nan world person already been capable to nutrient a scope of organoids — from gallbladders to hearts and brains — pinch nan purpose of utilizing them for investigation and, successful immoderate cases, pinch nan dream of 1 time utilizing them arsenic replacement organs.

'Each testicle organoid is highly mini — little than a millimetre,' explains Dr Gonen. 'It's for illustration a miniature functional portion of nan testicle alternatively than nan testicle arsenic a whole.

'But we are conscionable including nan elements we request to make sperm. We don't request full-blown size units.'

It took six years experimenting pinch different processes earlier Dr Gonen's squad deed connected 1 that worked.

The successful attack progressive taking nan testes of five-day-old mice and isolating nan Sertoli, germ and Leydig cells.

'Normally, if you put these cells into a Petri crockery they would conscionable beryllium dead,' says Dr Gonen.

But erstwhile Dr Gonen added hormones and maturation mean to effort to replicate nan situation of nan testes, nan squad had a 'wow' moment. 'Within days, we could spot that what had started arsenic a postulation of cells were forming into structures akin to those successful nan testes — cells assembled into tubules and nan germ cells were encapsulated successful nan tubules and nan Leydig cells were extracurricular of nan tubules — conscionable arsenic they should be.'

After nan results were published successful January successful nan International Journal of Biological Sciences, it made world news and Dr Gonen received emails from men astir nan world who were struggling to begetter a child, each wanting to cognize if she could thief them.

But nan mobility was if these organoids worked for illustration testicles.

The answer, astatine slightest successful part, was yes. 'We person first indications that nan germ cells tin participate meiosis,' says Dr Gonen. This is nan process by which germ cells halve nan DNA successful their cells, conscionable anterior to changing style into a sperm pinch a caput and tail.

All of which indicated that they had made sperm. 'But we can't corroborate that yet — we request to tally much tests,' says Dr Gonen.

They managed to support nan organoids live for 9 weeks, aft which they died naturally. Usually, successful mice, sperm accumulation takes 34 days, truthful successful rule it was agelong capable for sperm to beryllium produced.

Dr Gonen is now moving pinch a infirmary successful Jerusalem to effort to make organoids from stiff insubstantial from nan testicles of children undergoing chemotherapy.

As successful nan UK, children successful Israel astir to person chemotherapy (or different curen that whitethorn time off them infertile) are offered nan chance to person infinitesimal samples of their testes removed and frozen.

This is done successful nan dream that by nan clip they want a family, exertion will person moved connected truthful that their stored biopsies tin beryllium utilized to make sperm.

'But astatine nan infinitesimal location is thing we tin do pinch these biopsies,' says Dr Gonen.

She adds: 'Around 80 per cent of children past puerility cancer, but half of them will suffer their fertility.

'In girls, you tin region a portion of ovary and frost it, and erstwhile she is older transplant it backmost — and you tin get eggs that you tin use.

'For boys successful nan aforesaid position, astatine nan infinitesimal [if prepubescent, they're excessively young to nutrient sperm] location is nary solution and it tin person a large impact.'

The dream is they tin make an organoid from nan stiff sample tin of producing sperm.

Currently, says Dr Gonen, nan squad is practising freezing and unfreezing rodent testes 'to cleanable each measurement of nan method earlier we move connected to nan children's tissue'.

The organoids will beryllium grown successful a mean that will beryllium changed successful bid for nan miniature testicles to mature and spell done a type of adolescence — 'to effort to recreate precisely what happens successful nan body'.

Within 5 years, Dr Gonen hopes she will person perfected nan technique, enabling her to turn miniature testicles from a minuscule spot of tegument taken from an infertile man.

The tegument cells would first beryllium turned into pluripotent stem cells — maestro cells that tin move into conscionable astir immoderate compartment successful nan body. The thought is these will past beryllium turned into nan germ, Leydig and Sertoli cells needed to make nan mini organoids.

There are different teams trying to nutrient laboratory-made sperm. In 2016, a squad successful China managed to create a very primitive shape of sperm — spermatids (without a caput aliases tail). These were created utilizing stem cells from mice, and erstwhile injected into rodent eggs, resulted successful nan commencement of six rodent babies, according to nan researchers penning successful nan diary Cell Stem Cell.

And successful 2021, a squad from nan University of Georgia reported successful nan diary Fertility and Sterility Science that they had produced spermatids utilizing stem cells derived from monkeys. These spermatids seemed tin of fertilising an egg.

There are evidently ethical concerns astir specified work. For illustration 'there will request to beryllium very strict criteria for retention and tracking', says Professor Suks Minhas, a advisor urologist and andrologist astatine Imperial College London.

But nan statement is that Dr Gonen's investigation is exciting.

'It's fantastic, but it's very analyzable and it's going to return clip to perfect,' says Professor Barratt. 'I deliberation wrong nan adjacent 5 aliases 10 years we will astatine slightest beryllium capable to nutrient sperm-like cells successful nan trial conduit — and that successful itself will thief amended our investigation into antheral infertility.'

While making sperm successful a laboratory whitethorn beryllium immoderate measurement off, galore experts judge a large measurement guardant to amended antheral fertility could beryllium achieved correct now, by improving consciousness astir nan domiciled of men's age.

As Professor Pacey explains: 'We are successful a antheral fertility situation because men are leaving it until later successful life to effort for children [see box, above] and partially because reproductive medicine is focused connected women not men.

'Men person to stock immoderate of nan blasted for this, and I deliberation medicine besides has to stock immoderate of nan blame.'

Others reason that location is simply a pressing request for much investigation into nan underlying causes of antheral infertility — and that offering assisted reproduction options whitethorn beryllium 'bypassing normal selection' and perpetuating nan problem, which whitethorn beryllium genetic.

Professor Joris Veltman, a geneticist astatine nan University of Newcastle, points retired that 'some investigation has recovered that children calved via ICSI person a higher infertility complaint than nan remainder of nan population'.

He published investigation successful 2022 which identified familial faults connected to infertility that past made antheral children infertile — and successful 50 per cent of cases that familial responsibility could straight beryllium passed connected to offspring.

'When astir fertility clinics spot an infertile man, they don't think, 'why is he infertile?'; they think, 'let's usage artificial reproductive technologies to thief him to conceive',' he says.

'With nan mostly of men, we don't analyse what nan underlying origin is. That intends we don't cognize what we are handing on.'

Meanwhile, nan mobility remains: Will nan quality title ever beryllium capable to do without men?

'No, decidedly not,' laughs Dr Nitzan Gonen. 'We request their chromosomes — we person to instrumentality pinch them.'