It’s pre-ASRM week in the reproductive medicine world, time to check in on the industry and for me to reassess our progress towards a million IVF babies a month.

Lots to discuss this year, as always. And, as always, the work being done worldwide to help people become parents when they otherwise could not is humbling and inspiring. And often frustrating. Inevitably, when tackling a goal this big and this important, we will sometimes do the wrong thing for the right reasons and set ourselves back a step or two, by taking a path that we thought we lead us forward.

A few things stand out this year: one is still less than ideal fit between reproductive medicine and venture capital. I spend over half of my work time in the biotechnology industry, which is awash in venture capital, raising tens of billions of dollars a year seemingly by gravitational pull. We’ll address that, using AI in IVF as an example.

Speaking of AI, I’ll review what went on in Cascais, Portugal during AI Fertility III a few weeks ago, particularly The Rise of Physical AI, which is facilitating the second pillar of IVF innovation (the first is software, and third is alt delivery). My oft-repeated thesis on IVF access is that out of pocket cost needs to be matched with ease of expansion in supply in order for IVF to be truly available to everyone who needs it to have a baby who otherwise could not.

Speaking on IVF for everyone who needs it, how about IVF for those don’t need it, but want it anyway? I’ll be addressing where we may be going with IVF genetics: absolute indications, medically justifiable indications, and as well as IVF for recreational genetics. And while it’s not necessarily an outcome that I would welcome, I think that the IVF genetics segment is making itself a target for the type of heavy-handed regulation that gets in the way of the people who most need our help.

Finally, a family triumph with lessons for the IVF industry: we now have a certified service dog. Delphine, who I introduced last year, is now a gluten-detecting, celiac symptom preventing service animal, having graduated last week from an 18 month training process, and a perfect metaphor for the process of medical innovation.

More in the next few days.

#infertility #ivf #FDA #venturecapital #privateequity #ASRM

It’s been five years since I posted my population deficit estimates. Time for an update.

This was a down and dirty analysis. My methodology: I looked at the largest “population deficits” in the world ie the amount of the population that the current fertility rate is not adequately replacing. This is a simple calculation multiplying the number of women in the country * the TFR, or total fertility rate (reference: Population Reference Bureau). An equilibrium replacement rate is ~2.1, slightly over one baby per parent, with an adjustment for early childhood mortality.

Results from 2021, and now updated:

Most notable is the effect of the decrease in TFR for China.

I asked a second question: should any other countries now be included as major contributors to this list?

The answer: yes, 5. India, Turkey, Iran, Mexico and Vietnam. I updated the chart accordingly.

The total population deficit for these twenty countries is 17.7 million babies per year.

What is the ideal world population? And, in the absence of an answer to that question, should we formulate policy to provide incentives for fertile families to have more children than they would otherwise? While it’s true that the human population has grown for almost all of our 3000 centuries, it’s also true that nearly 7% of people who have ever lived are alive today. (8 billion of 117 billion per the Population Reference Bureau.) https://www.prb.org/news/how-many-people-have-ever-lived-on-earth/ ](https://www.prb.org/news/how-many-people-have-ever-lived-on-earth/))

I have a more modest proposal: let’s make it as easy as possible for those who want to create and grow families and let everyone else decide for themselves.

To come: if everyone with infertility conceived, how would that affect population declines?

Great work by the international group that published their work in The Lancet renaming polycystic ovary syndrome, or PCOS, now called polyendocrine metabolic ovarian syndrome, or PMOS.

Three points:

First, this was an enormous achievement, combining science, medical history — and politics. The international group did us a real service.

Second, the new name is better. It more accurately reflects what clinicians and patients have known for years: this is a complex syndrome with endocrine, reproductive, and metabolic dimensions.

Third, the new name is better, but it is still not good enough.

Lets talk medical history.

It’s 1935. Michael Resse Hospital in Chicago.

Irving Stein and Michael Leventhal publish a case series of seven women with enlarged ovaries identified at laparotomy, along with irregular cycles, hirsutism, and obesity. That report gave rise to what became known as Stein–Leventhal syndrome.

Of course “syndrome” suggests a superficial or observational understanding, not precision medicine.

Medical knowledge travels from the vague to the precise, from analog to digital. With hormonal assays and pelvic ultrasound, the PCOS picture emerges. The role of androgens gets clarified. Then, the metabolic dimension — particularly the role of insulin resistance. PMOS reflects that shift.

This is progress; medicine advances as it moves toward precision. We begin by naming clusters of symptoms. Then we define disease anatomically. Later, if we are successful, we define it by pathways, cells, molecules, and genes. That is what precision medicine promises, and patients deserve nothing less.

Women living with Stein–Leventhal syndrome, PCOS, or now PMOS still deserve a more precise understanding of the complex set(s) of symptoms that they have endured for 300,000 years.

Why? Because better understanding leads to better management. The earliest surgical approach — ovarian wedge resection — was crude and not all that effective. Later, systemic treatments such as oral contraceptives, clomiphene citrate, and gonadotropins improved care, but often imperfectly and sometimes with substantial risk, including multiple gestation and ovarian hyperstimulation.

The future will be better than the past. And the new name signals both progress, and the work still left to be done, work that will define, more precisely, what drives this heterogeneous condition in different patients.

It’s a Monday morning in July, 1991, and, like usual, sign out takes longer than expected. And I don’t have time to change out of my scrubs. This particular Monday is a special one, the first day of my vacation, a vacation during which I will travel back to New Jersey to get married. That story will wait for another time, but on this particular morning I have one last stop to make before I head home

I find a seat in the back of the auditorium at the Boston Public Library. I put my backpack on the floor and stuff my white coat inside, being careful not to disturb the two books that I brought with me. I don’t spend many mornings during fellowship at the Boston Public Library, but this was an event I did not want to miss.

Amy Tan is in town for a reading.

Three years before, I sat in the back seat of the livery car that shuttled us between New York Hospital and LaGuardia Hospital in Queens, our affiliate hospital, where for the prior 24 hours I was the only obstetrician-gynecologist in house.

The car radio was tuned to NPR, and a young author named Amy Tan is reading from her book, The Joy Luck Club. Suyuan Woo describes her escape from the invading Japanese army at Kweilin to her daughter Jing-Mei.

“I packed my things and my two babies into this wheelbarrow and began pushing to Chungking four days before the Japanese marched into Kweilin.”

The scene is a flashback. We learn at the start of the book that Suyuan Wu has just recently died, and Jing-Mei takes her seat at the mahjong table during meetings of the Joy Luck Club, four women from China who emigrated to San Francisco after the war. Each has a young adult daughter.

“I didn’t have enough feeling left in my body to cry. I tied scarves into slings and put a baby on each side of my shoulder. I carried a bag in each hand, one with clothes, the other with food. I carried these things until deep grooves grew in my hands. And I finally dropped one bag after the other when my hands began to bleed and became too slippery to hold onto anything.”

The other three women have a message for Jing-Mei.

“By the time I arrived in Chungking I had lost everything.”

“What do you mean by ‘everything?’” Jing-Mei asks.

“What happened to the babies?”

My plan is to attend the reading, rush home to Saint Germain Street, shower, pick up my suit and fly back to New Jersey. On stage, Amy Tan is reading from her second novel, The Kitchen God’s Wife. I lose myself in her storytelling, the plot and vivid characters, and in her mechanics: the strong sentences and flow of the paragraphs.

We planned the wedding in early July, shortly after Priya’s graduation from the New England Conservatory, and at the midway point of my two year fellowship in reproductive endocrinology and infertility at Brigham and Women’s Hospital. It has been an eventful year. I met Priya at the Trident Bookstore on Newbury and we were engaged six months later. Professionally, I had my own patients for the first time, women and couples for whom getting pregnant, being pregnant. or staying pregnant was the most important part of their lives.

Sujuan Wu’s friends have news for June-Mei, who knows very little about her mother’s life in China. Sujuan, exhausted and fearing death, left the babies at the side of the road, with a note for someone, anyone to take care of them.

I have very little time after the reading and a q and a session, but I stay anyway, and join the receiving line to greet the author.

Later, on the plane home, I reflect on the year past. As a resident at Cornell, I took care of others doctors’ patients with infertility, but had never realized just how much suffering it caused, how brutally it shoved the rest of life aside, and how it robbed people of the lives that they had always counted on.

How it made them question everything.

I reach the front of the line, and thank Amy Tan for the gift she gives her readers. I open my backpack and show her my well-worn copies of The Joy Luck Club and The Kitchen God’s Wife.

Sujuan Wu escapes to America, remarries, and gives birth to June-Mei. But Sujuan never forgets the baby girls she left behind in China. With the help of the other three members of The Joy Luck Club, searches for evidence of their survival.

The plane descends into LaGuardia. Infertility is suffering, but there’s more. My patients are in mourning too. They grew up picturing their children, picturing their lives as parents. Then infertility, or habitual pregnancy loss, forces them away from the life that they assumed would always be there. The babies, the children, the family, all left at the side of the road.

Shortly before she dies, Sujuan finds that her two daughters are alive and well and living in China. She never gets to see them. Instead, Jing-Mei travels to Shanghai to meet them in her mother’s place.

The livery car driver didn’t mind that I wouldn’t get out of the car back at New York Hospital. He wanted to hear what happened in Shanghai too. June-Mei and her half sisters do meet in the airport, fulfilling Sujuan’s dream.

“And although we don’t speak, I know we all see it: Together we look like our mother. Her same eyes, her same mouth, open in surprise to see, at last, her long-cherished wish.”

Priya and I have been married for 35 years. Amy Tan signed my copy of The Kitchen God’s Wife, “To David and Priya, Joy and Luck in your life together.”

If we ever meet again, I’ll thank Amy Tan for the wisdom that a young infertility doctor found in her story about Sujuan Wu, her daughter June Mei, and the babies left on the side of the road.

Of all the opinions that really smart and forward thinking people in our field (like Santiago Munne, for whom I have an abundance of respect and admiration for and who posted below), the concept that fertile people having children by sexual reproduction will be replaced by widespread use of assisted reproduction in order to design (yes, that is the most accurate word) their children’s traits is the most implausible and least defensible.

Why? Let’s start with three broad areas.

1) Hubris. Humans have been around for 300,000 years, accounting for 15,000 generations of evolution. The notion that we can do better 25 years after the human genome project, armed with WGS reports and a mixed bag of genetically and non-genetically characterized trait sets (what is the word “syndrome” if not an admission that we don’t know understand cause and effect) is a bit aggressive.

(To be clear, I am talking about unenriched populations, not families that carry arithmetically-defined genetic disease.)

2) Practical: who’s going to do the IVF or future equivalent to produce 130 million babies a year? Our 25 billion dollar, less than one million babies a year industry manages 4–8% growth a year. I worship at the temples of standardization, automation and scale as much as anyone, and I marvel at what AI can do, but sufficient growth in ART and sequencing throughout to achieve ART dominant human reproduction doesn’t model.

3) Opportunity cost. A lot of really smart and committed people are working their tails off to get the cost of an IVF cycle (without sequencing, embryo analysis and the requisite genetic counseling down to the mid to low thousands of dollars (regardless of who pays.) if we drive the cost down to $7500 per baby, not per cycle, including the genetic work, the bill (which someone has to pay) approaches a trillion dollars.

I am an amateur bioethicist at best, so I will leave the *many* issues of reproductive justice, fairness, medical overreach and resources being triaged away from medical indications (infertility, recurrent pregnancy loss, onco-fertility, LGBTQ fertility) to consumer discretionary uses to those better trained.

I am no Luddite. I did my first PGD cases (as they were called back then) in the mid 90’s and cofounded (with Santiago Munne and Jacques Cohen, as fine a scientists as our field has ever produced) one of the first reproductive genetics companies, Reprogenetics, later acquired by Cooper. We should be doing a hell of a lot more IVF than we do now, and a lot more disease prevention.

But most of our babies from IVF so that every can pick and choose what seems to be the optimal combination of 10,000 genes based on that particular year’s understanding of genetics?

Ain’t gonna happen.

(To be clear, I’m not calling for a ban and I’m not telling anyone what they should or should not do. Just handicapping what I think is a misguided, albeit fairly common, prediction.)

So unhappy I am missing ESHRE this year!

A big part of what I’ll miss are the first meetings with new founders, those brave and brilliant souls committed to making the IVF world a better place. I’ve had hundreds of these meeting, and they are the fresh air, pure water and dark espresso of the world of entrepreneurship.

If done right.

So to make myself feel less irrelevant on this New York City morning, I’m passing along a few tips on getting this right.

1) I want to hear your words. Clichés belong to others. Please please expunge phrase like “out of the box” from your pitch. Similarly, not everything is “game-changing” and almost nothing is “revolutionary.” Tell me what you do that’s different and potentially better and then let’s walk through whether and how it’s a good, or maybe great, business.

2) Show me your commitment, passion and enthusiasm without being promotional. What is promotional? It is when you pass everything you say through “what does he want to hear?” Try not to retrofit your business plan into “he likes hardware so how do I pitch my digital health business in a way that will make him care?” Let me decide whether I am a fit by hearing your best story, not some watered-down version of it.

3) You don’t need a script, but it helps to have structure. The approach I find most helpful is to lead with the problem you are solving (the specific problem, not “IVF needs to be more accessible”). When we agree on that, we’re on the same team — finding a way to best work together. Paint a picture for the people you are helping — at the moment they are being helped. (My fellow Aristotle fans recognize the adding pathos to the ethos of defining the problem.)

4) Once we are fellow members of Team Let’s Solve The Problem Together — then hit me with your idea. Time for Aristotle’s logos. What specifically — concretely and quantitatively — are you producing. This is the time when you win the next meeting and the ongoing relationship. AND THIS IS WHEN I AM MOST ASSESSING YOU. Make me a partner by using specific language — expect me to ask “what do you mean by (insert somewhat vague and nonspecific term)” and to be aggressive asking you to define and redefine your terminology. (Don’t roll your eyes when I ask “what do YOU mean by artificial intelligence.” The term has far too many meanings. Don’t assume I will insert the one that correctly clarifies your business plan.)

5) Most important — KNOW YOUR NUMBERS. Be prepared to provide (and be able to discuss the substance of) the source for any number in your presentation. Even better — be prepared to derive it. A good answer to “where did that number come from” can be the start of a long relationship. (Needless to say, if I think you’re making the number up or pulling it out of this air the meeting will pretty quickly.)

Enjoy Paris and enjoy ESHRE!

To help move things along, let me offer up six places to start:

1) Expand the Department of Defense and VA fertility coverage to include IVF. Currently it doesn’t.

2) Fund the approved but un-funded REI fellowship programs that currently are not accepting fellows. (investigating this now.)

3) Initiate and fund two pilot programs: one exclusively dedicated to providing IVF for the prevention of monogenic disease, and one dedicated solely to fertility preservation for young men and women undergoing fertility-depleting treatment for cancer or other diseases.

4) Mandate that the movement of embryos across state lines cannot be limited by state law.

5) Provide a priority review incentive voucher at the FDA for gene therapy treatments for monogenic diseases that can be prevented using IVF with PGT-M. Companies will qualify if they establish a mechanism to fund egg freezing for affected couples in order to prevent the disease that the gene therapy treats. Gene therapies costs can cost millions of dollars per patient. Setting aside $25,000 for disease prevention is a rational public health investment. Vouchers for a similar program for pediatric rare diseases have been valued at over $100 million dollars.

6) Reinstate the small CDC division that collected and published IVF outcome data. You can’t scale without data.

Open to other approaches. Let’s start moving forward.

She will always be Barb. The way Prince is Prince and Madonna Madonna.

And if you needed help starting a family, whether finding someone in your area code to talk through the stress of treatment, or finding that you have more insurance coverage than you thought you did because you live in one of the states that passed fertility insurance mandates under Barb’s watch as CEO and President of RESOLVE: the National Infertility Association, or because everyone from SART, the CDC, US Fertility, Serono, Ferring, Cornell and RMA answered Barb on the first ring and jotted down what she said because it always mattered, or because she coordinated swat teams that parachuted into state capitals to walk state senators through the realities of how possibly well-intended but ultimately harmful statutes affected their own neighbors and constituents, or because of the respect she commanded in Washington when face-to-face, I’m ok you’re ok, she reminded congressmen and women, senators, and presidents just how important, life-affirming, patriotic and party-affiliation agnostic support for sons and daughters can be.

When Barb assumed responsibility for RESOLVE, George W. Bush’s President’s Council on Bioethics, dubbed “all embryos all the time” by Leon Kass, the council’s first chairman, was still in place. Egg freezing was still considered experimental. IVF clinics in the United States were owned by doctors and hospitals. RESOLVE was the voice of the infertility community during these transitions. States would not enforce gestational carrier agreements and permitted discrimination against gay parents-to-be. RESOLVE fought all of these fights, often turning adversaries into allies — all a testament to its leadership.

And that leadership was Barb Collura.

I was privileged to serve on RESOLVE’s board of directors during Barb’s tenure, and learned up close the Collura leadership lessons, and I’m a better doctor, teacher, investor and manager because of it. I treasure our yearly Tuesday morning breakfast at ASRM.

Barb Collura will soon be passing the leadership of RESOLVE to a new generation. If the world is wise, it will tap into her knowledge and energy and savvy and ability to cut through BS and get things done and (sorry Barb) take advantage of her inability to say no to anything that helps someone else. It will reserve board seats, pencil “BC” for the keynote, make her first call for the op-ed. There will be portraits, a stature somewhere, certainly awards in her name, maybe a Kennedy Center honor.

But ultimately Barb Collura’s legacy will be the many children of future generations whose parents were nudged over the finish line into parenthood in no small part because of her decades of work and fearless leadership helping her neighbors, colleagues, friends and fellow citizens created families.

https://authors.elsevier.com/a/1k%7ENf5ErseEqyN

(No paywall, and no registration needed)

On an air conditioned but still hot July morning in 1986, a senior surgeon hands me a scalpel, addresses me as doctor, and tells me to make my first incision.

My hand and the knife hover over the patient’s abdomen like a helicopter over a traffic accident before I take a timid swipe and barely scratch the skin. My colleague waits patiently for me to shake off my nervousness, and a couple of hours later, the patient and I — an intern — are both in stable condition in the recovery room.

It’s 2011. I sit at my desk — a grid of PowerPoint slides on one computer monitor, my course outline on the other. I am a novice again, midway through preparing the 28 lectures that I will make up Entrepreneurship in Biotechnology.

Only for the moment, I’m doing a lot of staring and very little PowerPointing, and the prospect of teaching an entire course for the first time seems just as daunting as performing surgery. Medicine is a teaching culture. Second-year students show first-year students how to throw square knots, interns give impromptu seminars on fluid management during quiet moments in the intensive care unit, and bow-tied internists happily teach anyone, from the post call-chief resident to a flower-cart pushing volunteer. I left medicine, but I never stopped teaching.

My students-to-be are an extremely smart group: a mixture of undergrads, masters, and Ph.D.s in the sciences, hoping to cram as much of a business education as they can into one semester. I worry about letting them down. I focus on them and try to anticipate their expectations. I stop polishing my delivery and start listening for clarity. Ray Bradbury once said that living at risk is jumping off the cliff and building your wings on the way down. I used to think that cliff jumping was a young person’s sport, but fourteen years ago I walking along edges, wing blueprints in hand.

Entrepreneurship in Biotechnology, BIOT 4180, lasts ten semesters, with frequent breaks in between. It starts with thirty students and ends with thirty students, growing as large as 405 and shrinking to as small as seven. It changes from lectures to constant interaction, the students pitching their ideas over and over again, polishing the process by which they convince others to invest in them, work for them, collaborate with them.

Believe in them.

For a business course there was a lot of Aristotle and Maslow. There was no syllabus (does entrepreneurship have a syllabus?) Worse, students did not know how they would be graded. Attendance was mandatory. Exams were given (or not). Notebooks were randomly collected, read, and handed back a week later, unmarked. Maybe some of the students recognized that they were called to pitch more than others, and some may have realized that the quality of the questions they asked affected whether they were assigned to pitch to a fictitious friend of the family or the most misanthropic venture capitalist having a bad day. I could play either role, and by the end of the semester so could they.

Looking back, while I thought I was teaching the four tracks of company formation (organization, finding, serial proofs of concept and protecting the proprietary), in reality I was teaching precision and clarity. Painting pictures with words that transported a vision from one mind to the next and the next, being able to answer the question “where did that number come from” both by quoting the source and by deriving it on the spot. Every number was questioned. No imprecise term passed without a demand for a better definition. In Entrepreneurship in Biotechnology, if it couldn’t be measured it didn’t exist.

Without a formal syllabus, we let a life lessons sneak into the classroom too. Much of biotechnology is healthcare, so the students left knowing the importance of being anti-exploitative. Their tools box had separate compartments for ethos (but specific beliefs and assumptions, not lazily making the world a better place), logos (derive your numbers, build your model but be ready to defend and know the equation from which it was derived) and pathos. Who are you helping and how badly do they hurt?

It’s a cliche that teachers learn as much from their students as the students learn from them. An undergraduate chemist described a balance sheet as what we own on the left side and how we paid for it on the right — the best description I ever heard. My job was to give them a template with which to solve problems, to answer the most basic questions: what problem am I solving? Who am I helping? How do I travel from idea to tangible benefit? How do I define and measure progress?

To start: don’t make @#$ up. Remember that biology always wins. That concrete is easier to see than abstract, and that if you can only negotiate if you have options, and that being able to walk away is the best option. Think like an obstetrician and know that whatever the situation, you’ll do a better job if you’re calmer than everyone else.

Fourteen years, a thousand students, and a few dozen Entrepreneurship in Biotechnology rules later, it’s BIOT4180’s time for an exit.

Now on to the textbook.