Researchers at Ohana Biosciences are focusing on the biology of sperm to advance the field of fertility science.
Amber Salzman, CEO of Ohana Biosciences, and Ohana board member David Sable, who is an obstetrician-gynecologist and reproductive endocrinologist, discuss with Flagship senior advisor Jason Pontin why they are driven to pioneer novel therapies to address human reproduction and how those therapies might work.
Jason Pontin: Amber let’s start with you: What brought you to Ohana?
Amber Salzman: My career started in a large pharmaceutical company, GlaxoSmithKline. At GSK, I had the privilege of being a member of the R&D executive team, accountable for clinical trials around the world in all different therapeutic areas. While I was at GSK, I found that there was a rare, fatal neurodegenerative genetic disease in the family when my oldest nephew was diagnosed; we lost him to the disease. Learning that it's a genetic disease, you start testing all the family members. I found that my one-year-old son tested positive, as did another nephew.
While we looked to find treatments for them, I looked at the challenge we had—knowing that we wanted to have another child and not have them have the risk of being born with a genetic disease. At the time, about 20 years ago, I learned that you could use assisted reproductive technology to perform in vitro fertilization and test each of the embryos to see which one was affected with the disease and which one wasn't. And therefore you would only transfer those that were unaffected. So it sounded ideal. However, when I went through the process, I learned that the actual process sounded a lot better than it actually was, because it's pretty brutal. You're taking daily hormone shots, going under anesthesia to surgically have your oocytes removed, and waiting in a dire emotional state to see if any of the eggs fertilized and then which of the embryos are affected and, if any unaffected, would result in a pregnancy?
“When you look at science and medicine, they've basically been ignoring the role of the sperm. The focus has been on women and the eggs.”
I went through five cycles, and I now have a very healthy teenage daughter as a result. So for me, the net effect was obviously positive, but it was a grueling process to go through. Years later I learned about a company, Ohana, which hoped to transform reproductive health care. And I discovered that not much has changed in 20 years.
This is a problem not only for people who have a genetic disease or are carriers of a genetic disease, but for the seven million couples in the U.S. alone that have trouble with fertility. They really need better ways to go about having children. Knowing how devastating it was personally, I thought this is where I can make a difference and help people—I felt like this company had my name written all over it.
In addition to addressing the need to improve assisted reproductive technologies, Ohana, being a sperm biology company, holds the promise of addressing pregnancy complications and developmental disorders that are directly tied to sperm. I am passionate about the need to prevent disease and prevent pregnancy complications, and Ohana is truly unique in its ability to address this great need.
JP: David, tell us a bit about your career.
David Sable: I was trained as an obstetrician-gynecologist and a reproductive endocrinologist and started working in the IVF field in the early 1990s. Toward the end of that decade, I was very fortunate to work with one of the best in vitro fertilization labs in the world, St. Barnabas Medical Center in New Jersey. One of our scientists we worked with, a man named Santiago Munne, was one of the inventors of many of the genetic testing procedures that we incorporated into IVF. And he and I and another colleague of ours, Jacques Cohen, who was one of the foremost embryologists in the world—we formed a company called ReproGenetics, which was the first company that offered genetic testing.
“Infertility is really not a very precise diagnosis. It's an observation.”
In 2004, I took a one-year sabbatical from practicing. I thought it would be nice to get to know my own young children. And that sabbatical is now in its 17th year. Just to help defend that, I did some work at a trading desk at Deutsche Bank and about a year later was offered a job running health care investing for an investment group in New York, which I thought would be a good thing to do for six months to a year. And I've been there since 2005. Having thought that I'd left the IVF world behind, in 2012 I was asked to join the board of directors of the national nonprofit, the patient advocacy organization, Resolve.
And at the same time, I started writing about IVF for Forbes magazine. Afterward, everyone who was in the field, who was tinkering, who was trying to do something in an experimental, innovative way, seemed to find me. And in 2018 that led to my launching an IVF-only venture capital fund to seed some of these early-stage companies. Around that same time, I got a phone call from David Berry at Flagship. I'd never met David before.
One of his partners, Doug Cole, was a medical school classmate of mine. And David wanted to run this company by me, which was Ohana. He kind of had me at hello, because one of the great frustrations I had in trying to work innovation into assisted reproduction is that the male factor, the sperm side, was sort of ignored; everything we did was on the female side and working with the eggs. There were reasons for that—because it was always too hard to work with sperm. And here was David and Flagship, and later, Amber, kind of grabbing that challenge by the horns.
JP: David, why aren't sperm more studied than eggs?
DS: There's a couple reasons. One is sperm is smaller. It's very difficult to study it without harming it. And ironically, the fact that the eggs can give us so much information makes it easy to sort of ignore the sperm. So we look at the egg, an incredibly complex cell with very intricate machinery in it. It goes through some tremendous changes as it matures and then once it's fertilized. And it gives us opportunities to study it as it does its job, without destroying it.
The sperm is like a Ziploc bag full of DNA with a tail. You can look at the sperm and see how it moves. You try to extrapolate information from that, but you can't really study much about the genetics of the sperm—traditionally, we have not been able to without harming it. Really the only way we could learn about the sperm was letting the sperm fertilize the egg. Study the egg pre-fertilization, and then post-fertilization, look at the genetics of the resulting embryo, and kind of reverse engineer the genetics of the sperm—and that was state of the art for 20 years.
That's a very, very imperfect means of assessing that.
JP: Amber, describe the current state of reproductive health and how you would like to see that changed.
AS: Let me contrast it with my most recent experience leading a gene therapy company, Adverum. While I was working in that space, we were using so many innovative technologies and really leading the way in novel approaches. So I was startled that when I started to look at reproductive health, it was almost archaic by contrast. We’re all here because of reproductive biology, but yet reproductive medicine has not advanced as swiftly or as far as other areas of biological research.
“Men today are half as fertile as their fathers. Sperm counts are decreasing. Environmental, health, and age factors influence that.”
While the birth control pill was transformational approximately 50 years ago, contraception really hasn't advanced much. The pill can have mild to severe side effects, and in some cases can even cause fatalities. Yet chronic use of hormones is the primary way that people are preventing unwanted pregnancies. When people move from wanting to prevent pregnancies to wanting to have kids, infertility becomes a challenge. Infertility rates are skyrocketing. Men today are half as fertile as their fathers. Sperm counts are decreasing. Environmental, health, and age factors influence that.
And if you are fortunate enough to get pregnant, your pregnancy and your child face greater risks. And many of those risks are really directly related to the sperm. However, when you look at science and medicine, they've basically been ignoring the role of the sperm. The focus has been on women and the eggs. Reproductive health is in a crisis. And what I'd like to see change is that we leverage the other half of the equation, which is sperm. I’d like to see contraceptives that are not reliant on chronic use of hormones but rather leverage an understanding of sperm biology; I’d like to see infertility treatments with better success rates; and I’d like to see a reduction in the risk sperm has on the health of pregnancies and of children.
JP: How can it possibly be that despite the hundreds of thousands of babies born every year using assisted reproductive technologies, infertility itself is still insufficiently understood or badly characterized?
DS: It’s a great question. Within the larger context of our understanding of human physiology and health and disease, the past 20 to 30 years have seen medicine go from the analog to digital to the precise molecular—trying to achieve a precise molecular understanding of our processes versus the kind of pattern recognition “I know it when I see it” analog understanding.
And there you have fields like oncology and inflammation where we're now defining diseases down to the single amino acid mutation in an extremely precise way. And then we have areas like neuropsychiatry, where nature has done a phenomenal job of protecting the central nervous system, which is good for evolution. But it's been very bad for trying to study disease processes. And sadly, women's health in general is very much on that analog.
So, you know, the kind of analog category of medicine, you look at diagnoses by themselves—things like premenstrual syndrome, premature ovarian failure, infertility. Infertility is really not a very precise diagnosis. It's an observation. So from that, we extrapolate to, What are the variables, What are the things that we know how to measure, and How good is the data on which we're basing our characterization of the problem? And from that categorization, we've got a lot of diagnoses that we subgroup people with infertility into, but they're very imprecise.
Essentially, if you've got two blocked fallopian tubes or no sperm or you never ovulate, those are good, hard, reliable diagnoses. But that's a very small percentage of the population. Just about everyone else has a large component of unexplained infertility. I used to tell my patients that we're much, much better at giving results than giving answers, which if I had the choice of one or the other, yeah, that's what I'd want. But from the point of view of a physician or a scientist and mainly from a patient, we want to get much more precise as to what is going on.
“It could be that the next great vital sign is an assessment of sperm function.”
JP: Amber, David makes reproductive health seem pre-genomic or even pre-engineering. This wouldn't be acceptable in any other field of medicine. Why has there been so little process optimization within fertility medicine?
AS: Reproductive health isn't necessarily covered by most insurance plans. So when it comes to how much money and energy is being put into it, it's very disproportionate to the problem. When I mentioned earlier that seven million couples in the U.S. struggle with infertility, only a couple hundred thousand of those couples ever make it through treatment, and a lot of it is paid out of pocket. So in some cases, it’s really for the privileged. And medicine and science, therefore, have not caught up with the need and demand of that backdrop.
JP: Amber has described a market that is grossly underserved. If we understood the biological markers for infertility better, would assisted reproductive therapy be less expensive and more successful?
DS: Well, there's three ways, I think, of making it less expensive. One is just to cut the price. You go from country to country and the price tag for the same procedure is very different, as is the payer environment and the insurance coverage. For example, in Israel, nine times the amount of IVF is done per capita than the United States. That’s mainly because in Israel, it's covered by the government until you've had two children. So simply cutting the price is a big part of it.
But that's really not enough. We need to look at one of the input factors that provide limitations. In the United States, we've got 480 IVF clinics treating probably the same 125,000 to 150,000 people per year that can afford to spend $20,000 every few months to do [an aggregate total of] 300,000 IVF cycles. It's not a big enough capacity; we're practically operating close to capacity. The number of specialists doing IVF is about 1,300. There's only 42 or 43 training programs. So there are limitations there. But the third area, which is one that I've been trying to focus on, is we lack the automation that we've brought into so many other areas of the economy and some of the other areas of health care.
If you look at the typical IVF lab now, you've got a lot of repetitive tasks being done over and over and over again by highly trained people. So there’s a lot of pipetting; there's a lot of transferring things in and out of incubators. On the doctor side, you've got doctors taking patients through consent forms and doing ultrasound scans, which could be done more easily.
The way I've been characterizing it for years is we have a field that has tremendously good science and very rudimentary engineering, and the engineering has to catch up. Once we do that—I've always liked the term process optimization—we'll be in a position to really isolate the individual variables that point to major inefficiencies.
JP: But this is a thing we can do. As you say, we have the technology. We can prevent untold suffering, let alone cost, to parents. Shouldn't that just become part of public health?
AS: It is a public health problem that we're not making sure that we can have the healthier children that are within our reach. From a cost perspective, I should add that it is usually much cheaper to go through IVF and select a healthy embryo than to have to deal with the health and impact to families when you have a child with an illness. It's much cheaper to prevent it—besides all of the other good things that come with that.
JP: Why would single-cell analysis of sperm cells provide unprecedented insights into their molecular features and ultimately increase the likelihood of successful, healthy pregnancies?
DS: Several reasons. Certainly the simplest one is that if we can reliably find genetic markers that give us the same amount of information that we get from studying an egg, for example, or an embryo, then since we make so many sperm, we should—we would be able to—segregate populations of sperm to at-risk populations and safe populations. If we could segregate the safe populations of sperm, we could remove the risk of having an infected child even without doing IVF. You're just taking what nature gives us there.
Secondly, it would allow us to tease out the function of the sperm from the appearance of the sperm, the ability of sperm to swim, and the genetics. We can break down what is predicted about this. What can we extrapolate from the sperm in a noninvasive way that opens up therapies for treating male-factor infertility? For identifying and reducing or eliminating the extra risk that couples have for passing on a genetic disease in ways that are much less invasive to the couple and safer. There'd be no stimulation of the ovaries to make extra eggs. No surgical procedures. It would really revolutionize aspects of the assisted reproductive world.
Finally, there are correlations that we would be finding between sperm function and other parts of male health. It could be that the next great vital sign is an assessment of sperm function. We've never been able to make those connections between metabolic disease and, potentially, the GI tract, the central nervous system. For example, we can diagnose hypertension by looking at someone's eyes. We learn lots of things about the heart by checking the pulse of the feet. What parts of human physiology can be revealed to us by being able to analyze sperm one at a time, in real, measurable, reproducible scientific parameters, that we are just blind to at this point?
JP: How could we apply that type of single-cell analysis to a business? What is Ohana's fundamental breakthrough that makes that kind of single-cell analysis possible?
AS: Because we've done the single-cell sequencing of millions of sperm, we now have a unique understanding about how those molecular changes in sperm can drive disease risk. And those are the insights we're leveraging to develop new technologies and treatment options. For example, there are molecular changes in the sperm. We know that there's an increase in de novo mutations, for example, as men age. We know there's an increase in DNA oxidation, epigenetic changes, and more.
There's also data relative to how paternal age, for example, is a factor that impacts the health of the pregnancy and the health of the child. There was a study looking retrospectively at 40 million births that showed a much greater risk of a preterm labor if the father is older. So what we bring to the table is that unique understanding of how molecular changes in the sperm can drive disease risk.
JP: It sounds like this technology could be applied to male contraception also.
AS: Yes. What's interesting is that there are highly specific proteins on the sperm. But for whatever reason, up until now when we looked at contraception, it really wasn't necessarily imagined from that angle. A lot of focus has been on providing hormones to women. But it turns out that by targeting specific proteins on the sperm, we could have a nonhormonal, very long acting, and reversible contraceptive for either men or women.
For men, we would target the antibody in seminal fluid so that the sperm was incapacitated and not able to fertilize. Equally, you could deliver it systemically to women, and then it would make its way into the fallopian tube fluid. When the sperm made it that far, they would be incapacitated and unable to fertilize the egg. So that would be a way to go after a highly specific target, so you don't end up with all of these off-target effects when you're going after, for example, estrogen, which has receptors on almost every cell type.
JP: Reproductive health is an industry, from your vantage point. Do you think that reproductive clinics will be open to a disruptive revolution of this scale?
DS: Great question. I was a reproductive endocrinologist for 15 years and took care of thousands of patients. And anything that I could use to solve their problems, we were open to. It's a very science-driven field, it's a very ambitious field, it's a very entrepreneurial field. It's one where we've seen tremendous amounts of innovation over the years. But there's also big frustrations regarding our ability to give accurate answers. And I don't think anyone thinks that we are anywhere near as good as we should be able to be.
The best clinics in the world will enable the ability to have a baby with one optimally developed embryo. That's 65 percent of the time. I don't think anyone thinks that 65 percent of the time is the best we could do. Should we do 80 percent, 90 percent? 100 percent may be like running a one-minute mile, but we've got a long way to go. There's a lot of what we don't know that we don't know. Patients come into clinics with problems and it’s our job is to fix them. So, yes: I think reproductive health people will be very open to these approaches.
JP: If everything occurred according to plan and Ohana hit all your milestones, when might patients see technologies of this sort in the clinic?
AS: Our initial product, an ex vivo sperm treatment focused on improving the success rates of IVF and IUI [intrauterine insemination], has the likelihood of being commercialized toward the end of 2021. Right now it's in clinical trials. Some patients have already gone through it. The patients are excited. The physicians are excited. So this could be on the market in the relatively near term.
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