Lessons learnt from embryonal development

E.R. Barnea, SIEP chairman

CONTENTS

INTRODUCTION

EMBRYO FORMATION:A SUCCESSFUL CHAIN OF EVENTS AGAINST MOST ODDS

The chain of events

Some of the elements involved

ELEMENTS OF SOLUTION: CAN PREGNANCY GIVE BIRTH TO CURE?

Cancer

Infectious diseases

Environmental-induced injuries

Immunologic disorders

Neurologic disorders and injury

CONCLUSION

INTRODUCTION

Although, the odds are against success in mammalian reproduction - this complex process was meant to be very efficient. The lessons which we can draw from the embryo as privileged entity in a privileged site extend beyond the embryo's well being into bettering life in general. Whereas in the previous EPBM editorial with Paul N. Schofield from Cambridge we reflected on early pregnancy as organizing or as organized chaos, from a conceptual standpoint, this presentation aims to draw more practical lessons in order to better understand and potentially provide cure. Nonetheless, this presentation is intended only as an open-ended dialogue rather than a complete doctrinal statement, and it is at the basis and the raison d'etre of SIEP, our interdisciplinary society.

EMBRYO FORMATION:A SUCCESSFUL CHAIN OF EVENTS AGAINST MOST ODDS

Rather than go in detail through all the complex chain of difficult events leading to reproduction, some of the highlighted facts will help illustrate the chain of occurrences and happenings of embryo formation against most odds.

The chain of events

Fertilization can only occur after the sperm traveled a great distance to meet the egg which once released into the abdominal cavity, has readily to be picked-up by the fimbria and meet the sperm.

An embryo, a new entity, will develop by the merging of two disparate genomes to a common one.

Implantation process itself is phenomenal, since it again requires that two different entities by now - the embryo and the host - meet again, thus allowing invasion of one by the other through cooperation instead of brute aggressivity.

Furthermore, embryonal development occurs at low oxygen tension and with almost no blood supply, another rather difficult process to succeed.

Mostly, the rapid embryonal development creates an enormous vulnerability for mutations, altered gene expression, and if the blue print is not basically perfectly executed, it can cause the failure of the system.

Somehow, once embryogenesis is completed and placenta proper, starts developing from the trophoblastic layer, the whole array of pregnancy events become more predictable and are less prone to failure. In final analysis, the number of spontaneous losses or, the rate of congenital malformation markedly drops by the early second trimester.

Thus, it is the period of early first trimester pregnancy that provides a harsh and powerful though very effective test to determine whether pregnancy will be successful or not.

Some of the elements involved

There are several sets of elements that make this critical period so successful despite the difficulties and roadblocks in place. Again, without trying to be exhaustive and just to point out few among them, the similarity among the components of the reproductive system indicate an evolutionary-tested success. Compounding the difficulty per se, there is the timeliness of interaction and the resiliency of the gametes to endure and interact in an adverse environment.

This symbiosis is composed for the well prescribed scenario for control of host/graft relationship with powerful local safeguards that are ready to reject if the product turns out to be defective.

Very importantly within this set of events is the time-tested efficacy of the immune system (an ancestral system) which allows two quite dissimilar entities to coexist for a temporary mutual benefit - pregnancy for the embryo, and propagation of the genome for the mother.

With respect to the conceptus there is a preferential paternal genome expression through the trophoblast allowing implantation while shielding away the embryo. Actually, there is a delay in the start of the development of the embryo proper until that time that implantation has already been demonstrated to be successful. Moreover there is a tightly controlled (both in series and in parallel) sequence of gene expression in the embryo which allows for very few errors without fatal consequences.

To create a complete embryo, in the short first twelve weeks of gestation requires the development of multiple disparate organs in a tightly coordinated manner by over 250 different types of cells. This is intrinsically paired by the ability to acquire a very efficient system for control of cell proliferation with internal mechanisms that are capable of destroying abnormal cells and promote young cells' differentiation very rapidly. Finally, the ability to create a phenotype which is unique although being very similar intraspecies must be noted.

Overall, the first trimester of gestation represents a unique and very eventful time period where during a short time period more is accomplished than throughout adult life. Naturally the question arises: Can (the lessons learnt from the early) pregnancy give birth to cures?

ELEMENTS OF SOLUTION: CAN PREGNANCY GIVE BIRTH TO CURE?

Though we appear to comprehend the implications of all this unique phenomenon we have only recently come to realize how efficient are the mechanisms that are involved in early pregnancy development and maintenance and how their understanding and harnessing beyond improving reproduction herald major diagnostic and therapeutic promise.

But we should not lure ourselves by claiming novelty or revolution. In the fifteenth century Paracelsus was already claiming that from itself will come the cure: Similia similibus curantur, and eastern civilizations and cultures were applying such concepts before our civilization was one. At best we can now claim a better insight and better tools to transform philosophical thought into cure.

At this point in time, though, we can attempt to go much beyond: We can comprehend disease later in life for what it has departed from the embryo-like more smoothly running system. We can hope to harness know-how and actual compounds to help understand and cure disease.

In general, we just now start investigating the early pregnancy's intrinsic protective mechanisms, with their great a potential for therapeutic application in mind. Again, taking our cues from nature, the better we learn the early pregnancy phenomenon, the better we stand a chance to retrieve and adapt its teachings to ailments and injury later on in life.

Harnessing those potential wide- spectrum agents may be useful for combating various agents. A specific point of importance are biological weapons with their myriad variety which could benefit from such a broad range efficiency.

Again, only some recent examples will follow. They are intended more to provide food for thought rather than being exhaustive. These days this widely extends beyond the intuitive approach of curing self with self i.e. transplant of fetal cells for treating Parkinson's disease and fetal insulin cells for diabetics, a thought that has existed for over a hundred years.

Cancer

We can draw obvious parallels between early pregnancy and cancer: Both are characterized by rapid proliferation, however, only pregnancy contains its own intrinsic controls allowing very rapid cell proliferation while promoting differentiation or programmed cell death; Consequently, exploiting this analogy, we looked to early pregnancy to develop markers for tumors, to locate agents to control cell proliferation by acting as master switch accelerating or inhibiting replication in a specific manner as well as creating pregnancy-like conditions to protect against cancer.

Infectious diseases

A perfect example of such specific lesson is the case of HIV infection and its inherent paradox, where only about a quarter of babies from infected mothers will become HIV positive. This occurs despite massive and direct exposure to the virus throughout pregnancy. In contrast, such an intimate exposure in the adult to the infectious agent would inevitably lead to infection. Also in HIV1 transgenic mice pregnancy appears to confer protection since the viral gene expression is not present however after birth the transgene is expressed with serious consequences for the pups.

With respect to other infectious diseases the embryo, with few exceptions (i.e. Rubella) is by definition rather well, or at least better protected against both viral and bacterial agents as compared to the host and the population in general who are easily prone to such infection. The mechanisms involved are just being investigated and may involve presence of local infectives i.e. interferons, cell proliferation protectors, and this despite altered maternal immune system.

So, just as in the case of cancer, we start drawing parallels between the rather well protected embryo and the quite defenseless adult, with the aim of infusing embryo-like shielding to the adult exposed.

Environmental-induced injuries

Such parallel therefore can include the relative resilience of the conceptus against damage ensued from wide variety of compounds that are present in environmental toxins, chemicals and cigarette smoking, or mixtures thereof. As opposed to the adult, in the embryo it appears that in many instances there has to be a major exposure before injury becomes likely though active compounds do rather easily reach the conceptus.

Thus multiple intrinsic mechanisms of protection must be in play; among them shielding, enzymatic inactivation of oxygen radicals, and intrinsic control systems from preventing/controlling abnormal cell proliferation. We just start identifying the specific compounds involved which could be of use in adults where comparatively the vulnerability following environmental exposure is much higher.

This issue today becomes of great importance by the possibility of exposure to pathogens as in chemical weapons. Since the chosen route of exposure, nowadays, seems to be a mixture thereof rather than single agent, rather than combat it agent-by-agent, we could make inroads in limiting this threat by offering to institute generalized protective systems as it is the case in the embryo.

Immunologic disorders

Immunology of early pregnancy too has profound implications for developing transplant tolerance. There is evidence for better tolerance for xenotransplants during pregnancy. This way, we can thrive to identify the specific agents involved, and creating similar conditions which can make successful transplants without having to face a high rate of malignancies later in life due to harsh immunosuppressive therapy. The identification of embryo-derived signals that reflect viability and acceptance is in progress as well major efforts are being made in identifying the tolerance associated with pregnancy.

On the other hand there is a great similarity between methods employed by viruses (for example cytomegalovirus) to evade the immune system and attack the host and by the embryo to prevent rejection. As recently reported in both cases first the T cells are neutralized by suppressing the formation of cell surface identifier and than the natural killer cells ability to attack is minimized by creating false cell surface identifiers leading to recognition of the infected cell or the embryonal cell by the host as self.

This example illustrates the need for open mindness in exploring the relationship between pre and postnatal life.

Neurologic disorders and injury

In case of neurologic disorders, identification of specific growth factors that are highly expressed during development as promoters organ recovery is also currently pursued actively especially since in the adult there is also a small reserve of stem cells that could be modulated leading to potential nerve regeneration.

CONCLUSION

Throughout mammals the embryo is a privileged entity located in a sheltered environment. Furthermore, at early gestational period we can very often transpose from know-how and specific product present in one species towards the other. Our task is clearly set to understand how this occurs and learn practical lessons from it. It is evident that progress is already being made on all fronts.

Writer Disclosure: Dual Commitment

The author is concomitantly founder and chairman of SIEP, the Society for the Investigation of Early Pregnancy, and recipient of the DARPA, the Department of Defense agency R&D grant on Isolation of Developmental Factors to Prevent Human Injury from Pathogens. He has received from the US Patent office notices of allowance on two patents: Gestational Agents for Controlling Cell Proliferation and (w/ C.B. Coulam) Preimplantation Factor.

Send comments to: barnea@earlypregnancy.org

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