This article reported that scientists have succeeded in adding two new bases to the quartet of A, C, G and T, resulting in non-canonical amino acid. Additionally, the bacteria in which this was done were able to produce new proteins using the newly added bases. The article quotes the scientists as saying that the extra amino acids “might become building blocks for new drugs and novel materials”.

My question is that if new proteins are made from amino acids that don’t naturally occur, won’t the body reject them?


2 Answers 2



This question has two components. The first is the near rhetorical question whether proteins with unnatural amino acids will be considered by the immune system as ‘non-self’. Unless, by chance, the unnatural amino acid resembles some normal macromolecular component, the answer is obviously that it will be regarded as ‘non-self’.

The second question is, to my mind, much more interesting, but does not appear to be considered (or has been taken for granted) in the answer by @Astrolamb. This is whether the immune response would cause such artificial proteins to be eliminated, if administered therapeutically. It is important, at this juncture, to emphasize that proteins containing unnatural amino acids as the result of expanding the genetic code do not, in principle, raise any problems of immune ‘rejection’ that have not already been seen in ‘unnatural’ proteins containing normal amino acids. Any immune response should therefore be regarded as being to ‘non-self protein’ and rather than to ‘non-self amino acid’.

As there have been many such studies with the latter proteins (and with proteins containing unnatural amino acids introduced by chemical modification) there are extensive studies on which to base an answer. An immunologist would be a better person to do this, but in the absence of any “immune response” I will attempt an answer from my perusal of the literature, leaning particularly on:

K. Wals and H. Ovaa “Unnatural amino acid incorporation in E. coli: current and future applications in the design of therapeutic proteins” Front. Chem 2, 1–12 (2014)


B. Leader et al. “Protein therapeutics: a summary and pharmacological classification” Nature Reviews Drug Discovery 7, 21–39 (2008)

I welcome comments suggesting improvements or corrections.


The question asks:

“if new proteins are made from amino acids that don’t naturally occur, won’t the body reject them?”

which I take to mean:

“if new proteins are made from amino acids that don’t naturally occur, won’t they induce an immune response which will render them ineffective?”

The brief answer to this is:

  1. It depends — the immunogenicity of foreign proteins varies.
  2. Even if an immune response is elicited this may not necessarily render such proteins ineffective.
  3. In some cases the therapeutic intention is actually to provoke an immune response — to make a weakly immunogenic protein more so.

Foreign proteins vary in immunogenicity

The crux of the answer to this question lies in the following:

The fact that a protein used for therapeutic purposes differs from those in a human subject does not in itself mean that it will invoke an immune response.

Let us consider two examples to illustrate this.

The first is the case of porcine insulin, which has been administered to patients for many years, but has one amino acid different from human insulin. Regarding such non-human insulin this review states that “severe immunological complications occur rarely, and less severe events affect a small minority of patients”.

The second example is taken from more recent work by D-A. Silva et al. in designing artificial proteins. (See also Nature News & Views summary). They designed mimics of the cytokines, interleukin-2 and interleukin-5, that had extensive differences in helix organization and amino acid sequence from the native proteins. However they reported that “Immunogenicity against the de novo designed proteins appears to be low”.

It turns out that a wide variety of factors affect the immunogenicity of foreign macromolecules, so that even if a therapeutic protein elicits an immune response it may be weak enough to allow the therapeutic action to occur. In the work just cited, Silva et al. suggest that the reason for the low immunogenicity might be “the small size and high stability” of the proteins on the basis of previous work they had performed with 20,000 mini-proteins.

Admittedly, in some cases a strong immune response will occur and can obviously be a problem, so that measures need to be taken to reduce the immunogenicity. This is widely recognized and discussed in the following paper:

V. Brinks et al. “Immunogenicity of Therapeutic Proteins: The Use of Animal Models” Pharm Res (2011) 28:2379–2385

Sometimes chemical modification of proteins can actually reduce their immunogenicity, as is the case for polyethylene glycol in relation to interferon (B. Leader et al. review, cited above).

Use of therapeutic proteins to provoke an immune response

One use envisaged for modified proteins is in cancer immunotherapy. In brief, the objective is to try to make the body mount an immune response against cancer cells, which may exhibit ‘foreign’ tumour antigens. However, in many cases these differences from normal cells are not sufficient to provoke an adequate immune response. It is has been shown that modifying retinol binding protein by introducing an unnatural amino acid can help overcome the self-tolerance to tumours in mice, suggesting a possible use in cancer immunotherapy (J. Grünewald et al. “Mechanistic studies of the immunochemical termination of self-tolerance with unnatural amino acids” PNAS (2009) 106, 4337–4342).


Proteins containing unnatural amino acids as the result of expanding the genetic code do not, in principle, raise any problems of immune ‘rejection’ that have not already been seen in ‘unnatural’ proteins containing normal amino acids or chemically modified amino acids. The problem of potential immunogenicity is widely recognized and has been extensively studied by those wishing to develop the considerable therapeutic potential of all such proteins.

  • 1
    $\begingroup$ This is a lovely answer, and I'm not sure why someone downvoted it. $\endgroup$
    – De Novo
    Commented Jan 23, 2019 at 23:44
  • 1
    $\begingroup$ I think this answer is good, but sort of following from the cleaned up discussion in the comments, the problem I see is that you don't answer the interesting part of the question until your conclusion. The key important concept here, in my opinion, is that Proteins containing unnatural amino acids as the result of expanding the genetic code do not, in principle, raise any problems of immune ‘rejection’ that have not already been seen in ‘unnatural’ proteins containing normal amino acids. If there is an immune response issue, it's with non-self protein, not with non-self amino acids. $\endgroup$
    – Bryan Krause
    Commented Jan 24, 2019 at 17:31
  • $\begingroup$ @BryanKrause — Thank you for your suggestion. I have edited my answer accordingly. $\endgroup$
    – David
    Commented Jan 25, 2019 at 14:25

The body's mechanism for detecting foreign object has a built-in failsafe that minimizes the likelihood of misinterpreting a self-derived antigen as foreign.

Immunologic tolerance (unresponsiveness) normally prevents reactions against self-antigens; if immunologic tolerance is broken, autoimmune reactions may occur. Much of the development of tolerance occurs in the thymus by the elimination (clonal deletion) or inactivation (clonal anergy) of self-reactive clones of T cells. Other mechanisms of tolerance occur extrathymically and include activation of antigen-specific T suppressor cells and clonal deletion, which results in the elimination of self-reactive B cells or T cells, and clonal anergy.


Basically, before a T cell starts looking for potential antigens, it generally first spends some time in the thymus being tested against antigens which are native to the body. If it responds to such an antigen, the T cell will either be destroyed or deactivated.

Having unnatural amino acids as part of this process is unlikely to change its efficacy. T cells which would target peptides with these unnatural amino acids will still be checked against the body's cells before being sent out to do their work; the mechanism would work the same way. I suspect that the rate of autoimmune diseases would be unchanged compared to normal organisms.

  • 1
    $\begingroup$ @Astrolamb The question asks whether the body will reject proteins containing unnatural amino acids. Your answer focuses on the mechanism of tolerance, indicating that this will continue to operate as normal and that synthetic proteins will be treated by the immune system as non-self, a conclusion that few would disagree with. However it does not address the concern of the poster that synthetic proteins would be rejected by the body, implying that their use as "new drugs" would be doomed to failure. Please provide more information on this point. Does your argument imply rejection or not? $\endgroup$
    – David
    Commented Jan 20, 2019 at 13:48

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